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Hereditary late-onset chorea without significant dementia: genetic evidence for substantial phenotypic variation in
J W Britton1, R J Uitti, J E Ahlskog
1Department of Neurology, Mayo Clinic, Rochester, MN.
Insights
This study investigated familial chorea cases, initially thought distinct from Huntington's disease (HD). Genetic testing revealed these patients have HD, highlighting significant phenotypic variation in the disease.
Area of Science:
- Neurogenetics
- Neurology
Background:
- Familial chorea syndromes can present challenges in differential diagnosis.
- Distinguishing rare choreiform disorders from established genetic conditions like Huntington's disease (HD) is crucial for accurate prognosis and management.
Observation:
- A cohort of individuals from two families presented with late-onset chorea (after age 50), with minimal cognitive impairment even decades after symptom onset.
- Neuroimaging showed no significant caudate or putaminal atrophy in affected individuals.
- Clinical presentation initially suggested a chorea syndrome distinct from Huntington's disease.
Findings:
- Genetic analysis revealed trinucleotide (CAG) repeat lengths within the established range for Huntington's disease (HD) in affected individuals.
- Despite the genetic diagnosis of HD, patients exhibited delayed onset, slow progression, and preserved cognition for many years.
Implications:
- These cases demonstrate significant phenotypic variability in Huntington's disease (HD), including late onset and prolonged preservation of cognitive function.
- The findings underscore the importance of genetic testing in diagnosing familial chorea syndromes, even when clinical features deviate from typical HD presentations.
- Recognizing this phenotypic spectrum is vital for genetic counseling and understanding the full clinical landscape of HD.
Abstract:
We examined five individuals and obtained information concerning six other members from two unrelated families, nearly all of whom developed chorea after age 50 (one patient developed chorea at age 40). The severity of chorea progressed in all patients and became disabling in some individuals approximately 15 years after onset. Cognitive impairment was absent or minimal. All five examined patients were cognitively normal, even 10 to 30 years following the onset of chorea. Formal neuropsychometric testing demonstrated mild cognitive impairment in two individuals. Nevertheless, all patients were able to maintain employment or carry on with their usual household tasks until chorea was severe. One individual first became demented 30 years after the onset of chorea. Neuroimaging (with CT or MRI) in four patients failed to demonstrate significant caudate or putaminal atrophy 8 to 15 years following the onset of chorea. Three other family members (who were not available for examination) were said to have suffered chorea (without any mental decline) beginning after age 50, with subsequent survival of 20 years (in one) and 30 years (in two). Given this constellation of history and findings, three experienced neurologists and two medical geneticists concluded that these patients had a familial chorea syndrome distinct from Huntington's disease (HD). However, genetic analysis of the trinucleotide (CAG) repeat length associated with HD (in 4p16.3) determined repeat lengths of 44 and 46 in four patients tested (within the HD range). We conclude that these patients have HD and that such families represent further convincing examples of significant phenotypic variation for HD.