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Huntington's disease CAG trinucleotide repeats in pathologically confirmed post-mortem brains
F Persichetti1, J Srinidhi, L Kanaley
1Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, MA, 02129, USA.
Neurobiology of Disease
|December 1, 1994
Summary
Huntington's disease (HD) is primarily caused by expanded CAG repeats in the HD gene. Higher repeat numbers correlate with earlier onset and death, but some individuals show no pathology despite genetic risk.
Area of Science:
- Genetics
- Neuroscience
- Neuropathology
Background:
- Huntington's disease (HD) is a neurodegenerative disorder associated with CAG repeat expansions in the huntingtin gene.
- Understanding the correlation between CAG repeat length and disease phenotype is crucial for diagnosis and prognosis.
Purpose of the Study:
- To investigate the relationship between CAG repeat size and clinical presentation in Huntington's disease.
- To examine neuropathological findings in relation to genetic status in HD patients and at-risk individuals.
Main Methods:
- Analysis of postmortem brain samples from 310 clinically diagnosed HD patients and 15 at-risk individuals.
- CAG repeat length genotyping and correlation with clinical data (onset, age at death) and neuropathology.
Main Results:
- An expanded CAG allele (>37 repeats) was identified as the cause in nearly all diagnosed HD cases (307/310).
- Significant inverse correlations were observed between CAG repeat number and age at neurological/psychiatric onset and age at death.
- Three 'at risk' individuals with expanded CAG alleles showed no detectable neuropathology, while three diagnosed patients exhibited HD-like pathology without clear cause.
Conclusions:
- CAG repeat expansion is the primary genetic cause of Huntington's disease.
- CAG repeat length accurately predicts disease onset and progression.
- Pre-symptomatic neuropathology is not always evident, and atypical cases may involve phenocopies or alternative genetic mechanisms.