Cerebellar ataxia with oculomotor apraxia type 1: clinical and genetic studies

• Published in: Brain (London, England : 1878) Vol. 126; no. 12; pp. 2761 - 2772
• Main Authors: Le Ber, Isabelle, Moreira, Maria‐Ceù, Rivaud‐Péchoux, Sophie, Chamayou, Céline, Ochsner, François, Kuntzer, Thierry, Tardieu, Marc, Saïd, Gérard, Habert, Marie‐Odile, Demarquay, Geneviève, Tannier, Christian, Beis, Jean‐Marie, Brice, Alexis, Koenig, Michel, Dürr, Alexandra
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.12.2003; Oxford Publishing Limited (England)
• Subjects: Adult; AOA = autosomal recessive cerebellar ataxias with oculomotor apraxia; AOA1; AOA1 = ataxia with oculomotor apraxia type 1; AOA2 = ataxia with oculomotor apraxia type 2; Apraxias - genetics; Apraxias - pathology; Apraxias - psychology; APTX = gene encoding aprataxin; APTX gene; ARCA = autosomal recessive cerebellar ataxia; A–T = ataxia–telangiectasia; Biological and medical sciences; cerebellar ataxia; Cerebellar Ataxia - genetics; Cerebellar Ataxia - pathology; Cerebellar Ataxia - psychology; CMPA = compound muscle action potential; Cognition Disorders - etiology; CVLT = California Verbal Learning Test; Disease Progression; DNA-Binding Proteins - genetics; ECD‐SPECT = 99mTc technetium‐ethyl cysteinate dimmer single‐photon emission computed tomography; Electrooculography; Friedreich’s ataxia; Genetics; HIT = histidine triad; HSMN = hereditary sensorimotor neuropathy; Humans; Life Sciences; MADRS = Montgomery and Asberg Depression Rating Scale; Magnetic Resonance Imaging; Male; MDRS = Mattis Dementia Rating Scale; Medical sciences; MMSE = Mini‐Mental Status Examination; Mutation; Neurology; Neuropsychological Tests; Nuclear Proteins - genetics; Ocular Motility Disorders - genetics; Ocular Motility Disorders - pathology; Ocular Motility Disorders - psychology; oculomotor apraxia; OMA = oculomotor apraxia; Phenotype; PNKP = polynucleotide kinase‐3′‐phosphatase; SCA = spinocerebellar ataxia; SCAN = spinocerebellar ataxia with sensorimotor neuropathy; Sural Nerve - ultrastructure; VOR = vestibulo‐ocular reflex; WCST = Wisconsin Card Sorting Test; Cerebellum; APTX gene; Chorea; Axonal neuropathy; Variability; Central nervous system; Involuntary movement; Neurological mutation; Atrophy; Eye; Visual system; Missense mutation; Degenerative disease; Apraxia; Diagnosis; Neurological disorder; Child; Human; AOA1; Nervous system diseases; Cerebellar ataxia; Huntington disease; Mask; oculomotor apraxia; Nuclear magnetic resonance imaging; Cerebral disorder; Genetic disease; Friedreich's ataxia; Phenotype; Central nervous system disease; Young adult; Medical imagery; Friedreich ataxia; Spinal cord disease; Extrapyramidal syndrome
• ISSN: 0006-8950; 1460-2156; 1460-2156
• DOI: 10.1093/brain/awg283

Ataxia with ocular motor apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia (ARCA) associated with oculomotor apraxia, hypoalbuminaemia and hypercholesterolaemia. The gene APTX, which encodes aprataxin, has been identified recently. We studied a large series of 158 families with non‐Friedreich progressive ARCA. We identified 14 patients (nine families) with five different missense or truncating mutations in the aprataxin gene (W279X, A198V, D267G, W279R, IVS5+1), four of which were new. We determined the relative frequency of AOA1 which is 5%. Mutation carriers underwent detailed neurological, neuropsychological, electrophysiological, oculographic and biological examinations, as well as brain imaging. The mean age at onset was 6.8 ± 4.8 years (range 2–18 years). Cerebellar ataxia with cerebellar atrophy on MRI and severe axonal sensorimotor neuropathy were present in all patients. In contrast, oculomotor apraxia (86%), hypoalbuminaemia (83%) and hypercholesterolaemia (75%) were variable. Choreic movements were frequent at onset (79%), but disappeared in the course of the disease in most cases. However, a remarkably severe and persistent choreic phenotype was associated with one of the mutations (A198V). Cognitive impairment was always present. Ocular saccade initiation was normal, but their duration was increased by the succession of multiple hypometric saccades that could clinically be confused with ‘slow saccades’. We emphasize the phenotypic variability over the course of the disease. Cerebellar ataxia and/or chorea predominate at onset, but later on they are often partially masked by severe neuropathy, which is the most typical symptom in young adults. The presence of chorea, sensorimotor neuropathy, oculomotor anomalies, biological abnormalities, cerebellar atrophy on MRI and absence of the Babinski sign can help to distinguish AOA1 from Friedreich’s ataxia on a clinical basis. The frequency of chorea at onset suggests that this diagnosis should also be considered in children with chorea who do not carry the IT15 mutation responsible for Huntington’s disease.