SNOMEDCT: 719209002; ORPHA: 98768; DO: 0050963;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19q13.33 | Spinocerebellar ataxia 13 | 605259 | Autosomal dominant | 3 | KCNC3 | 176264 |
A number sign (#) is used with this entry because of evidence that spinocerebellar ataxia-13 (SCA13) is caused by heterozygous mutation in the KCNC3 gene (176264) on chromosome 19q13.
Spinocerebellar ataxia-13 (SCA13) is an autosomal dominant disorder characterized by slowly progressive gait and limb ataxia and dysarthria. Age at onset ranges from childhood to adulthood. Other features, including intellectual impairment, oculomotor disturbances, and pyramidal signs, are variable (Herman-Bert et al., 2000; Subramony et al., 2013).
For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).
Herman-Bert et al. (2000) described a large French family in which 8 members were affected with autosomal dominant spinocerebellar ataxia. There were 7 affected women and an affected 4-year-old boy. Clinical features included slowly progressive childhood-onset cerebellar gait ataxia associated with cerebellar dysarthria, moderate mental retardation (IQ, 62-76), and mild developmental delay in motor acquisition. Nystagmus and pyramidal signs were also observed in some patients. Cerebral magnetic resonance imaging in 2 patients showed moderate cerebellar and pontine atrophy.
Waters et al. (2005) reported a 3-generation Filipino family in which 11 members had autosomal dominant SCA. The 82-year-old proband was the oldest affected, with disease onset at age 60 years. Mean ages at onset in the second and third generations were 36.4 and 24.5 years, respectively. Clinical features included gait ataxia, limb ataxia/dysmetria, titubation, hypotonia, and dysarthria. Only 1 patient had nystagmus. Mental retardation was not a feature. Waters et al. (2005) noted that the phenotype in the Filipino family differed from that in the French family reported by Herman-Bert et al. (2000).
Subramony et al. (2013) provided detailed clinical features of the Filipino family reported by Waters et al. (2005). Twenty-one individuals were found to carry the R420H mutation (see 176264.0001); 9 of these had not yet developed symptoms. The mean age at onset in the 12 symptomatic individuals was 37.3 years (range 25 to 60). All had gait and limb ataxia, which were limited to the lower extremities in 2 patients. Most patients had dysarthria, 6 (including 2 with diabetes) had decreased vibration sense in the toes, 3 had mild bladder control issues, and 2 reported occasional myoclonic jerks. Five patients had brisk tendon reflexes, which was also observed in several asymptomatic family members. None had oculomotor disturbances or extrapyramidal signs. Three patients used canes after many years, and only one 73-year-old woman was wheelchair-bound. Brain imaging of 4 patients showed cerebellar atrophy without significant progression. Several patients had delayed recall and impaired visuospatial skills, but several family members who did not carry the mutation also had delayed recall. Subramony et al. (2013) emphasized the slowly progressive course of SCA13.
Pyle et al. (2015) reported 2 sisters (patients 7 and 8) with SCA13. One presented at age 23 with speech and balance problems. She later developed appendicular and ataxic gait, dysarthria, hearing impairment, jerky smooth pursuit, and pale optic discs. Her sister presented at age 57 with upper limb clumsiness, gait ataxia, jerky ocular pursuits, optic atrophy, and dysarthria. Brain imaging in both patients showed cerebellar atrophy. The patients were part of a large study of exome analysis of 35 patients from 22 families with ataxia.
Parolin Schnekenberg et al. (2015) reported a 12-year-old boy with genetically confirmed SCA13 who was originally clinically diagnosed with ataxic cerebral palsy. He presented in early childhood with delayed motor development and mild cognitive delay. With age, he developed marked disability due to ataxia and showed some school difficulties. Brain imaging was normal.
The transmission pattern of SCA13 in the families reported by Waters et al. (2006) was consistent with autosomal dominant inheritance.
By genomewide analysis of a French family with SCA, Herman-Bert et al. (2000) found significant evidence for linkage to an 8-cM interval on chromosome 19q13.3-q13.4 between markers D19S219 and D19S553. The locus was termed SCA13.
In a Filipino family with SCA, Waters et al. (2005) found linkage to a 4-cM region on 19q13 (lod score of 3.89) that overlapped with the SCA13 locus reported by Herman-Bert et al. (2000).
In affected members of a French family and a Filipino family with SCA13, Waters et al. (2006) identified 2 different heterozygous mutations in the KCNC3 gene (R420H, 176264.0001; F448L, 176264.0002).
In 2 sisters of European descent with SCA13, Pyle et al. (2015) identified a heterozygous R420H mutation in the KCNC3 gene. Functional studies of the variant were not performed.
In a 12-year-old boy with SCA13, Parolin Schnekenberg et al. (2015) identified a de novo heterozygous missense mutation in the KCNC3 gene (T428I; 176264.0003). In vitro electrophysiologic studies showed that the mutant protein resulted in a nonfunctional channel and acted in a dominant-negative manner when coexpressed with wildtype KCNC3.
Herman-Bert, A., Stevanin, G., Netter, J.-C., Rascol, O., Brassat, D., Calvas, P., Camuzat, A., Yuan, Q., Schalling, M., Durr, A., Brice, A. Mapping of spinocerebellar ataxia 13 to chromosome 19q13.3-q13.4 in a family with autosomal dominant cerebellar ataxia and mental retardation. Am. J. Hum. Genet. 67: 229-235, 2000. [PubMed: 10820125] [Full Text: https://doi.org/10.1086/302958]
Parolin Schnekenberg, R., Perkins, E. M., Miller, J. W., Davies, W. I. L., D'Adamo, M. C., Pessia, M., Fawcett, K. A., Sims, D., Gillard, E., Hudspith, K., Skehel, P., Williams, J., and 9 others. De novo point mutations in patients diagnosed with ataxic cerebral palsy. Brain 138: 1817-1832, 2015. Note: Erratum: Brain 139: e14, 2016. [PubMed: 25981959] [Full Text: https://doi.org/10.1093/brain/awv117]
Pyle, A., Smertenko, T., Bargiela, D., Griffin, H., Duff, J., Appleton, M., Douroudis, K., Pfeffer, G., Santibanez-Koref, M., Eglon, G., Yu-Wai-Man, P., Ramesh, V., Horvath, R., Chinnery, P. F. Exome sequencing in undiagnosed inherited and sporadic ataxias. Brain 138: 276-283, 2015. [PubMed: 25497598] [Full Text: https://doi.org/10.1093/brain/awu348]
Subramony, S. H., Advincula, J., Perlman, S., Rosales, R. L., Lee, L. V., Ashizawa, T., Waters, M. F. Comprehensive phenotype of the p.arg420his allelic form of spinocerebellar ataxia type 13. Cerebellum 12: 932-936, 2013. [PubMed: 23912307] [Full Text: https://doi.org/10.1007/s12311-013-0507-6]
Waters, M. F., Fee, D., Figueroa, K. P., Nolte, D., Muller, U., Advincula, J., Coon, H., Evidente, V. G., Pulst, S. M. An autosomal dominant ataxia maps to 19q13: allelic heterogeneity of SCA13 or novel locus? Neurology 65: 1111-1113, 2005. [PubMed: 16135769] [Full Text: https://doi.org/10.1212/01.wnl.0000177490.05162.41]
Waters, M. F., Minassian, N. A., Stevanin, G., Figueroa, K. P., Bannister, J. P. A., Nolte, D., Mock, A. F., Evidente, V. G. H., Fee, D. B., Muller, U., Durr, A., Brice, A., Papazian, D. M., Pulst, S. M. Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental nervous system phenotypes. Nature Genet. 38: 447-451, 2006. [PubMed: 16501573] [Full Text: https://doi.org/10.1038/ng1758]