Spinocerebellar Ataxia 15
A number sign (#) is used with this entry because of evidence that spinocerebellar ataxia-15 (SCA15) can be caused by heterozygous mutation in the ITPR1 gene as well as by deletions involving the ITPR1 gene (147265) on chromosome 3p26.
DescriptionSCA15 is an autosomal dominant, adult-onset, very slowly progressive form of cerebellar ataxia. Most patients also have disabling action and postural tremor, and some have pyramidal tract affection, dorsal column involvement, and gaze palsy. Brain imaging shows cerebellar atrophy mainly affecting the vermis (summary by Synofzik et al., 2011).
Heterozygous mutation in the ITPR1 gene can also cause SCA29 (117360), which is distinguished by onset in infancy of delayed motor development followed by nonprogressive ataxia and mild cognitive impairment.
Autosomal dominant 'pure' cerebellar ataxia, classified as ADCA type III by Harding (1983, 1993), is a genetically heterogeneous disorder (see, e.g., 117210).
For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).
Clinical FeaturesStorey et al. (2001) described an Australian kindred with a dominantly inherited 'pure' cerebellar ataxia in which linkage to known spinocerebellar ataxia loci was excluded by linkage studies and testing for trinucleotide repeat expansions. In 8 subjects studied, a notable clinical feature was slow progression, with the 3 least affected having only a mild degree of gait ataxia after 3 or more decades of disease duration. The name spinocerebellar ataxia-15 (SCA15) was applied.
Miyoshi et al. (2001) reported a 4-generation Japanese family with autosomal dominant spinocerebellar ataxia. The ages at onset of the 9 affected members (5 men and 4 women) ranged from 20 to 66 years. All showed pure cerebellar ataxia, and 3 patients also had head tremor. Head MRI demonstrated cerebellar atrophy without brainstem involvement. Mutation analysis by PCR excluded mutations in previously identified genes causing SCA. Based on initial mapping, the disorder was designated SCA16. Miura et al. (2006) provided follow-up on the family reported by Miyoshi et al. (2001). Three additional patients were ascertained and 1 individual previously reported as affected was determined to be unaffected. The main common clinical features were saccadic eye movements, horizontal gaze-evoked nystagmus, dysarthria, and limb and truncal ataxia. Two affected individuals had evidence of mental impairment.
Hara et al. (2004) reported 2 families with autosomal dominant spinocerebellar ataxia characterized by ataxic gait, cerebellar atrophy, and very slow progression. Several affected individuals also showed hyperreflexia and postural and action tremor of the hand, neck, and trunk. Both families originated from a northern province of Japan.
Synofzik et al. (2011) reported 5 German families in which 10 patients with SCA15 presented with slowly progressive cerebellar ataxia, requiring a walker or wheelchair 15 to 17 years after onset, and vermal cerebellar atrophy. Seven of 10 patients had action and postural tremor of the hands or head, while all had intention tremor. Clinical and electrophysiological signs of extracerebellar affection, including pyramidal tract or dorsal column involvement, were mild and more variable. Two had psychiatric manifestations before onset of ataxia.
MappingIn the Australian kindred with SCA15 reported by Storey et al. (2001), Knight et al. (2003) found linkage to an 11.6-cM region flanked by markers D3S3630 and D3S1304 on chromosome 3pter-p24.2 (maximum multipoint lod score of 3.54 at D3S1560). Mutation analysis excluded the ITPR1 gene (147265) from being involved in the pathogenesis of the disorder.
In 2 Japanese families with spinocerebellar ataxia, Hara et al. (2004) used genomewide linkage analysis to identify a 14.7-cM candidate region on chromosome 3p26.1-p25.3 between markers D3S1620 and D3S3691 (maximum multipoint lod score of 3.31 at D3S3728). The authors noted the overlap with the SCA15 region identified by Knight et al. (2003).
Although initial studies of an affected Japanese family with SCA16 suggested linkage to chromosome 8q22.1-24.1 (Miyoshi et al., 2001), additional studies of the same family by Miura et al. (2006) showed linkage to chromosome 3pter-p26.2 (maximum 2-point lod score of 5.17 at D3S2387). Haplotype analysis delineated a 6.4-Mb region between D3S2387 and D3S3050, and linkage to chromosome 8q was definitively excluded.
Molecular GeneticsVan de Leemput et al. (2007) identified heterozygous deletions involving the ITPR1 gene in affected members of 3 unrelated families with autosomal dominant spinocerebellar ataxia, including the SCA15 family of Australian origin used to map the locus (Storey et al., 2001; Knight et al., 2003). Using high-density genomewide SNP genotyping, Van de Leemput et al. (2007) identified a large deletion removing the first 3 exons of the SUMF1 gene (607939) and the first 10 exons of the ITPR1 gene in the family reported by Knight et al. (2003). Affected members of 2 additional families were found to have even larger deletions removing exons 1-44 and 1-40 of the ITPR1 gene, respectively. As homozygous mutations in the SUMF1 gene lead to a different phenotype (MSD; 272200) and heterozygous carriers of SUMF1 mutations do not exhibit a movement disorder, the authors concluded that deletions of the ITPR1 gene underlie the ataxia phenotype. Van de Leemput et al. (2007) noted that direct gene sequencing failed to identify mutations in the ITPR1 gene and that gene dosage studies were required for accurate diagnosis.
In affected members of a large Japanese family with autosomal dominant spinocerebellar ataxia reported by Miyoshi et al. (2001) and Miura et al. (2006), Iwaki et al. (2008) identified a heterozygous deletion of exons 1 to 48 of the ITPR1 gene (147265.0001). The SUMF1 gene was not affected. The findings indicated that SCA15 and SCA16 are the same disorder, due to haploinsufficiency of ITPR1.
In affected members of a Japanese family with SCA15 originally reported by Hara et al. (2004), Hara et al. (2008) identified a 414-kb deletion of chromosome 3p26 including all of the ITPR1 gene and exon 1 of the SUMF1 gene. Breakpoint analysis indicated that the deletion was mediated by nonhomologous end joining. RT-PCR showed that expression levels of both ITPR1 and SUMF1 in the patients were half of levels in normal controls. In affected members of a second unrelated Japanese family reported by Hara et al. (2004), Hara et al. (2008) identified a heterozygous mutation in the ITPR1 gene (147265.0002).
Synofzik et al. (2011) identified pathogenic ITPR1 deletions in 5 (8.9%) of 56 German families with autosomal dominant SCA who were negative for common SCA repeat expansions. All deletions detected by multiplex ligation-dependent probe amplification (MLPA) were confirmed by SNP array and spanned approximately 183 to 423 kb, and each family had a unique deletion. In 3 families, the deletions affected partly both the ITPR1 and SUMF1 genes, without including the 3-prime region of the ITPR1 gene. One family had a deletion preserving exons 1 and 2 in the 5-prime untranslated region of the ITPR1 gene.
Marelli et al. (2011) identified ITPR1 deletions in 6 (1.8%) of 333 families of European origin with autosomal dominant SCA who were negative for common SCA repeat expansions. In 3 families, the deletion included ITPR1 and SUMF1; in 1 family, the deletion included ITPR1, SUMF1, and SETMAR (609834); and in 2 families, the deletion was limited to ITPR1. Most presented with cerebellar gait ataxia and later developed ocular movement abnormalities and dysarthria. Two patients from 1 family had pyramidal signs, 2 additional patients from another family showed some executive decline, and some patients reported dysphagia.
Population GeneticsBased on their finding of SCA15 in 5 (8.9%) of 56 German families with unexplained SCAs, Synofzik et al. (2011) noted that SCA15 is the most common non-trinucleotide repeat SCA in Central Europe.
Animal ModelVan de Leemput et al. (2007) identified a spontaneous 18-bp deletion in exon 18 of the Itpr1 gene that caused a recessive movement disorder in mice. The deletion mutation resulted in markedly decreased levels of Itpr1 in cerebellar Purkinje cells.