Ataxia, Sensory, 1, Autosomal Dominant

A number sign (#) is used with this entry because autosomal dominant sensory ataxia-1 (SNAX1) is caused by heterozygous mutation in the RNF170 gene (614649) on chromosome 8.

Clinical Features

Valdmanis et al. (2004) reported a Canadian family of Anglo-Saxon origin from New Brunswick in which 10 members were affected with a sensory ataxia inherited in an autosomal dominant pattern. Age at onset ranged from 28 to 55 years, with no definite evidence of anticipation. Clinical features at onset included gait difficulty and instability, especially in the dark. Romberg sign was usually positive. Most patients had decreased distal sensation affecting all modalities, most often in the lower extremities. Physical examination revealed decreased or absent deep tendon reflexes; extensor plantar responses were present in 2 patients. No cerebellar signs were present and there were no autonomic abnormalities. Brain and spine MRI were normal in all 5 patients tested. Peripheral motor and sensory nerve action potentials were normal, and sural nerve biopsy of the most severely affected patient was normal. In the most severely affected patient, somatosensory evoked responses from upper limb stimulation showed a prolonged latency, and evoked responses from lower limb stimulation were unobtainable. Several patients had rapid progression, requiring cane or wheelchair within 10 years of disease onset. Valdmanis et al. (2004) concluded that the disorder represented a posterior column ataxia with pyramidal tract involvement. The combination of normal sensory nerve conductions and abnormal somatosensory evoked potentials suggested preganglionic posterior column abnormalities. The abnormal effects were thus more central than peripheral in nature.

Valdmanis et al. (2006) reported a second family from Eastern Canada with SNAX1. Between the fourth and eighth decades, affected individuals developed progressive gait abnormalities including mild instability in the dark and widened base leading to increased falls. There was also progressive distal sensory loss of all modalities and areflexia, more prominent in the lower limbs but also involving the upper limbs. Although some individuals showed mild pursuit abnormalities, other cerebellar signs such as dysmetria, dysphagia, and dysarthria were not present. Cognition was normal, and there were no brain MRI changes. Valdmanis et al. (2006) concluded that the gait abnormalities in this disorder are due to sensory loss in the extremities.

Moeller et al. (2008) reported the neuropathologic examination of a 61-year-old man with autosomal dominant sensory ataxia who died of congestive heart failure. There were occasional swollen axons within the cerebral cortex and deep nuclei, particularly the subthalamic nucleus, with no neuronal loss or gliosis. There were many axonal spheroids in the dorsal column and dorsal column nuclei. The findings were consistent with a neuroaxonal dystrophy affecting the dorsal columns, consistent with the clinical pattern of central sensory pathway degeneration.

Mapping

By linkage analysis in affected members of a family with autosomal dominant sensory ataxia, Valdmanis et al. (2004) localized the putative disease locus, termed SNAX1, to a 9.1-cM (24.9-Mb) region on chromosome 8p12-q12.1 (maximum 2-point lod score = 4.90 at theta = 0.0 for marker D8S1791). Gene sequencing excluded the FGFR1 (136350) and GSR (138300) genes.

In a second affected family, Valdmanis et al. (2006) found linkage to marker D8S1769 (maximum lod score of 3.56). In combination with the previous family (Valdmanis et al., 2004), there were 16 affected individuals who shared the same disease haplotype, suggesting a founder effect. The SNAX1 locus was refined to a 7.3-cM region on chromosome 8p12.1-q11.23. No mutations were identified in the NRG1 gene (142445).

Molecular Genetics

In affected members of 2 Canadian families with autosomal dominant sensory ataxia-1, Valdmanis et al. (2011) identified a heterozygous mutation in the RNF170 gene (R199C; 614649.0001). The mutation was found by exome sequencing of the candidate region on chromosome 8p12-q12 previously identified by linkage analysis (Valdmanis et al., 2006). Injection of the corresponding mutant mRNA in zebrafish resulted in moderate to severe developmental disruptions, including death, in the majority of injected embryos (79%). Coinjection of the mutant and wildtype mRNAs resulted in an intermediate number of disturbed embryos, suggesting a toxic gain of function.