SNOMEDCT: 715754007; ORPHA: 98761; DO: 0050960;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 22q13.31 | Spinocerebellar ataxia 10 | 603516 | Autosomal dominant | 3 | ATXN10 | 611150 |
A number sign (#) is used with this entry because spinocerebellar ataxia-10 (SCA10) is caused by a heterozygous expanded 5-bp repeat (ATTCT) in the ATXN10 gene (611150) on chromosome 22q13.
Normal alleles have 10 to 29 repeats, and pathologic alleles usually have 400 to 4,500 repeats, although a single patient with 280 repeats has been reported (Fang et al., 2002; Alonso et al., 2006).
The autosomal dominant cerebellar ataxias (ADCAs) are a clinically and genetically heterogeneous group of disorders characterized by ataxia, dysarthria, dysmetria, and intention tremor. All ADCAs involve some degree of cerebellar dysfunction and a varying degree of signs from other components of the nervous system. A commonly accepted clinical classification (Harding, 1993) divides ADCAs into 3 different groups based on the presence or absence of associated symptoms such as brainstem signs or retinopathy. The presence of pyramidal and extrapyramidal symptoms and ophthalmoplegia makes the diagnosis of ADCA I, the presence of retinopathy points to ADCA II, and the absence of associated signs to ADCA III. Genetic linkage and molecular analyses revealed that ADCAs are genetically heterogeneous even within the various subtypes.
For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).
Grewal et al. (1998) described a 4-generation mixed pedigree that segregated a distinct form of SCA. The clinical phenotypes were characterized by predominantly cerebellar symptoms and signs and thus fell within the ADCA III clinical classification. Two affected individuals also had seizures, but it could not be determined whether these were caused by focal CNS lesions or were part of the degenerative phenotype. All known SCA loci, as well as mutations in the DRPLA gene (607462), were excluded by direct mutation or linkage analysis.
Rasmussen et al. (2001) reported 18 affected individuals from 4 Mexican families who presented with gait ataxia, dysarthria, variable limb ataxia, and ocular movement abnormalities. Thirteen of the 18 had generalized motor seizures, 6 of whom also had partial seizures. Additional symptoms were mood disorders, pyramidal tract signs, EEG abnormalities, and sensorimotor polyneuropathy. Rasmussen et al. (2001) suggested that a wide range of tissues may be affected in SCA10.
Grewal et al. (2002) presented a genotype-phenotype analysis of 2 large Mexican American families, originally reported by Grewal et al. (1998) and Matsuura et al. (1999), respectively, with genetically confirmed SCA10. Of 22 affected individuals, seizure disorders developed in 11, although the seizure frequency varied markedly between the 2 families (25% in family 1 had seizures vs 80% in family 2). Anticipation was present in both families, although stronger in family 1. Several individuals in family 1 showed mild personality changes, including flat affect and general disinterest. Grewal et al. (2002) concluded that seizure is an integral part of the SCA10 phenotype, but that family-dependent factors play a role in variability.
Teive et al. (2004) reported 5 Brazilian families with SCA10 confirmed by genetic analysis (expanded alleles ranging from 1,350 to 2,400 ATTCT repeats). One of the families had multiple affected members spanning 6 generations. Age at onset in all the families ranged from 23 to 46 years, and genetic anticipation was observed. All patients had a cerebellar syndrome characterized by gait ataxia, dysarthria, dysmetria, dysdiadochokinesis, nystagmus, and cerebellar atrophy on brain imaging. In contrast to previous reports of SCA10, none of the Brazilian patients had seizures. Nerve conduction studies in all 10 patients tested were normal.
Previous reports have suggested that Mexican SCA10 families show a complicated phenotype of progressive ataxia associated with seizures, polyneuropathy, pyramidal signs, and cognitive and neuropsychiatric impairment, whereas Brazilian SCA10 families tend to show a pure cerebellar ataxia. Gatto et al. (2007) reported an Argentinian family with Spanish and Amerindian ancestries in which several members had a complicated form of SCA10. The proband was a woman who developed progressive gait instability and incoordination at age 35 years. She also had seizures, mild cognitive impairment, urinary urgency, and depression. Her brother developed similar but more severe symptoms at age 35, with seizures, dysmetria, dysphagia, scanning speech, dementia, hyperreflexia, and extrapyramidal signs. Family history revealed that the father had seizures and progressive ataxia, and 2 of his maternal half-sibs had a similar disorder. The proband and her brother had 1,100 ATTCT repeats in the SCA10 gene.
The transmission pattern of SCA10 in the families reported by Matsuura et al. (2000) was consistent with autosomal dominant inheritance.
By a genomewide linkage analysis of a family with SCA reported by Grewal et al. (1998), Zu et al. (1999) identified a candidate 15-cM region, designated SCA10, on chromosome 22q13. A maximum lod score of 4.3 at theta = 0.0 was obtained for D22S928 and D22S1161. Anticipation was observed in the available parent-child pairs, suggesting that dinucleotide repeat expansion may be the mutagenic mechanism.
In all affected patients from 5 Mexican families with spinocerebellar ataxia-10, Matsuura et al. (2000) found an expansion of a pentanucleotide (ATTCT) repeat in intron 9 of the ATXN10 gene (601150.0001).
In affected members of 4 Mexican families with SCA10, Rasmussen et al. (2001) identified expanded ATTCT repeats ranging from 920 to 4,140 repeats.
Fang et al. (2002) reported a 19-year-old Hispanic woman from the U.S. with SCA10 who was found to have a 280-repeat expansion. Her asymptomatic mother had the same expansion. This was the smallest SCA10 expansion mutation identified to date. Alonso et al. (2006) reported a Brazilian family in which the proband had a 400 repeat expansion in the ATXN10 gene. She was a 59-year-old woman with gait ataxia since age 50 years. She also had mild limb ataxia, dysarthria, extensor plantar responses, and moderate axonal peripheral neuropathy. Two unaffected sibs and her unaffected father, aged 65, 56, and 90, had alleles of 370 and 360. In another Brazilian family, the affected son inherited an allele of 750 repeats from his affected mother who had 760 repeats. Alonso et al. (2006) noted that the first family lowered the threshold of repeat numbers for pathogenesis down to 400. Combined with the report of Fang et al. (2002), the findings suggested that there may be reduced penetrance for SCA10 alleles of 280 to 370 repeats.
Raskin et al. (2007) reported a 28-year-old Brazilian women with early-onset SCA10 due to approximately 850 ATTCT repeats in the SCA10 gene. Similar 850-repeat expansions were found in 6 of 8 asymptomatic paternal relatives, including her unaffected 71-year-old father. The findings suggested stable transmission of this allele through 3 generations and incomplete penetrance. The patient had a severe form of the disorder with clear onset by age 14, severe and multiple seizures, deterioration of cognitive functions, and mutism. She was wheelchair-bound by age 24.
In a multigenerational study, Matsuura et al. (2004) demonstrated that (1) the expanded ATTCT repeats are highly unstable when paternally transmitted, whereas maternal transmission results in significantly smaller changes in repeat size; (2) blood leukocytes, lymphoblastoid cells, buccal cells, and sperm have a variable degree of mosaicism in ATTCT expansion; (3) the length of the expanded repeat was not observed to change in individuals over a 5-year period; and (4) clinically determined anticipation is sometimes associated with intergenerational contraction rather than expansion of the ATTCT repeat.
Matsuura et al. (2006) reported 2 SCA10 families showing distinct frequencies of seizures and correlations of repeat length with age at onset. One family displayed uninterrupted ATTCT expansions, whereas the other showed multiple interruptions of the repeat by nonconsensus repeat units, which differed both in the length and/or sequence of the repeat unit. Disease-causing microsatellite expansions had been assumed to be composed of uninterrupted pure repeats. The findings of Matsuura et al. (2006) challenged this convention and suggested that the purity of the expanded repeat element may be a disease modifier.
McFarland et al. (2013) identified 3 different repeat interruptions at the 5- and 3-prime ends of the ATTCT ATXN10 expansion. Two heptanucleotide repeats were found at the 5-prime end and a pentanucleotide repeat was found at the 3-prime end. A specifically designed PCR assay showed that in some cells derived from SCA10 patients, stretches of the pure ATTCT pathogenic repeat were frequently interrupted by combinations of the 3 repeats; the interruptions thus occurred within the pathogenic SCA10-specific repeat. Among 31 SCA10 families tested, the ATXN10 expansion size was larger in patients with an interrupted allele. However, there was no difference in the age at onset compared with those expansions without detectable interruptions. An inverse correlation between the expansion size and the age at onset was found only with SCA10 alleles without interruptions. Interrupted expansion alleles showed anticipation but were accompanied by a paradoxical contraction in intergenerational repeat size, and there was evidence of a paternal effect. The findings suggested that SCA10 expansions with ATCCT interruptions differ from SCA10 expansions without detectable ATCCT interruptions in repeat size-instability dynamics and pathogenicity.
In support of a founder mutation in the Mexican population, Rasmussen and Alonso (2002) noted that many SCA10 affected Mexican families carry a common haplotype, and that the SCA10 mutation accounts for almost 15% of autosomal dominant ataxia in Mexicans, second to SCA2. Fujigasaki et al. (2002) found no SCA10 repeat expansions in 123 French families with autosomal dominant ataxia. Matsuura et al. (2002) genotyped 478 patients with cerebellar ataxia from multiple ethnic groups (not including Mexican) and found no ATTCT expansions. They suggested that the expansion mutation originated in the New World and questioned the use of SCA10 genetic testing in populations other than Mexican.
Among 114 Brazilian families with autosomal dominant SCA, Trott et al. (2006) found that 2 (1.8%) had SCA10.
Alonso, I., Jardim, L. B., Artigalas, O., Saraiva-Pereira, M. L., Matsuura, T., Ashizawa, T., Sequeiros, J., Silveira, I. Reduced penetrance of intermediate size alleles in spinocerebellar ataxia type 10. Neurology 66: 1602-1604, 2006. [PubMed: 16717236] [Full Text: https://doi.org/10.1212/01.wnl.0000216266.30177.bb]
Fang, P., Matsuura, T., Teive, H. A. G., Raskin, S., Jayakar, P., Schmitt, E., Ashizawa, T., Roa, B. B. Spinocerebellar ataxia type 10 ATTCT repeat expansions in Brazilian patients and in a patient with early onset ataxia. (Abstract) Am. J. Med. Genet. 71 (Suppl.): 552 only, 2002.
Fujigasaki, H., Tardieu, S., Camuzat, A., Stevanin, G., LeGuern, E., Matsuura, T., Ashizawa, T., Durr, A., Brice, A. Spinocerebellar ataxia type 10 in the French population. Ann. Neurol. 51: 408 only, 2002. [PubMed: 11891842] [Full Text: https://doi.org/10.1002/ana.10126]
Gatto, E. M., Gao, R., White, M. C., Uribe Roca, M. C., Etcheverry, J. L., Persi, G., Ponderoso, J. J., Ashizawa, T. Ethnic origin and extrapyramidal signs in an Argentinean spinocerebellar ataxia type 10 family. Neurology 69: 216-218, 2007. [PubMed: 17620556] [Full Text: https://doi.org/10.1212/01.wnl.0000265596.72492.89]
Grewal, R. P., Achari, M., Matsuura, T., Durazo, A., Tayag, E., Zu, L., Pulst, S. M., Ashizawa, T. Clinical features and ATTCT repeat expansion in spinocerebellar ataxia type 10. Arch. Neurol. 59: 1285-1290, 2002. [PubMed: 12164725] [Full Text: https://doi.org/10.1001/archneur.59.8.1285]
Grewal, R. P., Tayag, E., Figueroa, K. P., Zu, L., Durazo, A., Nunez, C., Pulst, S. M. Clinical and genetic analysis of a distinct autosomal dominant spinocerebellar ataxia. Neurology 51: 1423-1426, 1998. [PubMed: 9818872] [Full Text: https://doi.org/10.1212/wnl.51.5.1423]
Harding, A. E. Clinical features and classification of inherited ataxias. Adv. Neurol. 61: 1-14, 1993. [PubMed: 8421960]
Matsuura, T., Achari, M., Khajavi, M., Bachinski, L. L., Zoghbi, H. Y., Ashizawa, T. Mapping of the gene for a novel spinocerebellar ataxia with pure cerebellar signs and epilepsy. Ann. Neurol. 45: 407-411, 1999. [PubMed: 10072060] [Full Text: https://doi.org/10.1002/1531-8249(199903)45:3<407::aid-ana21>3.0.co;2-d]
Matsuura, T., Fang, P., Lin, X., Khajavi, M., Tsuji, K., Rasmussen, A., Grewal, R. P., Achari, M., Alonso, M. E., Pulst, S. M., Zoghbi, H. Y., Nelson, D. L., Roa, B. B., Ashizawa, T. Somatic and germline instability of the ATTCT repeat in spinocerebellar ataxia type 10. Am. J. Hum. Genet. 74: 1216-1224, 2004. [PubMed: 15127363] [Full Text: https://doi.org/10.1086/421526]
Matsuura, T., Fang, P., Pearson, C. E., Jayakar, P., Ashizawa, T., Roa, B. B., Nelson, D. L. Interruptions in the expanded ATTCT repeat of spinocerebellar ataxia type 10: repeat purity as a disease modifier? Am. J. Hum. Genet. 78: 125-129, 2006. [PubMed: 16385455] [Full Text: https://doi.org/10.1086/498654]
Matsuura, T., Ranum, L. P. W., Volpini, V., Pandolfo, M., Sasaki, H., Tashiro, K., Watase, K., Zoghbi, H. Y., Ashizawa, T. Spinocerebellar ataxia type 10 is rare in populations other than Mexicans. Neurology 58: 983-984, 2002. [PubMed: 11914424] [Full Text: https://doi.org/10.1212/wnl.58.6.983]
Matsuura, T., Yamagata, T., Burgess, D. L., Rasmussen, A., Grewal, R. P., Watase, K., Khajavi, M., McCall, A. E., Davis, C. F., Zu, L., Achari, M., Pulst, S. M., Alonso, E., Noebels, J. L., Nelson, D. L., Zoghbi, H. Y., Ashizawa, T. Large expansion of the ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10. Nature Genet. 26: 191-194, 2000. [PubMed: 11017075] [Full Text: https://doi.org/10.1038/79911]
McFarland, K. N., Liu, J., Landrian, I., Gao, R., Sarkar, P. S., Raskin, S., Moscovich, M., Gatto, E. M., Teive, H. A. G., Ochoa, A., Rasmussen, A., Ashizawa, T. Paradoxical effects of repeat interruptions on spinocerebellar ataxia type 10 expansions and repeat instability. Europ. J. Hum. Genet. 21: 1272-1276, 2013. [PubMed: 23443018] [Full Text: https://doi.org/10.1038/ejhg.2013.32]
Raskin, S., Ashizawa, T., Teive, H. A. G., Arruda, W. O., Fang, P., Gao, R., White, M. C., Werneck, L. C., Roa, B. Reduced penetrance in a Brazilian family with spinocerebellar ataxia type 10. Arch. Neurol. 64: 591-594, 2007. [PubMed: 17420323] [Full Text: https://doi.org/10.1001/archneur.64.4.591]
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Teive, H. A. G., Roa, B. B., Raskin, S., Fang, P., Arruda, W. O., Correa Neto, Y., Gao, R., Werneck, L. C., Ashizawa, T. Clinical phenotype of Brazilian families with spinocerebellar ataxia 10. Neurology 63: 1509-1512, 2004. [PubMed: 15505178] [Full Text: https://doi.org/10.1212/01.wnl.0000142109.62056.57]
Trott, A., Jardim, L. B., Ludwig, H. T., Saute, J. A. M., Artigalas, O., Kieling, C., Wanderley, H. Y. C., Rieder, C. R. M., Monte, T. L., Socal, M., Alonso, I., Ferro, A., Carvalho, T., do Ceu Moreira, M., Mendonca, P., Ferreirinha, F., Silveira, I., Sequeiros, J., Giugliani, R., Saraiva-Pereira, M. L. Spinocerebellar ataxias in 114 Brazilian families: clinical and molecular findings. (Letter) Clin. Genet. 70: 173-176, 2006. [PubMed: 16879203] [Full Text: https://doi.org/10.1111/j.1399-0004.2006.00656.x]
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