Incidence of dominant spinocerebellar and Friedreich triplet repeats among 361 ataxia families

Moseley, Melinda L.; Benzow, Kellie A.; Schut, Lawrence J.; Bird, Thomas D.; Gómez, Carlos; Barkhaus, Paul E.; Blindauer, Karen; Labuda, Małgorzata; Pandolfo, Massimo; Koob, Mériam; Ranum, Laura P.W.

doi:10.1212/wnl.51.6.1666

Cited by 219 publications

(130 citation statements)

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“…7 Only 38% of children/adolescents and 11% of adults with recessive ataxia have a confirmed molecular diagnosis of FRDA, and proportions are even smaller for sporadic cases, leaving ample space for genetic heterogeneity. 16,17 The recent cloning of the gene involved in ARSACS, 10 encoding a new protein of unknown function, may facilitate the diagnosis of this rare condition, by a western blot approach, as is already the case for autosomal recessive muscular dystrophies. Several genes disrupted in recessive ataxias point to a pathological mechanism involving oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Homozygosity mapping of spinocerebellar ataxia with cerebellar atrophy and peripheral neuropathy to 9q33–34, and with hearing impairment and optic atrophy to 6p21–23

et al. 2000

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With the availability of a simple molecular test that distinguishes Friedreich ataxia, the most frequent form of inherited ataxia, from other recessive ataxias, it now becomes possible to unravel the genetic heterogeneity of the latter. We have now localised two genes causing autosomal recessive spinocerebellar ataxia in two consanguineous families. In the first family, the four affected Japanese sibs had spinocerebellar ataxia associated with elevated levels of serum creatine kinase, γ-globulin, and α-foetoprotein. Homozygosity over a 20 cM region allowed to demonstrate linkage at 9q33.3-34.3 with a lod score of 3.0. Genotyping two unrelated Japanese patients from first degree consanguineous parents revealed that one was homozygous for the same region but did not share the biochemical features. In the second family, an Israeli uncle and a niece were affected by an early-onset recessive ataxia and subsequently developed hearing impairment and optic atrophy. Homozygosity over a 17 cM region allowed demonstration of linkage at 6p21-23 with a lod score of 3.25. These two localisations of autosomal recessive ataxia genes represent a first step toward the identification of genetically homogenous, non-Friedreich, ataxic patients and subsequent cloning of the genes. European Journal of Human Genetics (2000) 8, 986-990.

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Section: Discussionmentioning

confidence: 99%

Homozygosity mapping of spinocerebellar ataxia with cerebellar atrophy and peripheral neuropathy to 9q33–34, and with hearing impairment and optic atrophy to 6p21–23

et al. 2000

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“…A recent study found evidence of frequency variation between different regions in Japan. 26 Data are based on a comprehensive study in the United States by Moseley et al 27 …”

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Hereditary ataxias: overview

Jayadev

Bird

2013

Genetics in Medicine

227

172

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“…Several geographically localised studies have been conducted on the prevalence of ADCAs, with the focus on the six SCA diseases. With regards to SCA3, the prevalence is at its highest in Brazil (69% of SCA cases), Portugal (58%) and China (49%) and relatively low in USA (21%), India (3%) and Italy (1%) [77,[79][80][81][82][83]. An interesting case is the founder effect of SCA7 in South Africa, where this disease represents 26.6% of SCA diseases [84], a figure that is significantly higher than the 2% occurrence worldwide [78].…”

Section: Prevalence and Incidencementioning

confidence: 99%

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

McIntosh¹,

Htut²,

Fletcher³

et al. 2017

J Genet Syndr Gene Ther

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Spinocerebellar ataxias are a large group of heterogeneous diseases that all involve selective neuronal degeneration and accompanied cerebellar ataxia. These diseases can be further broken down into discrete groups according to their underlying molecular genetic cause. The most common are the polyglutamine ataxias, of which there are six; Spinocerebellar ataxia type 1, 2, 3, 6, 7 and 17. These diseases are characterised by a pathological expanded cytosine-adenine-guanine (CAG) repeat sequence, in the protein coding region of a given gene. Common clinical features include lack of coordination and gait ataxia, speech and swallowing difficulties, as well as impaired hand and motor functions. The polyglutamine spinocerebellar ataxias are typically late onset diseases that are progressive in nature and often lead to premature death, for which there is currently no known cure or effective treatment strategy. Although caused by the same molecular mechanism, the causative gene and associated protein differ for each disease. The exact mechanism by which disease pathogenesis is caused remains elusive. However, the variable (CAG) n repeats are codons that may be translated to an expanded glutamine tract, leading to conformational changes in the protein, giving it a toxic gain of function. Several pathogenic pathways have been implicated in polyglutamine spinocerebellar ataxia diseases, such as the hallmark feature of neuronal nuclear inclusions, protein misfolding and aggregation, as well as transcriptional dysregulation. These pathways are attractive avenues for potential therapeutic interventions, as the potential to treat more than one disease exists. Research is ongoing, and several promising therapies are currently underway in an attempt to provide relief for this devastating class of diseases.. However, mutations can arise de novo, through errors in DNA replication such that two genetically healthy parents can give rise to an affected child.There are currently six characterised polyQ SCAs (1, 2, 3, 6, 7 and 17) (Table 1), and together with three other diseases, namely Huntington's disease, spinal and bulbar muscular atrophy and dentatorubropallidoluysian atrophy (DRPLA), form a larger category of polyQ diseases [7][8][9][10]. Th ere is little relief for individuals suffering from polyQ SCA disorders, with symptomatic treatments the only available option. Long term pharmacological treatment, although admirable, tends to fall short in an effective management strategy, as unwanted complications and low drug efficacy still exist. In addition, none of these diseases have any treatments that slow the progression of the disease; leaving affected individuals with the daunting reality that time may be a severe limiting factor. Several experimental approaches are currently being assessed to overcome these difficulties. This review will focus on the clinical and molecular features of polyQ SCA diseases (which will be referred to as SCA diseases), as well as highlight several promising and emerging therapeutic strategies...

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Incidence of dominant spinocerebellar and Friedreich triplet repeats among 361 ataxia families

Cited by 219 publications

References 13 publications

Homozygosity mapping of spinocerebellar ataxia with cerebellar atrophy and peripheral neuropathy to 9q33–34, and with hearing impairment and optic atrophy to 6p21–23

Homozygosity mapping of spinocerebellar ataxia with cerebellar atrophy and peripheral neuropathy to 9q33–34, and with hearing impairment and optic atrophy to 6p21–23

Hereditary ataxias: overview

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

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