Re: ALS(루게릭병) 2017년 NEJM 논문

[문형철]

Amyotrophic Lateral Sclerosis

Authors: Robert H. Brown, D.Phil., M.D., and Ammar Al-Chalabi, Ph.D., F.R.C.P., Dip.Stat.Author Info & Affiliations

Published July 13, 2017

N Engl J Med 2017;377:162-172

DOI: 10.1056/NEJMra1603471

VOL. 377 NO. 2

Copyright © 2017

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Amyotrophic lateral sclerosis (ALS) is a progressive, paralytic disorder characterized by degeneration of motor neurons in the brain and spinal cord. It begins insidiously with focal weakness but spreads relentlessly to involve most muscles, including the diaphragm. Typically, death due to respiratory paralysis occurs in 3 to 5 years.

Motor neurons are grouped into upper populations in the motor cortex and lower populations in the brain stem and spinal cord; lower motor neurons innervate muscle (Figure 1). When corticospinal (upper) motor neurons fail, muscle stiffness and spasticity result. When lower motor neurons become affected, they initially show excessive electrical irritability, leading to spontaneous muscle twitching (fasciculations); as they degenerate, they lose synaptic connectivity with their target muscles, which then atrophy.

근위축성 측삭 경화증(ALS)은

뇌와 척수 운동 뉴런의 퇴행을 특징으로 하는

진행성 마비성 질환입니다.

국소적 근력 약화(focal weakness)로 시작되지만,

점차적으로 확산되어 횡경막을 포함한 대부분의 근육을 침범합니다.

일반적으로 호흡 마비로 인한 사망은

3~5년 후에 발생합니다.

운동 뉴런은

운동 피질에서 상부 집단으로,

뇌간과 척수에서는 하부 집단으로 분류됩니다.

하부 운동 뉴런은

근육을 자극합니다(그림 1).

피질척수(상부) 운동 뉴런이 기능을 상실하면

근육 경직과 경련이 발생합니다.

하부 운동 신경이 영향을 받으면,

처음에는 과도한 전기적 과민성을 보이며,

이로 인해 자발적인 근육 경련(근육 수축)이 발생합니다.

퇴화하면서,

대상 근육과의 시냅스 연결이 끊어지면서,

근육이 위축됩니다.

When corticospinal (upper) motor neurons fail, muscle stiffness and spasticity result. When lower motor neurons become affected, they initially show excessive electrical irritability, leading to spontaneous muscle twitching (fasciculations); as they degenerate, they lose synaptic connectivity with their target muscles, which then atrophy.

Figure 1

상위운동뉴런(UMN; Upper Motor Neurons)
기원부위: 운동피질(Motor Cortex)

그림의 가장 위쪽, 뇌의 우측 운동겉질(motor cortex) 영역에서 시작하는 뉴런들이 바로 상위운동뉴런입니다.
이 UMN은 주로 피라미드로(corticospinal tract)를 통해 신호를 전달하며, 신호의 계획과 조절에 관여합니다.

주행 경로: 내림길(Descending Pathway)
UMN은 대뇌에서 뇌간(brainstem)을 지나 척수(spinal cord)로 하행합니다.
연수(medulla) 부근에서 교차(decussation)하는(대부분의 섬유) 것도 특징이며, 그 뒤 반대쪽 척수의 운동로를 타고 내려갑니다.
이 경로가 **외측 피질척수로(lateral corticospinal tract)**를 형성하여, 목(경부), 등(흉부), 허리(요부) 등 척수 분절별로 가지를 뻗어 갑니다.

종결부위: 척수 앞뿔(anterior horn)의 하위운동뉴런과 시냅스
UMN 자체는 직접 근육을 지배하지 않고, 최종적으로 척수 내부의 하위운동뉴런(LMN)에게 신호를 전달하는 시냅스를 형성합니다.

하위운동뉴런(LMN; Lower Motor Neurons)
척수 또는 뇌간에서 기원

그림에서 보이듯, 척수에서는 앞뿔(anterior horn) 영역에 위치한 운동뉴런이 말초신경을 통해 골격근(skeletal muscle)을 지배합니다(팔다리 근육 등).

뇌간(예: 연수, 다리뇌)에서는 뇌신경핵(cranial nerve nuclei)에 위치한 LMN이 안면·인후두·혀 등 머리/얼굴/연하 관련 근육을 지배합니다(이를 ‘bulbar motor neuron’이라 부릅니다).

말초 신경 통한 근육 지배

하위운동뉴런의 축삭(axon)은 척수신경(또는 뇌신경)을 통해 몸의 각 근육군에 연결됩니다. 이 LMN이 근육섬유에 직접 시냅스를 형성(신경근접합부)하여 실제 수축명령을 전달함으로써, 손, 발, 얼굴 등 특정 근육이 움직이도록 합니다.

임상적 구분: UMN vs. LMN 손상
UMN이 손상되면(예: 뇌졸중 등), 보통 근긴장도(spasticity) 증가, 바빈스키 징후 양성 등이 나타납니다.
LMN이 손상되면(예: 척수 앞뿔 세포 질환, 말초신경 병변), 일반적으로 근위축(atrophy), 근긴장도(flaccidity) 감소, 심부건반사(hyporeflexia) 감소 등이 주 증상입니다.

The Motor System.

ALS typically begins in the limbs, but about one third of cases are bulbar, heralded by difficulty chewing, speaking, or swallowing. Until late in the disease, ALS spares neurons that innervate the eye and sphincter muscles. The diagnosis is based primarily on clinical examination in conjunction with electromyography, to confirm‎ the extent of denervation, and laboratory testing, to rule out reversible disorders that may resemble ALS.1,2

A representative case involves a 55-year-old patient who was eval‎uated for foot drop, which had begun subtly 4 months earlier with the onset of muscle cramping in the right calf as a result of volitional movement (known as volitional cramping) and had progressed to severe weakness of ankle dorsiflexion and knee extension. In addition to these features, the physical examination revealed atrophy of the right calf and hyperreflexia of the right biceps and of deep tendon reflexes at both knees and both ankles. The neurologic examination was otherwise normal. Electromyography showed evidence of acute muscle denervation (fibrillations) in all four limbs and muscle reinnervation in the right calf (high-amplitude compound muscle action potentials). Imaging of the head and neck revealed no structural lesions impinging on motor tracts, and the results of laboratory studies were normal, findings that ruled out several disorders in the differential diagnosis, such as peripheral neuropathy, Lyme disease, vitamin B12 deficiency, thyroid disease, and metal toxicity.3 A full eval‎uation disclosed no evidence of a reversible motor neuron disorder, such as multifocal motor neuropathy with conduction block, which is typically associated with autoantibodies (e.g., anti-GM1 ganglioside antibodies) and can be effectively treated with intravenous immune globulin.4

The clinical presentation of ALS is heterogeneous with respect to the populations of involved motor neurons and survival (Figure 2).2 When there is prominent involvement of frontopontine motor neurons that serve bulbar functions, a striking finding is emotional lability, indicating pseudobulbar palsy, which is characterized by facial spasticity and a tendency to laugh or cry excessively in response to minor emotional stimuli.

운동 시스템.

ALS는

일반적으로 사지에서 시작되지만,

약 3분의 1의 경우

씹기, 말하기, 삼키기 등의 어려움으로 시작되는

구근성 bulbar ALS입니다.

질병이 진행될 때까지 ALS는

눈과 괄약근을 자극하는 신경세포를 보호합니다.

진단은

주로 근전도 검사와 함께 임상 검사를 통해 탈신경의 정도를 확인하고,

ALS와 유사한 가역성 장애를 배제하기 위한 실험실 검사를 통해 이루어집니다.1,2

대표적인 사례는 55세 환자입니다.

이 환자는 4개월 전부터

오른쪽 종아리에 의도적인 움직임(의도적 경련이라고도 함)으로 인한

근육 경련이 시작되어 발 마비가 발생했고,

발목 배측 굴곡과 무릎 신전 근력이 심하게 약화되는 증상을 보였습니다.

이러한 특징 외에도

신체 검사 결과

오른쪽 종아리의 위축과 오른쪽 이두근의 과반사,

양쪽 무릎과 양쪽 발목의 심부 건반사가 나타났습니다.

신경학적 검사는 정상으로 나타났습니다.

근전도 검사 결과,

사지 전체에 급성 근육 탈신경(섬유성)이 있었고,

오른쪽 종아리 근육에 재신경 분포가 나타났습니다(고진폭 복합 근육 활동 전위).

두경부 영상 검사 결과,

운동 신경에 영향을 미치는 구조적 병변이 발견되지 않았고,

실험실 검사 결과도 정상이었습니다.

이 결과는

말초 신경병증, 라임병, 비타민 B12 결핍, 갑상선 질환, 금속 독성과 같은

여러 가지 질환을 배제한 결과입니다. 3

전체 평가 결과,

전형적으로 자가 항체(예: 항-GM1 강글리오사이드 항체)와 관련이 있고

정맥 면역 글로불린으로 효과적으로 치료할 수 있는 전도 차단이 있는

다초점 운동 신경병증과 같은 가역성 운동 신경 장애의 증거는 발견되지 않았습니다.4

ALS의 임상 증상은

관련된 운동 신경 세포의 개체군과 생존에 따라 이질적입니다(그림 2).2

구근 기능을 담당하는

전두엽 운동 신경 세포가 두드러지게 관여하는 경우,

눈에 띄는 발견은 정서적 불안정성입니다.

이는 가성 구근 마비를 나타내며,

경미한 정서적 자극에 반응하여

얼굴 경련과 과도한 웃음 또는 울음을 보이는 경향이 특징입니다.

Figure 2

Phenotype and Survival in Amyotrophic Lateral Sclerosis (ALS).

In primary lateral sclerosis, there is selective involvement of corticospinal and corticopontine motor neurons, with few findings of lower motor neuron dysfunction.5 Primary lateral sclerosis is ruled out in the representative case described above because of the atrophy and electromyographic findings, which are indicative of lower motor neuron disease. Primary lateral sclerosis progresses slowly, with severe spastic muscle stiffness and little muscle atrophy. This disorder overlaps clinically with a broad category of corticospinal disorders designated as hereditary spastic paraplegias, which are typically symmetrical in onset, slowly progressive, and sometimes associated with sensory loss and other multisystem findings. In primary lateral sclerosis but not hereditary spastic paraplegias, bulbar involvement may be prominent. In progressive muscular atrophy, lower motor neuron involvement is predominant, with little spasticity. The hyperreflexia in the representative case is inconsistent with progressive muscular atrophy.

During the past two decades, it has been recognized that 15 to 20% of persons with ALS have progressive cognitive abnormalities marked by behavioral changes, leading ultimately to dementia.6 Since these behavioral alterations correlate with autopsy evidence of degeneration of the frontal and temporal lobes, the condition is designated frontotemporal dementia. It was formerly called Pick’s disease.

근위축성 측삭 경화증(ALS)의 표현형과 생존.

원발성 측삭 경화증에서는

피질척수 및 피질교두 운동 뉴런의 선택적 침범이 나타나며,

하부 운동 뉴런 기능 장애의 소견은 거의 없습니다.5

selective involvement of corticospinal and corticopontine motor neurons

위에서 설명한 대표적인 사례에서는 위축과 근전도 검사 결과로 인해 원발성 측삭 경화증이 배제되었습니다.

원발성 측삭 경화증은

진행이 느리고,

심한 경직과 근육 위축이 거의 없습니다.

이 장애는

임상적으로 유전성 경련성 하반신 마비로 지정된

광범위한 범주의 피질척수 장애와 겹칩니다.

유전성 경련성 하반신 마비는

일반적으로 발병이 대칭적이고,

서서히 진행되며, 때로는 감각 상실 및 기타 다중 시스템 소견과 관련이 있습니다.

유전성 경련성 하반신 마비가 아닌 원발성 측삭 경화증에서는

구근 침범이 두드러질 수 있습니다.

진행성 근위축증에서는

낮은 운동 신경의 침범이 우세하고,

경련이 거의 없습니다.

대표적인 사례의 과반사증은

진행성 근위축증과 일치하지 않습니다.

지난 20년 동안

ALS 환자의 15~20%가

행동 변화로 특징지어지는 점진적인 인지 이상으로 인해

결국 치매에 이르게 된다는 사실이 밝혀졌습니다.6

이러한 행동 변화는

전두엽과 측두엽의 퇴화에 대한 부검 증거와 관련이 있기 때문에,

이 질환은 전두측두치매로 지정됩니다.

이전에는 픽병이라고 불렸습니다.

Epidemiologic Features

In Europe and the United States, there are 1 or 2 new cases of ALS per year per 100,000 people; the total number of cases is approximately 3 to 5 per 100,000.7,8 These statistics are globally fairly uniform, although there are rare foci in which ALS is more common. The incidence and preval‎ence of ALS increase with age. In the United States and Europe, the cumulative lifetime risk of ALS is about 1 in 400; in the United States alone, 800,000 persons who are now alive are expected to die from ALS.9 About 10% of ALS cases are familial, usually inherited as dominant traits.10 The remaining 90% of cases of ALS are sporadic (occurring without a family history). In cases of sporadic ALS, the ratio of affected males to affected females may approach 2:1; in familial ALS, the ratio is closer to 1:1. ALS is the most frequent neurodegenerative disorder of midlife, with an onset in the middle-to-late 50s. An onset in the late teenage or early adult years is usually indicative of familial ALS. The time from the first symptom of ALS to diagnosis is approximately 12 months, a problematic delay if successful therapy requires early intervention. Because an abundance of ALS genes have now been identified, it will probably be informative to reanalyze this epidemiologic profile of ALS with stratification according to genetically defined subtypes.

역학적 특징

유럽과 미국에서는

인구 10만 명당 매년 1~2건의 새로운 ALS 사례가 발생하며,

전체 사례 수는 약 10만 명당 3~5건입니다.7,8

이러한 통계는 ALS가 더 흔하게 발생하는 드문 지역이 있기는

하지만 전 세계적으로 상당히 균일합니다.

ALS의 발병률과 유병률은 나이가 들수록 증가합니다.

미국과 유럽에서 ALS의 누적 평생 발병률은 약 400명 중 1명이고,

미국에서만 현재 생존 중인 80만 명이

ALS로 사망할 것으로 예상됩니다.9

ALS 사례의 약 10%는 가족성 질환으로,

일반적으로 우성 유전 형질로 유전됩니다.10

나머지 90%의 ALS 사례는

산발적(가족력 없이 발생하는)입니다.

산발성 ALS의 경우,

남성 대 여성 환자의 비율은 2:1에 가까울 수 있으며,

가족성 ALS의 경우, 그 비율은 1:1에 가깝습니다.

ALS는

중년기에 가장 흔하게 발생하는 신경 퇴행성 질환으로,

50대 중후반에 발병합니다.

10대 후반 또는 성인 초기에 발병하는 경우는

일반적으로 가족성 ALS를 나타냅니다.

ALS의 첫 증상이 나타난 후

진단을 받는 데까지 걸리는 시간은 약 12개월로,

성공적인 치료를 위해서는 조기 개입이 필요하기 때문에 문제가 되는 지연입니다.

현재 많은 ALS 유전자가 확인되었기 때문에,

유전적으로 정의된 하위 유형에 따라 계층화하여

ALS의 역학 프로파일을 재분석하는 것이 유익할 것입니다.

Pathological Characteristics

The core pathological finding in ALS is motor neuron death in the motor cortex and spinal cord; in ALS with frontotemporal dementia, neuronal degeneration is more widespread, occurring throughout the frontal and temporal lobes. Degeneration of the corticospinal axons causes thinning and scarring (sclerosis) of the lateral aspects of the spinal cord. In addition, as the brain stem and spinal motor neurons die, there is thinning of the ventral roots and denervational atrophy (amyotrophy) of the muscles of the tongue, oropharynx, and limbs. Until late in the disease, ALS does not affect neurons that innervate eye muscles or the bladder. Degeneration of motor neurons is accompanied by neuroinflammatory processes, with proliferation of astroglia, microglia, and oligodendroglial cells.11,12 A common feature in cases of both familial and sporadic ALS is aggregation of cytoplasmic proteins, prominently but not exclusively in motor neurons. Some of these proteins are common in most types of ALS. This is exemplified by the nuclear TAR DNA-binding protein 43 (TDP-43), which in many cases of ALS is cleaved, hyperphosphorylated, and mislocalized to the cytoplasm.13 Aggregates of ubiquilin 2 are also common,14 as are intracytoplasmic deposits of wild-type superoxide dismutase 1 (SOD1) in sporadic ALS.15 Many protein deposits show evidence of ubiquitination; threads of ubiquitinated TDP-43 are prominent in motor neurons, both terminally and before atrophy of the cell body. Given the diverse causes of ALS, it is not surprising that some types of aggregates are detected only in specific ALS subtypes (e.g., dipeptide aggregates and intranuclear RNA deposits in C9ORF72 ALS).

병리학적 특징

ALS의 핵심 병리학적 특징은

운동 피질과 척수에서의

운동 신경 세포의 죽음입니다;

전두측두치매가 동반된 ALS의 경우,

신경 변성이 더 광범위하게 발생하며,

전두엽과 측두엽 전체에 걸쳐 발생합니다.

피질척수 축삭의 퇴행은

척수 측면의 얇아짐과 흉터(경화증)를 유발합니다.

또한,

뇌간과 척수 운동 뉴런이 죽으면,

복부근의 얇아짐과 혀, 구인두, 사지 근육의 신경절 위축(근위축)이 발생합니다.

질병이 진행될 때까지 ALS는

안구 근육이나 방광을 자극하는 뉴런에는 영향을 미치지 않습니다.

운동 뉴런의 퇴화는

신경염증 과정과 함께

아스트로글리아, 미세아교세포, 그리고 올리고덴드로글리아 세포의 증식을 동반합니다.11,12

가족성 및 산발성 ALS의 경우 공통적인 특징은

운동 뉴런에서 두드러지게 나타나지만,

운동 뉴런에만 국한되지 않는 세포질 단백질의 응집입니다.

이러한 단백질 중 일부는

대부분의 ALS 유형에서 공통적으로 나타납니다.

이것은

ALS의 많은 사례에서 핵 TAR DNA 결합 단백질 43(TDP-43)이 절단되고,

과인산화되며, 세포질로 잘못 위치하는 것으로 예시됩니다.13

유비퀴린 2의 응집체도 흔하며,

산발적 ALS에서 야생형 슈퍼옥사이드 디스뮤타제 1(SOD1)의 세포질 내 침착물도

마찬가지입니다.14 15

많은 단백질 침착물에서

유비퀴틴화의 증거가 발견됩니다.

유비퀴틴화된 TDP-43의 실은

운동 뉴런의 말초와 세포체의 위축 전

모두에서 두드러집니다.

ALS의 다양한 원인을 고려할 때,

특정 ALS 아형(예: C9ORF72 ALS의 디펩티드 응집체 및 핵내 RNA 침착물)에서만

일부 유형의 응집체가 검출된다는 것은 놀라운 일이 아닙니다.

Genetic Features

Evolving technologies for gene mapping and DNA analysis have facilitated the identification of multiple ALS genes (Figure 3). SOD1 was the first ALS gene to be identified, in 1993.16 More than 120 genetic variants have been associated with a risk of ALS17 (http://alsod.iop.kcl.ac.uk). Several criteria assist in identifying those that are most meaningful. The strongest confirmation is validation in multiple independent families and cohorts. Also supportive are an increased burden of the variant in cases relative to controls and the predicted consequences of the variant (e.g., missense mutation vs. truncation). It has proved almost impossible to predict a variant’s relevance to ALS from the biologic features of the gene itself. As shown in Figure 3, at least 25 genes have now been reproducibly implicated in familial ALS, sporadic ALS, or both.18–20

유전적 특징

유전자 지도 작성 및 DNA 분석 기술의 발전으로 여러 개의 ALS 유전자를 식별하는 것이 가능해졌습니다(그림 3). SOD1은 1993년에 최초로 확인된 ALS 유전자입니다.16 120개가 넘는 유전자 변이가 ALS의 위험과 관련되어 있습니다17 (http://alsod.iop.kcl.ac.uk). 여러 가지 기준을 통해 가장 의미 있는 유전자 변이를 식별할 수 있습니다. 가장 강력한 확인 방법은 여러 개의 독립적인 가족과 집단에서 검증하는 것입니다. 또한 대조군과 비교했을 때 변이체의 부담이 증가하고 변이체의 예측 가능한 결과(예: 미스센스 돌연변이 대 절단)가 변이체를 지지합니다. 유전자 자체의 생물학적 특징으로부터 ALS와의 관련성을 예측하는 것은 거의 불가능하다는 것이 증명되었습니다.

그림 3에 표시된 것처럼,

현재 가족성 ALS,

산발성 ALS 또는 둘 다에 연관된 것으로

재현 가능한 유전자만 25개 이상입니다.18-20

Figure 3

ALS Gene Discovery since 1990.

A by-product of the genetic studies that is highly relevant to therapeutic development has been the generation of mouse models of ALS. Strikingly, transgenic expression‎ of mutant SOD1 protein21 and, more recently, profilin 1 (PFN1)22 generates a neurodegenerative, paralytic process in mice that mimics many aspects of human ALS. An important lesson from transgenic models of TDP-43 and FUS (fused in sarcoma) is that levels of the normal protein are tightly controlled. In contrast with SOD1, forced expression‎ of high levels of normal TDP-43 by itself triggers motor neuron degeneration.23 Mouse models of C9orf72 (the 72nd open reading frame identified on chromosome 9, the most commonly mutated gene in ALS) have now also been generated for C9ORF72 ALS and are discussed below.

Correlations between genetic variants and different clinical profiles in ALS, such as age at onset, disease duration, and site of onset, have been defined (Table 1). An important example is the gene that encodes the enzyme ephrin A4 (EPHA4)33 — lower levels of expression‎ of EPHA4 correlate with longer survival. Some genetic variants influence both susceptibility and phenotype. For example, progression is accelerated in patients with the common A4V mutation30 of SOD1 and in patients with the P525L mutation of FUS/TLS; the latter may lead to fulminant, childhood-onset motor neuron disease.28

ALS 유전자 발견 1990년부터.

치료법 개발과 밀접한 관련이 있는 유전자 연구의 부산물로서 ALS 마우스 모델의 생성이 이루어졌습니다. 놀랍게도, 돌연변이 SOD1 단백질21과 최근에는 프로필린 1(PFN1)22의 트랜스제닉 발현은 인간 ALS의 여러 측면을 모방하는 신경 퇴행성 마비 과정을 생쥐에서 생성합니다. TDP-43과 FUS(육종 융합)의 트랜스제닉 모델에서 얻은 중요한 교훈은 정상 단백질의 수준이 엄격하게 통제된다는 것입니다. SOD1과는 달리, 정상적인 TDP-43의 높은 수준을 강제적으로 발현하는 것만으로도 운동 신경 변성을 유발합니다. C9orf72(ALS에서 가장 흔하게 변이되는 유전자인 9번 염색체에서 확인된 72번째 오픈 리딩 프레임)의23가지 마우스 모델이 현재 C9ORF72 ALS에 대해서도 생성되었으며, 아래에서 논의됩니다.

ALS의 유전적 변이와 발병 연령, 질병 지속 기간, 발병 부위 등 다양한 임상적 프로파일 간의 상관관계가 정의되었습니다(표 1). 중요한 예로, 효소 에프린 A4(EPHA4)를 암호화하는 유전자33가 있는데, EPHA4의 발현 수준이 낮을수록 생존 기간이 더 길어집니다. 일부 유전적 변이는 감수성과 표현형 모두에 영향을 미칩니다. 예를 들어, SOD1의 일반적인 A4V 돌연변이30번과 FUS/TLS의 P525L 돌연변이를 가진 환자의 경우 진행이 가속화됩니다. 후자는 소아기에 발병하는 급성 운동신경질환으로 이어질 수 있습니다.28번

Table 1

Genetic Variants That Influence the Phenotype in Amyotrophic Lateral Sclerosis.

Concepts in Pathogenesis

A comprehensive explanation for ALS must include both its familial and sporadic forms, as well as categories of phenotypic divergence that arise even with the same proximal trigger, such as a gene mutation. A general presumption has been that the disease reflects an adverse interplay between genetic and environmental factors. An alternative view postulates that all cases of ALS are a consequence primarily of complex genetic factors. Several perspectives suggest that the pathogenesis of ALS entails a multistep process.34

Lessons from Familial ALS

There is striking heterogeneity in the genetic causes of familial ALS, but familial ALS and sporadic ALS have similarities in their pathological features, as well as in their clinical features, suggesting a convergence of the cellular and molecular events that lead to motor neuron degeneration. These points of convergence define targets for therapy.

A working view of the present panel of ALS genes is that they cluster in three categories,19 involving protein homeostasis, RNA homeostasis and trafficking, and cytoskeletal dynamics (Figure 4). These mechanisms are not exclusive. For example, protein aggregates may sequester proteins that are important in RNA binding, thereby perturbing RNA trafficking and homeostasis. Moreover, these mechanisms are detected in the context of both familial ALS and sporadic ALS; some nonmutant proteins also have a propensity to misfold and aggregate in ALS, much like their mutant counterparts (e.g., SOD1 and TDP-43).

병인 개념

ALS에 대한 포괄적인 설명에는 가족성 및 산발성 형태와 같은 근위 유발 요인(예: 유전자 돌연변이)이 동일한 경우에도 발생하는 표현형 분화 범주가 모두 포함되어야 합니다. 이 질병은 유전적 요인과 환경적 요인의 불리한 상호 작용을 반영한다는 것이 일반적인 가정입니다. 또 다른 견해는 모든 ALS 사례가 주로 복잡한 유전적 요인의 결과라고 가정합니다. 여러 관점에 따르면, ALS의 병인은 다단계 과정을 수반합니다.34

가족성 ALS로부터 얻은 교훈

가족성 ALS의 유전적 원인에 있어서는 현저한 이질성이 존재하지만,

가족성 ALS와 산발성 ALS는

병리학적 특징과 임상적 특징에 있어 유사성이 존재합니다.

이는 운동신경 변성을 유발하는 세포 및 분자적 사건의 수렴을 시사합니다.

이러한 수렴의 지점은 치료의 목표를 정의합니다.

ALS 유전자의 현재 패널에 대한 작업적 견해는 단백질 항상성, RNA 항상성 및 트래픽, 그리고 세포 골격 역학(그림 4)을 포함하는19가지 범주로 분류된다는 것입니다. 이러한 메커니즘은 배타적이지 않습니다. 예를 들어, 단백질 응집체는 RNA 결합에 중요한 단백질을 격리시켜, RNA 트래픽과 항상성을 교란시킬 수 있습니다. 또한, 이러한 메커니즘은 가족성 ALS와 산발성 ALS의 맥락에서 모두 발견됩니다. 일부 비돌연변이 단백질도 돌연변이 단백질(예: SOD1 및 TDP-43)과 마찬가지로 ALS에서 오접힘과 응집 경향이 있습니다.

Figure 4

이 그림은 루게릭병(ALS, amyotrophic lateral sclerosis) 등의 운동신경퇴행 질환과 관련된 병리적 기전을 다양한 분자·세포학적 측면에서 정리한 도식입니다. 크게 (A) 단백질 항상성·분해 경로 이상, (B) 유전자 변이(특히 반복서열 확장), 그리고 (C) 축삭 수송·신경돌기 성장 장애로 세 분야를 구분하여, ALS가 어떻게 발생·악화하는지 보여줍니다

(A) 단백질 항상성(Proteostasis) 및 스트레스 과응집
스트레스 과응집(Stress granules)

TDP-43, FUS, hnRNP A2/B1 등 RNA 결합단백질이 세포질로 잘못 이동하거나, 스트레스 과립을 형성하여 정상 기능을 잃거나 올리고머·응집체를 이룹니다. 이는 **단백질 분해·제거(autophagy, 유비퀴틴-프로테아좀 경로)**가 고장나거나 포화될 경우 독성 응집체가 축적되어 뉴런 손상을 야기합니다.

ER(소포체) 스트레스 & 분해 경로

ER 유래 단백질 품질관리(ERAD), VCP(p97) 등 분해보조 단백질, TBK1-OPTN-p62 경로 등이 교란되면 오토파지 및 염증반응(neuroinflammation)도 유발됩니다. 결과적으로 신경염증, 운동뉴런 퇴행이 가속화될 수 있습니다.

핵-세포질 수송 문제

일부 ALS 관련 유전자변이(FUS, TDP-43 등)는 핵·세포질 간 shuttling 이상을 일으켜, 핵 내 기능(전사조절)과 세포질 내 RNA대사 모두에 문제를 일으킵니다.

(B) 반복서열 확장(Repeat expansion)으로 인한 ALS 기전
C9ORF72 등에서의 6염기 반복서열 확장**

ALS와 전두측두엽치매(FTD)에서 공통적으로 발견되는 C9ORF72 유전자의 GGGGCC 반복 확장이 대표적 예시입니다.

반복서열 확장은 RNA 독성(RNA foci)이나 비정상적 이색펩타이드(dipeptide repeats, DPR) 합성을 유발해 세포에 해가 됩니다.

’Gain of function’ vs ‘Loss of function’

반복서열로 인한 비정상 단백질(또는 RNA) 발현은 독성(획득기능, gain of function)을 일으키고, 정작 C9orf72 자체 단백질은 감소(손실기능, loss of function)되어 세포 항상성에 이중 타격을 줍니다.

핵·세포질 수송 저해 & 스트레스 과립 연관

반복서열 확장된 RNA가 스트레스 과립이나 핵공(nuclear pore) 주변에서 단백질들과 비정상적인 결합을 일으켜, 핵-세포질 단백질 운반이 방해되고, TDP-43 등 다른 중요한 RNA 결합단백질도 교란됩니다.

(C) 축삭 수송 결핍(Axonal transport defect) & 신경돌기 성장 장애
마이크로튜불(microtubule) 기반 운반 이상

운동뉴런의 축삭은 매우 길어, 세포체에서 합성된 물질을 말단까지 효율적으로 운반해야 합니다.

ALS에서는 dynein, kinesin, dynactin(DCTN1) 등의 운반 단백질 또는 결합단백질 이상으로 축삭 수송이 저해되고, 시냅스 유지가 어려워집니다.

액틴/미세섬유 재배열 문제

프로필린1(Profilin 1) 등 ALS 연관 돌연변이 단백질은 액틴 필라멘트 조립·해체에 관여해, 성장콘(growth cone) 확장을 방해하여 신경재생에 장애를 초래합니다.

이로 인해 신경돌기(뉴리트, neurite)의 발달 및 재생이 억제되고, 근육과의 연결이 점차 소실됩니다.

성장 콘(growth cone) 지지 결핍

EPHA4(에프린 수용체 A4) 등 막단백질들도 신호 이상 시 뉴런 성장 및 시냅스 형성이 제대로 되지 않아, 근육 탈신경화와 약화가 진행됩니다.

결론
그림은 ALS 발병·진행에 관련된 3가지 핵심 병리 메커니즘을 한눈에 보여주며,

(A) 잘못 접힌 단백질과 스트레스 과립, 단백질 분해 시스템 이상,
(B) 반복서열 확장(C9ORF72 등)으로 인한 RNA 독성, 이색 펩타이드 생성,
(C) 뉴런의 축삭 수송 및 성장 콘 형성 장애가 뉴런의 기능 상실과 운동뉴런 퇴행을 일으켜 임상적 ALS 증상(근위축, 마비 등)으로 이어진다는 종합적 기전을 제시합니다.

Three Major Categories of Pathophysiological Processes in ALS.

Downstream of each category are diverse forms of cellular abnormalities, including the deposition of intranuclear and cytosolic protein and RNA aggregates, disturbances of protein degradative mechanisms, mitochondrial dysfunction, endoplasmic reticulum stress, defective nucleocytoplasmic trafficking, altered neuronal excitability, and altered axonal transport. In most cases, these events activate and recruit nonneuronal cells (astrocytes, microglia, and oligodendroglia), which exert both salutary and negative influences on motor neuron viability. The diverse downstream abnormalities may differentially affect subcellular compartments (dendrites, soma, axons, and neuromuscular junctions). One implication of this model is that successful therapy for ALS will require simultaneous interventions in multiple downstream pathways.

ALS의 병태생리학적 과정의 세 가지 주요 범주.

각 범주의 하류에는 

핵내 및 세포질 단백질과 RNA 응집체의 침착, 

단백질 분해 메커니즘의 장애, 

미토콘드리아 기능 장애, 

소포체 스트레스, 

핵세포질 이동의 결함, 

신경 흥분성의 변화, 

축삭 수송의 변화를 포함한 다양한 형태의 세포 이상들이 존재합니다. 

대부분의 경우, 

이러한 사건은 

운동 신경 세포의 생존에 긍정적인 영향과 부정적인 영향을 모두 미치는 

비신경 세포(성상교세포, 소교세포, 및 미엘린화교세포)를 

활성화하고 모집합니다. 

다양한 하류 이상은 

세포 내 구획(수지상 돌기, 체세포, 축삭, 신경근 접합부)에 다른 영향을 미칠 수 있습니다. 

이 모델의 한 가지 시사점은 

ALS에 대한 성공적인 치료가 여러 하류 경로에 대한 동시 개입을 필요로 한다는 것입니다.

Genes That Influence Protein Homoeostasis

The most extensively investigated pathological finding in ALS has been the accumulation of aggregated proteins and corresponding defects in the cellular pathways for protein degradation. Mutant SOD1 frequently forms intracellular aggregates. Genes that encode adapter proteins involved in protein maintenance and degradation are also implicated in ALS. These include valosin-containing protein (VCP)35 and the proteins optineurin (OPTN),36 TANK-binding kinase 1 (TBK1),37–39 and sequestosome 1 (SQSTM1/p62)40 (Figure 4A). The TBK1–OPTN axis is interwoven in other neurodegenerative disorders; for example, the Parkinson’s disease gene PINK1 encodes a protein that acts upstream of TBK1 in the mobilization of mitophagy.

단백질 항상성에 영향을 미치는 유전자

ALS에서 가장 광범위하게 연구된 병리학적 발견은 단백질 응집의 축적과 단백질 분해의 세포 경로에서의 결함입니다. 돌연변이 SOD1은 종종 세포 내 응집체를 형성합니다. 단백질 유지 및 분해에 관여하는 어댑터 단백질을 암호화하는 유전자도 ALS와 관련이 있습니다. 여기에는 발로신 함유 단백질(VCP)35과 옵티뉴린(OPTN)36, 탱크-결합 키나아제 1(TBK1)37-39, 그리고 시큐스토솜 1(SQSTM1/p62)40이 포함됩니다(그림 4A). TBK1-OPTN 축은 다른 신경 퇴행성 질환과도 관련이 있습니다. 예를 들어, 파킨슨병 유전자 PINK1은 미토파지의 활성화에서 TBK1의 상류에서 작용하는 단백질을 암호화합니다.

Genes That Influence RNA Homeostasis and Trafficking

The most rapidly expanding category of ALS genes encodes proteins that interact with RNA. The first protein to be discovered was TDP-43,13 whose mislocalization from the nucleus to the cytosol, cleavage, phosphorylation, and ubiquitination were initially illuminated in sporadic ALS and frontotemporal dementia. However, it became apparent that mutations in TARDBP, the gene encoding TDP-43, can cause familial ALS.41 Mislocalization and post-translational modification of TDP-43 are observed in many neurodegenerative diseases. FUS-TLS encodes another RNA-binding protein, homologous to TDP-43, which in mutant form also causes ALS.42,43 Why mutated genes encoding RNA-binding proteins cause ALS is not clear. These proteins have multiple functions in gene splicing, surveillance of transcripts after splicing, generation of microRNA, and axonal biologic processes. Most of these proteins have low-complexity domains that permit promiscuous binding not only to RNA but also to other proteins. The ALS-related mutations heighten this binding propensity, leading to self-assembly of the proteins and the formation of aggregates.44 This auto-aggregation is facilitated in stress granules, which are non–membrane-bound structures formed under cell stress that contain RNA complexes stalled in translation.45–47 The self-assembly of mutant RNA-binding proteins may induce toxic, self-propagating conformations that disseminate disease within and between cells in a manner analogous to that of prion proteins.

The most commonly mutated gene in ALS is C9ORF72.48–50 The C9ORF72 protein has a role in nuclear and endosomal membrane trafficking and autophagy. A noncoding stretch of six nucleotides is repeated up to approximately 30 times in normal persons. Expansions of this segment to hundreds or thousands of repeats cause familial ALS and frontotemporal dementia; in addition, these expansions sometimes cause sporadic ALS. Several mechanisms may contribute to the neurotoxicity of the hexanucleotide expansion (Figure 4B). Transcripts of the offending segments are deposited in the nucleus, forming RNA foci that sequester nuclear proteins. Some of the expanded RNA escapes to the cytoplasm, where it generates five potentially toxic repeat dipeptides through a noncanonical translation process. Recent studies have also shown a defect in transport across the nuclear membrane in cells with the C9ORF72 expansions.51,52 A reduction in the total levels of the normal C9ORF72 protein may also contribute to neurotoxicity.53–55 Transgenic mouse models of C9orf72 recapitulate the molecular features of C9ORF72 ALS in humans56–59 but, with one exception,59 do not show a strong motor phenotype.

RNA 항상성 및 트래픽에 영향을 미치는 유전자

ALS 유전자 중 가장 빠르게 확장되는 카테고리는 RNA와 상호 작용하는 단백질을 암호화하는 유전자입니다. 최초로 발견된 단백질은 TDP-43으로, 핵에서 세포질로의 잘못된 위치 이동, 절단, 인산화, 유비퀴틴화가 산발성 ALS와 전두측두엽 치매에서 처음 밝혀졌습니다. 그러나 TDP-43을 암호화하는 유전자인 TARDBP의 돌연변이가 가족성 ALS를 유발할 수 있다는 사실이 밝혀졌습니다.41 TDP-43의 잘못된 위치와 번역 후 변형은 많은 신경 퇴행성 질환에서 관찰됩니다. FUS-TLS는 TDP-43과 상동적인 또 다른 RNA 결합 단백질을 암호화하는데, 이 돌연변이 형태도 ALS를 유발합니다.42,43 RNA 결합 단백질을 암호화하는 돌연변이 유전자가 ALS를 유발하는 이유는 명확하지 않습니다. 이 단백질들은 유전자 스플라이싱, 스플라이싱 후 전사체의 감시, 마이크로RNA의 생성, 축삭 생물학적 과정 등 다양한 기능에 관여합니다. 이들 단백질의 대부분은 복잡도가 낮은 도메인을 가지고 있어서 RNA뿐만 아니라 다른 단백질에도 무차별적으로 결합할 수 있습니다. ALS 관련 돌연변이는 이러한 결합 성향을 강화하여 단백질의 자가 조립과 응집체의 형성을 유도합니다. 44 이러한 자동 집합은 스트레스 과립에서 촉진되는데, 이것은 세포 스트레스 하에서 형성되는 비막 결합 구조로, 번역 과정에서 정체된 RNA 복합체를 포함합니다.45-47 돌연변이 RNA 결합 단백질의 자가 조립은 프리온 단백질과 유사한 방식으로 세포 내 및 세포 간에 질병을 전파하는 독성 자가 증식 구조를 유발할 수 있습니다.

ALS에서 가장 흔하게 변이되는 유전자는 C9ORF72입니다.48-50 C9ORF72 단백질은 핵과 엔도소말 막의 트래픽과 자가포식에 관여합니다. 6개의 뉴클레오티드로 구성된 비코딩 영역이 정상인의 경우 약 30회 반복됩니다. 이 영역이 수백 또는 수천 번 반복되면 가족성 ALS와 전두측두치매가 발생합니다. 또한, 이러한 반복이 산발성 ALS를 유발하기도 합니다. 헥사뉴클레오티드 확장의 신경독성에 기여하는 여러 가지 메커니즘이 있을 수 있습니다(그림 4B). 문제가 되는 부분의 전사체가 핵에 축적되어 핵 단백질을 격리시키는 RNA 초점을 형성합니다. 확장된 RNA 중 일부는 세포질로 빠져나가 비정규 번역 과정을 통해 잠재적으로 독성이 있는 5개의 반복 디펩티드를 생성합니다. 최근 연구에 따르면 C9ORF72 돌연변이가 있는 세포의 핵막을 통과하는 데 결함이 있는 것으로 나타났습니다. 51,52 정상적인 C9ORF72 단백질의 총 수준이 감소하는 것도 신경독성에 기여할 수 있습니다.53-55 C9orf72의 형질전환 마우스 모델은 인간의 C9ORF72 ALS의 분자적 특징을 재현하지만56-59 한 가지 예외를 제외하고는 강력한 운동 표현형을 보이지 않습니다59.

Genes That Influence Cytoskeletal Dynamics

Three ALS genes encode proteins that are important in maintenance of normal cytoskeletal dynamics: dynactin 1 (DCTN1),60 PFN1,29 and tubulin 4A (TUBA4A) (Figure 4C).61 TUBA4A dimers are components of microtubules, whose integrity is essential for axonal structure; DCTN1 is implicated in retrograde axonal transport, whereas PFN1 participates in the conversion of globular to filamentous actin and nerve extension. Also implicated is the modifier gene EPHA4; lower levels of EPHA4 expression‎ correlate with longer survival in ALS, perhaps because they permit more exuberant axonal extension.

세포 골격 역학에 영향을 미치는 유전자들

세 가지 ALS 유전자는 정상적인 세포 골격 역학을 유지하는 데 중요한 단백질을 암호화합니다: 다이나카인 1(DCTN1),60 PFN1,29 그리고 튜불린 4A(TUBA4A) (그림 4C). 61개의 TUBA4A 이합체는 미세소관의 구성 요소이며, 이 미세소관의 완전성은 축삭 구조에 필수적입니다; DCTN1은 역행성 축삭 수송에 관여하는 반면, PFN1은 구형에서 필라멘트형 액틴으로의 전환과 신경 신장에 관여합니다. 또한, 조절 유전자인 EPHA4도 관여합니다; EPHA4 발현의 낮은 수준은 ALS 환자의 생존 기간이 더 길다는 것과 관련이 있는데, 아마도 이 유전자를 통해 축삭 신장이 더 활발하게 이루어지기 때문일 것입니다.

Insights into Sporadic ALS

Despite the absence of a family history in sporadic ALS, studies involving twins show that the heritability is about 60%.62 Furthermore, mutations usually found in familial ALS can be found in sporadic ALS. This can be partly explained by the difficulty in ascertaining whether patients with late-onset disease have a family history of ALS. The situation is confounded by the observation that some familial ALS gene variants increase the risk of phenotypes other than ALS, such as frontotemporal dementia.38,39,48 Unless these other phenotypes are recognized as relevant, the family history may be incorrectly recorded as negative. In addition, several familial ALS gene variants are of intermediate penetrance (e.g., the C9ORF72 hexanucleotide repeat expansion, ATXN2 repeat expansions,63 and TBK1 mutations).37–39 Thus, ALS might not be manifested in a gene carrier, in which case, the disease is characterized by familial clustering rather than mendelian inheritance and may appear to be sporadic.64 Combinations of such gene variants further increase the risk of ALS and may be another cause of apparently sporadic ALS.65

Recent genomewide association studies have shown that rare genetic variation is disproportionately frequent in sporadic ALS.66 The genetic architecture of sporadic ALS is markedly different from that of complex diseases such as schizophrenia in which there are additive effects of hundreds of common variants, each with a minute effect on risk. However, common variants still have a part to play in sporadic ALS. For example, variants in the genes UNC13A, MOBP, and SCFD1 all increase the risk by a small but significant degree.66

Heritability studies also show that a substantial fraction of cases of sporadic ALS cannot be attributed to genetic or biologic factors; these cases are ascribed to environmental or undefined factors. Attempts to identify occupations or common exposures that might increase the risk of ALS have been inconclusive. Environmental studies are challenging because the number of possible exposures is large, and a critical, disease-related exposure may have happened many years before the onset of the disease. A particular difficulty is that studies of ALS are susceptible to bias because of the poor prognosis. Patients who live long enough to attend a specialist research clinic are different from those identified in population studies, and this difference can cause bias in the results. For instance, smoking has been shown to shorten survival in a population study,67 so a case–control study selecting participants from clinics would find smokers underrepresented in the ALS group and would thus suggest that smoking either has no effect or might be protective. Similarly, ALS specialists report anecdotally that their patients tend to be athletic, slim, and very fit,68 but if these factors slow disease progression rather than increase risk, such patients will be overrepresented at specialist centers.

Notwithstanding the barriers to identifying environmental risk factors, some factors have been associated with ALS in multiple studies.69,70 The exposure with the strongest support is military service.71,72 In addition, smoking has been implicated as a dose-dependent risk factor for ALS.73 Exposure to heavy metals may be important; blood lead levels and cerebrospinal fluid manganese levels are higher in patients with ALS than in controls.70 People with occupations involving exposure to electromagnetic fields also appear to be at increased risk, but people living near power lines are not. Other risk factors with varying levels of support include pesticide exposure and neurotoxins such as those produced by cyanobacteria. Viruses have been studied as a possible explanation for sporadic ALS. Initial studies suggesting the role of an activated, endogenous retrovirus74 were followed by the identification of a possible candidate, human endogenous retrovirus K.75

There is increasing evidence that trauma precedes some individual cases of ALS.76 A meta-analysis has suggested that trauma overall, trauma occurring more than 5 years previously, bone fracture, and head injury are all associated with an increased risk.77 In recent years, it has been observed that persons engaged in sports that entail repetitive concussions or subconcussive head trauma are at increased risk for ALS and a concurrent behavioral disorder marked by impulsivity and memory loss. Autopsy studies in persons with this disorder, called chronic traumatic encephalopathy, have revealed frontotemporal atrophy associated with distinctive deposits of tau protein, as well as TDP-43, the characteristic inclusion protein in ALS.78

산발성 ALS에 대한 통찰력

산발성 ALS의 가족력이 없는 경우에도 쌍둥이를 대상으로 한 연구에 따르면 유전율은 약 60%에 달합니다.62 게다가, 가족성 ALS에서 흔히 발견되는 돌연변이가 산발성 ALS에서도 발견될 수 있습니다. 이는 발병이 늦은 환자가 ALS의 가족력이 있는지 확인하기가 어렵다는 사실에 부분적으로 기인합니다. 일부 가족성 ALS 유전자 변이체가 전두측두치매와 같은 ALS 이외의 표현형에 대한 위험을 증가시킨다는 관찰로 인해 상황이 복잡해졌습니다.38,39,48 이러한 다른 표현형이 관련성이 있다고 인식되지 않는 한, 가족력은 부정적으로 잘못 기록될 수 있습니다. 또한, 몇몇 가족성 ALS 유전자 변이(예: C9ORF72 6자 반복 증폭, ATXN2 반복 증폭,63번 및 TBK1 돌연변이)는 중간 정도의 침투력을 가지고 있습니다. 37-39 따라서, ALS는 유전자 운반자에게서 발현되지 않을 수 있으며, 이 경우, 이 질병은 멘델 유전보다는 가족 집단에 의해 특징지어지며 산발적으로 나타날 수 있습니다.64 이러한 유전자 변이의 조합은 ALS의 위험을 더욱 증가시키며, 명백히 산발적으로 나타나는 ALS의 또 다른 원인이 될 수 있습니다.65

최근 게놈 차원의 연관성 연구에 따르면, 희귀한 유전적 변이가 산발성 ALS에서 불균형적으로 빈번하게 발생한다는 사실이 밝혀졌습니다.66 산발성 ALS의 유전적 구조는 수백 개의 공통 변이체가 위험에 미미한 영향을 미치면서 추가적인 효과를 내는 정신분열증과 같은 복합 질환의 유전적 구조와 현저하게 다릅니다. 그러나 공통 변이체는 여전히 산발성 ALS에서 중요한 역할을 합니다. 예를 들어, 유전자 UNC13A, MOBP, 그리고 SCFD1의 변이는 모두 위험을 약간이지만 상당한 수준으로 증가시킵니다.66

유전성 연구에 따르면, 산발성 ALS 사례의 상당 부분은 유전적 또는 생물학적 요인에 기인하는 것이 아니라 환경적 또는 정의되지 않은 요인에 기인하는 것으로 나타났습니다. ALS의 위험을 증가시킬 수 있는 직업이나 일반적인 노출을 확인하려는 시도는 결정적이지 않았습니다. 환경 연구는 노출 가능성이 많다는 점에서 도전적입니다. 질병과 관련된 중요한 노출은 질병이 발병하기 수년 전에 일어날 수 있기 때문입니다. 특히, ALS 연구는 예후가 좋지 않다는 점에서 편향에 취약하다는 점이 문제입니다. 전문 연구 클리닉에 갈 수 있을 만큼 오래 사는 환자는 인구 연구에서 확인된 환자와 다르며, 이러한 차이로 인해 결과에 편향이 발생할 수 있습니다. 예를 들어, 흡연이 인구 연구에서 생존 기간을 단축시키는 것으로 나타났기 때문에67, 클리닉에서 참가자를 선택하는 사례-대조군 연구를 통해 ALS 그룹에서 흡연자가 과소 대표되는 것을 발견할 수 있으며, 따라서 흡연이 영향을 미치지 않거나 보호 효과가 있을 수 있음을 시사할 수 있습니다. 마찬가지로, ALS 전문의들은 환자들이 운동선수이고 날씬하며 매우 건강하다는 것을 일화적으로 보고하고 있지만68, 이러한 요인들이 위험을 증가시키는 대신 질병 진행을 늦춘다면, 그러한 환자들이 전문 센터에서 과대 대표될 것입니다.

환경적 위험 요인을 파악하는 데는 여러 가지 장애물이 있지만, 여러 연구에서 ALS와 관련된 몇 가지 요인이 확인되었습니다.69,70 가장 강력한 근거를 제공하는 노출은 군 복무입니다.71,72 또한, 흡연은 ALS의 용량 의존적 위험 요인으로 간주되어 왔습니다.73 중금속 노출이 중요할 수 있습니다. 혈액 내 납 농도와 뇌척수액 내 망간 농도는 대조군보다 ALS 환자에서 더 높습니다. 전자기장에 노출되는 직업을 가진 사람 70명도 위험이 높은 것으로 보이지만, 전력선 근처에 사는 사람들은 그렇지 않습니다. 다양한 수준의 근거를 가진 다른 위험 요인으로는 농약 노출과 시아노박테리아가 생성하는 신경독 등이 있습니다. 바이러스는 산발적 ALS의 가능한 원인으로 연구되어 왔습니다. 활성화된 내인성 레트로바이러스의 역할을 시사하는 초기 연구 74에 이어, 가능한 후보인 인간 내인성 레트로바이러스 K가 확인되었습니다 75.

ALS의 일부 개별 사례에 외상이 선행한다는 증거가 증가하고 있습니다.76 메타 분석에 따르면 전반적인 외상, 5년 이상 전에 발생한 외상, 골절, 두부 외상이 모두 위험 증가와 관련이 있는 것으로 나타났습니다.77 최근 몇 년 동안 반복적인 뇌진탕 또는 경미한 뇌진탕을 수반하는 스포츠에 종사하는 사람들이 ALS와 충동성과 기억 상실을 특징으로 하는 동시 행동 장애에 걸릴 위험이 더 높다는 사실이 관찰되었습니다. 만성 외상성 뇌병증이라고 불리는 이 질환을 가진 사람들의 부검 연구에 따르면, 전두측두엽 위축이 특징적인 타우 단백질 침착과 관련이 있으며, ALS의 특징적인 봉입체 단백질인 TDP-43과도 관련이 있는 것으로 밝혀졌습니다.78

Therapeutics and Beyond

No therapy offers a substantial clinical benefit for patients with ALS. The drugs riluzole79 and edaravone, which have been approved by the Food and Drug Administration for the treatment of ALS, provide a limited improvement in survival. Riluzole acts by suppressing excessive motor neuron firing, and edaravone by suppressing oxidative stress. Numerous other compounds that have been investigated have not been shown to be effective.80,81 Currently, the mainstay of care for patients with ALS is timely intervention to manage symptoms, including use of nasogastric feeding, prevention of aspiration (control of salivary secretions and use of cough-assist devices), and provision of ventilatory support (usually with bilevel positive airway pressure). Some interventions raise serious ethical issues, such as whether to perform tracheostomy for full ventilation and, if so, when and how to withdraw respiratory support once it has been instituted.

Despite the pipeline of potential treatments for ALS, reflecting the expanded list of targets identified through genetic studies and increasing numbers of ALS investigators, many of whom are in the pharmaceutical sector,80,82 no drugs are being investigated in late-phase clinical trials. Several innovative approaches to treating ALS (and other neurodegenerative diseases) are in development. Two examples include the use of adeno-associated viruses (AAV) to achieve widespread delivery of diverse cargoes (missing genes, therapeutic genes, or gene-silencing elements) to the central nervous system and the use of stem cells that provide neurotrophic factors to the central nervous system.83 Studies in cells, mice, and humans support the view that several types of reagents (e.g., antisense oligonucleotides and AAV-delivered microRNA) inactivate production of toxic gene products and thus may be therapeutic in ALS mediated by genes such as SOD184–87 and C9ORF72. Indeed, clinical trials investigating the use of antisense oligonucleotides to silence SOD1 have begun.

One can anticipate continued progress in understanding the biology of ALS. There is no doubt that high-throughput genetics, combined with improved clinical phenotyping, will further refine the genetic landscape of ALS. As thousands of full genome sequences become available, it will be feasible to explore the possibility that complex interactions among multiple gene variants explain not only familial ALS but also sporadic ALS. The exploration of environmental factors in sporadic ALS will expand, with a focus on the internal environment represented by the microbiome. The ultimate proof of our understanding of the biology of ALS will hinge on our ability to modify the clinical course of the disease.

치료와 그 너머

ALS 환자에게

실질적인 임상적 혜택을 제공하는 치료법은 없습니다.

미국 식품의약국(FDA)의 승인을 받아 ALS 치료제로 사용되고 있는

리루졸79과 에다라본은 생존율을 제한적으로 개선하는 효과를 제공합니다.

리루졸은 과도한 운동신경세포의 발화를 억제하는 작용을 하고,

에다라본은 산화 스트레스를 억제하는 작용을 합니다.

그 밖에도 수많은 다른 복합 요법이 연구되었지만, 효과가 있는 것으로 밝혀진 것은 없습니다.80,81 현재, ALS 환자의 치료의 주축은 비위관 영양 공급, 흡인 예방(침 분비 조절 및 기침 보조 장치 사용), 그리고 인공호흡 지원(보통 양압기도압을 통한)을 포함한 증상 관리를 위한 시기적절한 개입입니다. 일부 개입은 심각한 윤리적 문제를 야기합니다. 예를 들어, 완전 인공호흡을 위해 기관절개술을 시행할지 여부, 시행할 경우 인공호흡을 시작한 후 언제, 어떻게 호흡 지원을 중단할지 등이 그 예입니다.

ALS에 대한 잠재적 치료법이 계속 개발되고 있음에도 불구하고, 유전학 연구를 통해 밝혀진 표적의 목록이 늘어나고, 그 중 다수가 제약 분야에 종사하는 ALS 연구자의 수가 증가함에 따라, 후기 임상 시험 단계에 있는 약물은80,82 없습니다. ALS(및 기타 신경 퇴행성 질환) 치료에 대한 몇 가지 혁신적인 접근법이 개발되고 있습니다. 두 가지 예로는 다양한 화물(결핍된 유전자, 치료 유전자 또는 유전자 억제 요소)을 중추 신경계에 광범위하게 전달하기 위해 아데노 관련 바이러스(AAV)를 사용하는 것과 중추 신경계에 신경 영양 인자를 제공하는 줄기세포를 사용하는 것이 있습니다. 83 세포, 쥐, 인간을 대상으로 한 연구에 따르면, 여러 종류의 시약(예: 안티센스 올리고뉴클레오티드 및 AAV 전달 마이크로RNA)이 독성 유전자 제품의 생성을 비활성화하여 SOD184-87 및 C9ORF72와 같은 유전자에 의해 매개되는 ALS에 치료 효과가 있을 수 있다는 견해를 뒷받침합니다. 실제로, SOD1을 억제하기 위한 안티센스 올리고뉴클레오티드의 사용을 조사하는 임상 시험이 시작되었습니다.

ALS의 생물학적 이해가 계속해서 진전될 것으로 예상할 수 있습니다. 고처리량 유전학이 개선된 임상 표현형과 결합되어 ALS의 유전적 지형을 더욱 세분화할 것이라는 데는 의심의 여지가 없습니다. 수천 개의 전체 게놈 서열이 이용 가능해지면, 여러 유전자 변이체 간의 복잡한 상호작용이 가족성 ALS뿐만 아니라 산발성 ALS도 설명할 수 있는 가능성을 탐구하는 것이 가능해질 것입니다. 산발성 ALS의 환경적 요인 탐구는 미생물 군집으로 대표되는 내부 환경에 초점을 맞추어 확대될 것입니다. ALS의 생물학에 대한 우리의 이해에 대한 궁극적인 증거는 질병의 임상 경과를 수정할 수 있는 능력에 달려 있습니다.

Notes

Dr. Brown reports holding equity in AviTx, Amylyx Pharmaceuticals, and ImStar Therapeutics, receiving fees for serving on an advisory board from Voyager Therapeutics, negotiating a collaborative agreement with WAVE Biosciences, holding patents and receiving royalties for patents on “Method for the diagnosis of familial amyotrophic lateral sclerosis” (US 5,843,641) and “Mice having a mutant SOD1 encoding transgene” (US 6,723,893), holding a patent for “Compounds and method for the diagnosis, treatment and prevention of cell death” (US 5,849,290), and holding a pending patent for “Use of synthetic microRNA for AAV-mediated silencing of SOD1 in ALS”; and Dr. Al-Chalabi reports receiving consulting fees from GlaxoSmithKline, providing unpaid consulting for Mitsubishi Tanabe Pharma, Treeway, Chronos Therapeutics, and Avanir Pharmaceuticals, receiving consulting fees and serving as principal investigator in an international commercial clinical trial of tirasemtiv in ALS for Cytokinetics, and serving as chief investigator of an international commercial clinical trial of levosimendan in ALS for Orion Pharma. No other potential conflict of interest relevant to this article was reported.

참고
Dr. Brown은 AviTx, Amylyx Pharmaceuticals, ImStar Therapeutics의 지분을 보유하고 있으며, Voyager Therapeutics의 자문위원회 위원으로서 수수료를 받고, WAVE Biosciences와 협력 계약을 협상하고, “가족성 근위축성 측삭경화증 진단 방법”(US 5,843,641) 및 “돌연변이 SOD1을 코딩하는 형질전환체를 가진 마우스”에 대한 특허를 보유하고 있으며, 특허에 대한 로열티를 받고 있습니다. (미국 6,723,893), “세포 사멸의 진단, 치료 및 예방을 위한 화합물 및 방법”에 대한 특허(미국 5,849,290)를 보유하고 있으며, “ALS에서 SOD1의 AAV 매개 침묵화를 위한 합성 microRNA의 사용”에 대한 특허 출원 중입니다. 그리고 박사 알-칼라비는 글락소 스미스클라인으로부터 컨설팅 비용을 받고, 미쓰비시 다나베 제약, 트레웨이, 크로노스 테라퓨틱스, 아바니르 파마슈티컬즈에 무보수 컨설팅을 제공하고, Cytokinetics의 ALS에 대한 티라세미티브의 국제 상업 임상 시험에서 컨설팅 비용을 받고 수석 연구원으로 활동하고, Orion Pharma의 ALS에 대한 레보시멘단의 국제 상업 임상 시험에서 수석 연구원으로 활동하고 있다고 보고했습니다. 이 기사와 관련된 다른 잠재적 이해 충돌은 보고되지 않았습니다.

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References

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Rowland, LP, Shneider, NA. Amyotrophic lateral sclerosis. N Engl J Med 2001;344:1688-1700

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Amyotrophic Lateral Sclerosis

Authors: Robert H. Brown, D.Phil., M.D., and Ammar Al-Chalabi, Ph.D., F.R.C.P., Dip.Stat.Author Info & Affiliations

Published July 13, 2017

N Engl J Med 2017;377:162-172

DOI: 10.1056/NEJMra1603471

VOL. 377 NO. 2

Copyright © 2017

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Amyotrophic lateral sclerosis (ALS) is a progressive, paralytic disorder characterized by degeneration of motor neurons in the brain and spinal cord. It begins insidiously with focal weakness but spreads relentlessly to involve most muscles, including the diaphragm. Typically, death due to respiratory paralysis occurs in 3 to 5 years.

Motor neurons are grouped into upper populations in the motor cortex and lower populations in the brain stem and spinal cord; lower motor neurons innervate muscle (Figure 1). When corticospinal (upper) motor neurons fail, muscle stiffness and spasticity result. When lower motor neurons become affected, they initially show excessive electrical irritability, leading to spontaneous muscle twitching (fasciculations); as they degenerate, they lose synaptic connectivity with their target muscles, which then atrophy.

Figure 1

The Motor System.

ALS typically begins in the limbs, but about one third of cases are bulbar, heralded by difficulty chewing, speaking, or swallowing. Until late in the disease, ALS spares neurons that innervate the eye and sphincter muscles. The diagnosis is based primarily on clinical examination in conjunction with electromyography, to confirm‎ the extent of denervation, and laboratory testing, to rule out reversible disorders that may resemble ALS.1,2

A representative case involves a 55-year-old patient who was eval‎uated for foot drop, which had begun subtly 4 months earlier with the onset of muscle cramping in the right calf as a result of volitional movement (known as volitional cramping) and had progressed to severe weakness of ankle dorsiflexion and knee extension. In addition to these features, the physical examination revealed atrophy of the right calf and hyperreflexia of the right biceps and of deep tendon reflexes at both knees and both ankles. The neurologic examination was otherwise normal. Electromyography showed evidence of acute muscle denervation (fibrillations) in all four limbs and muscle reinnervation in the right calf (high-amplitude compound muscle action potentials). Imaging of the head and neck revealed no structural lesions impinging on motor tracts, and the results of laboratory studies were normal, findings that ruled out several disorders in the differential diagnosis, such as peripheral neuropathy, Lyme disease, vitamin B12 deficiency, thyroid disease, and metal toxicity.3 A full eval‎uation disclosed no evidence of a reversible motor neuron disorder, such as multifocal motor neuropathy with conduction block, which is typically associated with autoantibodies (e.g., anti-GM1 ganglioside antibodies) and can be effectively treated with intravenous immune globulin.4

The clinical presentation of ALS is heterogeneous with respect to the populations of involved motor neurons and survival (Figure 2).2 When there is prominent involvement of frontopontine motor neurons that serve bulbar functions, a striking finding is emotional lability, indicating pseudobulbar palsy, which is characterized by facial spasticity and a tendency to laugh or cry excessively in response to minor emotional stimuli.

Figure 2

Phenotype and Survival in Amyotrophic Lateral Sclerosis (ALS).

In primary lateral sclerosis, there is selective involvement of corticospinal and corticopontine motor neurons, with few findings of lower motor neuron dysfunction.5 Primary lateral sclerosis is ruled out in the representative case described above because of the atrophy and electromyographic findings, which are indicative of lower motor neuron disease. Primary lateral sclerosis progresses slowly, with severe spastic muscle stiffness and little muscle atrophy. This disorder overlaps clinically with a broad category of corticospinal disorders designated as hereditary spastic paraplegias, which are typically symmetrical in onset, slowly progressive, and sometimes associated with sensory loss and other multisystem findings. In primary lateral sclerosis but not hereditary spastic paraplegias, bulbar involvement may be prominent. In progressive muscular atrophy, lower motor neuron involvement is predominant, with little spasticity. The hyperreflexia in the representative case is inconsistent with progressive muscular atrophy.

During the past two decades, it has been recognized that 15 to 20% of persons with ALS have progressive cognitive abnormalities marked by behavioral changes, leading ultimately to dementia.6 Since these behavioral alterations correlate with autopsy evidence of degeneration of the frontal and temporal lobes, the condition is designated frontotemporal dementia. It was formerly called Pick’s disease.

Epidemiologic Features

In Europe and the United States, there are 1 or 2 new cases of ALS per year per 100,000 people; the total number of cases is approximately 3 to 5 per 100,000.7,8 These statistics are globally fairly uniform, although there are rare foci in which ALS is more common. The incidence and preval‎ence of ALS increase with age. In the United States and Europe, the cumulative lifetime risk of ALS is about 1 in 400; in the United States alone, 800,000 persons who are now alive are expected to die from ALS.9 About 10% of ALS cases are familial, usually inherited as dominant traits.10 The remaining 90% of cases of ALS are sporadic (occurring without a family history). In cases of sporadic ALS, the ratio of affected males to affected females may approach 2:1; in familial ALS, the ratio is closer to 1:1. ALS is the most frequent neurodegenerative disorder of midlife, with an onset in the middle-to-late 50s. An onset in the late teenage or early adult years is usually indicative of familial ALS. The time from the first symptom of ALS to diagnosis is approximately 12 months, a problematic delay if successful therapy requires early intervention. Because an abundance of ALS genes have now been identified, it will probably be informative to reanalyze this epidemiologic profile of ALS with stratification according to genetically defined subtypes.

Pathological Characteristics

The core pathological finding in ALS is motor neuron death in the motor cortex and spinal cord; in ALS with frontotemporal dementia, neuronal degeneration is more widespread, occurring throughout the frontal and temporal lobes. Degeneration of the corticospinal axons causes thinning and scarring (sclerosis) of the lateral aspects of the spinal cord. In addition, as the brain stem and spinal motor neurons die, there is thinning of the ventral roots and denervational atrophy (amyotrophy) of the muscles of the tongue, oropharynx, and limbs. Until late in the disease, ALS does not affect neurons that innervate eye muscles or the bladder. Degeneration of motor neurons is accompanied by neuroinflammatory processes, with proliferation of astroglia, microglia, and oligodendroglial cells.11,12 A common feature in cases of both familial and sporadic ALS is aggregation of cytoplasmic proteins, prominently but not exclusively in motor neurons. Some of these proteins are common in most types of ALS. This is exemplified by the nuclear TAR DNA-binding protein 43 (TDP-43), which in many cases of ALS is cleaved, hyperphosphorylated, and mislocalized to the cytoplasm.13 Aggregates of ubiquilin 2 are also common,14 as are intracytoplasmic deposits of wild-type superoxide dismutase 1 (SOD1) in sporadic ALS.15 Many protein deposits show evidence of ubiquitination; threads of ubiquitinated TDP-43 are prominent in motor neurons, both terminally and before atrophy of the cell body. Given the diverse causes of ALS, it is not surprising that some types of aggregates are detected only in specific ALS subtypes (e.g., dipeptide aggregates and intranuclear RNA deposits in C9ORF72 ALS).

Genetic Features

Evolving technologies for gene mapping and DNA analysis have facilitated the identification of multiple ALS genes (Figure 3). SOD1 was the first ALS gene to be identified, in 1993.16 More than 120 genetic variants have been associated with a risk of ALS17 (http://alsod.iop.kcl.ac.uk). Several criteria assist in identifying those that are most meaningful. The strongest confirmation is validation in multiple independent families and cohorts. Also supportive are an increased burden of the variant in cases relative to controls and the predicted consequences of the variant (e.g., missense mutation vs. truncation). It has proved almost impossible to predict a variant’s relevance to ALS from the biologic features of the gene itself. As shown in Figure 3, at least 25 genes have now been reproducibly implicated in familial ALS, sporadic ALS, or both.18–20

Figure 3

ALS Gene Discovery since 1990.

A by-product of the genetic studies that is highly relevant to therapeutic development has been the generation of mouse models of ALS. Strikingly, transgenic expression‎ of mutant SOD1 protein21 and, more recently, profilin 1 (PFN1)22 generates a neurodegenerative, paralytic process in mice that mimics many aspects of human ALS. An important lesson from transgenic models of TDP-43 and FUS (fused in sarcoma) is that levels of the normal protein are tightly controlled. In contrast with SOD1, forced expression‎ of high levels of normal TDP-43 by itself triggers motor neuron degeneration.23 Mouse models of C9orf72 (the 72nd open reading frame identified on chromosome 9, the most commonly mutated gene in ALS) have now also been generated for C9ORF72 ALS and are discussed below.

Correlations between genetic variants and different clinical profiles in ALS, such as age at onset, disease duration, and site of onset, have been defined (Table 1). An important example is the gene that encodes the enzyme ephrin A4 (EPHA4)33 — lower levels of expression‎ of EPHA4 correlate with longer survival. Some genetic variants influence both susceptibility and phenotype. For example, progression is accelerated in patients with the common A4V mutation30 of SOD1 and in patients with the P525L mutation of FUS/TLS; the latter may lead to fulminant, childhood-onset motor neuron disease.28

Table 1

Genetic Variants That Influence the Phenotype in Amyotrophic Lateral Sclerosis.

Concepts in Pathogenesis

A comprehensive explanation for ALS must include both its familial and sporadic forms, as well as categories of phenotypic divergence that arise even with the same proximal trigger, such as a gene mutation. A general presumption has been that the disease reflects an adverse interplay between genetic and environmental factors. An alternative view postulates that all cases of ALS are a consequence primarily of complex genetic factors. Several perspectives suggest that the pathogenesis of ALS entails a multistep process.34

Lessons from Familial ALS

There is striking heterogeneity in the genetic causes of familial ALS, but familial ALS and sporadic ALS have similarities in their pathological features, as well as in their clinical features, suggesting a convergence of the cellular and molecular events that lead to motor neuron degeneration. These points of convergence define targets for therapy.

A working view of the present panel of ALS genes is that they cluster in three categories,19 involving protein homeostasis, RNA homeostasis and trafficking, and cytoskeletal dynamics (Figure 4). These mechanisms are not exclusive. For example, protein aggregates may sequester proteins that are important in RNA binding, thereby perturbing RNA trafficking and homeostasis. Moreover, these mechanisms are detected in the context of both familial ALS and sporadic ALS; some nonmutant proteins also have a propensity to misfold and aggregate in ALS, much like their mutant counterparts (e.g., SOD1 and TDP-43).

Figure 4

Three Major Categories of Pathophysiological Processes in ALS.

Downstream of each category are diverse forms of cellular abnormalities, including the deposition of intranuclear and cytosolic protein and RNA aggregates, disturbances of protein degradative mechanisms, mitochondrial dysfunction, endoplasmic reticulum stress, defective nucleocytoplasmic trafficking, altered neuronal excitability, and altered axonal transport. In most cases, these events activate and recruit nonneuronal cells (astrocytes, microglia, and oligodendroglia), which exert both salutary and negative influences on motor neuron viability. The diverse downstream abnormalities may differentially affect subcellular compartments (dendrites, soma, axons, and neuromuscular junctions). One implication of this model is that successful therapy for ALS will require simultaneous interventions in multiple downstream pathways.

Genes That Influence Protein Homoeostasis

The most extensively investigated pathological finding in ALS has been the accumulation of aggregated proteins and corresponding defects in the cellular pathways for protein degradation. Mutant SOD1 frequently forms intracellular aggregates. Genes that encode adapter proteins involved in protein maintenance and degradation are also implicated in ALS. These include valosin-containing protein (VCP)35 and the proteins optineurin (OPTN),36 TANK-binding kinase 1 (TBK1),37–39 and sequestosome 1 (SQSTM1/p62)40 (Figure 4A). The TBK1–OPTN axis is interwoven in other neurodegenerative disorders; for example, the Parkinson’s disease gene PINK1 encodes a protein that acts upstream of TBK1 in the mobilization of mitophagy.

Genes That Influence RNA Homeostasis and Trafficking

The most rapidly expanding category of ALS genes encodes proteins that interact with RNA. The first protein to be discovered was TDP-43,13 whose mislocalization from the nucleus to the cytosol, cleavage, phosphorylation, and ubiquitination were initially illuminated in sporadic ALS and frontotemporal dementia. However, it became apparent that mutations in TARDBP, the gene encoding TDP-43, can cause familial ALS.41 Mislocalization and post-translational modification of TDP-43 are observed in many neurodegenerative diseases. FUS-TLS encodes another RNA-binding protein, homologous to TDP-43, which in mutant form also causes ALS.42,43 Why mutated genes encoding RNA-binding proteins cause ALS is not clear. These proteins have multiple functions in gene splicing, surveillance of transcripts after splicing, generation of microRNA, and axonal biologic processes. Most of these proteins have low-complexity domains that permit promiscuous binding not only to RNA but also to other proteins. The ALS-related mutations heighten this binding propensity, leading to self-assembly of the proteins and the formation of aggregates.44 This auto-aggregation is facilitated in stress granules, which are non–membrane-bound structures formed under cell stress that contain RNA complexes stalled in translation.45–47 The self-assembly of mutant RNA-binding proteins may induce toxic, self-propagating conformations that disseminate disease within and between cells in a manner analogous to that of prion proteins.

The most commonly mutated gene in ALS is C9ORF72.48–50 The C9ORF72 protein has a role in nuclear and endosomal membrane trafficking and autophagy. A noncoding stretch of six nucleotides is repeated up to approximately 30 times in normal persons. Expansions of this segment to hundreds or thousands of repeats cause familial ALS and frontotemporal dementia; in addition, these expansions sometimes cause sporadic ALS. Several mechanisms may contribute to the neurotoxicity of the hexanucleotide expansion (Figure 4B). Transcripts of the offending segments are deposited in the nucleus, forming RNA foci that sequester nuclear proteins. Some of the expanded RNA escapes to the cytoplasm, where it generates five potentially toxic repeat dipeptides through a noncanonical translation process. Recent studies have also shown a defect in transport across the nuclear membrane in cells with the C9ORF72 expansions.51,52 A reduction in the total levels of the normal C9ORF72 protein may also contribute to neurotoxicity.53–55 Transgenic mouse models of C9orf72 recapitulate the molecular features of C9ORF72 ALS in humans56–59 but, with one exception,59 do not show a strong motor phenotype.

Genes That Influence Cytoskeletal Dynamics

Three ALS genes encode proteins that are important in maintenance of normal cytoskeletal dynamics: dynactin 1 (DCTN1),60 PFN1,29 and tubulin 4A (TUBA4A) (Figure 4C).61 TUBA4A dimers are components of microtubules, whose integrity is essential for axonal structure; DCTN1 is implicated in retrograde axonal transport, whereas PFN1 participates in the conversion of globular to filamentous actin and nerve extension. Also implicated is the modifier gene EPHA4; lower levels of EPHA4 expression‎ correlate with longer survival in ALS, perhaps because they permit more exuberant axonal extension.

Insights into Sporadic ALS

Despite the absence of a family history in sporadic ALS, studies involving twins show that the heritability is about 60%.62 Furthermore, mutations usually found in familial ALS can be found in sporadic ALS. This can be partly explained by the difficulty in ascertaining whether patients with late-onset disease have a family history of ALS. The situation is confounded by the observation that some familial ALS gene variants increase the risk of phenotypes other than ALS, such as frontotemporal dementia.38,39,48 Unless these other phenotypes are recognized as relevant, the family history may be incorrectly recorded as negative. In addition, several familial ALS gene variants are of intermediate penetrance (e.g., the C9ORF72 hexanucleotide repeat expansion, ATXN2 repeat expansions,63 and TBK1 mutations).37–39 Thus, ALS might not be manifested in a gene carrier, in which case, the disease is characterized by familial clustering rather than mendelian inheritance and may appear to be sporadic.64 Combinations of such gene variants further increase the risk of ALS and may be another cause of apparently sporadic ALS.65

Recent genomewide association studies have shown that rare genetic variation is disproportionately frequent in sporadic ALS.66 The genetic architecture of sporadic ALS is markedly different from that of complex diseases such as schizophrenia in which there are additive effects of hundreds of common variants, each with a minute effect on risk. However, common variants still have a part to play in sporadic ALS. For example, variants in the genes UNC13A, MOBP, and SCFD1 all increase the risk by a small but significant degree.66

Heritability studies also show that a substantial fraction of cases of sporadic ALS cannot be attributed to genetic or biologic factors; these cases are ascribed to environmental or undefined factors. Attempts to identify occupations or common exposures that might increase the risk of ALS have been inconclusive. Environmental studies are challenging because the number of possible exposures is large, and a critical, disease-related exposure may have happened many years before the onset of the disease. A particular difficulty is that studies of ALS are susceptible to bias because of the poor prognosis. Patients who live long enough to attend a specialist research clinic are different from those identified in population studies, and this difference can cause bias in the results. For instance, smoking has been shown to shorten survival in a population study,67 so a case–control study selecting participants from clinics would find smokers underrepresented in the ALS group and would thus suggest that smoking either has no effect or might be protective. Similarly, ALS specialists report anecdotally that their patients tend to be athletic, slim, and very fit,68 but if these factors slow disease progression rather than increase risk, such patients will be overrepresented at specialist centers.

Notwithstanding the barriers to identifying environmental risk factors, some factors have been associated with ALS in multiple studies.69,70 The exposure with the strongest support is military service.71,72 In addition, smoking has been implicated as a dose-dependent risk factor for ALS.73 Exposure to heavy metals may be important; blood lead levels and cerebrospinal fluid manganese levels are higher in patients with ALS than in controls.70 People with occupations involving exposure to electromagnetic fields also appear to be at increased risk, but people living near power lines are not. Other risk factors with varying levels of support include pesticide exposure and neurotoxins such as those produced by cyanobacteria. Viruses have been studied as a possible explanation for sporadic ALS. Initial studies suggesting the role of an activated, endogenous retrovirus74 were followed by the identification of a possible candidate, human endogenous retrovirus K.75

There is increasing evidence that trauma precedes some individual cases of ALS.76 A meta-analysis has suggested that trauma overall, trauma occurring more than 5 years previously, bone fracture, and head injury are all associated with an increased risk.77 In recent years, it has been observed that persons engaged in sports that entail repetitive concussions or subconcussive head trauma are at increased risk for ALS and a concurrent behavioral disorder marked by impulsivity and memory loss. Autopsy studies in persons with this disorder, called chronic traumatic encephalopathy, have revealed frontotemporal atrophy associated with distinctive deposits of tau protein, as well as TDP-43, the characteristic inclusion protein in ALS.78

Therapeutics and Beyond

No therapy offers a substantial clinical benefit for patients with ALS. The drugs riluzole79 and edaravone, which have been approved by the Food and Drug Administration for the treatment of ALS, provide a limited improvement in survival. Riluzole acts by suppressing excessive motor neuron firing, and edaravone by suppressing oxidative stress. Numerous other compounds that have been investigated have not been shown to be effective.80,81 Currently, the mainstay of care for patients with ALS is timely intervention to manage symptoms, including use of nasogastric feeding, prevention of aspiration (control of salivary secretions and use of cough-assist devices), and provision of ventilatory support (usually with bilevel positive airway pressure). Some interventions raise serious ethical issues, such as whether to perform tracheostomy for full ventilation and, if so, when and how to withdraw respiratory support once it has been instituted.

Despite the pipeline of potential treatments for ALS, reflecting the expanded list of targets identified through genetic studies and increasing numbers of ALS investigators, many of whom are in the pharmaceutical sector,80,82 no drugs are being investigated in late-phase clinical trials. Several innovative approaches to treating ALS (and other neurodegenerative diseases) are in development. Two examples include the use of adeno-associated viruses (AAV) to achieve widespread delivery of diverse cargoes (missing genes, therapeutic genes, or gene-silencing elements) to the central nervous system and the use of stem cells that provide neurotrophic factors to the central nervous system.83 Studies in cells, mice, and humans support the view that several types of reagents (e.g., antisense oligonucleotides and AAV-delivered microRNA) inactivate production of toxic gene products and thus may be therapeutic in ALS mediated by genes such as SOD184–87 and C9ORF72. Indeed, clinical trials investigating the use of antisense oligonucleotides to silence SOD1 have begun.

One can anticipate continued progress in understanding the biology of ALS. There is no doubt that high-throughput genetics, combined with improved clinical phenotyping, will further refine the genetic landscape of ALS. As thousands of full genome sequences become available, it will be feasible to explore the possibility that complex interactions among multiple gene variants explain not only familial ALS but also sporadic ALS. The exploration of environmental factors in sporadic ALS will expand, with a focus on the internal environment represented by the microbiome. The ultimate proof of our understanding of the biology of ALS will hinge on our ability to modify the clinical course of the disease.

Notes

Dr. Brown reports holding equity in AviTx, Amylyx Pharmaceuticals, and ImStar Therapeutics, receiving fees for serving on an advisory board from Voyager Therapeutics, negotiating a collaborative agreement with WAVE Biosciences, holding patents and receiving royalties for patents on “Method for the diagnosis of familial amyotrophic lateral sclerosis” (US 5,843,641) and “Mice having a mutant SOD1 encoding transgene” (US 6,723,893), holding a patent for “Compounds and method for the diagnosis, treatment and prevention of cell death” (US 5,849,290), and holding a pending patent for “Use of synthetic microRNA for AAV-mediated silencing of SOD1 in ALS”; and Dr. Al-Chalabi reports receiving consulting fees from GlaxoSmithKline, providing unpaid consulting for Mitsubishi Tanabe Pharma, Treeway, Chronos Therapeutics, and Avanir Pharmaceuticals, receiving consulting fees and serving as principal investigator in an international commercial clinical trial of tirasemtiv in ALS for Cytokinetics, and serving as chief investigator of an international commercial clinical trial of levosimendan in ALS for Orion Pharma. No other potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

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References

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Rowland, LP, Shneider, NA. Amyotrophic lateral sclerosis. N Engl J Med 2001;344:1688-1700

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Al-Chalabi, A, Hardiman, O, Kiernan, MC, Chiò, A, Rix-Brooks, B, van den Berg, LH. Amyotrophic lateral sclerosis: moving towards a new classification system. Lancet Neurol 2016;15:1182-1194

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Amyotrophic Lateral Sclerosis

Authors: Robert H. Brown, D.Phil., M.D., and Ammar Al-Chalabi, Ph.D., F.R.C.P., Dip.Stat.Author Info & Affiliations

Published July 13, 2017

N Engl J Med 2017;377:162-172

DOI: 10.1056/NEJMra1603471

VOL. 377 NO. 2

Copyright © 2017

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Amyotrophic lateral sclerosis (ALS) is a progressive, paralytic disorder characterized by degeneration of motor neurons in the brain and spinal cord. It begins insidiously with focal weakness but spreads relentlessly to involve most muscles, including the diaphragm. Typically, death due to respiratory paralysis occurs in 3 to 5 years.

Motor neurons are grouped into upper populations in the motor cortex and lower populations in the brain stem and spinal cord; lower motor neurons innervate muscle (Figure 1). When corticospinal (upper) motor neurons fail, muscle stiffness and spasticity result. When lower motor neurons become affected, they initially show excessive electrical irritability, leading to spontaneous muscle twitching (fasciculations); as they degenerate, they lose synaptic connectivity with their target muscles, which then atrophy.

Figure 1

The Motor System.

ALS typically begins in the limbs, but about one third of cases are bulbar, heralded by difficulty chewing, speaking, or swallowing. Until late in the disease, ALS spares neurons that innervate the eye and sphincter muscles. The diagnosis is based primarily on clinical examination in conjunction with electromyography, to confirm‎ the extent of denervation, and laboratory testing, to rule out reversible disorders that may resemble ALS.1,2

A representative case involves a 55-year-old patient who was eval‎uated for foot drop, which had begun subtly 4 months earlier with the onset of muscle cramping in the right calf as a result of volitional movement (known as volitional cramping) and had progressed to severe weakness of ankle dorsiflexion and knee extension. In addition to these features, the physical examination revealed atrophy of the right calf and hyperreflexia of the right biceps and of deep tendon reflexes at both knees and both ankles. The neurologic examination was otherwise normal. Electromyography showed evidence of acute muscle denervation (fibrillations) in all four limbs and muscle reinnervation in the right calf (high-amplitude compound muscle action potentials). Imaging of the head and neck revealed no structural lesions impinging on motor tracts, and the results of laboratory studies were normal, findings that ruled out several disorders in the differential diagnosis, such as peripheral neuropathy, Lyme disease, vitamin B12 deficiency, thyroid disease, and metal toxicity.3 A full eval‎uation disclosed no evidence of a reversible motor neuron disorder, such as multifocal motor neuropathy with conduction block, which is typically associated with autoantibodies (e.g., anti-GM1 ganglioside antibodies) and can be effectively treated with intravenous immune globulin.4

The clinical presentation of ALS is heterogeneous with respect to the populations of involved motor neurons and survival (Figure 2).2 When there is prominent involvement of frontopontine motor neurons that serve bulbar functions, a striking finding is emotional lability, indicating pseudobulbar palsy, which is characterized by facial spasticity and a tendency to laugh or cry excessively in response to minor emotional stimuli.

Figure 2

Phenotype and Survival in Amyotrophic Lateral Sclerosis (ALS).

In primary lateral sclerosis, there is selective involvement of corticospinal and corticopontine motor neurons, with few findings of lower motor neuron dysfunction.5 Primary lateral sclerosis is ruled out in the representative case described above because of the atrophy and electromyographic findings, which are indicative of lower motor neuron disease. Primary lateral sclerosis progresses slowly, with severe spastic muscle stiffness and little muscle atrophy. This disorder overlaps clinically with a broad category of corticospinal disorders designated as hereditary spastic paraplegias, which are typically symmetrical in onset, slowly progressive, and sometimes associated with sensory loss and other multisystem findings. In primary lateral sclerosis but not hereditary spastic paraplegias, bulbar involvement may be prominent. In progressive muscular atrophy, lower motor neuron involvement is predominant, with little spasticity. The hyperreflexia in the representative case is inconsistent with progressive muscular atrophy.

During the past two decades, it has been recognized that 15 to 20% of persons with ALS have progressive cognitive abnormalities marked by behavioral changes, leading ultimately to dementia.6 Since these behavioral alterations correlate with autopsy evidence of degeneration of the frontal and temporal lobes, the condition is designated frontotemporal dementia. It was formerly called Pick’s disease.

Epidemiologic Features

In Europe and the United States, there are 1 or 2 new cases of ALS per year per 100,000 people; the total number of cases is approximately 3 to 5 per 100,000.7,8 These statistics are globally fairly uniform, although there are rare foci in which ALS is more common. The incidence and preval‎ence of ALS increase with age. In the United States and Europe, the cumulative lifetime risk of ALS is about 1 in 400; in the United States alone, 800,000 persons who are now alive are expected to die from ALS.9 About 10% of ALS cases are familial, usually inherited as dominant traits.10 The remaining 90% of cases of ALS are sporadic (occurring without a family history). In cases of sporadic ALS, the ratio of affected males to affected females may approach 2:1; in familial ALS, the ratio is closer to 1:1. ALS is the most frequent neurodegenerative disorder of midlife, with an onset in the middle-to-late 50s. An onset in the late teenage or early adult years is usually indicative of familial ALS. The time from the first symptom of ALS to diagnosis is approximately 12 months, a problematic delay if successful therapy requires early intervention. Because an abundance of ALS genes have now been identified, it will probably be informative to reanalyze this epidemiologic profile of ALS with stratification according to genetically defined subtypes.

Pathological Characteristics

The core pathological finding in ALS is motor neuron death in the motor cortex and spinal cord; in ALS with frontotemporal dementia, neuronal degeneration is more widespread, occurring throughout the frontal and temporal lobes. Degeneration of the corticospinal axons causes thinning and scarring (sclerosis) of the lateral aspects of the spinal cord. In addition, as the brain stem and spinal motor neurons die, there is thinning of the ventral roots and denervational atrophy (amyotrophy) of the muscles of the tongue, oropharynx, and limbs. Until late in the disease, ALS does not affect neurons that innervate eye muscles or the bladder. Degeneration of motor neurons is accompanied by neuroinflammatory processes, with proliferation of astroglia, microglia, and oligodendroglial cells.11,12 A common feature in cases of both familial and sporadic ALS is aggregation of cytoplasmic proteins, prominently but not exclusively in motor neurons. Some of these proteins are common in most types of ALS. This is exemplified by the nuclear TAR DNA-binding protein 43 (TDP-43), which in many cases of ALS is cleaved, hyperphosphorylated, and mislocalized to the cytoplasm.13 Aggregates of ubiquilin 2 are also common,14 as are intracytoplasmic deposits of wild-type superoxide dismutase 1 (SOD1) in sporadic ALS.15 Many protein deposits show evidence of ubiquitination; threads of ubiquitinated TDP-43 are prominent in motor neurons, both terminally and before atrophy of the cell body. Given the diverse causes of ALS, it is not surprising that some types of aggregates are detected only in specific ALS subtypes (e.g., dipeptide aggregates and intranuclear RNA deposits in C9ORF72 ALS).

Genetic Features

Evolving technologies for gene mapping and DNA analysis have facilitated the identification of multiple ALS genes (Figure 3). SOD1 was the first ALS gene to be identified, in 1993.16 More than 120 genetic variants have been associated with a risk of ALS17 (http://alsod.iop.kcl.ac.uk). Several criteria assist in identifying those that are most meaningful. The strongest confirmation is validation in multiple independent families and cohorts. Also supportive are an increased burden of the variant in cases relative to controls and the predicted consequences of the variant (e.g., missense mutation vs. truncation). It has proved almost impossible to predict a variant’s relevance to ALS from the biologic features of the gene itself. As shown in Figure 3, at least 25 genes have now been reproducibly implicated in familial ALS, sporadic ALS, or both.18–20

Figure 3

ALS Gene Discovery since 1990.

A by-product of the genetic studies that is highly relevant to therapeutic development has been the generation of mouse models of ALS. Strikingly, transgenic expression‎ of mutant SOD1 protein21 and, more recently, profilin 1 (PFN1)22 generates a neurodegenerative, paralytic process in mice that mimics many aspects of human ALS. An important lesson from transgenic models of TDP-43 and FUS (fused in sarcoma) is that levels of the normal protein are tightly controlled. In contrast with SOD1, forced expression‎ of high levels of normal TDP-43 by itself triggers motor neuron degeneration.23 Mouse models of C9orf72 (the 72nd open reading frame identified on chromosome 9, the most commonly mutated gene in ALS) have now also been generated for C9ORF72 ALS and are discussed below.

Correlations between genetic variants and different clinical profiles in ALS, such as age at onset, disease duration, and site of onset, have been defined (Table 1). An important example is the gene that encodes the enzyme ephrin A4 (EPHA4)33 — lower levels of expression‎ of EPHA4 correlate with longer survival. Some genetic variants influence both susceptibility and phenotype. For example, progression is accelerated in patients with the common A4V mutation30 of SOD1 and in patients with the P525L mutation of FUS/TLS; the latter may lead to fulminant, childhood-onset motor neuron disease.28

Table 1

Genetic Variants That Influence the Phenotype in Amyotrophic Lateral Sclerosis.

Concepts in Pathogenesis

A comprehensive explanation for ALS must include both its familial and sporadic forms, as well as categories of phenotypic divergence that arise even with the same proximal trigger, such as a gene mutation. A general presumption has been that the disease reflects an adverse interplay between genetic and environmental factors. An alternative view postulates that all cases of ALS are a consequence primarily of complex genetic factors. Several perspectives suggest that the pathogenesis of ALS entails a multistep process.34

Lessons from Familial ALS

There is striking heterogeneity in the genetic causes of familial ALS, but familial ALS and sporadic ALS have similarities in their pathological features, as well as in their clinical features, suggesting a convergence of the cellular and molecular events that lead to motor neuron degeneration. These points of convergence define targets for therapy.

A working view of the present panel of ALS genes is that they cluster in three categories,19 involving protein homeostasis, RNA homeostasis and trafficking, and cytoskeletal dynamics (Figure 4). These mechanisms are not exclusive. For example, protein aggregates may sequester proteins that are important in RNA binding, thereby perturbing RNA trafficking and homeostasis. Moreover, these mechanisms are detected in the context of both familial ALS and sporadic ALS; some nonmutant proteins also have a propensity to misfold and aggregate in ALS, much like their mutant counterparts (e.g., SOD1 and TDP-43).

Figure 4

Three Major Categories of Pathophysiological Processes in ALS.

Downstream of each category are diverse forms of cellular abnormalities, including the deposition of intranuclear and cytosolic protein and RNA aggregates, disturbances of protein degradative mechanisms, mitochondrial dysfunction, endoplasmic reticulum stress, defective nucleocytoplasmic trafficking, altered neuronal excitability, and altered axonal transport. In most cases, these events activate and recruit nonneuronal cells (astrocytes, microglia, and oligodendroglia), which exert both salutary and negative influences on motor neuron viability. The diverse downstream abnormalities may differentially affect subcellular compartments (dendrites, soma, axons, and neuromuscular junctions). One implication of this model is that successful therapy for ALS will require simultaneous interventions in multiple downstream pathways.

Genes That Influence Protein Homoeostasis

The most extensively investigated pathological finding in ALS has been the accumulation of aggregated proteins and corresponding defects in the cellular pathways for protein degradation. Mutant SOD1 frequently forms intracellular aggregates. Genes that encode adapter proteins involved in protein maintenance and degradation are also implicated in ALS. These include valosin-containing protein (VCP)35 and the proteins optineurin (OPTN),36 TANK-binding kinase 1 (TBK1),37–39 and sequestosome 1 (SQSTM1/p62)40 (Figure 4A). The TBK1–OPTN axis is interwoven in other neurodegenerative disorders; for example, the Parkinson’s disease gene PINK1 encodes a protein that acts upstream of TBK1 in the mobilization of mitophagy.

Genes That Influence RNA Homeostasis and Trafficking

The most rapidly expanding category of ALS genes encodes proteins that interact with RNA. The first protein to be discovered was TDP-43,13 whose mislocalization from the nucleus to the cytosol, cleavage, phosphorylation, and ubiquitination were initially illuminated in sporadic ALS and frontotemporal dementia. However, it became apparent that mutations in TARDBP, the gene encoding TDP-43, can cause familial ALS.41 Mislocalization and post-translational modification of TDP-43 are observed in many neurodegenerative diseases. FUS-TLS encodes another RNA-binding protein, homologous to TDP-43, which in mutant form also causes ALS.42,43 Why mutated genes encoding RNA-binding proteins cause ALS is not clear. These proteins have multiple functions in gene splicing, surveillance of transcripts after splicing, generation of microRNA, and axonal biologic processes. Most of these proteins have low-complexity domains that permit promiscuous binding not only to RNA but also to other proteins. The ALS-related mutations heighten this binding propensity, leading to self-assembly of the proteins and the formation of aggregates.44 This auto-aggregation is facilitated in stress granules, which are non–membrane-bound structures formed under cell stress that contain RNA complexes stalled in translation.45–47 The self-assembly of mutant RNA-binding proteins may induce toxic, self-propagating conformations that disseminate disease within and between cells in a manner analogous to that of prion proteins.

The most commonly mutated gene in ALS is C9ORF72.48–50 The C9ORF72 protein has a role in nuclear and endosomal membrane trafficking and autophagy. A noncoding stretch of six nucleotides is repeated up to approximately 30 times in normal persons. Expansions of this segment to hundreds or thousands of repeats cause familial ALS and frontotemporal dementia; in addition, these expansions sometimes cause sporadic ALS. Several mechanisms may contribute to the neurotoxicity of the hexanucleotide expansion (Figure 4B). Transcripts of the offending segments are deposited in the nucleus, forming RNA foci that sequester nuclear proteins. Some of the expanded RNA escapes to the cytoplasm, where it generates five potentially toxic repeat dipeptides through a noncanonical translation process. Recent studies have also shown a defect in transport across the nuclear membrane in cells with the C9ORF72 expansions.51,52 A reduction in the total levels of the normal C9ORF72 protein may also contribute to neurotoxicity.53–55 Transgenic mouse models of C9orf72 recapitulate the molecular features of C9ORF72 ALS in humans56–59 but, with one exception,59 do not show a strong motor phenotype.

Genes That Influence Cytoskeletal Dynamics

Three ALS genes encode proteins that are important in maintenance of normal cytoskeletal dynamics: dynactin 1 (DCTN1),60 PFN1,29 and tubulin 4A (TUBA4A) (Figure 4C).61 TUBA4A dimers are components of microtubules, whose integrity is essential for axonal structure; DCTN1 is implicated in retrograde axonal transport, whereas PFN1 participates in the conversion of globular to filamentous actin and nerve extension. Also implicated is the modifier gene EPHA4; lower levels of EPHA4 expression‎ correlate with longer survival in ALS, perhaps because they permit more exuberant axonal extension.

Insights into Sporadic ALS

Despite the absence of a family history in sporadic ALS, studies involving twins show that the heritability is about 60%.62 Furthermore, mutations usually found in familial ALS can be found in sporadic ALS. This can be partly explained by the difficulty in ascertaining whether patients with late-onset disease have a family history of ALS. The situation is confounded by the observation that some familial ALS gene variants increase the risk of phenotypes other than ALS, such as frontotemporal dementia.38,39,48 Unless these other phenotypes are recognized as relevant, the family history may be incorrectly recorded as negative. In addition, several familial ALS gene variants are of intermediate penetrance (e.g., the C9ORF72 hexanucleotide repeat expansion, ATXN2 repeat expansions,63 and TBK1 mutations).37–39 Thus, ALS might not be manifested in a gene carrier, in which case, the disease is characterized by familial clustering rather than mendelian inheritance and may appear to be sporadic.64 Combinations of such gene variants further increase the risk of ALS and may be another cause of apparently sporadic ALS.65

Recent genomewide association studies have shown that rare genetic variation is disproportionately frequent in sporadic ALS.66 The genetic architecture of sporadic ALS is markedly different from that of complex diseases such as schizophrenia in which there are additive effects of hundreds of common variants, each with a minute effect on risk. However, common variants still have a part to play in sporadic ALS. For example, variants in the genes UNC13A, MOBP, and SCFD1 all increase the risk by a small but significant degree.66

Heritability studies also show that a substantial fraction of cases of sporadic ALS cannot be attributed to genetic or biologic factors; these cases are ascribed to environmental or undefined factors. Attempts to identify occupations or common exposures that might increase the risk of ALS have been inconclusive. Environmental studies are challenging because the number of possible exposures is large, and a critical, disease-related exposure may have happened many years before the onset of the disease. A particular difficulty is that studies of ALS are susceptible to bias because of the poor prognosis. Patients who live long enough to attend a specialist research clinic are different from those identified in population studies, and this difference can cause bias in the results. For instance, smoking has been shown to shorten survival in a population study,67 so a case–control study selecting participants from clinics would find smokers underrepresented in the ALS group and would thus suggest that smoking either has no effect or might be protective. Similarly, ALS specialists report anecdotally that their patients tend to be athletic, slim, and very fit,68 but if these factors slow disease progression rather than increase risk, such patients will be overrepresented at specialist centers.

Notwithstanding the barriers to identifying environmental risk factors, some factors have been associated with ALS in multiple studies.69,70 The exposure with the strongest support is military service.71,72 In addition, smoking has been implicated as a dose-dependent risk factor for ALS.73 Exposure to heavy metals may be important; blood lead levels and cerebrospinal fluid manganese levels are higher in patients with ALS than in controls.70 People with occupations involving exposure to electromagnetic fields also appear to be at increased risk, but people living near power lines are not. Other risk factors with varying levels of support include pesticide exposure and neurotoxins such as those produced by cyanobacteria. Viruses have been studied as a possible explanation for sporadic ALS. Initial studies suggesting the role of an activated, endogenous retrovirus74 were followed by the identification of a possible candidate, human endogenous retrovirus K.75

There is increasing evidence that trauma precedes some individual cases of ALS.76 A meta-analysis has suggested that trauma overall, trauma occurring more than 5 years previously, bone fracture, and head injury are all associated with an increased risk.77 In recent years, it has been observed that persons engaged in sports that entail repetitive concussions or subconcussive head trauma are at increased risk for ALS and a concurrent behavioral disorder marked by impulsivity and memory loss. Autopsy studies in persons with this disorder, called chronic traumatic encephalopathy, have revealed frontotemporal atrophy associated with distinctive deposits of tau protein, as well as TDP-43, the characteristic inclusion protein in ALS.78

Therapeutics and Beyond

No therapy offers a substantial clinical benefit for patients with ALS. The drugs riluzole79 and edaravone, which have been approved by the Food and Drug Administration for the treatment of ALS, provide a limited improvement in survival. Riluzole acts by suppressing excessive motor neuron firing, and edaravone by suppressing oxidative stress. Numerous other compounds that have been investigated have not been shown to be effective.80,81 Currently, the mainstay of care for patients with ALS is timely intervention to manage symptoms, including use of nasogastric feeding, prevention of aspiration (control of salivary secretions and use of cough-assist devices), and provision of ventilatory support (usually with bilevel positive airway pressure). Some interventions raise serious ethical issues, such as whether to perform tracheostomy for full ventilation and, if so, when and how to withdraw respiratory support once it has been instituted.

Despite the pipeline of potential treatments for ALS, reflecting the expanded list of targets identified through genetic studies and increasing numbers of ALS investigators, many of whom are in the pharmaceutical sector,80,82 no drugs are being investigated in late-phase clinical trials. Several innovative approaches to treating ALS (and other neurodegenerative diseases) are in development. Two examples include the use of adeno-associated viruses (AAV) to achieve widespread delivery of diverse cargoes (missing genes, therapeutic genes, or gene-silencing elements) to the central nervous system and the use of stem cells that provide neurotrophic factors to the central nervous system.83 Studies in cells, mice, and humans support the view that several types of reagents (e.g., antisense oligonucleotides and AAV-delivered microRNA) inactivate production of toxic gene products and thus may be therapeutic in ALS mediated by genes such as SOD184–87 and C9ORF72. Indeed, clinical trials investigating the use of antisense oligonucleotides to silence SOD1 have begun.

One can anticipate continued progress in understanding the biology of ALS. There is no doubt that high-throughput genetics, combined with improved clinical phenotyping, will further refine the genetic landscape of ALS. As thousands of full genome sequences become available, it will be feasible to explore the possibility that complex interactions among multiple gene variants explain not only familial ALS but also sporadic ALS. The exploration of environmental factors in sporadic ALS will expand, with a focus on the internal environment represented by the microbiome. The ultimate proof of our understanding of the biology of ALS will hinge on our ability to modify the clinical course of the disease.

Notes

Dr. Brown reports holding equity in AviTx, Amylyx Pharmaceuticals, and ImStar Therapeutics, receiving fees for serving on an advisory board from Voyager Therapeutics, negotiating a collaborative agreement with WAVE Biosciences, holding patents and receiving royalties for patents on “Method for the diagnosis of familial amyotrophic lateral sclerosis” (US 5,843,641) and “Mice having a mutant SOD1 encoding transgene” (US 6,723,893), holding a patent for “Compounds and method for the diagnosis, treatment and prevention of cell death” (US 5,849,290), and holding a pending patent for “Use of synthetic microRNA for AAV-mediated silencing of SOD1 in ALS”; and Dr. Al-Chalabi reports receiving consulting fees from GlaxoSmithKline, providing unpaid consulting for Mitsubishi Tanabe Pharma, Treeway, Chronos Therapeutics, and Avanir Pharmaceuticals, receiving consulting fees and serving as principal investigator in an international commercial clinical trial of tirasemtiv in ALS for Cytokinetics, and serving as chief investigator of an international commercial clinical trial of levosimendan in ALS for Orion Pharma. No other potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Supplementary Material

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References

1.

Rowland, LP, Shneider, NA. Amyotrophic lateral sclerosis. N Engl J Med 2001;344:1688-1700

Go to Citation

Crossref

PubMed

Web of Science

Google Scholar

2.

Al-Chalabi, A, Hardiman, O, Kiernan, MC, Chiò, A, Rix-Brooks, B, van den Berg, LH. Amyotrophic lateral sclerosis: moving towards a new classification system. Lancet Neurol 2016;15:1182-1194

Crossref

PubMed

Web of Science

Google Scholar

3.

Rezania, K, Roos, RP. Spinal cord: motor neuron diseases. Neurol Clin 2013;31:219-239

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Crossref

PubMed

Web of Science

Google Scholar

Amyotrophic Lateral Sclerosis

Authors: Robert H. Brown, D.Phil., M.D., and Ammar Al-Chalabi, Ph.D., F.R.C.P., Dip.Stat.Author Info & Affiliations

Published July 13, 2017

N Engl J Med 2017;377:162-172

DOI: 10.1056/NEJMra1603471

VOL. 377 NO. 2

Copyright © 2017

• Information & Authors
• Metrics & Citations
• View Options
• References
• Media
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Amyotrophic lateral sclerosis (ALS) is a progressive, paralytic disorder characterized by degeneration of motor neurons in the brain and spinal cord. It begins insidiously with focal weakness but spreads relentlessly to involve most muscles, including the diaphragm. Typically, death due to respiratory paralysis occurs in 3 to 5 years.

Motor neurons are grouped into upper populations in the motor cortex and lower populations in the brain stem and spinal cord; lower motor neurons innervate muscle (Figure 1). When corticospinal (upper) motor neurons fail, muscle stiffness and spasticity result. When lower motor neurons become affected, they initially show excessive electrical irritability, leading to spontaneous muscle twitching (fasciculations); as they degenerate, they lose synaptic connectivity with their target muscles, which then atrophy.

Figure 1

The Motor System.

ALS typically begins in the limbs, but about one third of cases are bulbar, heralded by difficulty chewing, speaking, or swallowing. Until late in the disease, ALS spares neurons that innervate the eye and sphincter muscles. The diagnosis is based primarily on clinical examination in conjunction with electromyography, to confirm‎ the extent of denervation, and laboratory testing, to rule out reversible disorders that may resemble ALS.1,2

A representative case involves a 55-year-old patient who was eval‎uated for foot drop, which had begun subtly 4 months earlier with the onset of muscle cramping in the right calf as a result of volitional movement (known as volitional cramping) and had progressed to severe weakness of ankle dorsiflexion and knee extension. In addition to these features, the physical examination revealed atrophy of the right calf and hyperreflexia of the right biceps and of deep tendon reflexes at both knees and both ankles. The neurologic examination was otherwise normal. Electromyography showed evidence of acute muscle denervation (fibrillations) in all four limbs and muscle reinnervation in the right calf (high-amplitude compound muscle action potentials). Imaging of the head and neck revealed no structural lesions impinging on motor tracts, and the results of laboratory studies were normal, findings that ruled out several disorders in the differential diagnosis, such as peripheral neuropathy, Lyme disease, vitamin B12 deficiency, thyroid disease, and metal toxicity.3 A full eval‎uation disclosed no evidence of a reversible motor neuron disorder, such as multifocal motor neuropathy with conduction block, which is typically associated with autoantibodies (e.g., anti-GM1 ganglioside antibodies) and can be effectively treated with intravenous immune globulin.4

The clinical presentation of ALS is heterogeneous with respect to the populations of involved motor neurons and survival (Figure 2).2 When there is prominent involvement of frontopontine motor neurons that serve bulbar functions, a striking finding is emotional lability, indicating pseudobulbar palsy, which is characterized by facial spasticity and a tendency to laugh or cry excessively in response to minor emotional stimuli.

Figure 2

Phenotype and Survival in Amyotrophic Lateral Sclerosis (ALS).

In primary lateral sclerosis, there is selective involvement of corticospinal and corticopontine motor neurons, with few findings of lower motor neuron dysfunction.5 Primary lateral sclerosis is ruled out in the representative case described above because of the atrophy and electromyographic findings, which are indicative of lower motor neuron disease. Primary lateral sclerosis progresses slowly, with severe spastic muscle stiffness and little muscle atrophy. This disorder overlaps clinically with a broad category of corticospinal disorders designated as hereditary spastic paraplegias, which are typically symmetrical in onset, slowly progressive, and sometimes associated with sensory loss and other multisystem findings. In primary lateral sclerosis but not hereditary spastic paraplegias, bulbar involvement may be prominent. In progressive muscular atrophy, lower motor neuron involvement is predominant, with little spasticity. The hyperreflexia in the representative case is inconsistent with progressive muscular atrophy.

During the past two decades, it has been recognized that 15 to 20% of persons with ALS have progressive cognitive abnormalities marked by behavioral changes, leading ultimately to dementia.6 Since these behavioral alterations correlate with autopsy evidence of degeneration of the frontal and temporal lobes, the condition is designated frontotemporal dementia. It was formerly called Pick’s disease.

Epidemiologic Features

In Europe and the United States, there are 1 or 2 new cases of ALS per year per 100,000 people; the total number of cases is approximately 3 to 5 per 100,000.7,8 These statistics are globally fairly uniform, although there are rare foci in which ALS is more common. The incidence and preval‎ence of ALS increase with age. In the United States and Europe, the cumulative lifetime risk of ALS is about 1 in 400; in the United States alone, 800,000 persons who are now alive are expected to die from ALS.9 About 10% of ALS cases are familial, usually inherited as dominant traits.10 The remaining 90% of cases of ALS are sporadic (occurring without a family history). In cases of sporadic ALS, the ratio of affected males to affected females may approach 2:1; in familial ALS, the ratio is closer to 1:1. ALS is the most frequent neurodegenerative disorder of midlife, with an onset in the middle-to-late 50s. An onset in the late teenage or early adult years is usually indicative of familial ALS. The time from the first symptom of ALS to diagnosis is approximately 12 months, a problematic delay if successful therapy requires early intervention. Because an abundance of ALS genes have now been identified, it will probably be informative to reanalyze this epidemiologic profile of ALS with stratification according to genetically defined subtypes.

Pathological Characteristics

The core pathological finding in ALS is motor neuron death in the motor cortex and spinal cord; in ALS with frontotemporal dementia, neuronal degeneration is more widespread, occurring throughout the frontal and temporal lobes. Degeneration of the corticospinal axons causes thinning and scarring (sclerosis) of the lateral aspects of the spinal cord. In addition, as the brain stem and spinal motor neurons die, there is thinning of the ventral roots and denervational atrophy (amyotrophy) of the muscles of the tongue, oropharynx, and limbs. Until late in the disease, ALS does not affect neurons that innervate eye muscles or the bladder. Degeneration of motor neurons is accompanied by neuroinflammatory processes, with proliferation of astroglia, microglia, and oligodendroglial cells.11,12 A common feature in cases of both familial and sporadic ALS is aggregation of cytoplasmic proteins, prominently but not exclusively in motor neurons. Some of these proteins are common in most types of ALS. This is exemplified by the nuclear TAR DNA-binding protein 43 (TDP-43), which in many cases of ALS is cleaved, hyperphosphorylated, and mislocalized to the cytoplasm.13 Aggregates of ubiquilin 2 are also common,14 as are intracytoplasmic deposits of wild-type superoxide dismutase 1 (SOD1) in sporadic ALS.15 Many protein deposits show evidence of ubiquitination; threads of ubiquitinated TDP-43 are prominent in motor neurons, both terminally and before atrophy of the cell body. Given the diverse causes of ALS, it is not surprising that some types of aggregates are detected only in specific ALS subtypes (e.g., dipeptide aggregates and intranuclear RNA deposits in C9ORF72 ALS).

Genetic Features

Evolving technologies for gene mapping and DNA analysis have facilitated the identification of multiple ALS genes (Figure 3). SOD1 was the first ALS gene to be identified, in 1993.16 More than 120 genetic variants have been associated with a risk of ALS17 (http://alsod.iop.kcl.ac.uk). Several criteria assist in identifying those that are most meaningful. The strongest confirmation is validation in multiple independent families and cohorts. Also supportive are an increased burden of the variant in cases relative to controls and the predicted consequences of the variant (e.g., missense mutation vs. truncation). It has proved almost impossible to predict a variant’s relevance to ALS from the biologic features of the gene itself. As shown in Figure 3, at least 25 genes have now been reproducibly implicated in familial ALS, sporadic ALS, or both.18–20

Figure 3

ALS Gene Discovery since 1990.

A by-product of the genetic studies that is highly relevant to therapeutic development has been the generation of mouse models of ALS. Strikingly, transgenic expression‎ of mutant SOD1 protein21 and, more recently, profilin 1 (PFN1)22 generates a neurodegenerative, paralytic process in mice that mimics many aspects of human ALS. An important lesson from transgenic models of TDP-43 and FUS (fused in sarcoma) is that levels of the normal protein are tightly controlled. In contrast with SOD1, forced expression‎ of high levels of normal TDP-43 by itself triggers motor neuron degeneration.23 Mouse models of C9orf72 (the 72nd open reading frame identified on chromosome 9, the most commonly mutated gene in ALS) have now also been generated for C9ORF72 ALS and are discussed below.

Correlations between genetic variants and different clinical profiles in ALS, such as age at onset, disease duration, and site of onset, have been defined (Table 1). An important example is the gene that encodes the enzyme ephrin A4 (EPHA4)33 — lower levels of expression‎ of EPHA4 correlate with longer survival. Some genetic variants influence both susceptibility and phenotype. For example, progression is accelerated in patients with the common A4V mutation30 of SOD1 and in patients with the P525L mutation of FUS/TLS; the latter may lead to fulminant, childhood-onset motor neuron disease.28

Table 1

Genetic Variants That Influence the Phenotype in Amyotrophic Lateral Sclerosis.

Concepts in Pathogenesis

A comprehensive explanation for ALS must include both its familial and sporadic forms, as well as categories of phenotypic divergence that arise even with the same proximal trigger, such as a gene mutation. A general presumption has been that the disease reflects an adverse interplay between genetic and environmental factors. An alternative view postulates that all cases of ALS are a consequence primarily of complex genetic factors. Several perspectives suggest that the pathogenesis of ALS entails a multistep process.34

Lessons from Familial ALS

There is striking heterogeneity in the genetic causes of familial ALS, but familial ALS and sporadic ALS have similarities in their pathological features, as well as in their clinical features, suggesting a convergence of the cellular and molecular events that lead to motor neuron degeneration. These points of convergence define targets for therapy.

A working view of the present panel of ALS genes is that they cluster in three categories,19 involving protein homeostasis, RNA homeostasis and trafficking, and cytoskeletal dynamics (Figure 4). These mechanisms are not exclusive. For example, protein aggregates may sequester proteins that are important in RNA binding, thereby perturbing RNA trafficking and homeostasis. Moreover, these mechanisms are detected in the context of both familial ALS and sporadic ALS; some nonmutant proteins also have a propensity to misfold and aggregate in ALS, much like their mutant counterparts (e.g., SOD1 and TDP-43).

Figure 4

Three Major Categories of Pathophysiological Processes in ALS.

Downstream of each category are diverse forms of cellular abnormalities, including the deposition of intranuclear and cytosolic protein and RNA aggregates, disturbances of protein degradative mechanisms, mitochondrial dysfunction, endoplasmic reticulum stress, defective nucleocytoplasmic trafficking, altered neuronal excitability, and altered axonal transport. In most cases, these events activate and recruit nonneuronal cells (astrocytes, microglia, and oligodendroglia), which exert both salutary and negative influences on motor neuron viability. The diverse downstream abnormalities may differentially affect subcellular compartments (dendrites, soma, axons, and neuromuscular junctions). One implication of this model is that successful therapy for ALS will require simultaneous interventions in multiple downstream pathways.

Genes That Influence Protein Homoeostasis

The most extensively investigated pathological finding in ALS has been the accumulation of aggregated proteins and corresponding defects in the cellular pathways for protein degradation. Mutant SOD1 frequently forms intracellular aggregates. Genes that encode adapter proteins involved in protein maintenance and degradation are also implicated in ALS. These include valosin-containing protein (VCP)35 and the proteins optineurin (OPTN),36 TANK-binding kinase 1 (TBK1),37–39 and sequestosome 1 (SQSTM1/p62)40 (Figure 4A). The TBK1–OPTN axis is interwoven in other neurodegenerative disorders; for example, the Parkinson’s disease gene PINK1 encodes a protein that acts upstream of TBK1 in the mobilization of mitophagy.

Genes That Influence RNA Homeostasis and Trafficking

The most rapidly expanding category of ALS genes encodes proteins that interact with RNA. The first protein to be discovered was TDP-43,13 whose mislocalization from the nucleus to the cytosol, cleavage, phosphorylation, and ubiquitination were initially illuminated in sporadic ALS and frontotemporal dementia. However, it became apparent that mutations in TARDBP, the gene encoding TDP-43, can cause familial ALS.41 Mislocalization and post-translational modification of TDP-43 are observed in many neurodegenerative diseases. FUS-TLS encodes another RNA-binding protein, homologous to TDP-43, which in mutant form also causes ALS.42,43 Why mutated genes encoding RNA-binding proteins cause ALS is not clear. These proteins have multiple functions in gene splicing, surveillance of transcripts after splicing, generation of microRNA, and axonal biologic processes. Most of these proteins have low-complexity domains that permit promiscuous binding not only to RNA but also to other proteins. The ALS-related mutations heighten this binding propensity, leading to self-assembly of the proteins and the formation of aggregates.44 This auto-aggregation is facilitated in stress granules, which are non–membrane-bound structures formed under cell stress that contain RNA complexes stalled in translation.45–47 The self-assembly of mutant RNA-binding proteins may induce toxic, self-propagating conformations that disseminate disease within and between cells in a manner analogous to that of prion proteins.

The most commonly mutated gene in ALS is C9ORF72.48–50 The C9ORF72 protein has a role in nuclear and endosomal membrane trafficking and autophagy. A noncoding stretch of six nucleotides is repeated up to approximately 30 times in normal persons. Expansions of this segment to hundreds or thousands of repeats cause familial ALS and frontotemporal dementia; in addition, these expansions sometimes cause sporadic ALS. Several mechanisms may contribute to the neurotoxicity of the hexanucleotide expansion (Figure 4B). Transcripts of the offending segments are deposited in the nucleus, forming RNA foci that sequester nuclear proteins. Some of the expanded RNA escapes to the cytoplasm, where it generates five potentially toxic repeat dipeptides through a noncanonical translation process. Recent studies have also shown a defect in transport across the nuclear membrane in cells with the C9ORF72 expansions.51,52 A reduction in the total levels of the normal C9ORF72 protein may also contribute to neurotoxicity.53–55 Transgenic mouse models of C9orf72 recapitulate the molecular features of C9ORF72 ALS in humans56–59 but, with one exception,59 do not show a strong motor phenotype.

Genes That Influence Cytoskeletal Dynamics

Three ALS genes encode proteins that are important in maintenance of normal cytoskeletal dynamics: dynactin 1 (DCTN1),60 PFN1,29 and tubulin 4A (TUBA4A) (Figure 4C).61 TUBA4A dimers are components of microtubules, whose integrity is essential for axonal structure; DCTN1 is implicated in retrograde axonal transport, whereas PFN1 participates in the conversion of globular to filamentous actin and nerve extension. Also implicated is the modifier gene EPHA4; lower levels of EPHA4 expression‎ correlate with longer survival in ALS, perhaps because they permit more exuberant axonal extension.

Insights into Sporadic ALS

Despite the absence of a family history in sporadic ALS, studies involving twins show that the heritability is about 60%.62 Furthermore, mutations usually found in familial ALS can be found in sporadic ALS. This can be partly explained by the difficulty in ascertaining whether patients with late-onset disease have a family history of ALS. The situation is confounded by the observation that some familial ALS gene variants increase the risk of phenotypes other than ALS, such as frontotemporal dementia.38,39,48 Unless these other phenotypes are recognized as relevant, the family history may be incorrectly recorded as negative. In addition, several familial ALS gene variants are of intermediate penetrance (e.g., the C9ORF72 hexanucleotide repeat expansion, ATXN2 repeat expansions,63 and TBK1 mutations).37–39 Thus, ALS might not be manifested in a gene carrier, in which case, the disease is characterized by familial clustering rather than mendelian inheritance and may appear to be sporadic.64 Combinations of such gene variants further increase the risk of ALS and may be another cause of apparently sporadic ALS.65

Recent genomewide association studies have shown that rare genetic variation is disproportionately frequent in sporadic ALS.66 The genetic architecture of sporadic ALS is markedly different from that of complex diseases such as schizophrenia in which there are additive effects of hundreds of common variants, each with a minute effect on risk. However, common variants still have a part to play in sporadic ALS. For example, variants in the genes UNC13A, MOBP, and SCFD1 all increase the risk by a small but significant degree.66

Heritability studies also show that a substantial fraction of cases of sporadic ALS cannot be attributed to genetic or biologic factors; these cases are ascribed to environmental or undefined factors. Attempts to identify occupations or common exposures that might increase the risk of ALS have been inconclusive. Environmental studies are challenging because the number of possible exposures is large, and a critical, disease-related exposure may have happened many years before the onset of the disease. A particular difficulty is that studies of ALS are susceptible to bias because of the poor prognosis. Patients who live long enough to attend a specialist research clinic are different from those identified in population studies, and this difference can cause bias in the results. For instance, smoking has been shown to shorten survival in a population study,67 so a case–control study selecting participants from clinics would find smokers underrepresented in the ALS group and would thus suggest that smoking either has no effect or might be protective. Similarly, ALS specialists report anecdotally that their patients tend to be athletic, slim, and very fit,68 but if these factors slow disease progression rather than increase risk, such patients will be overrepresented at specialist centers.

Notwithstanding the barriers to identifying environmental risk factors, some factors have been associated with ALS in multiple studies.69,70 The exposure with the strongest support is military service.71,72 In addition, smoking has been implicated as a dose-dependent risk factor for ALS.73 Exposure to heavy metals may be important; blood lead levels and cerebrospinal fluid manganese levels are higher in patients with ALS than in controls.70 People with occupations involving exposure to electromagnetic fields also appear to be at increased risk, but people living near power lines are not. Other risk factors with varying levels of support include pesticide exposure and neurotoxins such as those produced by cyanobacteria. Viruses have been studied as a possible explanation for sporadic ALS. Initial studies suggesting the role of an activated, endogenous retrovirus74 were followed by the identification of a possible candidate, human endogenous retrovirus K.75

There is increasing evidence that trauma precedes some individual cases of ALS.76 A meta-analysis has suggested that trauma overall, trauma occurring more than 5 years previously, bone fracture, and head injury are all associated with an increased risk.77 In recent years, it has been observed that persons engaged in sports that entail repetitive concussions or subconcussive head trauma are at increased risk for ALS and a concurrent behavioral disorder marked by impulsivity and memory loss. Autopsy studies in persons with this disorder, called chronic traumatic encephalopathy, have revealed frontotemporal atrophy associated with distinctive deposits of tau protein, as well as TDP-43, the characteristic inclusion protein in ALS.78

Therapeutics and Beyond

No therapy offers a substantial clinical benefit for patients with ALS. The drugs riluzole79 and edaravone, which have been approved by the Food and Drug Administration for the treatment of ALS, provide a limited improvement in survival. Riluzole acts by suppressing excessive motor neuron firing, and edaravone by suppressing oxidative stress. Numerous other compounds that have been investigated have not been shown to be effective.80,81 Currently, the mainstay of care for patients with ALS is timely intervention to manage symptoms, including use of nasogastric feeding, prevention of aspiration (control of salivary secretions and use of cough-assist devices), and provision of ventilatory support (usually with bilevel positive airway pressure). Some interventions raise serious ethical issues, such as whether to perform tracheostomy for full ventilation and, if so, when and how to withdraw respiratory support once it has been instituted.

Despite the pipeline of potential treatments for ALS, reflecting the expanded list of targets identified through genetic studies and increasing numbers of ALS investigators, many of whom are in the pharmaceutical sector,80,82 no drugs are being investigated in late-phase clinical trials. Several innovative approaches to treating ALS (and other neurodegenerative diseases) are in development. Two examples include the use of adeno-associated viruses (AAV) to achieve widespread delivery of diverse cargoes (missing genes, therapeutic genes, or gene-silencing elements) to the central nervous system and the use of stem cells that provide neurotrophic factors to the central nervous system.83 Studies in cells, mice, and humans support the view that several types of reagents (e.g., antisense oligonucleotides and AAV-delivered microRNA) inactivate production of toxic gene products and thus may be therapeutic in ALS mediated by genes such as SOD184–87 and C9ORF72. Indeed, clinical trials investigating the use of antisense oligonucleotides to silence SOD1 have begun.

One can anticipate continued progress in understanding the biology of ALS. There is no doubt that high-throughput genetics, combined with improved clinical phenotyping, will further refine the genetic landscape of ALS. As thousands of full genome sequences become available, it will be feasible to explore the possibility that complex interactions among multiple gene variants explain not only familial ALS but also sporadic ALS. The exploration of environmental factors in sporadic ALS will expand, with a focus on the internal environment represented by the microbiome. The ultimate proof of our understanding of the biology of ALS will hinge on our ability to modify the clinical course of the disease.

Notes

Dr. Brown reports holding equity in AviTx, Amylyx Pharmaceuticals, and ImStar Therapeutics, receiving fees for serving on an advisory board from Voyager Therapeutics, negotiating a collaborative agreement with WAVE Biosciences, holding patents and receiving royalties for patents on “Method for the diagnosis of familial amyotrophic lateral sclerosis” (US 5,843,641) and “Mice having a mutant SOD1 encoding transgene” (US 6,723,893), holding a patent for “Compounds and method for the diagnosis, treatment and prevention of cell death” (US 5,849,290), and holding a pending patent for “Use of synthetic microRNA for AAV-mediated silencing of SOD1 in ALS”; and Dr. Al-Chalabi reports receiving consulting fees from GlaxoSmithKline, providing unpaid consulting for Mitsubishi Tanabe Pharma, Treeway, Chronos Therapeutics, and Avanir Pharmaceuticals, receiving consulting fees and serving as principal investigator in an international commercial clinical trial of tirasemtiv in ALS for Cytokinetics, and serving as chief investigator of an international commercial clinical trial of levosimendan in ALS for Orion Pharma. No other potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Supplementary Material

Disclosure Forms (nejmra1603471_disclosures.pdf)

• Download
• 111.68 KB

References

1.

Rowland, LP, Shneider, NA. Amyotrophic lateral sclerosis. N Engl J Med 2001;344:1688-1700

Go to Citation

Crossref

PubMed

Web of Science

Google Scholar

2.

Al-Chalabi, A, Hardiman, O, Kiernan, MC, Chiò, A, Rix-Brooks, B, van den Berg, LH. Amyotrophic lateral sclerosis: moving towards a new classification system. Lancet Neurol 2016;15:1182-1194

Crossref

PubMed

Web of Science

Google Scholar

3.

Rezania, K, Roos, RP. Spinal cord: motor neuron diseases. Neurol Clin 2013;31:219-239

Go to Citation

Crossref

PubMed

Web of Science

Google Scholar

Amyotrophic Lateral Sclerosis

Authors: Robert H. Brown, D.Phil., M.D., and Ammar Al-Chalabi, Ph.D., F.R.C.P., Dip.Stat.Author Info & Affiliations

Published July 13, 2017

N Engl J Med 2017;377:162-172

DOI: 10.1056/NEJMra1603471

VOL. 377 NO. 2

Copyright © 2017

• Information & Authors
• Metrics & Citations
• View Options
• References
• Media
• Tables
• Share

Amyotrophic lateral sclerosis (ALS) is a progressive, paralytic disorder characterized by degeneration of motor neurons in the brain and spinal cord. It begins insidiously with focal weakness but spreads relentlessly to involve most muscles, including the diaphragm. Typically, death due to respiratory paralysis occurs in 3 to 5 years.

Motor neurons are grouped into upper populations in the motor cortex and lower populations in the brain stem and spinal cord; lower motor neurons innervate muscle (Figure 1). When corticospinal (upper) motor neurons fail, muscle stiffness and spasticity result. When lower motor neurons become affected, they initially show excessive electrical irritability, leading to spontaneous muscle twitching (fasciculations); as they degenerate, they lose synaptic connectivity with their target muscles, which then atrophy.

Figure 1

The Motor System.

ALS typically begins in the limbs, but about one third of cases are bulbar, heralded by difficulty chewing, speaking, or swallowing. Until late in the disease, ALS spares neurons that innervate the eye and sphincter muscles. The diagnosis is based primarily on clinical examination in conjunction with electromyography, to confirm‎ the extent of denervation, and laboratory testing, to rule out reversible disorders that may resemble ALS.1,2

A representative case involves a 55-year-old patient who was eval‎uated for foot drop, which had begun subtly 4 months earlier with the onset of muscle cramping in the right calf as a result of volitional movement (known as volitional cramping) and had progressed to severe weakness of ankle dorsiflexion and knee extension. In addition to these features, the physical examination revealed atrophy of the right calf and hyperreflexia of the right biceps and of deep tendon reflexes at both knees and both ankles. The neurologic examination was otherwise normal. Electromyography showed evidence of acute muscle denervation (fibrillations) in all four limbs and muscle reinnervation in the right calf (high-amplitude compound muscle action potentials). Imaging of the head and neck revealed no structural lesions impinging on motor tracts, and the results of laboratory studies were normal, findings that ruled out several disorders in the differential diagnosis, such as peripheral neuropathy, Lyme disease, vitamin B12 deficiency, thyroid disease, and metal toxicity.3 A full eval‎uation disclosed no evidence of a reversible motor neuron disorder, such as multifocal motor neuropathy with conduction block, which is typically associated with autoantibodies (e.g., anti-GM1 ganglioside antibodies) and can be effectively treated with intravenous immune globulin.4

The clinical presentation of ALS is heterogeneous with respect to the populations of involved motor neurons and survival (Figure 2).2 When there is prominent involvement of frontopontine motor neurons that serve bulbar functions, a striking finding is emotional lability, indicating pseudobulbar palsy, which is characterized by facial spasticity and a tendency to laugh or cry excessively in response to minor emotional stimuli.

Figure 2

Phenotype and Survival in Amyotrophic Lateral Sclerosis (ALS).

In primary lateral sclerosis, there is selective involvement of corticospinal and corticopontine motor neurons, with few findings of lower motor neuron dysfunction.5 Primary lateral sclerosis is ruled out in the representative case described above because of the atrophy and electromyographic findings, which are indicative of lower motor neuron disease. Primary lateral sclerosis progresses slowly, with severe spastic muscle stiffness and little muscle atrophy. This disorder overlaps clinically with a broad category of corticospinal disorders designated as hereditary spastic paraplegias, which are typically symmetrical in onset, slowly progressive, and sometimes associated with sensory loss and other multisystem findings. In primary lateral sclerosis but not hereditary spastic paraplegias, bulbar involvement may be prominent. In progressive muscular atrophy, lower motor neuron involvement is predominant, with little spasticity. The hyperreflexia in the representative case is inconsistent with progressive muscular atrophy.

During the past two decades, it has been recognized that 15 to 20% of persons with ALS have progressive cognitive abnormalities marked by behavioral changes, leading ultimately to dementia.6 Since these behavioral alterations correlate with autopsy evidence of degeneration of the frontal and temporal lobes, the condition is designated frontotemporal dementia. It was formerly called Pick’s disease.

Epidemiologic Features

In Europe and the United States, there are 1 or 2 new cases of ALS per year per 100,000 people; the total number of cases is approximately 3 to 5 per 100,000.7,8 These statistics are globally fairly uniform, although there are rare foci in which ALS is more common. The incidence and preval‎ence of ALS increase with age. In the United States and Europe, the cumulative lifetime risk of ALS is about 1 in 400; in the United States alone, 800,000 persons who are now alive are expected to die from ALS.9 About 10% of ALS cases are familial, usually inherited as dominant traits.10 The remaining 90% of cases of ALS are sporadic (occurring without a family history). In cases of sporadic ALS, the ratio of affected males to affected females may approach 2:1; in familial ALS, the ratio is closer to 1:1. ALS is the most frequent neurodegenerative disorder of midlife, with an onset in the middle-to-late 50s. An onset in the late teenage or early adult years is usually indicative of familial ALS. The time from the first symptom of ALS to diagnosis is approximately 12 months, a problematic delay if successful therapy requires early intervention. Because an abundance of ALS genes have now been identified, it will probably be informative to reanalyze this epidemiologic profile of ALS with stratification according to genetically defined subtypes.

Pathological Characteristics

The core pathological finding in ALS is motor neuron death in the motor cortex and spinal cord; in ALS with frontotemporal dementia, neuronal degeneration is more widespread, occurring throughout the frontal and temporal lobes. Degeneration of the corticospinal axons causes thinning and scarring (sclerosis) of the lateral aspects of the spinal cord. In addition, as the brain stem and spinal motor neurons die, there is thinning of the ventral roots and denervational atrophy (amyotrophy) of the muscles of the tongue, oropharynx, and limbs. Until late in the disease, ALS does not affect neurons that innervate eye muscles or the bladder. Degeneration of motor neurons is accompanied by neuroinflammatory processes, with proliferation of astroglia, microglia, and oligodendroglial cells.11,12 A common feature in cases of both familial and sporadic ALS is aggregation of cytoplasmic proteins, prominently but not exclusively in motor neurons. Some of these proteins are common in most types of ALS. This is exemplified by the nuclear TAR DNA-binding protein 43 (TDP-43), which in many cases of ALS is cleaved, hyperphosphorylated, and mislocalized to the cytoplasm.13 Aggregates of ubiquilin 2 are also common,14 as are intracytoplasmic deposits of wild-type superoxide dismutase 1 (SOD1) in sporadic ALS.15 Many protein deposits show evidence of ubiquitination; threads of ubiquitinated TDP-43 are prominent in motor neurons, both terminally and before atrophy of the cell body. Given the diverse causes of ALS, it is not surprising that some types of aggregates are detected only in specific ALS subtypes (e.g., dipeptide aggregates and intranuclear RNA deposits in C9ORF72 ALS).

Genetic Features

Evolving technologies for gene mapping and DNA analysis have facilitated the identification of multiple ALS genes (Figure 3). SOD1 was the first ALS gene to be identified, in 1993.16 More than 120 genetic variants have been associated with a risk of ALS17 (http://alsod.iop.kcl.ac.uk). Several criteria assist in identifying those that are most meaningful. The strongest confirmation is validation in multiple independent families and cohorts. Also supportive are an increased burden of the variant in cases relative to controls and the predicted consequences of the variant (e.g., missense mutation vs. truncation). It has proved almost impossible to predict a variant’s relevance to ALS from the biologic features of the gene itself. As shown in Figure 3, at least 25 genes have now been reproducibly implicated in familial ALS, sporadic ALS, or both.18–20

Figure 3

ALS Gene Discovery since 1990.

A by-product of the genetic studies that is highly relevant to therapeutic development has been the generation of mouse models of ALS. Strikingly, transgenic expression‎ of mutant SOD1 protein21 and, more recently, profilin 1 (PFN1)22 generates a neurodegenerative, paralytic process in mice that mimics many aspects of human ALS. An important lesson from transgenic models of TDP-43 and FUS (fused in sarcoma) is that levels of the normal protein are tightly controlled. In contrast with SOD1, forced expression‎ of high levels of normal TDP-43 by itself triggers motor neuron degeneration.23 Mouse models of C9orf72 (the 72nd open reading frame identified on chromosome 9, the most commonly mutated gene in ALS) have now also been generated for C9ORF72 ALS and are discussed below.

Correlations between genetic variants and different clinical profiles in ALS, such as age at onset, disease duration, and site of onset, have been defined (Table 1). An important example is the gene that encodes the enzyme ephrin A4 (EPHA4)33 — lower levels of expression‎ of EPHA4 correlate with longer survival. Some genetic variants influence both susceptibility and phenotype. For example, progression is accelerated in patients with the common A4V mutation30 of SOD1 and in patients with the P525L mutation of FUS/TLS; the latter may lead to fulminant, childhood-onset motor neuron disease.28

Table 1

Genetic Variants That Influence the Phenotype in Amyotrophic Lateral Sclerosis.

Concepts in Pathogenesis

A comprehensive explanation for ALS must include both its familial and sporadic forms, as well as categories of phenotypic divergence that arise even with the same proximal trigger, such as a gene mutation. A general presumption has been that the disease reflects an adverse interplay between genetic and environmental factors. An alternative view postulates that all cases of ALS are a consequence primarily of complex genetic factors. Several perspectives suggest that the pathogenesis of ALS entails a multistep process.34

Lessons from Familial ALS

There is striking heterogeneity in the genetic causes of familial ALS, but familial ALS and sporadic ALS have similarities in their pathological features, as well as in their clinical features, suggesting a convergence of the cellular and molecular events that lead to motor neuron degeneration. These points of convergence define targets for therapy.

A working view of the present panel of ALS genes is that they cluster in three categories,19 involving protein homeostasis, RNA homeostasis and trafficking, and cytoskeletal dynamics (Figure 4). These mechanisms are not exclusive. For example, protein aggregates may sequester proteins that are important in RNA binding, thereby perturbing RNA trafficking and homeostasis. Moreover, these mechanisms are detected in the context of both familial ALS and sporadic ALS; some nonmutant proteins also have a propensity to misfold and aggregate in ALS, much like their mutant counterparts (e.g., SOD1 and TDP-43).

Figure 4

Three Major Categories of Pathophysiological Processes in ALS.

Downstream of each category are diverse forms of cellular abnormalities, including the deposition of intranuclear and cytosolic protein and RNA aggregates, disturbances of protein degradative mechanisms, mitochondrial dysfunction, endoplasmic reticulum stress, defective nucleocytoplasmic trafficking, altered neuronal excitability, and altered axonal transport. In most cases, these events activate and recruit nonneuronal cells (astrocytes, microglia, and oligodendroglia), which exert both salutary and negative influences on motor neuron viability. The diverse downstream abnormalities may differentially affect subcellular compartments (dendrites, soma, axons, and neuromuscular junctions). One implication of this model is that successful therapy for ALS will require simultaneous interventions in multiple downstream pathways.

Genes That Influence Protein Homoeostasis

The most extensively investigated pathological finding in ALS has been the accumulation of aggregated proteins and corresponding defects in the cellular pathways for protein degradation. Mutant SOD1 frequently forms intracellular aggregates. Genes that encode adapter proteins involved in protein maintenance and degradation are also implicated in ALS. These include valosin-containing protein (VCP)35 and the proteins optineurin (OPTN),36 TANK-binding kinase 1 (TBK1),37–39 and sequestosome 1 (SQSTM1/p62)40 (Figure 4A). The TBK1–OPTN axis is interwoven in other neurodegenerative disorders; for example, the Parkinson’s disease gene PINK1 encodes a protein that acts upstream of TBK1 in the mobilization of mitophagy.

Genes That Influence RNA Homeostasis and Trafficking

The most rapidly expanding category of ALS genes encodes proteins that interact with RNA. The first protein to be discovered was TDP-43,13 whose mislocalization from the nucleus to the cytosol, cleavage, phosphorylation, and ubiquitination were initially illuminated in sporadic ALS and frontotemporal dementia. However, it became apparent that mutations in TARDBP, the gene encoding TDP-43, can cause familial ALS.41 Mislocalization and post-translational modification of TDP-43 are observed in many neurodegenerative diseases. FUS-TLS encodes another RNA-binding protein, homologous to TDP-43, which in mutant form also causes ALS.42,43 Why mutated genes encoding RNA-binding proteins cause ALS is not clear. These proteins have multiple functions in gene splicing, surveillance of transcripts after splicing, generation of microRNA, and axonal biologic processes. Most of these proteins have low-complexity domains that permit promiscuous binding not only to RNA but also to other proteins. The ALS-related mutations heighten this binding propensity, leading to self-assembly of the proteins and the formation of aggregates.44 This auto-aggregation is facilitated in stress granules, which are non–membrane-bound structures formed under cell stress that contain RNA complexes stalled in translation.45–47 The self-assembly of mutant RNA-binding proteins may induce toxic, self-propagating conformations that disseminate disease within and between cells in a manner analogous to that of prion proteins.

The most commonly mutated gene in ALS is C9ORF72.48–50 The C9ORF72 protein has a role in nuclear and endosomal membrane trafficking and autophagy. A noncoding stretch of six nucleotides is repeated up to approximately 30 times in normal persons. Expansions of this segment to hundreds or thousands of repeats cause familial ALS and frontotemporal dementia; in addition, these expansions sometimes cause sporadic ALS. Several mechanisms may contribute to the neurotoxicity of the hexanucleotide expansion (Figure 4B). Transcripts of the offending segments are deposited in the nucleus, forming RNA foci that sequester nuclear proteins. Some of the expanded RNA escapes to the cytoplasm, where it generates five potentially toxic repeat dipeptides through a noncanonical translation process. Recent studies have also shown a defect in transport across the nuclear membrane in cells with the C9ORF72 expansions.51,52 A reduction in the total levels of the normal C9ORF72 protein may also contribute to neurotoxicity.53–55 Transgenic mouse models of C9orf72 recapitulate the molecular features of C9ORF72 ALS in humans56–59 but, with one exception,59 do not show a strong motor phenotype.

Genes That Influence Cytoskeletal Dynamics

Three ALS genes encode proteins that are important in maintenance of normal cytoskeletal dynamics: dynactin 1 (DCTN1),60 PFN1,29 and tubulin 4A (TUBA4A) (Figure 4C).61 TUBA4A dimers are components of microtubules, whose integrity is essential for axonal structure; DCTN1 is implicated in retrograde axonal transport, whereas PFN1 participates in the conversion of globular to filamentous actin and nerve extension. Also implicated is the modifier gene EPHA4; lower levels of EPHA4 expression‎ correlate with longer survival in ALS, perhaps because they permit more exuberant axonal extension.

Insights into Sporadic ALS

Despite the absence of a family history in sporadic ALS, studies involving twins show that the heritability is about 60%.62 Furthermore, mutations usually found in familial ALS can be found in sporadic ALS. This can be partly explained by the difficulty in ascertaining whether patients with late-onset disease have a family history of ALS. The situation is confounded by the observation that some familial ALS gene variants increase the risk of phenotypes other than ALS, such as frontotemporal dementia.38,39,48 Unless these other phenotypes are recognized as relevant, the family history may be incorrectly recorded as negative. In addition, several familial ALS gene variants are of intermediate penetrance (e.g., the C9ORF72 hexanucleotide repeat expansion, ATXN2 repeat expansions,63 and TBK1 mutations).37–39 Thus, ALS might not be manifested in a gene carrier, in which case, the disease is characterized by familial clustering rather than mendelian inheritance and may appear to be sporadic.64 Combinations of such gene variants further increase the risk of ALS and may be another cause of apparently sporadic ALS.65

Recent genomewide association studies have shown that rare genetic variation is disproportionately frequent in sporadic ALS.66 The genetic architecture of sporadic ALS is markedly different from that of complex diseases such as schizophrenia in which there are additive effects of hundreds of common variants, each with a minute effect on risk. However, common variants still have a part to play in sporadic ALS. For example, variants in the genes UNC13A, MOBP, and SCFD1 all increase the risk by a small but significant degree.66

Heritability studies also show that a substantial fraction of cases of sporadic ALS cannot be attributed to genetic or biologic factors; these cases are ascribed to environmental or undefined factors. Attempts to identify occupations or common exposures that might increase the risk of ALS have been inconclusive. Environmental studies are challenging because the number of possible exposures is large, and a critical, disease-related exposure may have happened many years before the onset of the disease. A particular difficulty is that studies of ALS are susceptible to bias because of the poor prognosis. Patients who live long enough to attend a specialist research clinic are different from those identified in population studies, and this difference can cause bias in the results. For instance, smoking has been shown to shorten survival in a population study,67 so a case–control study selecting participants from clinics would find smokers underrepresented in the ALS group and would thus suggest that smoking either has no effect or might be protective. Similarly, ALS specialists report anecdotally that their patients tend to be athletic, slim, and very fit,68 but if these factors slow disease progression rather than increase risk, such patients will be overrepresented at specialist centers.

Notwithstanding the barriers to identifying environmental risk factors, some factors have been associated with ALS in multiple studies.69,70 The exposure with the strongest support is military service.71,72 In addition, smoking has been implicated as a dose-dependent risk factor for ALS.73 Exposure to heavy metals may be important; blood lead levels and cerebrospinal fluid manganese levels are higher in patients with ALS than in controls.70 People with occupations involving exposure to electromagnetic fields also appear to be at increased risk, but people living near power lines are not. Other risk factors with varying levels of support include pesticide exposure and neurotoxins such as those produced by cyanobacteria. Viruses have been studied as a possible explanation for sporadic ALS. Initial studies suggesting the role of an activated, endogenous retrovirus74 were followed by the identification of a possible candidate, human endogenous retrovirus K.75

There is increasing evidence that trauma precedes some individual cases of ALS.76 A meta-analysis has suggested that trauma overall, trauma occurring more than 5 years previously, bone fracture, and head injury are all associated with an increased risk.77 In recent years, it has been observed that persons engaged in sports that entail repetitive concussions or subconcussive head trauma are at increased risk for ALS and a concurrent behavioral disorder marked by impulsivity and memory loss. Autopsy studies in persons with this disorder, called chronic traumatic encephalopathy, have revealed frontotemporal atrophy associated with distinctive deposits of tau protein, as well as TDP-43, the characteristic inclusion protein in ALS.78

Therapeutics and Beyond

No therapy offers a substantial clinical benefit for patients with ALS. The drugs riluzole79 and edaravone, which have been approved by the Food and Drug Administration for the treatment of ALS, provide a limited improvement in survival. Riluzole acts by suppressing excessive motor neuron firing, and edaravone by suppressing oxidative stress. Numerous other compounds that have been investigated have not been shown to be effective.80,81 Currently, the mainstay of care for patients with ALS is timely intervention to manage symptoms, including use of nasogastric feeding, prevention of aspiration (control of salivary secretions and use of cough-assist devices), and provision of ventilatory support (usually with bilevel positive airway pressure). Some interventions raise serious ethical issues, such as whether to perform tracheostomy for full ventilation and, if so, when and how to withdraw respiratory support once it has been instituted.

Despite the pipeline of potential treatments for ALS, reflecting the expanded list of targets identified through genetic studies and increasing numbers of ALS investigators, many of whom are in the pharmaceutical sector,80,82 no drugs are being investigated in late-phase clinical trials. Several innovative approaches to treating ALS (and other neurodegenerative diseases) are in development. Two examples include the use of adeno-associated viruses (AAV) to achieve widespread delivery of diverse cargoes (missing genes, therapeutic genes, or gene-silencing elements) to the central nervous system and the use of stem cells that provide neurotrophic factors to the central nervous system.83 Studies in cells, mice, and humans support the view that several types of reagents (e.g., antisense oligonucleotides and AAV-delivered microRNA) inactivate production of toxic gene products and thus may be therapeutic in ALS mediated by genes such as SOD184–87 and C9ORF72. Indeed, clinical trials investigating the use of antisense oligonucleotides to silence SOD1 have begun.

One can anticipate continued progress in understanding the biology of ALS. There is no doubt that high-throughput genetics, combined with improved clinical phenotyping, will further refine the genetic landscape of ALS. As thousands of full genome sequences become available, it will be feasible to explore the possibility that complex interactions among multiple gene variants explain not only familial ALS but also sporadic ALS. The exploration of environmental factors in sporadic ALS will expand, with a focus on the internal environment represented by the microbiome. The ultimate proof of our understanding of the biology of ALS will hinge on our ability to modify the clinical course of the disease.

Notes

Dr. Brown reports holding equity in AviTx, Amylyx Pharmaceuticals, and ImStar Therapeutics, receiving fees for serving on an advisory board from Voyager Therapeutics, negotiating a collaborative agreement with WAVE Biosciences, holding patents and receiving royalties for patents on “Method for the diagnosis of familial amyotrophic lateral sclerosis” (US 5,843,641) and “Mice having a mutant SOD1 encoding transgene” (US 6,723,893), holding a patent for “Compounds and method for the diagnosis, treatment and prevention of cell death” (US 5,849,290), and holding a pending patent for “Use of synthetic microRNA for AAV-mediated silencing of SOD1 in ALS”; and Dr. Al-Chalabi reports receiving consulting fees from GlaxoSmithKline, providing unpaid consulting for Mitsubishi Tanabe Pharma, Treeway, Chronos Therapeutics, and Avanir Pharmaceuticals, receiving consulting fees and serving as principal investigator in an international commercial clinical trial of tirasemtiv in ALS for Cytokinetics, and serving as chief investigator of an international commercial clinical trial of levosimendan in ALS for Orion Pharma. No other potential conflict of interest relevant to this article was reported.

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