Re: ADCK3 유전자 문제로 인한 운동실조증 - 코큐 10 복용으로 개선

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Clin Genet

. Author manuscript; available in PMC: 2017 Aug 1.

Published in final edited form as: Clin Genet. 2016 Feb 16;90(2):156–160. doi: 10.1111/cge.12742

Cerebellar ataxia and severe muscle CoQ10 deficiency in a patient with a novel mutation in ADCK3

E Barca a,b,†, O Musumeci b,c,†, F Montagnese b, S Marino c,d, F Granata d, D Nunnari c, L Peverelli a, S DiMauro a, CM Quinzii a, A Toscano b,c

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PMCID: PMC4950673  NIHMSID: NIHMS802238  PMID: 26818466

The publisher's version of this article is available at Clin Genet

Abstract

Inherited ataxias are a group of heterogeneous disorders in children or adults but their genetic definition remains still undetermined in almost half of the patients. However, CoQ10 deficiency is a rare cause of cerebellar ataxia and ADCK3 is the most frequent gene associated with this defect. We herein report a 48 year old man, who presented with dysarthria and walking difficulties. Brain magnetic resonance imaging showed a marked cerebellar atrophy. Serum lactate was elevated. Tissues obtained by muscle and skin biopsies were studied for biochemical and genetic characterization. Skeletal muscle biochemistry revealed decreased activities of complexes I+III and II+III and a severe reduction of CoQ10, while skin fibroblasts showed normal CoQ10 levels. A mild loss of maximal respiration capacity was also found by high-resolution respirometry. Molecular studies identified a novel homozygous deletion (c.504del_CT) in ADCK3, causing a premature stop codon. Western blot analysis revealed marked reduction of ADCK3 protein levels. Treatment with CoQ10 was started and, after 1 year follow-up, patient neurological condition slightly improved. This report suggests the importance of investigating mitochondrial function and, in particular, muscle CoQ10 levels, in patients with adult-onset cerebellar ataxia. Moreover, clinical stabilization by CoQ10 supplementation emphasizes the importance of an early diagnosis.

유전성 운동 실조증은

어린이 또는 성인의 이질적인 장애 그룹이지만

, 환자의 거의 절반에서 유전적 정의가 아직 결정되지 않았습니다.

그러나,

CoQ10 결핍은

소뇌 운동 실조의 드문 원인이고,

ADCK3는 이 결함과 관련된 가장 빈번한 유전자입니다.

여기에서는 구

음 장애와 보행 장애를 보인 48세 남성에 대한 보고를 합니다.

뇌 자기 공명 영상은

현저한 소뇌 위축을 보여주었습니다.

혈청 젖산이 상승했습니다.

근육과 피부 생검을 통해 얻은 조직은 생화학 및 유전적 특성을 연구했습니다.

골격근 생화학 검사 결과,

복합체 I+III와 II+III의 활동이 감소하고

CoQ10이 크게 감소한 것으로 나타났습니다.

반면,

피부 섬유 아세포에서는

정상적인 CoQ10 수치가 관찰되었습니다.

고해상도 호흡 측정법(high-resolution respirometry)을 통해

최대 호흡 용량의 약간의 감소가 관찰되었습니다.

분자 연구 결과,

ADCK3에서 새로운 동형접합 결실(c.504del_CT)이 확인되어

조기 정지 코돈이 발생했습니다.

웨스턴 블롯 분석 결과,

ADCK3 단백질 수치가 현저하게 감소한 것으로 나타났습니다.

CoQ10 치료를 시작했고,

1년간의 추적 관찰 결과 환자의 신경학적 상태가 약간 개선되었습니다.

이 보고서는

성인 발병 소뇌 운동 실조증 환자의 경우,

미토콘드리아 기능,

특히 근육의 CoQ10 수치를 조사하는 것이 중요하다는 것을 시사합니다.

또한,

CoQ10 보충제를 통한 임상적 안정화는

조기 진단의 중요성을 강조합니다.

Keywords: ADCK3, cerebellar ataxia, CoQ10, mitochondrial disorders, neurodegenerative diseases

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Autosomal recessive cerebellar ataxias (ARCAs) are genetically heterogeneous neurodegenerative disorders characterized by slow progressive gait impairment with an onset usually in childhood or adolescence (1–5). ARCAs are quite heterogeneous for age at onset, severity of disease progression and frequency of extra-cerebellar and systemic signs. Mitochondrial dysfunction is often present in ARCAs, and mutations of proteins related to CoQ10 biosynthesis and regulation (ADCK3, Aprataxin, Anoctamin 10) have often been linked to ARCA (6). CoQ10 biosynthesis is a highly conserved mechanism among the species and requires the synergic work of several enzymes. Deficiency of biosynthetic enzymes usually leads to very severe and multisystemic phenotypes.

The ADCK3 gene encodes the homologue of the yeast protein coq8, a putative protein kinase involved in the regulation of CoQ biosynthesis (7). ADCK3 mutations have been identified in patients with early-onset cerebellar ataxia (ARCA2). The clinical course is variable, ranging from mild forms with slowly progressive pure cerebellar ataxia to severe entities with early-onset ataxia, seizures, and stroke-like episodes (8). In patients with mutations in ADCK3, CoQ10 levels are frequently decreased in skeletal muscle and/or fibroblasts (2); adult-onset is very rare and has been reported only in two patients (3) with normal CoQ10 levels in muscle.

We report herein a patient with late-onset cerebellar ataxia, slow progression, severe CoQ10 deficiency in muscle and a new homozygous mutation in ADCK3.

상염색체 열성 소뇌 운동 실조증(ARCAs)은

유전적으로 이질적인 신경 퇴행성 질환으로,

보통 소아기나 청소년기에 발병하며, 서

서히 진행되는 보행 장애가 특징입니다(1-5).

Autosomal recessive cerebellar ataxias 

ARCAs는

발병 연령, 질병 진행의 심각성, 소뇌 외 및 전신 징후의 빈도가

매우 이질적입니다.

미토콘드리아 기능 장애는

종종 ARCAs에서 나타나며,

CoQ10 생합성 및 조절과 관련된 단백질(ADCK3,

아프라타신,

아노크타민 10)의 돌연변이는

종종 ARCAs와 관련이 있습니다(6).

CoQ10 생합성은

종들 사이에서 매우 보존된 메커니즘이며,

여러 효소의 시너지 작용이 필요합니다.

생합성 효소의 결핍은

일반적으로 매우 심각하고

다중 시스템적 표현형을 유발합니다.

ADCK3 유전자는

CoQ 생합성 조절에 관여하는

추정 단백질 키나아제인 효모 단백질 coq8의 동족체를 암호화합니다(7).

ADCK3 돌연변이는

초기 소뇌 운동 실조증(ARCA2) 환자에서 확인되었습니다.

임상 경과는

천천히 진행되는 순수 소뇌 운동 실조증을 동반한 경미한 형태부터

초기 운동 실조증,

발작,

뇌졸중과 유사한 증상을 동반한 중증 질환에 이르기까지 다양합니다(8).

ADCK3 돌연변이가 있는 환자의 경우,

골격근 및/또는 섬유모세포에서

CoQ10 수치가 감소하는 경우가 많습니다(2).

성인 발병은 매우 드물며,

근육의 CoQ10 수치가 정상인 환자 2명(3)에서만 보고된 바 있습니다.

본 논문에서는

늦은 발병의 소뇌 운동 실조증,

느린 진행,

근육의 심각한 CoQ10 결핍, 그리고

ADCK3의 새로운 동형접합 돌연변이가 있는 환자에 대해 보고합니다.

Patient and methodsClinical history

A 48 year old man with slurred speech and difficult walking was admitted to our department. He was born from an uncomplicated pregnancy; his parents were healthy and non-consanguineous; he had four brothers and five sisters but only one woman showed similar clinical features and died at 50 years of breast cancer. Since he was 20 years old, he started to complain of subtle gait imbalance; symptoms progressed very slowly, and at 48 years of age, he firstly sought medical assistance, because of frequent falling and dysarthria.

Neurological examination revealed mild bilateral ptosis, head tremor, wide-based gait, and slurred speech; he was not able to walk in tandem. Muscle strength was normal at all four limbs. At finger-to-nose test, he had bilateral dysmetria with intentional tremor and dysdiadochokinesia was also present. Deep tendon reflexes were increased at lower limbs with bilateral Babinski sign.

Routine blood tests, including vitamin E, autoantibodies, alpha-fetoprotein, thyroid function and screening for celiac disease, were normal as well as Creatine Kinase (CK) levels. Serum lactate showed normal elevation at rest but resulted abnormally increased after an aerobic exercise reaching 9.3 mmol/l (normal range: 1.5 ± 0.6 mmol/l).

The patient underwent brain magnetic resonance imaging (MRI) on a system operating at 3.0 T (Achieva, Philips Healthcare, Best, Netherlands) that showed millimetric hyper-intense lesions in temporo-parietal bilateral cortical areas and a cerebellar vermis atrophy (Fig. 1a). Moreover, MRI spectroscopy did not reveal any lactate peak in the ventricles or in the cerebellar lobe. Electromyography and nerve conduction studies were unremarkable. Axial and proximal limb muscles MRI was also performed, and no relevant changes were observed.

환자 및 방법 임상 병력

발음이 불분명하고 걷기가 어려운 48세 남성이 저희 병원에 입원했습니다.

그는 복잡하지 않은 임신으로 태어났고,

부모는 건강했으며,

형제자매는 4남매였지만,

비슷한 임상 특징을 보이는 여성은 한 명뿐이었고,

유방암으로 50세에 사망했습니다.

그는 20살 때부터 미묘한 걸음걸이 불균형에 대해 불평하기 시작했습니다.

증상은 매우 느리게 진행되었고,

48살 때 자주 넘어지고

구음 장애가 발생하여 처음으로 의료 지원을 요청했습니다.

신경학적 검사 결과, 양측 안검하수, 머리 떨림, 넓은 보폭의 걸음걸이, 그리고 쉰 목소리가 나타났습니다. 그는 걸을 수 없었습니다. 네 팔다리의 근육 강도는 모두 정상 수준이었습니다. 손가락-코 테스트에서 그는 양측 운동 실조증과 의도적인 떨림이 있었고, 운동 실조성 운동 실조증도 나타났습니다. 심부 건반사는 양측 바빈스키 징후와 함께 하지에서 증가했습니다.

비타민 E,

자가 항체,

알파 태아 단백,

갑상선 기능,

체강 질병 검사 등 일상적인 혈액 검사 결과는 정상 수준이었고,

크레아틴 키나아제(CK) 수치도 정상 수준이었습니다.

혈청 젖산은

휴식 시 정상적인 수준을 보였지만,

유산소 운동을 한 후에는 9.3mmol/l(정상 범위: 1.5±0.6mmol/l)로 비정상적으로 증가했습니다.

환자는 3.0T(Achieva, Philips Healthcare, Best, Netherlands)로 작동하는 시스템에서 뇌 자기공명영상(MRI)을 받았는데, 측두엽-두정엽 양측 피질 영역에 밀리미터 단위의 고강도 병변과 소뇌 소뇌핵 위축이 나타났습니다(그림 1a).

또한,

MRI 분광분석 결과 심실이나 소뇌엽에서 젖산염 피크가 발견되지 않았습니다.

근전도 검사 및 신경전도 검사 결과는 특이 사항이 없었습니다.

또한, 축 및 근위 사지 근육 MRI도 실시되었지만, 관련 변화는 관찰되지 않았습니다.

Fig. 1.

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(a) Brain magnetic resonance imaging (MRI) showing cerebellar atrophy. (b, c) Muscle biopsy with rare COX-negative fibers (b) and few hyper-reactive SDH fibers (c). (d) Electropherogram of one control (Ctrl) and the patient (Pt). (e) Western blot of ADCK3 protein from patients’ fibroblasts and three controls.

At neuropsychological assessment, the patient showed a mild impairment in working memory and executive functions. Genetic tests for Friedreich’s ataxia, spinocerebellar ataxias (SCA 1, 2, 3, 6, 17), and apraxia with oculomotor ataxia types 1 and 2 were negative.

Muscle biopsy

After informed consent, an open biopsy of vastus lateralis was performed. Frozen samples were processed for histological (H&E and Gomori trichrome) and histochemical for cytochome oxidase (COX) and succinate dehydrogenase (SDH) studies, as well as for biochemical analysis according to standard techniques (9).

Cell culture

Primary fibroblasts were obtained from skin biopsy. Fibroblasts from our patient and from five age- and passage-matched controls were cultured in Dulbecco’s modified Eagle medium, supplemented with 10% fetal bovine serum and 1% penicillin–streptomycin and maintained at 37°C humidified and 5% CO2.

Biochemical studies

To measure mitochondrial respiratory chain enzymes activities in skeletal muscle, 40 mg of tissue was homogenized in 9 volumes of 0.15M KCl, 50mM Tris-HCl, pH 7.4 (CPT medium), and centrifuged at 2500 g for 20 min at 4°C. The supernatant was used also for protein determination. About 1.5 × 106 cells were harvested and suspended in phosphate buffer saline pH 7, sonicated in ice for 10 s and protein was determined by Bradford assay. Activities of mitochondrial respiratory chain complexes were assessed spectrophotometrically (9).

CoQ10 assessment in fibroblasts and skeletal muscle was performed as previously described (9). Oxygen consumption rate (OCR) in fibroblasts was measured using a XF24 Seahorse® instrument as previously described (10)

Molecular genetic studies

ADCK3 gene amplification and Sanger sequencing were performed following standard protocols (6). To measure ADCK3 mRNA expression‎ levels, total RNA was extracted from patient’s skin fibroblasts, and quantitative Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed using TaqMan assays for ADCK3 and GAPDH (Applied Biosystems

Foster City, CA).

To assess ADCK3 protein level, 30 μg of proteins extracted from the patient’s skin fibroblasts were loaded in sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) gel and immunoblotted with anti ADCK3 antibody (CABC1 monoclonal antibody M04A, clone 7G1) (1:200) and with control anti-vinculin antibody (ab73412).

Results

Muscle biopsy showed increased fiber size variation, some SDH hyperactive fibers and few COX-negative fibers (Fig. 1b,c). Muscle mitochondrial respiratory chain activities evidenced reduction of complex I + III (34.9; normal range 50 ± 6 nmol/min/mg prot) and II + III activity (3.5; normal range: 17.5 ± 4.02 nmol/min/mg prot), whereas SDH and COX activities were normal (Table 1). Muscle CoQ10 was severely decreased (1.14 μg/g; normal range 32 ± 6 μg/g). Activities of complex I + III and II + III as well as CoQ10 concentration resulted normal in fibroblasts (Table 1). However, OCR measured by XF24 Seahorse® in the patient’s fibroblasts, showed maximal respiration capacity in the lower range of controls.

Table 1.

Biochemical feature of fibroblasts and muscle

FibroblastsMusclePtCtrPtCtr

CoQ10	45.2 ± 1.3	47.4 ± 2.4 (μg/mg Prot)	1.14*	32 ± 6 (μg/mg tissue)
I + III	0.08 ± 0.02	0.18 ± 0.08 (nmol/min/mg Prot)	34.9*	50 ± 6 (nmol/min/mg Prot)
II + III	0.01 ± 0.001	0.01 ± 0.003 (nmol/min/mg Prot)	3.5*	17.5 ± 4 (nmol/min/mg Prot)
COX	0.044 ± 0.004	0.048 ± 0.002 (nmol/min/mg Prot)	55.8	48 ± 10 (nmol/min/mg Prot)
SDH	0.064 ± 0.003	0.059 ± 0.004 (nmol/min/mg Prot)	11.3	11 ± 3 (nmol/min/mg Prot)
CS	0.089 ± 0.017	0.091 ± 0.001 (nmol/min/mg Prot)	98	130 ± 45 (nmol/min/mg Prot)

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Ctrl, control; Pt, patient.

*

abnormal values

Molecular studies revealed a homozygous novel deletion (c1511_1512delCT) in ADCK3, which causes a premature stop codon in the kinase domain of the protein (p.Ala504fs) (Fig. 1d). The mutation was heterozygous in two asymptomatic sisters of the proband and absent in 104 controls. Analysis of cDNA did not show reduction of ADCK3 expression‎ in cultured skin fibroblasts from the patient, thus excluding mRNA decay. However, Western blot analysis showed about 60% reduction of ADCK3 protein levels when normalized over beta-actin (Fig. 1e).

The patient started supplementation with 400 mg/day of CoQ10 and, at 1 year follow-up, he reported clinical improvement as showed by Scale for the Assessment and Rating of Ataxia (SARA) score, more evident at speech and gait items (total SARA score 13 at baseline and 10 after 1 year).

Discussion

ARCAs are a heterogeneous group of diseases, and genetic diagnosis is a real challenge for neurologists. ADCK3 biochemical function has been only partially characterized; phylogenic analysis showed that ADCK3 is an atypical kinase orthologous to yeast protein Coq8p (2). Coq8p is known to stabilize the complex of CoQ biosynthetic proteins in yeast, but the underlying mechanism is still undefined.

Mutations in ADCK3, even if rare, represent the most common cause of primary CoQ10 deficiency (8). So far, only 33 patients with ADCK3 mutation have been reported (2, 3, 11, 12). In these patients, usually central nervous system involvement is the predominant feature, gait ataxia being the most frequent sign at disease onset. In some patients, hand clumsiness, myoclonus and choreic movements have been also observed. Individuals rarely present seizures, stroke-like episodes, and developmental delay. In almost half of the patients, involvement of the corticospinal tract is present, but spasticity seldom reaches clinical significance.

We herein report a new mutation in ADCK3 in a patient with late-onset cerebellar ataxia; such late-onset is quite uncommon, considering that the majority of ADCK3 patients develop symptoms in childhood or adolescence. In 2012, Horvath et al. described two patients with an adult-onset form, who were still ambulating in their late forties, thus resembling our patient from the clinical point of view. However, biochemical analysis in the reported case disclosed normal CoQ10 levels in muscle, whereas in our patient CoQ10 level was severely reduced.

We observed slow progression of the disease in accordance with previous observations (11) and a moderate response to CoQ10 supplementation. The absence of any stroke-like lesions at MRI confirm‎s the heterogeneity of this disorder and the lack of correlation between CoQ10 residual levels and disease severity. Our patient had a mild alteration in the executive functions, suggesting that, in ARCA2, cognitive alteration might not be related to the stroke-like episodes.

In ARCA2, exercise intolerance and muscle weakness have been mentioned (3) but our patient, although presenting with a severe CoQ10 deficiency in muscle, did not exhibit any clinical sign of myopathy. This surprising finding supports the hypothesis that tissue damage in CoQ10 deficiency is a complex phenomenon that depends upon the delicate balance between electron transport respiratory chain defects and excessive reactive oxygen species (ROS), buffering activity of CoQ10. In particular, it has been shown that very low levels of CoQ (<30% of normal) lead to a dramatic reduction of mitochondrial bioenergetics but no increased ROS levels, while intermediate values of CoQ10 (40–50% residual), cause increased ROS production, mitochondrial hyperpolarization and more prominent cell death (13).

By direct sequencing, we identified a homozygous two base pair deletion in ADCK3: mutation is localized in the protein kinase-like fold residue of the protein that recently has been documented to be responsible for the kinase activity (14). Moreover, the deletion causes a shift of the reading frame and leads to a shorter protein, lacking 130 amino acids at the C-terminal domain with loss of the F-helix region. Surprisingly, for the first time we observed, in human tissues, that, although mRNA was normal, protein levels were severely reduced. These results suggest that the mutation impairs protein stability, causing a posttranslational degradation. The wild-type size band observed in the western blot analysis may represent a protein generated by stop codon read through, or a posttranslational modified mutant protein.

Diagnosis of ataxias because of mitochondrial impairment is quite difficult, and these cases are easily underestimated because of the lack of reliable biomarkers (15). In our patient, although skin fibroblasts showed only mild decreased bioenergetic capacity by high-resolution respirometry analyses, CoQ10 was severely decreased in muscle, raising a strong suspicion of mitochondrial disease (16). These features also support the usefulness of a muscle biopsy in such cases.

Treatment with CoQ10 caused a mild improvement of symptoms in our patient. Up to day, cerebellar ataxia due to CoQ10 deficiency includes a group of disorders where an etiological approach is available (8), for which a prompt identification and characterization of patients is required.

Acknowledgments

The authors acknowledge the Ministry of Health GR2009-1606283.

Footnotes

Conflict of interest

The authors have no conflicts of interest.

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