A novel autosomal dominant spinocerebellar ataxia (SCA22) linked to chromosome 1p21‐q23

Abstract

The autosomal dominant cerebellar ataxias (ADCA) are a clinically, pathologically and genetically heterogeneous group of disorders. Ten responsible genes have been identified for spinocerebellar ataxia types SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA10, SCA12 and SCA17, and dentatorubral pallidoluysian atrophy (DRPLA). The mutation is caused by an expansion of a CAG, CTG or ATTCT repeat sequence of these genes. Six additional loci, SCA4, SCA5, SCA11, SCA13, SCA14 and SCA16 have also been mapped. The growing heterogeneity of the autosomal dominant forms of these diseases shows that the genetic aetiologies of at least 20% of ADCA have yet to be elucidated. We ascertained and clinically characterized a four-generation Chinese pedigree segregating an autosomal dominant phenotype for cerebellar ataxia. Direct mutation analysis, linkage analysis for all known SCA loci and a genome-wide linkage study were performed. Direct mutation analysis excluded SCA1, 2, 3, 6, 7, 8, 10, 12, 17 and DRPLA, and genetic linkage analysis excluded SCA4, 5, 11, 13, 14 and 16. The genome-wide linkage study suggested linkage to a locus on chromosome 1p21-q23, with the highest two-point LOD score at D1S1167 (Zmax = 3.46 at theta = 0.00). Multipoint analysis and haplotype reconstruction traced this novel SCA locus (SCA22) to a 43.7-cM interval flanked by D1S206 and D1S2878 (Zmax = 3.78 under four liability classes, and 2.67 using affected-only method). The age at onset ranged from 10 to 46 years. All affected members had gait ataxia with variable features of dysarthria and hyporeflexia. Head MRI showed homogeneous atrophy of the cerebellum without involvement of the brainstem. In six parent-child pairs, median onset occurred 10 years earlier in offspring than in their parents, suggesting anticipation. This family is distinct from other families with SCA and is characterized by a slowly progressive, pure cerebellar ataxia.

SCA-LSVD: A repeat-oriented locus-specific variation database for genotype to phenotype correlations in spinocerebellar ataxias

“…SCAs have been broadly grouped into three categories, as proposed by Harding based on cerebellar ataxia, ophthalmoplegia, and associated clinical symptoms [Harding, 1993;Duenas et al, 2006;Everett and Wood, 2004]. Autosomal dominant cerebellar ataxia (ADCA)-I, a more heterogeneous group that includes SCA1, SCA2, SCA3, SCA4, SCA8, SCA12, SCA13, SCA18-25, SCA27-29, and dentatorubral-pallidoluysian atrophy (DRPLA), presents with pyramidal features, extrapyramidal signs, and amyotrophy [Orr et al, 1993;Imbert et al, 1996;Pulst et al, 1996;Kawaguchi et al, 1994;Flanigan et al, 1996;Koob et al, 1999;Holmes et al, 1999;Waters et al, 2006;Devos et al, 2001;Verbeek et al, 2004;Knight et al, 2004;Vuillaume et al, 2002;Chung et al, 2003;Schelhaas et al, 2004;Swartz et al, 2002;Stevanin et al, 2005;Yu et al, 2005;van Swieten et al, 2003;Cagnoli et al, 2006;Koide et al, 1994]. Additionally, pigmentary retinal degeneration and seizures are observed in ADCA-II (SCA7) and ADCA-IV (SCA10 and SCA17), respectively [David et al, 1997;Matsuura et al, 2000;Nakamura et al, 2001].…”

Spectrum and prevalence of autosomal dominant spinocerebellar ataxia in Hokkaido, the northern island of Japan: a study of 113 Japanese families

“…To date, 29 different genetic loci have been reported to be responsible for ADCA (http://www.gene.ucl.ac.uk/cgi-bin/nomenclature): spinocerebellar ataxia type 1 (SCA1) on chromosome 6p22-p23 (Orr et al 1993); SCA2 on 12q23-q24.1 (Imbert et al 1996;Sanpei et al 1996); Machado-Joseph disease (MJD)/ SCA3 on 14q24.3-q32.1 (Kawaguchi et al 1994); SCA4 on 16q22.1 (Flanigan et al 1996); SCA5 on 11q13.2 (Ranum et al 1994); SCA6 on 19p13.1 (Zhuchenko et al 1997); SCA7 on 3p12-p13 (David et al 1997); SCA8 on 13p (Koob et al 1999); SCA10 on 22q13-qter. (Matsuura et al 2000); SCA11 on 15q14-q21.3 (Worth et al 1999); SCA12 on 5q31-33 (Holmes et al 1999);SCA13 on 19q13.3-q13.4 (Waters et al 2006); SCA14 on 19q13.42 Chen et al 2003;Yabe et al 2003); SCA15 on 3p24.2 (Gardner et al 2005); SCA16 on 8q23-q24.1 (Miyoshi et al 2001); SCA17 on 6q27 (Nakamura et al 2001); SCA18 on 7q22 (Brkanac et al 2002); SCA19 on 1p21-q21 (Verbeek et al 2002); SCA20 on 11p11.2-q13.3 (Knight et al 2004); SCA21 on 7p21.3-p15.1 (Vuillaume et al 2002); SCA22 on 1p21-q23 (Chung et al 2003); SCA23 on 20p13-p12 (Verbeek et al 2004); SCA24 on 1p26 (Swartz et al 2002); SCA25 on 2p21-p15 (Stevanin et al 2004); SCA26 on 19p13.3 (Yu et al 2005); SCA27 on 13q33.1 (Van Swieten et al 2003); SCA28 on 18p11.22-q11.2 (Cagnoli et al 2006); SCA 29 on 3p26 (Dudding et al 2004) and dentatorubral pallidoluysian atrophy (DRPLA) on 12p13.31 (Koide et al 1994;Nagafuchi et al 1994). Among these loci, causative genes have been further identified containing trinucleotide repeats (CAG) in S...…”

Regional features of autosomal-dominant cerebellar ataxia in Nagano: clinical and molecular genetic analysis of 86 families

“…More recently, point mutations in the protein kinase C gamma gene (PRKCG) have been proven to be pathogenic for SCA14 (van de Warrenburg et al 2003;Yabe et al 2003). Eight additional gene loci have also been mapped: SCA4 on 16q (Flanigan et al 1996), SCA5 on 11p (Ranum et al 1994), SCA11 on 15q (Worth et al 1999), SCA15 on 3p (Knight et al 2003), SCA16 on 8q (Miyoshi et al 2001), SCA19 on 1p (Verbeek et al 2002), SCA21 on 7p (Vuillaume et al 2002), SCA22 on 1p (Chung et al 2003), and SCA 25 on 2p (Stevanin et al 2004).…”