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Adult-onset spinocerebellar ataxia syndromes due to MTATP6 mutations.

ABSTRACT: BACKGROUND:Spinocerebellar ataxia syndromes presenting in adulthood have a broad range of causes, and despite extensive investigation remain undiagnosed in up to ?50% cases. Mutations in the mitochondrially encoded MTATP6 gene typically cause infantile-onset Leigh syndrome and, occasionally, have onset later in childhood. The authors report two families with onset of ataxia in adulthood (with pyramidal dysfunction and/or peripheral neuropathy variably present), who are clinically indistinguishable from other spinocerebellar ataxia patients. METHODS:Genetic screening study of the MTATP6 gene in 64 pedigrees with unexplained ataxia, and case series of two families who had MTATP6 mutations. RESULTS:Three pedigrees had mutations in MTATP6, two of which have not been reported previously and are detailed in this report. These families had the m.9185T>C and m.9035T>C mutations, respectively, which have not previously been associated with adult-onset cerebellar syndromes. Other investigations including muscle biopsy and respiratory chain enzyme activity were non-specific or normal. CONCLUSIONS:MTATP6 sequencing should be considered in the workup of undiagnosed ataxia, even if other investigations do not suggest a mitochondrial DNA disorder.

SUBMITTER: Pfeffer G

PROVIDER: S-EPMC4034166 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Adult-onset spinocerebellar ataxia syndromes due to MTATP6 mutations.

Pfeffer Gerald G Blakely Emma L EL Alston Charlotte L CL Hassani Adam A Boggild Mike M Horvath Rita R Samuels David C DC Taylor Robert W RW Chinnery Patrick F PF

Journal of neurology, neurosurgery, and psychiatry 20120510 9

<h4>Background</h4>Spinocerebellar ataxia syndromes presenting in adulthood have a broad range of causes, and despite extensive investigation remain undiagnosed in up to ∼50% cases. Mutations in the mitochondrially encoded MTATP6 gene typically cause infantile-onset Leigh syndrome and, occasionally, have onset later in childhood. The authors report two families with onset of ataxia in adulthood (with pyramidal dysfunction and/or peripheral neuropathy variably present), who are clinically indisti ...[more]

PMID: 22577227

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Project description:BackgroundSpinocerebellar ataxia type 29 (SCA29) is an autosomal dominant, non-progressive cerebellar ataxia characterized by infantile-onset hypotonia, gross motor delay and cognitive impairment. Affected individuals exhibit cerebellar dysfunction and often have cerebellar atrophy on neuroimaging. Recently, missense mutations in ITPR1 were determined to be responsible.ResultsClinical information on 21 individuals from 15 unrelated families with ITPR1 mutations was retrospectively collected using standardized questionnaires, including 11 previously unreported singletons and 2 new patients from a previously reported family. We describe the genetic, clinical and neuroimaging features of these patients to further characterize the clinical features of this rare condition and assess for any genotype-phenotype correlation for this disorder. Our cohort consisted of 9 males and 12 females, with ages ranging from 28 months to 49 years. Disease course was non-progressive with infantile-onset hypotonia and delays in motor and speech development. Gait ataxia was present in all individuals and 10 (48%) were not ambulating independently between the ages of 3-12 years of age. Mild-to-moderate cognitive impairment was present in 17 individuals (85%). Cerebellar atrophy developed after initial symptom presentation in 13 individuals (72%) and was not associated with disease progression or worsening functional impairment. We identified 12 different mutations including 6 novel mutations; 10 mutations were missense (with 4 present in >1 individual), 1 a splice site mutation leading to an in-frame insertion and 1 an in-frame deletion. No specific genotype-phenotype correlations were observed within our cohort.ConclusionsOur findings document significant clinical heterogeneity between individuals with SCA29 in a large cohort of molecularly confirmed cases. Based on the retrospective observed clinical features and disease course, we provide recommendations for management. Further research into the natural history of SCA29 through prospective studies is an important next step in better understanding the condition.

Dataset Information

Adult-onset spinocerebellar ataxia syndromes due to MTATP6 mutations.

Publications

Adult-onset spinocerebellar ataxia syndromes due to MTATP6 mutations.

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