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SKY-0515

Huntington's disease

Last updated
211 sources

Product information and disease descriptionPlace of product in therapyDisease description

Definition and etiology

6 evidence topics · 6 sources

Definition: progressive motor, cognitive, and psychiatric disorder

“Huntington disease (HD) is a progressive disorder of motor, cognitive, and psychiatric manifestations.” (opens the source at this quote in a new tab)

“HD is inherited in an autosomal dominant manner. Offspring of an individual with a heterozygous CAG repeat expansion in HTT have a 50% chance of inheriting a CAG repeat expansion.” (opens the source at this quote in a new tab)

Etiology: expanded CAG repeat in HTT encoding a polyglutamine tract

“The disease is caused by an expanded CAG trinucleotide repeat (of variable length) in HTT, the gene that encodes the protein huntingtin.” (opens the source at this quote in a new tab)

“Huntington's disease is an autosomal-dominant, progressive neurodegenerative disorder with a distinct phenotype, including chorea and dystonia, incoordination, cognitive decline, and behavioural difficulties.” (opens the source at this quote in a new tab)

CAG repeat length thresholds
Allele categoryCAG repeat length
Normal alleles“26 or fewer CAG repeats”
Intermediate alleles“27 to 35 CAG repeats”
Reduced-penetrance HD-causing alleles“36 to 39 CAG repeats”
Full-penetrance HD-causing alleles“40 or more CAG repeats”
Reduced penetrance of 36 to 39 CAG repeat alleles

“Variable penetrance for alleles carrying 36-39 repeats has been noted, but the disease appears fully penetrant when the repeat numbers are >40.” (opens the source at this quote in a new tab)

“A total of 18 of 7,315 individuals had ≥36 CAG, revealing that approximately 1 in 400 individuals from the general population have an expanded CAG repeat associated with HD (0.246%).” (opens the source at this quote in a new tab)

“The infrequent diagnosis of HD at this CAG length is likely due to low penetrance.” (opens the source at this quote in a new tab)

CAG repeat length and age of onset

“A significant inverse correlation exists between the number of HTT CAG repeats and the age of onset of HD” (opens the source at this quote in a new tab)

“On average, CAG repeat length accounts for up to 70% of the variability in age of onset, with an estimated 10%-20% of the residual variability being accounted for by heritable factors” (opens the source at this quote in a new tab)

“For example, our model predicts a 91% chance that a 40-year-old individual with 42 repeats will have onset by the age of 65, with a 95% confidence interval from 90 to 93%.” (opens the source at this quote in a new tab)

Juvenile Huntington's disease and anticipation

“Juvenile HD is rare and historically defined as HD with an onset of symptoms before age 20 years” (opens the source at this quote in a new tab)

“The proportion of individuals with juvenile HD varies from 1% to 15% of individuals diagnosed with HD” (opens the source at this quote in a new tab)

“Large expansions (i.e., an increase in allele size of >7 CAG repeats) occur almost exclusively through paternal transmission.” (opens the source at this quote in a new tab)

“HTT CAG repeat length in individuals with juvenile HD is usually >55 CAG repeats and is often caused by anticipation, usually via paternal transmission” (opens the source at this quote in a new tab)