Huntington's Disease

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Huntington’s disease (HD)

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relatively rare, inherited neurodegenerative disorder

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Worldwide prevalence of 5 per 100,000

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(Medina et al. 2022)

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HD is a repeat length expansion disorder

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caused by mutation in the huntingtin (HTT) gene, the function of which remains relatively unclear

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Consequential polyglutamine (CAG) expansion leads to

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accumulation of mutant Htt protein (mHtt) and the formation of dense, intraneuronal inclusion bodies which ultimately compromise cell viability and neuronal survival

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Mean age of HD onset is 30-50 years with a mean life expectancy of

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17-20 years

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In some cases, symptoms can present prior to 20 years of age

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with juvenile HD associated with behaviour disturbances and learning difficulties at school

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HD is primarily characterised by motor, cognitive and psychiatric disturbances

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with metabolic and mitochondrial dysfunction commonly observed in HD patients as well as an aberrant inflammatory response

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Motor symptoms are perhaps the most common manifestation of HD

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with Huntington’s chorea defined as non-rhythmic jerking movements of arms and legs

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Can also include facial grimacing as well as

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shoulder raising and finger extension

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Chorea is present while the individual is awake however

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absence of unwanted movements during sleep is postulated to involve the anti-inflammatory role of sleep

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As HD progresses

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difficulties with talking and swallowing can lead to choking as well as patients becoming mute

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Mild cognitive symptoms may initially appear in forms of irritability depression and incoordination

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which eventually progresses towards dementia and epileptic seizures

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Psychiatric disturbances may be present during the pre-manifest stage

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with apathy the only neuropsychiatric symptom shown to consistently progress with disease

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Suicide rates are the second most common death in HD

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following respiratory complications

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The anatomical basis of chorea is believed to be the basal ganglia (BG)

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where HD brains present with enlargement of the lateral ventricles and thus atrophy of the dorsal striatal regions, the caudate and the putament.

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Associated degeneration in the frontal and temporal cortices is potentially the cause of

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behavioural and cognitive deficits

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A 5 grade classification system exists for HD pathology

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grade 0 - demonstrates clinical evidence for HD without microscopic abnormalities

grade 4 - characterised by shrunken yellow-brown caudate with widened anterior horn of lateral ventricle and smaller nucleus accumbens

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MRI advances have confirmed early pathological findings of grey matter volume decline

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in caudate and putamen and loss of white matter in striatum and cortex

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The pathophysiological mechanism behind hyperkinetic activity in HD involves

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degeneration of medium spiny GABAergic interneurons of the caudate and putamen

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Loss of these inhibitory projections to the external globus pallidus

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leads to decreased activity of the indirect pathway of the BG

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External GP cells become abnormally active reducing the

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excitatory output of the subthalamic nucleus to the internal GP

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Inhibitory outflow of the BG reduced

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shifting balance in favour of direct pathway and thalamic overexcitation of the frontal cortex

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In contrast, cognitive and psychiatric decline in HD

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associated with disruption of non-motor BG loops i.e prefrontal, limbic

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According to the WHO by 2040

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neurodegenerative diseases will have surpassed cancer to become the second leading cause of death worldwide emphasising the need for suitable treatment options to improve quality of life of individuals suffering from these debilitating conditions

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While there is currently no cure for HD

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several treatments are available in order to manage these fatal symptoms with ongoing research into future therapeutic possibilities

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Tetrabenzazine is the only

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drug specifically licensed to treat HD chorea

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TB acts primarily as a reversible high-affinity inhibitor of

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monoamine uptake into granular vesicles of presynaptic neurons by binding selectively to VMAT-2

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As a result of VMAT2 inhibition

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monoamine degradation in neuron is increased, depletion of monoamines particularly dopamine

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Side effects of TB however

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sleep disturbances anxiety depression

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While antidepressants are often prescribed to manage cognitive and psych symptoms

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In recent years researchers have become increasingly aware of potential therapies that extend beyond those commonly used to treat disorders of the CNS

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Metformin

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widely established drug T2DM

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Gene therapy is at forefront of current research

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with antisense oligonucleotides (ASOs) showing promise as potential treatment for HD

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ASOs consist of single stranded synthetic DNA molecules

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that selectively bind target mRNA producing RNAse H-mediated degradation of the target

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Previous studies have demonstrated the ability of ASOs to reduce the level of mHTT mRNA in transgenic mouse models

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While human trials initially reproduced these findings data from phase III clinical trials have proved discouraging highlighting need for further research in this area