Ataxia-ocular apraxia 2 (AOA2) was recently identified as a new autosomal recessive ataxia. We have now identified causative mutations in 15 families, which allows us to clinically define this entity by onset between 10 and 22 years, cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia and elevated alpha-fetoprotein (AFP). Ten of the fifteen mutations cause premature termination of a large DEAxQ-box helicase, the human ortholog of yeast Sen1p, involved in RNA maturation and termination.We previously identified a 16-cM interval on chromosome 9q34 associated with an autosomal recessive adolescent-onset cerebellar ataxia segregating in two families 1,2 , one with additional oculomotor apraxia 1 and the second with associated elevated serum AFP, immunoglobulins and creatine kinase levels but no oculomotor apraxia 2,3 . We identified nine additional families with ataxia linked to 9q34 by homozygosity mapping (Supplementary Methods online). As most affected individuals had both oculomotor apraxia and elevated AFP levels we assumed that they were affected by the same disorder, which we named AOA2 (OMIM 606002). We identified distal and proximal recombinations in families with two affected individuals (Fig. 1a), localizing the defective gene underlying AOA2 to a 1.1-Mb interval containing 13 genes ( Fig. 1b) and three groups of overlapping spliced expressed-sequence tags, which we analyzed for nucleotide changes but found no mutations. We also found that the unspliced mRNA AK024331 overlaps with the KIAA0625 cDNA and is part of a larger transcript overlapping with additional exons on the 5′ side. We obtained an open reading frame of 8,031 nucleotides and 24 exons (Fig. 1c), of which exon 8 was 4,177 nucleotides long. We confirmed the prediction and size of the transcript by long-range RT-PCR experiments spanning the putative exon 1 and 3′ untranslated region in human fibroblast and lymphoblastoid cell lines (data not shown) and by hybridization of a human northern blot with a probe spanning putative exons 8-24 (Fig. 1d). We also identified an alternative transcript that is 2.4 kb longer, resulting from a second polyadenylation site (human mRNAs AB014525 and AK022902; Fig. 1d).We sequenced exons 1-18 and flanking intronic sequences in families with ataxia linked to this region and in additional individuals with either AOA or ataxia with elevated AFP levels and found 15 different disease-associated mutations in 15 families ( Table 1). Ten of these mutations, including mutations in the two families in whom we first identified AOA2, cause truncation of the protein, indicating that this is the gene underlying AOA2. We found the nonsense mutation R1363X in three unrelated families originating from Portugal, Cabo Verde (once a Portuguese colony) and Spain, suggestive of an Iberian founder event, although recurrent C→T changes on this CpG dinucleotide cannot be formally excluded. Absence of the five missense mutations in 150 unrelated and unaffected individuals sharing the same ethnic origin as the affected in...

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The clinical and genetic features of three non-Portuguese and non-Japanese patients with aprataxin gene mutations are reported. Patient 1 came from Italy and presented with typical ataxia with ocular motor apraxia (OMA). She was homozygous for the W279X nonsense mutation, which is associated with the Portuguese founding haplotype. Patients 2 and 3 were French siblings and did not present with either OMA or hypoalbuminemia. They were compound heterozygous for the nonsense W279X mutation and a missense K197Q mutation.