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...

Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC) is a neurodegenerative disease marked by early-onset cataract and hearing loss, retinitis pigmentosa, and involvement of both the central and peripheral nervous systems, including demyelinating sensorimotor polyneuropathy and cerebellar ataxia. Previously, we mapped this Refsum-like disorder to a 16 Mb region on chromosome 20. Here we report that mutations in the ABHD12 gene cause PHARC disease and we describe the clinical manifestations in a total of 19 patients from four different countries. The ABHD12 enzyme was recently shown to hydrolyze 2-arachidonoyl glycerol (2-AG), the main endocannabinoid lipid transmitter that acts on cannabinoid receptors CB1 and CB2. Our data therefore represent an example of an inherited disorder related to endocannabinoid metabolism. The endocannabinoid system is involved in a wide range of physiological processes including neurotransmission, mood, appetite, pain appreciation, addiction behavior, and inflammation, and several potential drugs targeting these pathways are in development for clinical applications. Our findings show that ABHD12 performs essential functions in both the central and peripheral nervous systems and the eye. Any future drug-mediated interference with this enzyme should consider the potential risk of long-term adverse effects.

Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive disease due to mutations in the senataxin gene, causing progressive cerebellar ataxia with peripheral neuropathy, cerebellar atrophy, occasional oculomotor apraxia and elevated alpha-feto-protein (AFP) serum level. We compiled a series of 67 previously reported and 58 novel ataxic patients who underwent senataxin gene sequencing because of suspected AOA2. An AOA2 diagnosis was established for 90 patients, originating from 15 countries worldwide, and 25 new senataxin gene mutations were found. In patients with AOA2, median AFP serum level was 31.0 microg/l at diagnosis, which was higher than the median AFP level of AOA2 negative patients: 13.8 microg/l, P = 0.0004; itself higher than the normal level (3.4 microg/l, range from 0.5 to 17.2 microg/l) because elevated AFP was one of the possible selection criteria. Polyneuropathy was found in 97.5% of AOA2 patients, cerebellar atrophy in 96%, occasional oculomotor apraxia in 51%, pyramidal signs in 20.5%, head tremor in 14%, dystonia in 13.5%, strabismus in 12.3% and chorea in 9.5%. No patient was lacking both peripheral neuropathy and cerebellar atrophy. The age at onset and presence of occasional oculomotor apraxia were negatively correlated to the progression rate of the disease (P = 0.03 and P = 0.009, respectively), whereas strabismus was positively correlated to the progression rate (P = 0.03). An increased AFP level as well as cerebellar atrophy seem to be stable in the course of the disease and to occur mostly at or before the onset of the disease. One of the two patients with a normal AFP level at diagnosis had high AFP levels 4 years later, while the other had borderline levels. The probability of missing AOA2 diagnosis, in case of sequencing senataxin gene only in non-Friedreich ataxia non-ataxia-telangiectasia ataxic patients with AFP level > or =7 microg/l, is 0.23% and the probability for a non-Friedreich ataxia non-ataxia-telangiectasia ataxic patient to be affected with AOA2 with AFP levels > or =7 microg/l is 46%. Therefore, selection of patients with an AFP level above 7 microg/l for senataxin gene sequencing is a good strategy for AOA2 diagnosis. Pyramidal signs and dystonia were more frequent and disease was less severe with missense mutations in the helicase domain of senataxin gene than with missense mutations out of helicase domain and deletion and nonsense mutations (P = 0.001, P = 0.008 and P = 0.01, respectively). The lack of pyramidal signs in most patients may be explained by masking due to severe motor neuropathy.

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IMPORTANCE Ataxia with oculomotor apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia due to mutations in the aprataxin gene (APTX) that is characterized by early-onset cerebellar ataxia, oculomotor apraxia, axonal motor neuropathy, and eventual decrease of albumin serum levels. OBJECTIVES To improve the clinical, biomarker, and molecular delineation of AOA1 and provide genotype-phenotype correlations. DESIGN, SETTING, AND PARTICIPANTS This retrospective analysis included the clinical, biological (especially regarding biomarkers of the disease), electrophysiologic, imaging, and molecular data of all patients consecutively diagnosed with AOA1 in a single genetics laboratory from