Mutations in senataxin responsible for Quebec cluster of ataxia with neuropathy

Abstract

Senataxin recently was identified as the mutated gene in ataxia-oculomotor apraxia 2, which is characterized by ataxia, oculomotor apraxia, and increased alpha-fetoprotein levels. In this study, we evaluated 24 ataxic patients from 10 French-Canadian families. All cases have a homogeneous phenotype consisting of a progressive ataxia appearing between 2 and 20 (mean age, 14.8) years of age with associated dysarthria, saccadic ocular pursuit, distal amyotrophy, sensory and motor neuropathy, and increased alpha-fetoprotein levels but absence of oculomotor apraxia. Linkage disequilibrium was observed with markers in the ataxia-oculomotor apraxia 2 locus on chromosome 9q34. We have identified four mutations in senataxin in the French-Canadian population including two novel missense mutations: the 5927T-->G mutation changes the leucine encoded by codon 1976 to an arginine in the helicase domain (L1976R), and the 193G-->A mutation changes a glutamic acid encoded by codon 65 into a lysine in the N-terminal domain of the protein (E65K). The common L1976R mutation is shared by 17 of 20 (85%) carrier chromosomes. The study of this large French-Canadian cohort better defines the phenotype of this ataxia and presents two novel mutations in senataxin including the more common founder mutation in the French-Canadian population.

Autosomal recessive ataxias: 20 types, and counting

“…Brain MRI discloses diffuse cerebellar atrophy, more intense in the vermis, occasionally associated with pontine atrophy 50 . Nerve conduction studies detect sensory-motor axonal neuropathy and nerve biopsy demonstrates that large myelinated fibers are more severely affected than thin ones 48,50 .…”

“…Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by global progressive ataxia with onset usually between 8 and 25 years of age 48,49 , dysarthria, axonal motor sensory neuropathy, and oculomotor apraxia, which is seen in less than 50% of cases [48][49][50] . Saccadic pursuit is seen in all patients, gaze evoked nystagmus in 89%, and bilateral limited abduction of the eyes with strabismus in 61% of the patients 48 .…”

“…Dystonia, head and postural tremor, chorea, dysphagia, pes cavus, and scoliosis are occasionally seen. Cognitive function is usually preserved, but executive dysfunction is sometimes observed [48][49][50] . Premature ovarian failure was also reported in some patients 48 .…”

“…Serum alpha-fetoprotein is mildly to moderately elevated in all patients with AOA2 39,[48][49][50] . Increased serum creatine kinase, cholesterol, and immunoglobulin IgG and IgA, and reduced serum albumin are inconstantly seen 48,50 .…”

“…Increased serum creatine kinase, cholesterol, and immunoglobulin IgG and IgA, and reduced serum albumin are inconstantly seen 48,50 . Brain MRI discloses diffuse cerebellar atrophy, more intense in the vermis, occasionally associated with pontine atrophy 50 .…”