The hereditary adult-onset ataxias in South Africa

https://doi.org/10.1016/S0022-510X(03)00209-0Get rights and content

Abstract

There is little data on the spectrum and frequencies of the autosomal dominant spinocerebellar ataxias (SCAs) from the African continent. We undertook a large prospective population-based study over a 10-year period in South Africa (SA). Affected persons were clinically evaluated, and the molecular analysis for the SCA1, 2, 3, 6 and 7 expansions was undertaken. Of the 54 SA families with dominant ataxia, SCA1 accounted for 40.7%, SCA2 for 13%, SCA3 for 3.7%, SCA6 for 1.9%, SCA7 for 22.2% and 18.5% were negative for all these mutations. The frequency of the SCA1 and SCA7 expansions in SA represents one of the highest frequencies for these expansions reported in any country. In this study, the SCA7 mutations have only been found in SA families of Black ethnic origin.

Introduction

On the African continent, clinical and molecular genetic information concerning the spinocerebellar group of disorders is scant. Many of the developing countries do not have the resources to investigate uncommon genetic disorders at a clinical or molecular level because of other pressing demands on their health budgets. Even in most of the developed countries, comprehensive epidemiological data on the inherited ataxias are incomplete. There is no published data on the spectrum and prevalence of the familial adult ataxias in South Africa (SA), and this study is the first to address this.

The late-onset autosomal dominant spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous group of inherited progressive neurological disorders. Age of onset of symptoms is typically between 20 and 50 years, and progressive disability culminates in death 10–20 years after onset. Cerebellar ataxia is the predominant manifestation. To date, 16 different loci, some of which are of childhood onset, have been identified viz. SCA1 (6p), SCA2 (12q), SCA 3/Machado–Joseph Disease (14q), SCA4 (16q), SCA5 (11), SCA6 (19p), SCA 7(3P) and SCA8 (13q21), SCA10 (22q13), SCA11 (15q), SCA12 (5q31), SCA13 (19q13), SCA14(19q13.4), SCA15(6q27), SCA16(8q) and SCA17 (6q27).

Subsequent to an early study looking at vestibular function in a single kindred with spinocerebellar ataxia [1], a large population-based study was undertaken in the Western Cape region of SA over a 12-year period. Different forms of the disorder have been delineated and their natural history documented. Following this, the study was extended to the other provinces, and blood samples were received from affected kindreds from all over SA. Molecular genetic investigations were undertaken to determine genotype status in the families from the different population groups.

Section snippets

Ascertainment of affected families in the Western Cape

In the Western Cape province of South Africa, patients with SCA have been assessed as inpatients and outpatients in the neurology units over many years at the two academic tertiary hospitals, Groote Schuur and Tygerberg Hospitals, that service the region. A case finding pilot study in the form of a retrospective analysis of all patients admitted to Groote Schuur Hospital over a 10-year period (1982–1992) was undertaken. In this study, 29 individuals with familial SCA were initially identified.

Results

A total of 54 families with SCA have been identified in SA; 234 DNA samples have been banked from SCA family members of which 132 are from affected individuals. Molecular analysis revealed that 22 families have the SCA1 genotype (accounting for 40.7% of SA ataxia families), 7 families have the SCA2 genotype (13%), 2 families have the SCA3 genotype (3.7%), 1 family has the SCA6 genotype (1.9%) and 12 families have the SCA7 genotype (22.2%). Not all alleles have been accurately sized to date, but

Discussion

The frequencies of the dominant SCAs vary in different populations, presumably due to founder effects. Apart from a clustering of families with SCA1. In the Western Cape region (45.5% of our SCA1 families), the other genotypes were found scattered widely across SA. It is unlikely that our data is significantly skewed because of ascertainment bias, as the national neurology fraternity is small, though with a high level of awareness of this project through the Neurological Association of South

Acknowledgements

This work was supported by the South African Medical Research Council.

References (49)

  • Y. Onodera et al.

    High prevalence of spinocerebellar ataxia type 1 (SCA1) in an isolated region of Japan

    J. Neurol. Sci.

    (2000 (Sep 15))
  • Y. Nagai et al.

    Clinical and molecular genetic study in seven Japanese families with spinocerebellar ataxia type 6

    J. Neurol. Sci.

    (1998 (Apr 15))
  • D.V. Philcox et al.

    Vestibular dysfunction in hereditary ataxia

    Brain

    (1975 (Jun))
  • A.E. Harding

    The clinical features and classification of the late onset autosomal dominant cerebellar ataxias. A study of 11 families, including descendants of the ‘the Drew family of Walworth’

    Brain

    (1982 (Mar))
  • A. Filla et al.

    Relative frequencies of CAG expansions in spinocerebellar ataxia and dentatorubropallidoluysian atrophy in 116 Italian families

    Eur. Neurol.

    (2000)
  • O. Dubourg et al.

    Analysis of the SCA1 CAG repeat in a large number of families with dominant ataxia: clinical and molecular correlations

    Ann. Neurol.

    (1995 (Feb))
  • M.A. Pujana et al.

    Spinocerebellar ataxias in Spanish patients: genetic analysis of familial and sporadic cases. The Ataxia Study Group

    Hum. Genet.

    (1999 (Jun))
  • L. Schols et al.

    Autosomal dominant cerebellar ataxia: phenotypic differences in genetically defined subtypes?

    Ann. Neurol.

    (1997 (Dec))
  • D.H. Geschwind et al.

    The prevalence and wide clinical spectrum of the spinocerebellar ataxia type 2 trinucleotide repeat in patients with autosomal dominant cerebellar ataxia

    Am. J. Hum. Genet.

    (1997 (Apr))
  • M.L. Moseley et al.

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

    Neurology

    (1998 (Dec))
  • L.P. Ranum et al.

    Spinocerebellar ataxia type 1 and Machado–Joseph disease: incidence of CAG expansions among adult-onset ataxia patients from 311 families with dominant, recessive, or sporadic ataxia

    Am. J. Hum. Genet.

    (1995 (Sep))
  • I. Lopes-Cendes et al.

    Frequency of the different mutations causing spinocerebellar ataxia (SCA1, SCA2, MJD/SCA3 and DRPLA) in a large group of Brazilian patients

    Arq. Neuropsiquiatr.

    (1997 (Sep))
  • D.K. Jin et al.

    Frequency of spinocerebellar ataxia types 1,2,3,6,7 and dentatorubral pallidoluysian atrophy mutations in Korean patients with spinocerebellar ataxia

    J. Neurol.

    (1999 (Mar))
  • S.N. Illarioshkin et al.

    Spinocerebellar ataxia type 1 in Russia

    J. Neurol.

    (1996 (Jul))
  • T. Kameya et al.

    Analysis of spinocerebellar ataxia type 1 (SCA1)-related CAG trinucleotide expansion in Japan

    Neurology

    (1995 (Aug))
  • R.S. Ramesar et al.

    Expanded CAG repeats in spinocerebellar ataxia (SCA1) segregate with distinct haplotypes in South african families

    Hum. Genet.

    (1997 (Jul))
  • L.P. Ranum et al.

    Molecular and clinical correlations in spinocerebellar ataxia type I: evidence for familial effects on the age at onset

    Am. J. Hum. Genet.

    (1994 (Aug))
  • G. Orozco Diaz et al.

    Autosomal dominant cerebellar ataxia: clinical analysis of 263 patients from a homogeneous population in Holguin, Cuba

    Neurology

    (1990 (Sep))
  • M. Spadaro et al.

    Clinical study of large kindreds with autosomal dominant HLA-linked spinocerebellar ataxia (SCA1) of late onset

    Ital. J. Neurol. Sci.

    (1993 (Jan))
  • P. Giunti et al.

    The role of the SCA2 trinucleotide repeat expansion in 89 autosomal dominant cerebellar ataxia families. Frequency, clinical and genetic correlates

    Brain

    (1998 (Mar))
  • J. Leggo et al.

    Analysis of spinocerebellar ataxia types 1, 2, 3, and 6, dentatorubral-pallidoluysian atrophy, and Friedreich's ataxia genes in spinocerebellar ataxia patients in the UK

    J. Med. Genet.

    (1997 (Dec))
  • Q. Saleem et al.

    Molecular analysis of autosomal dominant hereditary ataxias in the Indian population: high frequency of SCA2 and evidence for a common founder mutation

    Hum. Genet.

    (2000 (Feb))
  • P. Basu et al.

    Analysis of CAG repeats in SCA1, SCA2, SCA3, SCA6, SCA7 and DRPLA loci in spinocerebellar ataxia patients and distribution of CAG repeats at the SCA1, SCA2 and SCA6 loci in nine ethnic populations of eastern India

    Hum. Genet.

    (2000 (Jun))
  • K. Burk et al.

    Cognitive deficits in spinocerebellar ataxia 2

    Brain

    (1999 (Apr))
  • Cited by (76)

    • Spinocerebellar ataxias

      2018, Handbook of Clinical Neurology
    • Voice Alterations in Patients With Spinocerebellar Ataxia Type 7 (SCA7): Clinical-Genetic Correlations

      2017, Journal of Voice
      Citation Excerpt :

      SCA7 is considered one of the rarest forms of autosomal-dominant inherited ataxias, with very few studies demonstrating clinical characterization of patients.1–3 However, an increased number of SCA7 cases have been reported recently in various populations, including Swedish, Finnish, South African, and Mexican,7–9 which would allow for a better description of the disease. In addition to the cerebellar ataxia, SCA7 is often accompanied by other neurological features, including pyramidal symptoms, oculomotor disturbances, peripheral neuropathy, cognitive impairment, and sleep disorders, and could eventually develop more extensive neurological deficits that include dysphagia, hypoacusis, and dysarthria.3,10

    View all citing articles on Scopus
    View full text