What is Huntington's Disease?
Huntington's disease (HD) is an autosomal-dominant neurodegenerative disease of mid-life onset caused by expansion of a CAG trinucleotide repeat in the HTT gene (formerly IT-15), producing choreic movements, cognitive decline, and psychiatric changes. 1
Genetic Basis
HD results from an expanded CAG repeat in exon 1 of the HTT gene located on chromosome 4p16.3. The CAG expansion is translated into an abnormally long polyglutamine tract in the huntingtin protein, leading to toxic gain-of-function properties and neuronal death 1.
CAG Repeat Ranges and Clinical Significance:
- ≤26 CAG repeats: Never associated with HD phenotype
- 27-35 CAG repeats: Not convincingly associated with HD phenotype (may be mutable)
- 36-39 CAG repeats: Variable penetrance—reported in both affected and unaffected individuals
- ≥40 CAG repeats: Fully penetrant disease; 100% specific for HD 1
The longer the CAG repeat length, the earlier the disease onset. Juvenile-onset HD (before age 20) typically involves repeat lengths exceeding 55 2.
Clinical Manifestations
Classic Triad of Symptoms:
Motor symptoms: Progressive chorea (involuntary, dance-like movements) that gradually spreads to all muscles. In juvenile-onset cases, rigidity and spasticity predominate rather than chorea 1.
Cognitive decline: Progressive dementia with severe retardation of all psychomotor processes. HD is the most common genetic dementia in the developed world 3.
Psychiatric disturbances: Behavioral changes, depression, and aggressive behavior often accompany or precede motor symptoms 1, 2.
Neuropathology
The disease causes selective neuronal loss, most notably in the caudate nucleus and putamen (striatum), though cortical and other extrastriatal structures are also affected 1, 4. This selective vulnerability occurs despite ubiquitous expression of mutant huntingtin protein throughout the body.
Epidemiology
- Prevalence: Approximately 3-5 per 100,000 individuals in most populations
- Higher prevalence: Exceeds 15 per 100,000 in populations of western European origin 1
- Mean age of onset: 30-50 years
- Juvenile-onset HD: Approximately 5% of cases, presenting before age 20 1
Disease Course and Prognosis
HD progresses relentlessly over 15-20 years, leading to complete dependency in daily activities and eventual death 3, 2. The most common cause of death is pneumonia, followed by suicide 2. There is currently no effective disease-modifying treatment 1.
Inheritance Pattern
HD follows autosomal dominant inheritance, meaning each child of an affected parent has a 50% chance of inheriting the mutation. The abnormal CAG repeat may expand, contract, or be stably transmitted from parent to child, with paternal transmission more likely to result in expansion 1.
Diagnosis
Diagnosis is confirmed by genetic testing demonstrating CAG repeat expansion ≥36 in the HTT gene, combined with clinical evaluation and family history 1, 4. Genetic testing has been available since 1993 for both diagnostic confirmation in symptomatic individuals and presymptomatic testing in at-risk family members 5, 4.
Important Caveat:
Presymptomatic testing should only be performed by multidisciplinary teams in healthy at-risk adults who voluntarily seek testing, given the profound psychological and social implications 2.