Secondary to a mutation on the short arm of chromosome 4, in the HTT (aka IT15) gene: a CAG trinucleotide repeat, which encodes for the huntingtin protein.
HD is an autosomal dominant disorder with significant genetic anticipation: the sequence length is unstable and can expand during meiosis, especially down paternal inheritance lines.
It encodes a polyglutamine ('polyQ') stretch at the N-terminus of the huntingtin protein.
The anticipation helps us remember that this is a trinucleotide repeat disorder, specifically a CAG repeat disorder:
Classic trinucleotide repeat expansion disorders
Huntington's disease (CAG), myotonic dystrophy (CTG), and fragile X syndrome CGG) are the three classic trinucleotide repeat expansion disorders: the trinucleotide sequence is repeated many times in a row.
Additional CAG repeat disorders include: Kennedy's disease (aka X-linked spinal and bulbar muscular atrophy), spinocerebellar ataxia type 1 (SCA 1) and type 3 (SCA3, aka Machado-Joseph disease).
Pathology ("CAG" mneomnic)
We use the acronym CAG to highlight some key aspects of HD neuropathology:
On gross examination, there is caudate (C) and putamen (aka striatum) atrophy (A) with resultant anterior horn dilatation.
Accordingly, there is a loss of striatal GABAergic (G) medium spiny neurons, which is what primarily constitutes the striatum.
The HD gene is on chromosome 4
Greater than 40 CAG repeats is abnormal (but, truly, anything more than 36 can be symptomatic)
The average age of onset is 40 years-old but the longer the repeat length, the earlier the age of onset.
Onset younger than 20 years old, is referred to as Juvenile HD; it manifests with an akinetic-rigid syndrome, rather than chorea, referred to as the Westphal variant, which is typically the end-stage of HD in adults.
HD is predominantly a neuropsychiatric and movement disorder.
It's often mistaken as alcoholism early on but ultimately becomes parkinsonian, later.
Typical survival from onset is 15 years, much like the timeline of degeneration in Parkinson's disease.
Key domains:
Psychiatric. Depression and anxiety, early, and obsessive/compulsive thoughts, profound apathy, and physical aggression, later. Note that suicide is the 2nd most common cause of death in HD.
Cognitive. Executive dysfunction, early, such as trouble with organizational tasks, planning, and task sequencing.
Simple abnormal involuntary movements: tics, dystonia, myoclonus.
Complex abnormal involuntary movements: Chorea (excessive movements that flow from body part to body part).
Failure of voluntary movements: Akinetic, rigid syndrome (parkinsonism).