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Hereditary ataxias: overview

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• Review
• Published: 28 March 2013

Hereditary ataxias: overview

• Suman Jayadev MD & 
• Thomas D. Bird MD 

Genetics in Medicine volume 15, pages673–683 (2013)Cite this article

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Abstract

The hereditary ataxias are a highly heterogeneous group of disorders phenotypically characterized by gait ataxia, incoordination of eye movements, speech, and hand movements, and usually associated with atrophy of the cerebellum. There are more than 35 autosomal dominant types frequently termed spinocerebellar ataxia and typically having adult onset. The most common subtypes are spinocerebellar ataxia 1, 2, 3, 6, and 7, all of which are nucleotide repeat expansion disorders.

Autosomal recessive ataxias usually have onset in childhood; the most common subtypes are ­Friedreich, ataxia-telangiectasia, ataxia with oculomotor apraxia type 1, and ataxia with oculomotor apraxia type 2. Four autosomal recessive types have dietary or biochemical treatment modalities (ataxia with vitamin E deficiency, cerebrotendinous xanthomatosis, Refsum, and coenzyme Q10 deficiency), whereas there are no specific treatments for other ataxias. Diagnostic genetic testing is complicated because of the large number of relatively uncommon subtypes with extensive phenotypic overlap. However, the best testing strategy is based on assessing relative frequencies, ethnic predilections, and recognition of associated phenotypic features such as seizures, visual loss, or associated movement abnormalities.

요약

유전성 운동 실조증은 

보행 운동 실조증, 

안구 운동의 조정 장애, 

언어 장애, 

손의 움직임 장애를 특징으로 하는 매우 이질적인 장애군으로, 

보통 소뇌 위축과 관련이 있습니다. 

gait ataxia,

incoordination of eye movements,

speech, and

hand movements

The hereditary ataxias

35가지 이상의 상염색체 우성 유형이 있으며, 

흔히 척수소뇌성 운동 실조증이라고 불리며, 

일반적으로 성인이 발병합니다. 

가장 흔한 하위 유형은 

핵산 반복 증폭 장애인 척수소뇌성 운동 실조증 1, 2, 3, 6, 7입니다. 

spinocerebellar ataxia

상염색체 열성 운동 실조증은 

보통 어린 시절에 발병합니다. 

Autosomal recessive ataxias 

가장 흔한 하위 유형은 

프리드리히 운동 실조증, 

모세혈관 확장성 운동 실조증, 

안구 운동 실조증 1형 운동 실조증, 

안구 운동 실조증 2형 운동 실조증입니다. 

Friedreich,

ataxia-telangiectasia,

ataxia with oculomotor apraxia type 1, and

ataxia with oculomotor apraxia type 2

https://my.clevelandclinic.org/health/diseases/23415-ataxia-telangiectasia

Ataxia-telangiectasia: Symptoms, Causes and Outlook

4가지 상염색체 열성 유형(비타민 E 결핍으로 인한 운동 실조증, 뇌와 힘줄의 황색반증, 레프섬병, 코엔자임 Q10 결핍)은 

식이요법이나 생화학 요법으로 치료할 수 있지만, 

다른 운동 실조증에 대해서는 특별한 치료법이 없습니다. 

ataxia with vitamin E deficiency,

cerebrotendinous xanthomatosis,

Refsum, and

coenzyme Q10 deficiency

진단 유전자 검사는 광범위한 표현형 중복을 보이는 

비교적 흔하지 않은 아형이 많기 때문에 복잡합니다. 

그러나 

가장 좋은 검사 전략은 발작, 시력 상실, 또는 관련된 운동 이상과 같은

 관련 표현형 특징의 상대적 빈도, 민족적 선호도, 인식 등을 평가하는 것입니다.

Genet Med 15 9, 673–683.

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Hereditary Ataxia

The hereditary ataxias are a clinically and genetically heterogeneous group of disorders characterized by slowly progressive incoordination of gait and often associated with poor coordination of hands, speech, and eye movements. Frequently, atrophy of the cerebellum occurs ( Figure 1 ). In this review, the hereditary ataxias are categorized by mode of inheritance and gene in which causative mutations occur, or chromosomal locus. The hereditary ataxias can be inherited in an autosomal dominant, autosomal recessive, X-linked manner or through maternal inheritance if part of a mitochondrial genetic syndrome. The genetic forms of ataxia are diagnosed by family history, physical examination, ­neuroimaging, and molecular genetic testing. The clinical manifestations may result from one or a combination of dysfunction of the cerebellar systems, lesions in the spinal cord, and peripheral sensory loss.

유전성 운동 실조증

유전성 운동 실조증은

임상적, 유전적으로 이질적인 장애군으로,

보행의 느린 진행성 협응력 저하를 특징으로 하며,

종종 손, 언어, 눈의 협응력 저하와 관련이 있습니다.

종종 소뇌 위축이 발생합니다( 그림 1).

이 리뷰에서

유전성 운동 실조증은

유전 방식과 원인 돌연변이가 발생하는 유전자 또는 염색체 위치에 따라 분류됩니다.

유전성 운동 실조증은

상염색체 우성, 상염색체 열성, X-연관 유전, 또는

미토콘드리아 유전 증후군의 일부인 경우 모계 유전을 통해 유전될 수 있습니다.

유전적 형태의 운동 실조증은

가족력, 신체 검사, 신경 영상, 분자 유전 검사를 통해 진단됩니다.

임상 증상은

소뇌 시스템의 기능 장애, 척수 병변, 말초 감각 상실의 하나 또는

여러 가지 조합으로 인해 발생할 수 있습니다.

Figure 1

Coronal brain MRI showing atrophy of both cerebellar hemispheres (arrows) in a 28-year-old woman with SCA2. MRI, magnetic resonance imaging; SCA, spinocerebellar ataxia.

Full size image

Clinical manifestations

The clinical manifestations of the hereditary ataxias are progressive incoordination of movement and speech, and a wide-based, uncoordinated, unsteady gait. In addition, patients may develop ophthalmoplegia (limitations of eye movement), spasticity, neuropathy, and cognitive/behavioral difficulties. Particular signs beyond ataxia may guide the clinician in pursuit of directed genetic testing when investigating the cause of ataxia. For instance, cone–rod retinal dystrophy in conjunction with familial ataxia may suggest spinocerebellar ataxia (SCA)7; Native American origin or co-occurrence of epilepsy would raise the possibility of SCA10.

임상 증상

유전성 운동 실조증의 임상 증상은 

운동과 언어의 점진적인 조정 장애, 그리고 

넓고, 조정되지 않고, 불안정한 걸음걸이입니다. 

또한, 환자들은 안구 운동 장애(안구 운동의 제한), 

경련, 신경병증, 인지/행동 장애를 겪을 수 있습니다. 

운동 실조증의 원인을 조사할 때, 

운동 실조증 이외의 특별한 징후가 있다면, 

의사는 유전적 검사를 진행할 수 있습니다.

 예를 들어, 가족성 운동 실조증과 함께 나타나는 원추-막 망막 변성은 척수 소뇌성 운동 실조증(SCA)을 시사할 수 있습니다7; 아메리카 원주민 출신이거나 간질이 동반되는 경우 SCA10의 가능성을 높일 수 있습니다.

Establishing the diagnosis

Establishing the diagnosis of hereditary ataxia requires:

1. 1
2. 2
3. 3

진단의 확립

유전성 운동 실조증의 진단을 확립하기 위해서는 다음이 필요합니다.

1. 1. 신경학적 검사에서 보행 및 손가락/손 움직임의 협응력 저하, 구음장애(언어 협응력 저하), 안진, 이상성 운동실조, 안구 운동 마비 등의 전형적인 임상 징후를 감지합니다.
2. 2. 비유전적 운동 실조증의 원인을 배제합니다(아래의 감별 진단 참조).
3. 3 운동 실조증의 유전적 특성을 입증하는 가족력, 운동 실조증을 유발하는 돌연변이 확인, 또는 유전적 형태의 운동 실조증의 특징적인 임상 표현형 확인을 통해 운동 실조증의 유전적 특성을 입증하는 문서화.

Differential diagnosis

Differential diagnosis of hereditary ataxia includes acquired, nongenetic causes of ataxia, such as alcoholism, vitamin deficiencies, multiple sclerosis, vascular disease, primary or metastatic tumors, and paraneoplastic diseases associated with occult carcinoma of the ovary, breast, or lung, and the idiopathic degenerative disease multiple system atrophy (spinal muscular atrophy). The possibility of an acquired cause of ataxia needs to be considered in each individual with ataxia because a specific treatment may be available.

감별 진단

유전성 운동 실조증의 감별 진단에는 

알코올 중독, 

비타민 결핍, 

다발성 경화증, 

혈관 질환, 

원발성 또는 전이성 종양, 

난소, 유방 또는 폐의 신비로운 암종과 관련된 부신 생물 질환, 

특발성 퇴행성 질환인 다발성 시스템 위축증(척추 근육 위축증)과 같은 

후천성, 비유전적 운동 실조증의 원인이 포함됩니다. 

특정 치료법이 있을 수 있기 때문에 

운동 실조증의 후천적 원인에 대해서도 

각 운동 실조증 환자에 대해 고려해야 합니다.

Types of Hereditary Ataxia

As discussed above, the hereditary ataxias can be subdivided by mode of inheritance, (i.e., autosomal dominant, autosomal recessive, X-linked, and mitochondrial), gene in which causative mutations occur, or chromosomal locus.1,2,3

Autosomal dominant cerebellar ataxias

Synonyms for autosomal dominant cerebellar ataxias (ADCAs) used prior to the identification of the molecular genetic basis of these disorders were Marie’s ataxia, inherited olivopontocerebellar atrophy, cerebello-olivary atrophy, or the more generic term, spinocerebellar degeneration.

유전성 운동 실조증의 유형

위에서 논의한 바와 같이,

유전성 운동 실조증은

유전 방식(즉, 상염색체 우성, 상염색체 열성, X-연관, 미토콘드리아),

원인 돌연변이가 발생하는 유전자, 또는 염색체 위치에 따라 세분화될 수 있습니다.1,2,3

상염색체 우성 소뇌 운동 실조증

상염색체 우성 소뇌 운동 실조증(ADCAs)의 동의어는

이러한 질환의 분자 유전학적 근거가 밝혀지기 전에 사용된

마리 증후군,

유전성 소뇌-시신경 위축,

소뇌-시신경 위축, 또는 보다 일반적인 용어인 척수 소뇌 변성입니다.

Clinical features of ADCA. The age of onset and physical findings in the autosomal dominant ataxias overlap. Table 1 indicates a few distinguishing clinical features for each type.4,5,6,7,8 Scales for rating symptoms and signs of ataxia have been published.9 Often the autosomal dominant ataxias cannot be differentiated by clinical or neuroimaging studies; they are usually slowly progressive and often associated with cerebellar atrophy, as seen from brain imaging studies ( Figure 1 ). The frequency of the occurrence of each disease within the autosomal dominant cerebellar ataxia (ADCA) population is noted in Table 1 . Pyramidal signs (hyperreflexia and spasticity) are commonly found in patients with SCA1 and SCA3; cognitive impairment has been reported in association with SCA2, SCA12, SCA13, SCA17; chorea may manifest in patients with SCA17 or dentatorubral-pallidoluysian atrophy (DRPLA). Many of the ADCAs in addition to limb and truncal ataxia cause dysarthria, dysphagia, and neuropathy. The clinical syndrome associated with SCA2 may include parkinsonism or motor neuron disease (amyotrophic lateral sclerosis)10,11 Age of onset is quite variable and usually in adulthood. Disease course is also variable, although generally the disease progresses over decades. Life span may be shortened in SCA1, -2, -3, and -7 or normal in SCA5, -6, and -14.5 The most common form of episodic ataxia is EA2, caused by a variety of point mutations in the same calcium channel gene (CACNA1A) associated with SCA6 and familial hemiplegic migraine.12

ADCA의 임상적 특징.

발병 연령과 신체적 소견은 상염색체 우성 운동 실조증에서 겹칩니다.

표 1 은 각 유형의 몇 가지 특징적인 임상 특징을 보여줍니다.4,5,6,7,8

운동 실조증의 증상과 징후를 평가하기 위한 척도가 발표되었습니다.9

종종 상염색체 우성 운동 실조증은 임상 또는 신경 영상 연구로 구분할 수 없습니다.

이 질환은

일반적으로 천천히 진행되며,

뇌 영상 연구에서 볼 수 있듯이 소뇌 위축과 관련이 있는 경우가 많습니다( 그림 1 ).

상염색체 우성 소뇌 운동 실조증(ADCA) 집단 내에서

각 질병의 발생 빈도는 표 1 에 나와 있습니다.

피라미드 징후(과반사 및 경련)는

SCA1과 SCA3 환자들에게서 흔히 발견되며,

인지 장애는 SCA2, SCA12, SCA13, SCA17과 관련되어 보고되었습니다.

무도병은

SCA17 또는 구강-뇌하수체-팔다리 위축증(DRPLA) 환자들에게서 나타날 수 있습니다.

사지 운동 실조증과 중추성 운동 실조증 외에

많은 ADCAs가 구음 장애, 연하 곤란, 신경병증을 유발합니다.

SCA2와 관련된 임상 증후군에는

파킨슨증 또는 운동 신경 질환(근위축성 측삭 경화증)이 포함될 수 있습니다10,11

발병 연령은

매우 다양하며, 보통 성인기에 발병합니다.

질병의 경과도 다양하지만,

일반적으로 수십 년에 걸쳐 진행됩니다.

SCA1, -2, -3, -7에서는 수명이 단축될 수 있고,

SCA5, -6, -14에서는 정상일 수 있습니다.5

가장 흔한 형태의 일시적 운동 실조증은

SCA6 및 가족성 편마비성 편두통과 관련된 동일한 칼슘 채널 유전자(CACNA1A)의

다양한 점 돌연변이로 인해 발생하는 EA2입니다.12

Table 1 Autosomal dominant hereditary ataxias

Full size table

Genetics. The ADCAs for which specific genetic information is available are summarized in Table 1 . Most are SCAs; one is a complex form with additional phenotypic features in addition to ataxia; four are episodic ataxias; and one is a spastic ataxia. In addition to ADCAs described in Table 1 , ADCAs include:

1. 1
2. 2
3. 3
4. 4

유전학. 특정 유전 정보가 이용 가능한 ADCAs는 표 1 에 요약되어 있습니다. 대부분은 SCA이고, 하나는 운동 실조증 외에 추가적인 표현형 특징을 가진 복합 형태이고, 4개는 일시적 운동 실조증이고, 1개는 경련성 운동 실조증입니다. 표 1 에 설명된 ADCAs 외에도 ADCAs에는 다음이 포함됩니다.

1. 1조기 감각/운동 신경병증(7q22-q32에 연결됨)을 동반한 운동 실조증; IFRD1의 돌연변이에 의해 발생합니다.13,14
2. 2소뇌 운동 실조증, 난청, 기면증, 시신경 위축(한 가족에서 6p21-p23에 연결됨).15
3. 3Ataxia, 소뇌 위축, 지적 장애, 그리고 주의력 결핍/과잉 행동 장애 가능성(SCN8A의 이형 접합 돌연변이와 관련됨, 나트륨 채널을 암호화함).16
4. 4수년 동안 지속된 경련성 기침이 선행된 후기 발병(40대-60대) 소뇌 운동 실조증. 한 명의 개인은 자기 공명 영상(MRI)에서 치아핵의 석회화를 보였습니다.17

Molecular genetic testing. Mutations associated with the ADCAs include nucleotide expansions occurring in either expressed or nonexpression‎ regions of the gene, point mutations, duplications, and deletions.

Some of the earliest identified and most common ADCAs result from CAG trinucleotide expansions. SCA1, SCA2, SCA3, SCA6, SCA7, SCA12, SCA17, and DRPLA are all caused by CAG repeats within the coding region of the respective genes translating into an elongated polyglutamine tract in the protein. Molecular genetic testing for CAG repeat length is a highly specific and sensitive diagnostic test. The sizes of the normal CAG repeat allele and of the full-penetrance disease-causing CAG expansion vary among the disorders (for individual reviews of each disorder see GeneReviews.org).

분자 유전 검사. ADCAs와 관련된 돌연변이에는 유전자의 발현 영역 또는 비발현 영역에서 발생하는 뉴클레오티드 확장, 점 돌연변이, 중복, 결실 등이 포함됩니다.

가장 초기에 확인된 가장 흔한 ADCAs 중 일부는 CAG 삼중염기 확장으로 인해 발생합니다. SCA1, SCA2, SCA3, SCA6, SCA7, SCA12, SCA17, DRPLA는 모두 각 유전자의 코딩 영역 내의 CAG 반복이 단백질에서 길어진 폴리글루타민 트랙으로 번역되어 발생합니다. CAG 반복 길이에 대한 분자 유전학적 검사는 매우 구체적이고 민감한 진단 검사입니다. 정상적인 CAG 반복 대립 유전자와 질병을 유발하는 완전 침투성 CAG 확장의 크기는 장애에 따라 다릅니다(각 장애에 대한 개별 리뷰는 GeneReviews.org 참조).

Although ordering molecular testing for the polyglutamine ataxia disorders listed above is straightforward and tests are commercially available, there are two notes of caution in the interpretation of results:

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위에 열거된 폴리글루타민 아타슘 장애에 대한 분자 검사를 주문하는 것은 간단하고, 검사 결과는 상업적으로 이용 가능하지만, 결과 해석에 있어 주의해야 할 두 가지 사항이 있습니다.

1. 1 일부 장애는 정상 범위의 상한과 비정상 범위의 하한 사이에 중복이 존재하는 대립 유전자와 관련이 있습니다. 일반적으로 이러한 대립 유전자는 변이성 정상 또는 감소된 침투성으로 분류됩니다. 변이성 정상 대립 유전자(이전에는 중간 대립 유전자라고 불림)는 개인에게 질병을 유발하지 않지만, 전염이 확대되어 감소 또는 완전 침투성 대립 유전자로 전이될 수 있습니다. 따라서, 변이성 정상 대립 유전자를 가진 개인의 자녀는 질병을 유발하는 대립 유전자를 물려받을 위험이 높습니다. 또한, 개인에게 질병을 유발할 수도 있고 그렇지 않을 수도 있는 감소 침투성 대립 유전자도 있습니다. 이러한 대립 유전자를 가진 사람의 질병 발생 가능성은 일반적으로 알려져 있지 않습니다. CAG 반복 길이가 돌연변이 유형 범주인 가변성 정상/감소된 발현률과 감소된 발현률/질병 유발 사이의 경계에 있는 경우, 검사 결과를 해석하는 것이 어려울 수 있습니다. 이러한 경우, CAG 반복 길이 측정의 정확성을 확인하기 위해 검사 기관과 상담하는 것이 도움이 될 수 있습니다.
2. 2경우에 따라, SCA2, SCA7, SCA8, SCA10은 매우 큰 CAG 확장으로 인해 발생하며, 이는 Southern blot 분석으로만 검출될 수 있습니다. 이러한 장애의 경우, CAG 반복 증폭 돌연변이의 존재 여부를 검사하는 Southern blot 분석이 적절한지 여부를 결정하기 위해 임상 소견, 가족력, 증상 발현 연령 등 여러 요인을 고려하여 명백한 동형접합성(PCR 분석에 의한 단일 대립 유전자 검출)의 검사 결과를 해석해야 합니다.

Other repeat expansions. SCA8 has a CTG trinucleotide repeat expansion in ATXN8OS.18 Extremely large repeats (~800) in ATXN8OS may be associated with an absence of clinical symptoms.19 The pathogenesis of the SCA8 phenotype is complex and also involves a (CAG)n repeat in a second overlapping gene, ATXN8.

SCA10 has a large expansion of an ATTCT pentanucleotide repeat in ATXN10, with the abnormal expansion range being much larger than that seen in the CAG repeat disorders.20

Anticipation. Anticipation is observed in the autosomal dominant ataxias in which CAG trinucleotide repeats occur. Anticipation refers to earlier onset of an increasing severity of disease in subsequent generations of a family. In the trinucleotide repeat diseases, anticipation results from expansion in the number of CAG repeats that occurs with transmission of the gene to the next generation. ATN1 (DRPLA) and ATXN7 (SCA7) have particularly unstable CAG repeats.21 In SCA7, anticipation may be so extreme that children with early-onset, severe disease die of the disorder long before the affected parent or grandparent is symptomatic.

Anticipation is a significant issue in the genetic counseling of asymptomatic at-risk family members and in prenatal testing. Although general correlations exist between earlier age of onset and more severe disease with increasing number of CAG repeats, the age of onset, severity of disease, specific symptoms, and rate of disease progression are variable and cannot be accurately predicted by the family history or molecular genetic testing. Attention has been focused on the phenomena of anticipation and trinucleotide repeat expansion, but it is important to note that the number of trinucleotide repeats can also remain stable or even contract on transmission to subsequent generations.

In the CAG repeat disorders, expansion of the repeat is more likely to occur with paternal than with maternal transmission of the expanded allele. By contrast, in SCA8, the majority of expansions of the CTG repeat occur during maternal transmission.

Preval‎ence. The preval‎ence of these rare diseases is not widely known. The preval‎ence of the ADCAs in the Netherlands is estimated to be at least 3:100,000.22 The preval‎ence of individual subtypes of ADCA may vary from region to region, frequently because of founder effects. For example, DRPLA is more common in Japan and SCA3 in Portugal; SCA2 is common in Korea and SCA3 is much more common in Japan and Germany than in the United Kingdom.23,24,25 SCA3 was originally described in Portuguese families from the Azores and called Machado-Joseph disease. DRPLA is rare in North America and common in Japan. A recent study found evidence of frequency variation between different regions in Japan.26 Data are based on a comprehensive study in the United States by Moseley et al.27

Autosomal recessive hereditary ataxias

Numerous recent reviews have detailed the clinical findings, genetics, and pathogenesis of the autosomal recessive ataxias.28 The autosomal recessive ataxias may present with additional extra–central nervous system signs and symptoms. Table 2 summarizes information for 13 typical autosomal recessive disorders in which ataxia is a prominent feature. The disorders are selected to indicate the range of genetic understanding that currently exists regarding recessive causes of ataxia.

Table 2 Autosomal recessive ataxias

Full size table

Friedreich ataxia (FRDA) is the most common autosomal recessive ataxia, with a population frequency of 1–2:50,000. FRDA is characterized by slowly progressive ataxia with onset usually before 25 years of age and is typically associated with depressed tendon reflexes, dysarthria, Babinski responses, and loss of position and vibration senses.29 About 25% of affected individuals have an “atypical” presentation with later onset (age >25 years), retained tendon reflexes, or unusually slow progression of disease. The vast majority of individuals have a GAA triplet-repeat expansion in FXN. Unlike the ADCAs caused by CAG trinucleotide repeats, FRDA is not associated with anticipation.

Ataxia-telangiectasia (A-T) is characterized by progressive cerebellar ataxia beginning between 1 and 4 years of age, oculomotor apraxia, frequent infections, choreoathetosis, telangiectasias of the conjunctivae, immunodeficiency, and an increased risk for malignancy, particularly leukemia and lymphoma. Testing that supports the diagnosis of individuals with A-T is identification of a 7;14 chromosome translocation on routine karyotype of peripheral blood, the presence of immunodeficiency and elevated serum α-fetoprotein, and in vitro radiosensitivity assay. Molecular genetic testing of A-T is available clinically.

Ataxia with vitamin E deficiency (AVED) generally manifests in late childhood or early teens with dysarthria, poor balance when walking (especially in the dark), and progressive clumsiness resulting from early loss of proprioception. Some individuals experience dystonia, psychotic episodes (paranoia), pigmentary retinopathy, and/or intellectual decline. Most individuals become wheelchair bound as a result of ataxia and/or leg weakness between the ages 11 and 50 years. Although phenotypically similar to FRDA, AVED is more likely to be associated with head titubation or dystonia, and less likely to be associated with cardiomyopathy. It is important to consider the diagnosis of AVED (which can be made by measuring serum concentration of vitamin E) because it is treatable with vitamin E supplementation.30,31

A different autosomal recessive ataxia occurring on Grand Cayman Island is caused by mutations in ATCAY, the gene encoding the protein CRAL-TRIO, which may also be involved in vitamin E metabolism.32

Ataxia with oculomotor apraxia type 1 (AOA1) is characterized by childhood onset of slowly progressive cerebellar ataxia (mean onset age ~7 years), followed in a few years by oculomotor apraxia that progresses to external ophthalmoplegia. All affected individuals have a severe primary motor peripheral neuropathy leading to quadriplegia with loss of ambulation about 7–10 years after onset. Intellect remains normal in affected individuals of Portuguese ancestry, but mental deterioration has been seen in affected individuals of Japanese ancestry. The diagnosis of AOA1 is based on clinical findings and confirmed by molecular genetic testing.33,34,35

Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by onset between ages 10 and 22 years, cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia, and elevated serum concentration of α-fetoprotein.36,37 The diagnosis of AOA2 is based on clinical and biochemical findings, family history, and exclusion of the diagnoses of A-T and AOA1; it is confirmed by molecular genetic testing.

Infantile-onset SCA is a rare disorder reported in Finland with degeneration of the cerebellum, spinal cord, and brain stem, and sensory axonal neuropathy.38

Marinesco–Sjögren syndrome is a rare disorder in which ataxia is associated with intellectual disability, cataract, short stature, and hypotonia.39,40

Polymerase γ-1-associated hereditary ataxias. Mutations in mitochondrial genes can result in an ataxia phenotype (see below). In addition, nuclear genes regulating mitochondrial processes can also result in a hereditary ataxia. Autosomal recessive mutations in polymerase γ-1 are associated with a broad spectrum of central nervous system and systemic phenotypes, but two in particular manifest with ataxia as a prominent feature.

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Autosomal recessive spastic ataxia of Charlevoix-Saguenay is characterized by early onset (age 12–18 months) difficulty in walking and gait unsteadiness. Ataxia, dysarthria, spasticity, extensor plantar reflexes, distal muscle wasting, a distal sensorimotor neuropathy predominantly in the legs, and horizontal gaze nystagmus constitute the major neurologic signs, which are most often progressive. Yellow streaks of hypermyelinated fibers radiate from the edges of the optic fundi in the retina of Quebec-born individuals with autosomal recessive spastic ataxia of Charlevoix-Saguenay,43 whereas the retinal changes are uncommon in French, Tunisian, and Turkish individuals with the condition.44,45 Individuals with autosomal recessive spastic ataxia of Charlevoix-Saguenay become wheelchair bound at the average age of 41 years; cognitive skills are preserved long term, and individuals are able to accomplish activities of daily living late into adulthood. Death commonly occurs in the sixth decade.

Refsum disease generally presents in childhood or young adulthood; in addition to ataxia, there may be peripheral neuropathy, deafness, ichthyosis, or retinitis pigmentosa.46

Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC), a syndrome similar to Refsum disease, is caused by mutations in ABHD12.47

Coenzyme Q10 (CoQ10) deficiency is often associated with seizures, cognitive decline, pyramidal track signs, and myopathy but may also include prominent cerebellar ataxia.48,49 The symptoms may respond to CoQ10 treatment.

Cerebrotendinous xanthomatosis has characteristic thickening of tendons often associated with cognitive decline, dystonia, cataract, and white matter changes on brain MRI.

Other autosomal recessive ataxias

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8. 8

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X-linked hereditary ataxias

X-linked sideroblastic anemia and ataxia are characterized by early-onset ataxia, dysmetria, and dysdiadochokinesis. The ataxia is either nonprogressive or slowly progressive. Upper motor neuron signs (brisk deep tendon reflexes, unsustained ankle clonus, and equivocal or extensor plantar responses) are present in some males. Mild learning disability is seen. Anemia is mild without symptoms. Carrier females have a normal neurologic examination. Causative mutations are present in ABC7, encoding a protein involved with mitochondrial iron transport, suggesting a common pathogenesis with FRDA.66

Adult-onset ataxia, especially in men, may be part of the fragile X-associated tremor/ataxia syndrome.67,68

Ataxias with mitochondrial gene mutations

A progressive ataxia is sometimes associated with mitochondrial disorders including myoclonic epilepsy with ragged red fibers; neuropathy, ataxia, and retinitis pigmentosa;1 and Kearns–Sayre syndrome. Mitochondrial disorders are often associated with additional clinical manifestations, such as seizures, deafness, diabetes mellitus, cardiomyopathy, retinopathy, and short stature.69 Pfeffer et al.70 report that missense mutations in MTATP6 can cause both childhood- and adult-onset cerebellar ataxia sometimes associated with abnormal eye movements, dysarthria, weakness, axonal neuropathy, and hyperreflexia.

Eval‎uation Strategy

Once a hereditary ataxia is considered in an individual, the following approach can be used to determine the specific cause to aid in discussions of prognosis and genetic counseling. Establishing the specific cause of hereditary ataxia for a given individual usually involves a medical history, physical examination, neurologic examination, neuroimaging, detailed family history, and molecular genetic testing.

Because of extensive clinical overlap among all of the forms of hereditary ataxia, it is difficult in any given individual with ataxia and a family history consistent with autosomal dominant inheritance to establish a diagnosis without molecular genetic testing. Clinical findings may help distinguish among some of the autosomal recessive ataxias.

A three-generation family history with attention to other ­relatives with neurologic signs and symptoms should be obtained. Documentation of relevant findings in relatives can be accomplished either through direct examination of those individuals or review of their medical records, including the results of molecular genetic testing, neuroimaging studies, and autopsy examinations.

NonDNA testing. Plasma clinical tests are available that suggest the presence of five autosomal recessive hereditary ataxias: elevated α-fetoprotein in A-T and AOA2, low serum vitamin E in AVED, elevated cholestenol in cerebrotendinous xanthomatosis, and hypoalbuminemia in AOA1. Normal values of these tests may sometimes represent false negatives and do not exclude a specific type of ataxia.

Testing strategy when family history suggests autosomal dominant inheritance. There has been much progress in our ability to identify causative genes for a significant proportion of autosomal dominantly inherited ataxias. An estimated 50–60% of the dominant hereditary ataxias (see Table 1 ) can be identified with highly accurate and specific molecular genetic testing for SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA10, SCA12, SCA17, and DRPLA; all have nucleotide repeat expansions in the pertinent genes. Of note, the interpretation of test results can be complex because (i) the exact range for the abnormal repeat expansion has not been fully established for many of these disorders; and (ii) only a few families have been reported with SCA8 and thus penetrance and gender effects have not been completely resolved.71 Thus, diagnosis and genetic counseling of individuals undergoing such testing require the support of an experienced laboratory, medical geneticist, and genetic counselor.

Because of the broad clinical overlap, most laboratories that test for the hereditary ataxias have a battery of tests including testing for SCA1, SCA2, SCA3, SCA6, SCA7, SCA10, SCA12, SCA14, and SCA17. Many laboratories offer them as two groups in stepwise fashion based on population frequency, testing first for the more common ataxias, SCA1, SCA2, SCA3, SCA6, and SCA7. Although pursuing multiple genes simultaneously may seem less optimal than serial genetic testing, it is important to recognize that the cost of the battery of ataxia tests often is equivalent to that of an MRI. Positive results from the molecular genetic testing are more specific than MRI findings in the hereditary ataxias. Guidelines for genetic testing of hereditary ataxia have been published.72

Testing is also available for some autosomal dominant forms of SCA that are not associated with repeat expansions, namely SCA5, SCA13, SCA14, SCA15, SCA27, SCA28, and 16q22-linked SCA.

Testing for the less common hereditary ataxias should be individualized and may depend on factors such as ethnic background (SCA3 in the Portuguese, SCA10 in the Native American population with some exceptions73); seizures (SCA10); presence of tremor (SCA12, fragile X-associated tremor/ataxia syndrome); presence of psychiatric disease or chorea (SCA17); or uncomplicated ataxia with long duration (SCA6, SCA8, and SCA14). Dysphonia and palatal myoclonus are associated with calcification of the dentate nucleus of cerebellum (SCA20).

If a strong clinical indication of a specific diagnosis exists based on the affected individual’s examination (e.g., the presence of retinopathy, which suggests SCA7) or if family history is positive for a known type, testing can be performed for a single disease.

Testing strategy when the family history suggests autosomal recessive inheritance. A family history in which only sibs are affected and/or when the parents are consanguineous suggests autosomal recessive inheritance. Because of their frequency and/or treatment potential, FRDA, A-T, AOA1, AOA2, AVED, and metabolic or lipid storage disorders such as Refsum disease and mitochondrial diseases should be considered.

Testing simplex cases. A simplex case is a single occurrence of a disorder in a family, sometimes incorrectly referred to as a “sporadic” case. If no acquired cause of the ataxia is identified, the probability is ~13% that the affected individual has SCA1, SCA2, SCA3, SCA6, SCA8, SCA17, or FRDA,74 and mutations in rare ataxia genes are even less common.75 Other possibilities to consider are a de novo mutation in a different autosomal dominant ataxia, decreased penetrance, alternative paternity, or a single occurrence of an autosomal recessive or X-linked disorder in a family such as fragile X-associated tremor/ataxia syndrome. Although the probability of a positive result from molecular genetic testing is low in an individual with ataxia who has no family history of ataxia, such testing is usually justified to establish a specific diagnosis for the individual’s medical eval‎uation and for genetic counseling. Always consider a possible nongenetic cause such as multiple system atrophy, cerebellar type in simplex cases.76

Genetic Counseling

Risk to family members: autosomal dominant hereditary ataxia

Most individuals diagnosed as having autosomal dominant ataxia have an affected parent, although occasionally the family history is negative. For instance, family history may not be obvious because of early death of a parent, failure to recognize autosomal dominant ataxia in family members, late onset in a parent, reduced penetrance of the mutant allele in an asymptomatic parent, or a de novo mutation. The risk to siblings depends on the genetic status of the proband’s parents. If one of the proband’s parents has a mutant allele, the risk to the sibs of inheriting the mutant allele is 50%. Individuals with autosomal dominant ataxia have a 50% chance of transmitting the mutant allele to each child.

Risk to family members: autosomal recessive hereditary ataxia

The parents of an individual affected with an autosomal recessive ataxia are obligate heterozygotes and therefore carry a single copy of a disease-causing mutation. In general, the heterozygotes are asymptomatic. Siblings of a proband have a 25% chance of being affected, a 50% chance of being a heterozygote carrier, and a 25% chance of being unaffected and not a carrier. Once it is established that an at-risk sib is unaffected, the chance of his/her being a carrier is two-thirds. All offspring of affected patients are obligate carriers.

Risk to family members: X-linked hereditary ataxia

The father of an affected male will not have the disease nor will he be a carrier of the mutation. However, women with an affected son and another affected male relative are obligate heterozygotes. The risk to siblings depends on the carrier status of the mother. If the mother of the proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Male siblings who inherit the mutation will be affected whereas female siblings inheriting the mutation will be carriers and usually not affected. If the proband with an X-linked disease represents a simplex (single occurrence in the family) and if the disease-causing mutation cannot be detected in the leukocyte DNA of the mother, the risk to siblings is low but greater than that of the general population because of the possibility of maternal germline mosaicism. The daughters of an affected male are all carriers whereas none of his sons will be affected or be carriers.

Related genetic counseling issues

Testing of at-risk asymptomatic adult relatives of individuals with autosomal dominant cerebellar ataxia is possible after molecular genetic testing has identified the specific disorder and mutation in the family. Such testing should be performed in the context of formal genetic counseling. This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. Testing of asymptomatic at-risk individuals with nonspecific or equivocal symptoms is predictive testing, not diagnostic testing. When testing at-risk individuals, an affected family member should be tested first to confirm‎ that the mutation is identifiable by currently available techniques. Results of testing of 29 asymptomatic persons at risk for autosomal dominant ataxias have been reported.77

Molecular genetic testing of asymptomatic individuals younger than 18 years who are at risk for adult-onset disorders for which no treatment exists is not considered appropriate, primarily because it negates the autonomy of the child with no compelling benefit. Furthermore, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.

For more information, see also the National Society of Genetic Counselors resolution on genetic testing of children and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.

DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal testing. Prenatal diagnosis for some of the hereditary ataxias is possible by analyzing fetal DNA (extracted from cells obtained by chorionic villus sampling at about 10–12 weeks’ gestation or amniocentesis, usually performed at about 15–18 weeks’ gestation) for disease-causing mutations. The disease-causing allele(s) of an affected family member must be identified before prenatal testing can be performed.

Requests for prenatal testing for (typically) adult-onset diseases are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis may be available for families in which the disease-causing mutation has been identified.

Management

Treatment of manifestations

Management of ataxias is usually directed at providing assistance for coordination problems through established methods of rehabilitation medicine and occupational and physical therapy. Patients can be eval‎uated for mobility-assist devices such as canes, walkers, and wheelchairs, which are useful for gait ataxia. Similarly, special devices are available to assist with handwriting, buttoning, and use of eating utensils.

Speech therapy may benefit persons with dysarthria. Computer devices are available to assist persons with severe speech deficits.

Parkinsonian features may respond to L-Dopa, and spasticity may respond to Baclofen or tizanadine.

Prevention of primary manifestations

Treatments are available for a few autosomal recessive ataxias: Vitamin E therapy for AVED, chenodeoxycholic acid for cerebrotendinous xanthomatosis, CoQ10 for CoQ10 deficiency, and dietary restriction of phytanic acid for Refsum disease. Idebenone may ameliorate the cardiac and neurologic manifestations of FRDA.78 No other specific treatments exist for hereditary ataxias.

Therapies under investigation

Underwood and Rubinsztein79 review potential strategies for treating ataxias associated with trinucleotide repeat expansions. RNA interference strategies have been suggested for some autosomal dominant SCAs.80 For further and up-to-date information, readers may search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Resource

National Ataxia Foundation, 2600 Fernbrook Lane Suite 119, Minneapolis, MN 55447; Phone: 763.553.0020; http://www.ataxia.org.

Disclosure

T.D.B. received licensing fees from and is on the speaker’s bureau of Athena Diagnostics. S.J. declares no conflict of interest.

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