A new locus for spinocerebellar ataxia (SCA21) maps to chromosome 7p21.3-p15.1

Centre National de Génotypage, Évry-Petit-Bourg, Île-de-France, France
Annals of Neurology (Impact Factor: 9.98). 12/2002; 52(5):666-70. DOI: 10.1002/ana.10344
Source: PubMed


We investigated a French family with a new type of autosomal dominant spinocerebellar ataxia that was excluded from all previously identified genes and loci. The patients exhibited a slowly progressive gait and limb ataxia variably associated with akinesia, rigidity, tremor, and hyporeflexia. A mild cognitive impairment also was observed in some cases. We performed a genomewide search and found significant evidence for linkage to chromosome 7p21.3-p15.1. Analysis of key recombinants and haplotype reconstruction traced this novel spinocerebellar ataxia locus to a 24cM interval flanked by D7S2464 and D7S516.

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Available from: Francis Vasseur, Dec 09, 2014
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    • "However, the authors provide no pathological counterpoint to the cerebellum-ascause hypothesis, and there are no published reports of SCA21 neuropathology. Further, the brain imaging in this and previous reports (Vuillaume et al., 2002) spares the brainstem, with only non-specific T 2 and FLAIR hyperintensities noted in periventricular white matter (ages of affected individuals not provided), with the brunt of pathology located in the cerebellum, including the vermis, previously implicated as the limbic cerebellum (Schmahmann, 2010). Delplanque and colleagues add to our knowledge of the genetic and clinical characteristics of SCA21. "
    Brain 01/2015; 138(7). DOI:10.1093/brain/awu382 · 9.20 Impact Factor
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    • "In previous work, we characterized a 24-member French family pedigree, 11 members of which were affected by a new form of SCA (Devos et al., 2001). The disease locus was initially mapped to chromosome 7 and designated as SCA21 (Vuillaume et al., 2002). After examination of 12 additional family members, we reconsidered our linkage analysis. "
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    ABSTRACT: Autosomal dominant cerebellar ataxia corresponds to a clinically and genetically heterogeneous group of neurodegenerative disorders that primarily affect the cerebellum. Here, we report the identification of the causative gene in spinocerebellar ataxia 21, an autosomal-dominant disorder previously mapped to chromosome 7p21.3-p15.1. This ataxia was firstly characterized in a large French family with slowly progressive cerebellar ataxia, accompanied by severe cognitive impairment and mental retardation in two young children. Following the recruitment of 12 additional young family members, linkage analysis enabled us to definitively map the disease locus to chromosome 1p36.33-p36.32. The causative mutation, (c.509C>T/p.P170L) in the transmembrane protein gene TMEM240, was identified by whole exome sequencing and then was confirmed by Sanger sequencing and co-segregation analyses. Index cases from 368 French families with autosomal-dominant cerebellar ataxia were also screened for mutations. In seven cases, we identified a range of missense mutations (c.509C>T/p.P170L, c.239C>T/p.T80M, c.346C>T/p.R116C, c.445G>A/p.E149K, c.511C>T/p.R171W), and a stop mutation (c.489C>G/p.Y163*) in the same gene. TMEM240 is a small, strongly conserved transmembrane protein of unknown function present in cerebellum and brain. Spinocerebellar ataxia 21 may be a particular early-onset disease associated with severe cognitive impairment.
    Brain 07/2014; 137(10). DOI:10.1093/brain/awu202 · 9.20 Impact Factor
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    • "Age of onset is 17.4 years and is relatively earlier than for most ADCA Type I SCAs. The parkinsonism was not responsive to L-dopa [109]. MRI revealed cerebellar and brainstem atrophy. "
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    ABSTRACT: Type I autosomal dominant cerebellar ataxia (ADCA) is a type of spinocerebellar ataxia (SCA) characterized by ataxia with other neurological signs, including oculomotor disturbances, cognitive deficits, pyramidal and extrapyramidal dysfunction, bulbar, spinal and peripheral nervous system involvement. The global prevalence of this disease is not known. The most common type I ADCA is SCA3 followed by SCA2, SCA1, and SCA8, in descending order. Founder effects no doubt contribute to the variable prevalence between populations. Onset is usually in adulthood but cases of presentation in childhood have been reported. Clinical features vary depending on the SCA subtype but by definition include ataxia associated with other neurological manifestations. The clinical spectrum ranges from pure cerebellar signs to constellations including spinal cord and peripheral nerve disease, cognitive impairment, cerebellar or supranuclear ophthalmologic signs, psychiatric problems, and seizures. Cerebellar ataxia can affect virtually any body part causing movement abnormalities. Gait, truncal, and limb ataxia are often the most obvious cerebellar findings though nystagmus, saccadic abnormalities, and dysarthria are usually associated. To date, 21 subtypes have been identified: SCA1-SCA4, SCA8, SCA10, SCA12-SCA14, SCA15/16, SCA17-SCA23, SCA25, SCA27, SCA28 and dentatorubral pallidoluysian atrophy (DRPLA). Type I ADCA can be further divided based on the proposed pathogenetic mechanism into 3 subclasses: subclass 1 includes type I ADCA caused by CAG repeat expansions such as SCA1-SCA3, SCA17, and DRPLA, subclass 2 includes trinucleotide repeat expansions that fall outside of the protein-coding regions of the disease gene including SCA8, SCA10 and SCA12. Subclass 3 contains disorders caused by specific gene deletions, missense mutation, and nonsense mutation and includes SCA13, SCA14, SCA15/16, SCA27 and SCA28. Diagnosis is based on clinical history, physical examination, genetic molecular testing, and exclusion of other diseases. Differential diagnosis is broad and includes secondary ataxias caused by drug or toxic effects, nutritional deficiencies, endocrinopathies, infections and post-infection states, structural abnormalities, paraneoplastic conditions and certain neurodegenerative disorders. Given the autosomal dominant pattern of inheritance, genetic counseling is essential and best performed in specialized genetic clinics. There are currently no known effective treatments to modify disease progression. Care is therefore supportive. Occupational and physical therapy for gait dysfunction and speech therapy for dysarthria is essential. Prognosis is variable depending on the type of ADCA and even among kindreds.
    Orphanet Journal of Rare Diseases 05/2011; 6(1):33. DOI:10.1186/1750-1172-6-33 · 3.36 Impact Factor
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