What Causes Huntington's Disease
Huntington's disease is caused by an abnormal expansion of CAG trinucleotide repeats in exon 1 of the HTT gene (historically known as IT-15) located on chromosome 4p16.3 1.
Genetic Mechanism
The disease results from a specific molecular defect where the CAG repeat sequence expands beyond normal limits. The HTT gene normally contains a polymorphic CAG repeat region, but when this expands, it produces a mutant huntingtin protein with an abnormally long polyglutamine tract 1.
CAG Repeat Thresholds
The number of CAG repeats determines disease status 2, 1:
- Normal alleles: <26 CAG repeats (never cause disease)
- Mutable normal alleles: 27-35 CAG repeats (not associated with disease but may be unstable during transmission)
- Reduced penetrance alleles: 36-39 CAG repeats (variable penetrance—may or may not cause disease)
- Full penetrance HD alleles: ≥40 CAG repeats (disease appears fully penetrant)
Individuals with ≥40 CAG repeats will develop HD if they live a normal lifespan, making this threshold essentially 100% specific for disease 1.
Inheritance Pattern
HD follows an autosomal dominant inheritance pattern, meaning only one mutated copy of the gene is sufficient to cause disease 1. Each child of an affected parent has a 50% chance of inheriting the expanded allele.
Meiotic Instability
A critical feature is that CAG repeats can expand, contract, or remain stable when transmitted from parent to child 1. This meiotic instability has been demonstrated directly in sperm DNA and inferred in oocytes 2. Paternal transmission is particularly associated with larger expansions, which explains why juvenile-onset HD (occurring before age 20) typically involves paternal inheritance 1.
Pathophysiology
The expanded CAG repeat is translated into an elongated polyglutamine tract in the huntingtin protein 1. This mutant huntingtin (mHtt) causes:
- Protein misfolding and aggregation
- Selective neuronal loss, particularly in the caudate nucleus and putamen (striatum)
- Disruption of multiple cellular processes including autophagy, mitochondrial function, lysosomal function, transcriptional regulation, and oxidative stress responses 3
The striatal medium-sized spiny neurons are preferentially vulnerable, followed by cortical pyramidal neurons in layers V and VI 4.
Clinical Caveat
While the genetic cause is well-defined and testing is highly accurate, the diagnosis of HD in the family should ideally be confirmed by molecular studies in an affected individual before performing predictive testing in at-risk relatives 2. This ensures the relevance and accuracy of predictive test results, as the clinical diagnosis can sometimes be uncertain without genetic confirmation.