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Spinocerebellar ataxia type 3/Machado-Joseph disease: segregation patterns and factors influencing instability of

G N Souza1, N Kersting1, A C Krum-Santos2

  • 1Programa de Pós-Graduação em Ciências Médicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

Clinical Genetics
|December 24, 2015
PubMed

Insights

Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) exhibits meiotic instability and anticipation, with paternal transmissions showing greater CAG expansion instability. Parent and sibling age influences expansion dynamics.

Area of Science:

  • Genetics and Molecular Biology
  • Neurodegenerative Diseases
  • Population Studies

Background:

  • Mendelian segregation and CAG repeat expansion (CAGexp) instabilities in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) during meiosis require further investigation.
  • Previous studies have indicated potential issues with genetic transmission, but comprehensive data from large cohorts are limited.

Purpose of the Study:

  • To clarify controversies surrounding Mendelian segregation and CAGexp instabilities in SCA3/MJD during meiosis.
  • To provide additional evidence on these genetic transmission issues using a comprehensive cohort of SCA3/MJD individuals in South Brazil.

Main Methods:

  • Conducted a survey of all SCA3/MJD individuals in South Brazil, updating information registered since 2001.
  • Analyzed data on anticipation and delta-CAGexp from parent-offspring pairs and between siblings.
  • Utilized the Public Information System to verify deaths and anonymize data; performed statistical analyses on genetic transmission patterns.

Main Results:

  • A minimal prevalence of 6:100,000 was established for SCA3/MJD in the studied population.
  • CAGexp instability was significantly higher in paternal transmissions compared to maternal ones and correlated with anticipation (r = 0.38; p = 0.001).
  • Parental age at conception and age differences between siblings showed correlations with delta-CAGexp, indicating age-related influences on expansion instability.

Conclusions:

  • SCA3/MJD demonstrates segregation distortion favoring the expanded allele in this South Brazilian cohort.
  • Meiotic instability of CAG expansion is influenced by the transmitting parent's age at conception and sibling age differences.
  • Findings contribute to understanding the complex genetic dynamics of SCA3/MJD, highlighting paternal transmission risks and age-related factors.

Keywords:
CAG expansion instabilitiesCAG expansion transmissionMJDMachado-Joseph diseaseSCA3minimal prevalencesegregation distortionspinocerebellar ataxia type 3

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