ORIGINAL ARTICLE Ataxia with oculomotor apraxia type1 (AOA1): novel and recurrent aprataxin mutations, coenzyme Q10 analyses, and clinical findings in Italian patients Barbara Castellotti & Caterina Mariotti & Marco Rimoldi & Roberto Fancellu & Massimo Plumari & Sara Caimi & Graziella Uziel & Nardo Nardocci & Isabella Moroni & Giovanna Zorzi & Davide Pareyson & Daniela Di Bella & Stefano Di Donato & Franco Taroni & Cinzia Gellera Received: 2 September 2010 / Accepted: 9 March 2011 / Published online: 5 April 2011 # Springer-Verlag 2011 Abstract 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 neurop- athy, 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. Keywords Aprataxin . APTX . Oculomotor apraxia . Recessive ataxia Introduction Autosomal recessive cerebellar ataxias (ARCA) are a hetero- geneous group of hereditary neurodegenerative diseases characterized by degeneration of cerebellum often associated with peripheral nervous system involvement, ophthalmologic disturbances, and systemic abnormalities [10, 33]. In recent years, a subgroup of recessive ataxias associated with oculomotor apraxia (OMA) has been clinically and geneti- cally characterized [13, 19, 32]. OMA has been originally defined as an impaired ability to generate saccades on command [4]. In ataxia with OMA, the oculomotor disturbance is rather characterized by the inability to coordinate eyes/head movements to reach a lateral target, since the head turns and reaches the target before the eyes [21]. At present, the group of ataxias with OMA includes four distinct entities: ataxia-telangectasia (AT), AT-like disorder (ATLD), ataxia with oculomotor apraxia type 1 (AOA1), and ataxia with oculomotor apraxia type 2 (AOA2). AOA 1 (MIM 208920) was initially described in Japanese patients as a new clinical entity characterized by B. Castellotti : C. Mariotti (*) : M. Rimoldi : R. Fancellu : M. Plumari : S. Caimi : D. Di Bella : S. Di Donato : F. Taroni : C. Gellera SOSD Genetics of Neurodegenerative and Metabolic Diseases, Fondazione-IRCCS, Istituto Neurologico “Carlo Besta”, via Celoria11, 20133 Milan, Italy e-mail: mariotti.c@istituto-besta.it G. Uziel : N. Nardocci : I. Moroni : G. Zorzi Child Neurology Department, Fondazione-IRCCS, Istituto Neurologico “Carlo Besta”, via Celoria11, 20133 Milan, Italy D. Pareyson SOSD Central and Peripheral Degenerative Neuropathies, Department of Clinical Neurosciences, Fondazione-IRCCS, Istituto Neurologico “Carlo Besta”, via Celoria11, 20133 Milan, Italy Neurogenetics (2011) 12:193–201 DOI 10.1007/s10048-011-0281-x