Huntington's Disease (HD)

Introduction of Huntington's Disease (HD)

Huntington's disease (HD) is a rare dominantly neuropsychiatric disorder involving the basal ganglia and cerebral cortex that typically strikes midlife. It is caused by an unstable expansion in the number of CAG (glutamine) repeats in exon 1 of the IT15 gene, which encodes huntingtin (HTT). The results in the production of mutant HTT protein with an abnormally long polyglutamine repeat. In the average population, the number of CAG repeats varies from 6 to 35, but 36 to 41 are associated with an increased risk for HD. However, psychiatric and motor symptoms often precede detectable neuronal loss in HD, and many neurological syndromes proceed without apparent cell death.

Clinical Description

Individuals suffering from HD develop psychiatric disturbances, motor movement disorder, mood disorders, and cognitive impairment. Symptoms typically begin at the age of 35-50 years, with a substantial variation that depends on the length of the polyglutamine stretch. The progression of HD is inexorable and usually leads to death within 15 to 20 years, with immobile and severely demented patients. The cause of death with HD is typically related to complications of immobility, such as skin breakdown, pneumonia, cardiac disease, or infection.

The most obvious symptoms of HD involve involuntary hyperkinetic (choreaform) movements of the arms, legs, and face. When patients exhibit more hypokinetic features (bradykinesia and dystonia) than hyperkinetic features (chorea), they have the Westphal variant of HD. Neuropsychiatric symptoms, especially depression and anxiety, are common and often precede the onset of motor disturbance.

Risk Factors for HD

• Huntingtin Protein

Mutant huntingtin has been shown to impair directly the cellular machinery involved in synaptic transmission. Mutant huntingtin can downregulate several Sp1-dependent neuronal genes, including those encoding the dopamine D1, D2, and D3 receptors localized in postsynaptic components. In HD, mutant huntingtin selectively decreases the expression of N-methyl-D-aspartic acid (NMDA) receptors at presymptomatic stages. In addition, there is a selective loss of kainic acid and AMPA binding in the frontal cortex.

It is worth mentioning that selective reduction of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) has been observed in presymptomatic mouse models of HD. DARPP-32 is involved in dopamine signal transduction and signaling via many other neurotransmitters, including glutamate and serotonin. Therefore, reducing DARPP-32 in HD might contribute to the dysfunction of NMDA, AMPA and dopamine receptors and disrupt standard synaptic transmission.

Fig.1 Major cellular pathways disrupted in HD. (Labbadia, 2013)

• Other Genetic Modifiers

Many other genetic factors have also been shown to modify HD. On chromosome 8, significant associations were seen with RRM2B (a subunit of DNA damage p53-inducible ribonucleotide reductase M2 B) and URB5 (HECT domain E3 ubiquitin-protein ligase). A recent GWAS has revealed the association between HD progression and a genetic variant in MSH3 associated with CAG somatic instability.

Biomarkers of HD

The primary studies mainly focus on the pathophysiology, and the search for biomarkers to early detect the disease. Many potential blood biomarkers have emerged. A promising biomarker is neurofilament light (NFL) protein. Baseline plasma levels of NFL protein correlate with progression in brain atrophy and motor and cognitive measures over time. Other markers are also linked to disease stage, such as tau and measures of inflammation.

Treatment of HD

Treatment of HD consists of drug prescription and non-medication advice. Environmental approaches and cognitive interventions are the mainstays of treatments, but pharmacological interventions typically address the hyperkinetic movement disorders associated with HD. Although not well-studied, cognitive approaches to treat behavior may be more effective than pharmacotherapy for some aspects of the disease.

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Reference

1. Labbadia, J.; Morimoto, R. I. Huntington's disease: underlying molecular mechanisms and emerging concepts. Trends in biochemical sciences. 2013, 38(8), 378-385.