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

Abstract

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 α‐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.

cerebellar ataxia; ocular motor apraxia; AOA1; AOA2; α‐foetoprotein

 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 = α‐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