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Brain Advance Access originally published online on September 23, 2003
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Brain, Vol. 126, No. 12, 2761-2772, December 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg283

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

Isabelle Le Ber1,2, Maria-Ceù Moreira3, Sophie Rivaud-Péchoux2, Céline Chamayou4, François Ochsner5, Thierry Kuntzer5, Marc Tardieu6, Gérard Saïd7, Marie-Odile Habert8, Geneviève Demarquay9, Christian Tannier10, Jean-Marie Beis11, Alexis Brice1,2,12, Michel Koenig3 and Alexandra Dürr2,12

1 Fédération de Neurologie, Hôpital de la SalpêtrièreAP-HP, Paris, 2 INSERM U289, Hôpital de la Salpêtrière AP-HP, Paris, 3 Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis-Pasteur, Illkirch, CU de Strasbourg, 4 Centre du Langage, Hôpital de la Salpêtrière AP-HP, Paris, France, 5 Service de Neurologie, CHUV Lausanne, Suisse, 6 Service de Neurologie Pédiatrique, Hôpital BicêtreAP-HP, Kremlin-Bicêtre, 7 Service de Neurologie andlaboratoire Louis Ranvier, Hôpital Bicêtre AP-HP, Kremlin-Bicêtre, 8 Médecine Nucléaire, Hôpital de la Salpêtrière AP-HP, Paris, 9 Service de Neurologie, CHU, Lyon, 10 Service de Neurologie, Centre Hospitalier de Carcassonne, 11 Centre de réadaptation, Lay-Saint Christophe and 12 Département de Génétique, Cytogénétique et Embryologie, Hôpital de la Salpêtrière AP-HP, Paris, France

Correspondence to: Dr Alexandra Dürr, INSERM U289, Hôpital de la Salpêtrière, 47, boulevard de l’Hôpital, 75651 Paris cedex 13, France E-mail: durr{at}ccr.jussieu.fr

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.


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