SNOMEDCT: 765091006; ORPHA: 94124; DO: 0090115;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 14q32.11 | ?Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1 | 607250 | Autosomal recessive | 3 | TDP1 | 607198 |
A number sign (#) is used with this entry because of evidence that autosomal recessive spinocerebellar ataxia with axonal neuropathy-1 (SCAN1) is caused by homozygous mutation in the TDP1 gene (607198) on chromosome 14q31. One such family has been reported.
Spinocerebellar ataxia with axonal neuropathy-1 (SCAN1) is an autosomal recessive neurologic disorder characterized by onset of gait disturbances in the first or second decades of life. Affected individuals have cerebellar ataxia associated with cerebellar atrophy on brain imaging, as well as an axonal sensorimotor neuropathy with distal sensory impairment, hypo- or areflexia, pes cavus, and steppage gait (summary by Takashima et al., 2002).
Genetic Heterogeneity of Spinocerebellar Ataxia with Axonal Neuropathy
See also SCAN2 (606002), caused by mutation in the SETX gene (608465) on chromosome 9q34, and SCAN3 (618387), caused by mutation in the COA7 gene (615623) on chromosome 1p32.
Takashima et al. (2002) investigated a large multigenerational consanguineous Saudi Arabian family segregating an autosomal recessive ataxia with peripheral axonal motor and sensory neuropathy, distal muscular atrophy, pes cavus, and steppage gait. Detailed evaluation of 3 of the 9 affected individuals confirmed that they had cerebellar ataxia and axonal neuropathy, a combination that the authors designated SCAN1. All had cerebellar atrophy on brain imaging, and 2 had mild cerebral atrophy. One patient had a history of seizures, but all had normal intelligence. All 3 individuals had mild hypercholesterolemia and borderline hypoalbuminemia. The patients tested negative for mutations in most genes known to be associated with ataxia and neuropathy.
The transmission pattern of SCAN1 in the family reported by Takashima et al. (2002) was consistent with autosomal recessive inheritance.
El-Khamisy et al. (2005) showed that in human cells TDP1 is required for repair of chromosomal single-strand breaks arising independently of DNA replication from abortive topoisomerase-1 (TOP1; 126420) activity or oxidative stress. They reported that TDP1 is sequestered into multiprotein single-strand break repair (SSBR) complexes by direct interaction with DNA ligase III-alpha (600940) and that these complexes are catalytically inactive in SCAN1 cells. El-Khamisy et al. (2005) concluded that their data identified a defect in SSBR in a neurodegenerative disease, and implicated this process in the maintenance of genetic integrity in postmitotic neurons.
In affected members of a multigenerational consanguineous Saudi Arabian family with SCAN1, Takashima et al. (2002) identified a homozygous missense mutation in the TDP1 gene (H493R; 607198.0001). The mutation was found by genomewide linkage mapping and analysis of candidate genes. Functional studies of the variant and studies of patient cells were not performed, but molecular modeling suggested that the mutation would disrupt the active site of the enzyme.
El-Khamisy, S. F., Saifi, G. M., Weinfeld, M., Johansson, F., Helleday, T., Lupski, J. R., Caldecott, K. W. Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1. Nature 434: 108-113, 2005. [PubMed: 15744309] [Full Text: https://doi.org/10.1038/nature03314]
Takashima, H., Boerkoel, C. F., John, J., Saifi, G. M., Salih, M. A. M., Armstrong, D., Mao, Y., Quiocho, F. A., Roa, B. B., Nakagawa, M., Stockton, D. W., Lupski, J. R. Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy. Nature Genet. 32: 267-272, 2002. [PubMed: 12244316] [Full Text: https://doi.org/10.1038/ng987]