Ataxia with oculomotor apraxia type1 (AOA1): novel and recurrent aprataxin mutations, coenzyme Q10 analyses, and clinical findings in Italian patients

Neurogenetics - Tập 12 - Trang 193-201 - 2011
Barbara Castellotti1, Caterina Mariotti1, Marco Rimoldi1, Roberto Fancellu1, Massimo Plumari1, Sara Caimi1, Graziella Uziel2, Nardo Nardocci3, Isabella Moroni2, Giovanna Zorzi2, Davide Pareyson4, Daniela Di Bella1, Stefano Di Donato1, Franco Taroni1, Cinzia Gellera1
1SOSD Genetics of Neurodegenerative and Metabolic Diseases, Fondazione-IRCCS, Istituto Neurologico “Carlo Besta”, Milan, Italy
2Child Neurology Department, Fondazione-IRCCS, Istituto Neurologico “Carlo Besta”, Milan, Italy
3Child Neurology Department, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy
4SOSD Central and Peripheral Degenerative Neuropathies, Department of Clinical Neurosciences, Fondazione-IRCCS, Istituto Neurologico “Carlo Besta”, Milan, Italy

Tóm tắt

Ataxia with oculomotor apraxia type1 (AOA1, MIM 208920) is a rare autosomal recessive disease caused by mutations in the APTX gene. We screened a cohort of 204 patients with cerebellar ataxia and 52 patients with early-onset isolated chorea. APTX gene mutations were found in 13 ataxic patients (6%). Eleven patients were homozygous for the known p.W279X, p.W279R, and p.P206L mutations. Three novel APTX mutations were identified: c.477delC (p.I159fsX171), c.C541T (p.Q181X), and c.C916T (p.R306X). Expression of mutated proteins in lymphocytes from these patients was greatly decreased. No mutations were identified in subjects with isolated chorea. Two heterozygous APTX sequence variants (p.L248M and p.D185E) were found in six families with ataxic phenotype. Analyses of coenzyme Q10 in muscle, fibroblasts, and plasma demonstrated normal levels of coenzyme in five of six mutated subjects. The clinical phenotype was homogeneous, irrespectively of the type and location of the APTX mutation, and it was mainly characterized by early-onset cerebellar signs, sensory neuropathy, cognitive decline, and oculomotor deficits. Three cases had slightly raised alpha-fetoprotein. Our survey describes one of the largest series of AOA1 patients and contributes in defining clinical, molecular, and biochemical characteristics of this rare hereditary neurological condition.

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