Huntington disease (HD), also known as Huntington chorea, is one of the trinucleotide repeat disorders with an autosomal dominant neurodegenerative disease caused by a loss of GABAergic neurons of the basal ganglia, especially atrophy of the caudate nucleus and putamen. Huntington disease is clinically characterised by progressive unintentional choreoathetoid movements, subcortical type dementia, behavioural changes, and psychosis which starts in midlife.
On imaging, it is classically characterised by atrophy of the caudate nucleus with concomitant enlargement of the frontal horns of the lateral ventricles.
Huntington disease has a prevalence of 5-10 per 100,000 and is typically diagnosed between 30 and 50 years of age 3. Incidence is equal in both genders, although there appears to be an effect depending on the gender of the parent from whom the defect was inherited: if inherited from the father, presentation is earlier. The cause for this effect is as yet uncertain 3.
In approximately 1-6% symptoms occur before the age of 20 years, so-called 'juvenile' form, which appears to be a variant of the usual adult form, with a different pattern of symptoms. In juvenile cases having inherited the disease from the father is far more common 3.
Presentation is typically with progressive rigidity, choreoathetosis, dementia, psychosis and emotional lability 2.
The juvenile form has a different presentation, with cerebellar symptoms, rigidity and hypokinesia being prominent.
It is a autosomal dominant with complete penetrance and genetic anticipation (i.e. next generation will have more repeats of CAG and a more severe course of the disease or show symptoms earlier) particularly if the inherited mutated allele is paternal. The mutation responsible is on chromosome 4p16:3, and consists of a CAG trineucleotide repeat. The usual 10-30 copies are amplified to >36, and the greater the number of repeats the earlier the age of onset 3.
Microscopically, there are Huntington nuclear inclusion bodies 8. Both deep grey matter and to a lesser degree white matter are involved in HD.
Although all modalities capable of structural brain imaging will demonstrate morphological changes of Huntington disease, MRI has the greatest spatial and contrast resolution and is thus preferred.
The most striking, and best known, feature is that of caudate head atrophy resulting in enlargement of the frontal horns, often giving them a "box" like configuration 2-4. This can be quantified by an number of measurements:
- frontal horn width to intercaudate distance ratio (FH/CC)
- intercaudate distance to inner table width ratio (CC/IT)
Additionally in juvenile form putamen are also atrophied, and demonstrate increased T2 signal 4. In some case basal ganglia may show decrease T2 signal and blooming on SWI in keeping with iron deposition 7. Generalised age inappropriate cortical volume loss is also recognised 4.
MR spectroscopy may demonstrate elevation of lactate in the occipital cortex and basal ganglia which correlates with duration of symptoms. There is also decrease in NAA/creatine ratio in keeping with neuronal loss in basal ganglia.
PET scan demonstrates hypometabolism by decrease FDG uptake in basal ganglia and frontal cortex even before noticeable caudate nucleus volume loss 6.
Treatment and prognosis
No treatment is currently generally available 4.
The adult onset form is slower in its course and inevitably leads to death in 14-15 years, whereas the juvenile form has a more rapidly progressive course, with death occurring in in 7-8 years 3.
History and etymology
It is named after George Huntington, an American physician (1850-1916) 1.
- Wilson disease: more commonly involves white matter, thalamus, cerebellum and brainstem 3
- Leigh disease: more commonly involves white matter, thalamus, cerebellum and brainstem
- Hallervorden-Spatz syndrome
- acute hypoxic encephalopathy
- carbon monoxide poisoning
- hypoglycaemic encephalopathy
Neurodegenerative diseases are legion and their classification just as protean. A useful approach is to divide them according to underlying pathological process, although even using this schema, there is much overlap and thus resulting confusion.
neurodegenerative MRI brain (an approach)
- measurements and ratios
- midbrain to pons area ratio (for PSP)
- Magnetic Resonance Parkinsonism Index (MRPI) (for PSP)
- frontal horn width to intercaudate distance ratio (FH/CC) (for Huntington disease)
- intercaudate distance to inner table width ratio (CC/IT) (for Huntington disease)
- scoring systems
- measurements and ratios
- typical/classical Alzheimer disease
- variant (e.g. posterior cortical atrophy)
- chronic traumatic encephalopathy (CTE)
- corticobasal degeneration
- frontotemporal lobar degeneration (FTLD) (not all are tau)
- Pick disease
- progressive supranuclear palsy (PSP)
- Alzheimer disease
- cerebral amyloidosis
- spinocerebellar ataxias
- Huntington disease
- hereditary spastic paraplegia
- amyotrophic lateral sclerosis (ALS)
- clinically unclassifiable parkinsonism (CUP)
- Unverricht-Lundborg disease
- prion diseases (not always included as neurodegenerative)
- 1. George Huntington from whonamedit.com, the dictionary of medical eponyms. George Huntington
- 2. Dormont D, Seidenwurm DJ. Dementia and movement disorders. AJNR Am J Neuroradiol. 2008;29 (1): 204-6. AJNR Am J Neuroradiol (full text) - Pubmed citation
- 3. Ho VB, Chuang HS, Rovira MJ et-al. Juvenile Huntington disease: CT and MR features. AJNR Am J Neuroradiol. 1995;16 (7): 1405-12. AJNR Am J Neuroradiol (abstract) - Pubmed citation
- 4. Paulsen JS, Zimbelman JL, Hinton SC et-al. fMRI biomarker of early neuronal dysfunction in presymptomatic Huntington's Disease. AJNR Am J Neuroradiol. 2004;25 (10): 1715-21. AJNR Am J Neuroradiol (full text) - Pubmed citation
- 5. Imarisio S, Carmichael J, Korolchuk V et-al. Huntington's disease: from pathology and genetics to potential therapies. Biochem. J. 2008;412 (2): 191-209. doi:10.1042/BJ20071619 - Pubmed citation
- 6. Ahmad R, Bourgeois S, Postnov A et-al. PET imaging shows loss of striatal PDE10A in patients with Huntington disease. Neurology. 2014;82 (3): 279-81. doi:10.1212/WNL.0000000000000037 - Pubmed citation
- 7. Macerollo A, Perry R, Stamelou M et-al. Susceptibility-weighted imaging changes suggesting brain iron accumulation in Huntington's disease: an epiphenomenon which causes diagnostic difficulty. Eur. J. Neurol. 2014;21 (2): e16-7. doi:10.1111/ene.12298 - Pubmed citation
- 8. Sieradzan KA, Mechan AO, Jones L et-al. Huntington's disease intranuclear inclusions contain truncated, ubiquitinated huntingtin protein. Exp. Neurol. 1999;156 (1): 92-9. doi:10.1006/exnr.1998.7005 - Pubmed citation