Spinocerebellar ataxia with sensory neuropathy (SCA25) maps to chromosome 2p.
Autosomal dominant cerebellar ataxias constitute one of the most clinically, neuropathologically, and genetically heterogeneous groups of neurodegenerative disorders. Approximately 50 to 80% of the families carry mutations in genes known to be implicated in spinocerebellar ataxias (SCAs). Numerous loci (SCAn) also have been mapped, often in single families, but the responsible genes have not yet been identified. This suggests further genetic heterogeneity. We have ascertained 18 subjects from a large French family in which cerebellar ataxia and prominent sensory neuropathy segregated as a dominant trait. Intrafamilial variability was high regarding age at onset (17 months to 39 years), severity, and the clinical picture that ranged from pure sensory neuropathy with little cerebellar involvement to a Friedreich's ataxia-like phenotype. After excluding known genes/loci responsible for SCA and hereditary sensory neuropathies, we detected linkage with chromosome 2p markers in a genomewide screen. We designated this new locus SCA25 after testing of 16 additional markers. Maximum two-point logarithm of odds scores of 3.15 and 3.10 were obtained at D2S2378 and D2S2734, respectively. Haplotype analysis defined a critical 12.6cM region of 15Mb between D2S2174 and D2S2736. No linkage to this locus was found in four other families. This interval contains several genes that could be responsible for the disease. One of these genes, CRIPT, encodes a postsynaptic protein, but no mutations were found by direct sequencing, excluding its responsibility in the disease. CAG repeat expansions often are involved in SCA pathogenesis, but no pathological expansions were found at the protein or at the DNA level using the 1C2 antibody and the repeat expansion detection method, respectively. The gene responsible for SCA25 remains to be identified.
Stevanin
Giovanni
G
INSERM U289, Federative Institute for Neuroscience Research (IFR-70), Paris. stevanin@ccr.jussieu.fr
Bouslam
Naima
N
Thobois
Stéphane
S
Azzedine
Hamid
H
Ravaux
Lucas
L
Boland
Anne
A
Schalling
Martin
M
Broussolle
Emmanuel
E
Dürr
Alexandra
A
Brice
Alexis
A
D000200:Action Potentials / Q000502:physiology; D000328:Adult; D001921:Brain / Q000473:pathology; D002648:Child; D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D006239:Haplotypes; D006801:Humans; D007223:Infant; D008126:Lod Score; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009431:Neural Conduction / Q000502:physiology; D009475:Neurons, Afferent / Q000473:pathology; D010375:Pedigree; D016133:Polymerase Chain Reaction; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology