J Neurol (2008) 255:495–501 DOI 10.1007/s00415-008-0707-z ORIGINAL COMMUNICATION Ludger Schöls Larissa Arning Rebecca Schüle Jörg T. Epplen Dagmar Timmann “Pseudodominant inheritance” of ataxia with ocular apraxia type 2 (AOA2) Introduction Ataxia with ocular apraxia type 2 (AOA2) is an autoso- mal recessive early onset cerebellar ataxia caused by mu- tations in the senataxin (SETX) gene [20]. AOA2 was named after a characteristic oculomotor disturbance with impaired initiation of saccades that necessitates head movements to shift gaze. First signs typically occur between 10–25 years of age with progressive gait insta- bility and impaired dexterity due to pronounced cere- bellar atrophy. Sensory-motor neuropathy is present in 93% of patients [16, 20]. Increased alpha-fetoprotein (AFP) is a frequent serum marker of the disease but is neither specific nor obligatory [20]. Ocular apraxia is observed in AOA2 but also occurs in ataxia with ocular apraxia type 1 (AOA1) caused by APTX mutations, ataxia telangiectasia (AT) with ATM mutations and ataxia-telangiectasia-like disorder (ATLD) with muta- tions in MRE11 [9, 11, 17, 21, 30]. AOA2 (OMIM 606002) is allelic to ALS4 (OMIM 602433), a juvenile onset form of amyotrophic lateral JON 2707 Received: 19 April 2007 Received in revised form: 22 June 2007 Accepted: 19 July 2007 Published online: 20 March 2008 L. Schöls, MD () · R. Schüle Hertie-Institute for Clinical Brain Research and Department of Neurology Eberhard Karls-University Tübingen Hoppe-Seyler-Str. 3 72076 Tübingen, Germany Tel.: +49-7071/2980445 Fax: +49-7071/294839 E-Mail: Ludger.Schoels@uni-tuebingen.de L. Arning · J. T. Epplen Human Genetics Ruhr-University Bochum, Germany D. Timmann Dept. of Neurology University of Essen, Germany * Drs. Schöls and Arning contributed equally to this work. ■ Abstract Ataxia with ocular apraxia type 2 (AOA2) is an auto- somal recessive, early onset ataxia caused by mutations in the sen- ataxin (SETX) gene. Ocular apraxia and increased levels of alpha-feto- protein are characteristic but not obligate markers of the disease. AOA2 is allelic with ALS4, a motor neuron disorder of early onset and autosomal dominant inheritance. We observed a two generation fam- ily with ataxia which started at age 14 and 17 in two sibs and at age 23 in their paternal uncle. Oculomotor disturbances included strabismus, saccadic pursuit and gaze evoked nystagmus. MRI revealed severe cerebellar atrophy. All patients pre- sented pronounced peripheral neu- ropathy with wasting of hand and leg muscles resembling distal mo- tor neuronopathy. Increased alpha- fetoprotein levels triggered genetic analyses of SETX.We found the sib pair to be compound heterozygous for a single base deletion c.2835delC, resulting in a frameshift mutation and causing nonsense related mRNA decay, and a base exchange c.6106G > A, re- sulting in abnormal splicing and skipping of exon 15. The similarly affected uncle was homozygous for the c.6106G > A mutation probably due to distant consanguinity in the paternal branch of the family. Pseu- dodominant occurrence in two generations has not been described before in AOA2 and led, in this family, to false categorization as dominant ataxia before SETX mu- tations were detected. Clinically this family presented with a pheno- type combining typical features of AOA2 and ALS4; thus extending the phenotypic spectrum of SETX mutations. ■ Key words ataxia · ALS4 · ocular apraxia · peripheral neuropathy · dermatofibrosarcoma protuberans