Spinocerebellar Ataxia 18

For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).

Clinical Features

Brkanac et al. (2002) reported a 5-generation American family of Irish ancestry in which 26 members were affected with a unique neurologic disorder with motor and sensory features displaying an autosomal dominant pattern of inheritance. Age of onset was in the second and third decades, and gait difficulty was the most common initial symptom. Other features included dysmetria, hyporeflexia, muscle weakness and atrophy, and decreased vibratory and proprioceptive sense. Several affected members had pes cavus. Brkanac et al. (2002) designated this disorder sensorimotor neuropathy with ataxia (SMNA).

Mapping

By haplotype analysis in a 5-generation American family of Irish ancestry, Brkanac et al. (2002) identified a 14-cM region at 7q22-q32 between markers D7S2418 and D7S1804 that segregated with the disorder.

Molecular Genetics

Brkanac et al. (2009) undertook a comprehensive genomic evaluation of the region of linkage for SMNA, including evaluation for repeat expansion and small deletions or duplications, capillary sequencing of candidate genes, and massively parallel sequencing of all coding exons. Brkanac et al. (2009) excluded repeat expansion and small deletions or duplications as causative, and through microarray-based hybrid capture and massively parallel short-read sequencing identified a nonsynonymous variant in the human interferon-related developmental regulator gene-1 (IFRD1; 603502) as a disease-causing candidate. Sequence conservation, animal models, and protein structure evaluation support the involvement of IFRD1 in SMNA. Brkanac et al. (2009) identified a A-to-G transition at nucleotide 743 that resulted in an isoleucine to valine substitution at codon 172 (I172V) in the IFRD1 gene. Isoleucine-172 is highly conserved across species, but valine at this codon is present in elephant, chicken, Xenopus tropicalis, and zebrafish. The mutation segregated perfectly with the phenotype in the family. While Brkanac et al. (2009) suggested that this was likely the causative allele, they concluded that mutation analysis of IFRD1 in additional patients with similar phenotypes was needed for demonstration of causality and further evaluation of its importance in neurologic diseases.