Pathophysiology
1) progressive neurodegenerative disease with selective neuronal loss – caused by an excessive repeat of the CAG nucleic acid sequence in the gene on chromosome 4 that codes for the Huntington protein 2) unclear how altered Huntington protein contributes to the specific symptoms 3) the protein HAP-1, which binds to the Huntingtin protein, possibly contributes to the pathogenesis 4) usual duration from onset of symptoms to death is about 15 years 5) marked by involuntary movements, progressive dementia, striking emotional changes
Signs and Symptoms
1) the greater the expansion, the earlier the onset of disease 2) onset is earlier by 3-4 years if condition is inherited from father 3) usual presenting signs – emotional and cognitive deficits (often by years) 4) most striking sign – choreoathetoid movements
Characteristic Test Findings
Brain biopsy – marked decrease in brain levels of GABA, glutamic acid decarboxylase, and acetylcholine
Histology/Gross Pathology
1) atrophic frontal cortex 2) striking atrophy of caudate nucleus and to lesser degree the putamen 3) lateral ventricles appear enlarged owing to caudate nucleus atrophy 4) protein aggregrations and intranuclear inclusions
Associated Conditions
some pateints also develop a parkinsonism with rigidity in late disease
Biochemistry
1) the normal number of repeats of CAG, which codes for glutamine is 10-35; Huntington’s disease has 40-100 repeats 2) effect is probably an altered protein-protein interaction secondary to the polyglutamate area at the N-terminal of the protein
Inheritance/Epidemiology
1) affected chromosome region is 4p16.3 2) autosomal dominant 3) occurs in 1/15,000 births in affected populations, mostly in western European and Scandinavian descent 4) some spontaneous mutations are known to exist 5) heterozygotes have same severity of disease as homozygotes 6) age of onset is typically 30-50 years
Tips for USMLE
1) other diseases caused by a CAG trinucleotide repeat expansion – Machado-Joseph disease, spinal-bulbar musculat atrophy, olivopontocerebellar disease, dentatorubro-pallidoluysian atrophy (DRPLA) 2) if a brain biopsy shows loss of striatal neurons, think Huntington’s
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