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Brain Advance Access originally published online on January 21, 2004
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Brain, Vol. 127, No. 4, 759-767, 2004
© 2004 Guarantors of Brain
doi: 10.1093/brain/awh080

Frequency and phenotypic spectrum of ataxia with oculomotor apraxia 2: a clinical and genetic study in 18 patients

Isabelle Le Ber1,2, Naïma Bouslam2,8, Sophie Rivaud-Péchoux2, João Guimarães9, Ali Benomar8, Céline Chamayou3, Cyril Goizet6, Maria-Ceù Moreira7, Sandra Klur7, Mohamed Yahyaoui8, Yves Agid1,4, Michel Koenig7, Giovanni Stevanin2, Alexis Brice1,2,5 and Alexandra Dürr2,5

1 Fédération de Neurologie, 2 INSERM U289, 3 Centre du Langage, 4 Centre d’Investigation Clinique and 5 Département de Génétique, Cytogénétique et Embryologie, Hôpital Pitié-Salpêtrière AP-HP, Paris, 6 Service de Génétique, Centre Hospitalo-Universitaire, Bordeaux, 7 Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis-Pasteur, Illkirch, CU de Strasbourg, France, 8 Laboratoire de Neurogénétique, Service de Neurologie, Hôpital des Spécialités, Rabat, Morocco and 9 University Department of Neurology, Hospital de Egas Moniz, Lisboa, Portugal

Correspondence to: Alexandra Dürr, MD, PhD, INSERM U289 and Département de Génétique, Cytogénétique et Embryologie, Hôpital Pitié-Salpêtrière, 47, boulevard de l’Hôpital, 75651 Paris Cedex 13, FranceE-mail: durr{at}ccr.jussieu.fr

Ataxia with oculomotor apraxia type 2 (AOA2) is a newly described autosomal recessive cerebellar ataxia (ARCA) defined by genetic location to 9q34 of three families sharing gait ataxia, oculomotor apraxia and/or elevated {alpha}-foetoprotein (AFP) levels. We have evaluated 77 families with progressive non-Friedreich ARCA and have identified six families with a phenotype suggestive of AOA2. Linkage was confirmed in all six families, with a maximal lod score of 5.91 at D9S1830. We report the first detailed phenotypic study, including neuropsychological, oculographic and brain imaging investigations, in the largest series of AOA2 patients yet recruited. The mean age at onset was 15.1 ± 3.8 years. Sensory motor neuropathy (92%) and choreic or dystonic movements (44%) were frequent. Oculomotor apraxia was observed in 56% of patients and characterized by increased horizontal saccade latencies and hypometria. AFP levels were elevated in 100% of the families, making it a useful biological marker. This study shows for the first time that AOA2 can be found in Europe, North Africa and the West Indies, and its relative frequency represents ~8% of non-Friedreich ARCA, which is more frequent than ataxia telangiectasia and ataxia with oculomotor apraxia type 1 (AOA1), in our series of adult patients. In adults, AOA2 may be, therefore, the most frequent cause of ARCA identified so far, after Friedreich’s ataxia.

Key Words: cerebellar ataxia; ocular motor apraxia; AOA1; AOA2; {alpha}-foetoprotein

Abbreviations: AOA1 = ataxia with oculomotor apraxia type 1; AOA2 = ataxia with oculomotor apraxia type 2; ARCA = autosomal recessive cerebellar ataxia; A-T = ataxia telangiectasia; APTX = aprataxin gene; ATM = ataxia-telangiectasia mutated gene; AFP = {alpha}-foetoprotein; CA = cerebellar ataxia; CK = creatine phosphokinase; CVLT = California Verbal Learning Test; FA = Friedreich’s ataxia; MADRS = Montgomery and Asberg Depression Rating Scale; MDRS = Mattis Dementia Rating Scale; MMSE = Mini-mental State Examination; VOR = vestibulo-ocular reflex; WCST = Wisconsin Card Sorting Test

Received September 22, 2003. Revised November 21, 2003. Accepted November 22, 2003.


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