Huntington's disease Flashcards
Genetics
Hungtingtin gene (HTT) is located on the short arm of chromosome 4.
An autosomal dominant mutation results in an increased length (>40) of CAG repeats in the Huntigtin protein, creating an extended polyglutamine tail.
If repeats are between 27-39, you might not have the disease but your children might develop it.
Huntingtin protein
Ubiquitous cytoplasmic protein.
Essential for embryonic development.
Involved in: intracellular transport and signalling, metabolism, neurogenesis, synaptic activity, transcription regulation, anti-apoptotic activity.
Mutated proteins aggregate - targeting this is difficult as oligomers and fibrils tend to be toxic but larger aggregates may be protective.
Mutated proteins are involved in: proteosome inhibition, transcriptional dysregulation of BDNF, mitochondrial dysfunction, dysfunction of Ca signalling, binding to other proteins to inhibit function, and vesicular transport defects.
Pathology - brain structure changes
10-20% reduction in brain weight
Striatal and cortical volumes decrease, with the caudate nucleus and putamen being particularly affected.
Ventricle size increases.
Proteinous inclusions throughout the brain.
Pathology - neuronal changes
Selective loss of GABAergic medium spiny neurons (MSN) in the striatum.
D2-activated enkephalin-containing MSN in the indirect pathway are affected first → excess involuntary movement.
D1-activated substance P-containing neurons in the direct pathway are affected later → lack of voluntary movement.
Basal ganglia circuity
The indirect and direct pathways start in the striatum. The indirect pathway neurons have D2 receptors and project to the external globus pallidus. The direct pathway neurons have D1 receptors and project to the internal globus pallidus.
Both release GABA, but the indirect pathway releases enkephalin as a cotransmitter and the direct pathway substance P.
Activation of the direct pathway causes the release of glutamate onto the cortex to initiate movement.
The indirect pathway goes to the external segment first between signalling with the internal one. Activation of D2 receptors inhibits the external globus pallidus, causing the release of less GABA onto the subthalamic nucleus. This allows an increase of activity of the internal segment, causing more inhibition of the thalamus and so less activation of the cortex.
In early HD, medium spiny neurons of the indirect pathway start to degenerate, so there is less inhibition of the thalamus and more glutamate released onto the cerebral cortex, causing an excess of involuntary movement.
Basal ganglia parallel loops
Along with the motor cortex, the dorsolateral prefrontal, lateral orbitofrontal and medial orbitofrontal cortices are also regulated by the basal ganglia.
Dorsolateral prefrontal cortex runs through the caudate nucleus and is involved in decision making and executive function. Along with the lateral orbitofrontal cortex, it is involved in cognition.
The medial orbitofrontal cortex loop runs through the nucleus accumbens, which plays an important role in reward and addiction. Damage to this loop causes psychiatric symptoms.
Motor phenotype
Early: abnormal eye movements, inappropriate hand and toe movements and general restlessness.
Midcourse: chorea, hypertonic rigidity, dystonia.
Late: impaired voluntary movements leading to rigidity, bradykinesia, dystonia, convulsions and weight loss.
Death can occur due to pneumonia, choking, chronic skin ulcers or nutritional deficits as voluntary movements are impaired so much, patients can no longer carry out daily functions like eating or walking.
Cognitive phenotype
May precede motor onset by over a decade.
Dysexecutive syndrome: attention deficits, impaired insight and judgement, forgetfulness, language deficits.
Psychiatric phenotype
Highly variable symptoms, can precede motor onset by over a decade.
Include: irritability, apathy, depression, anxiety, disinhibition, obsessive-compulsive behaviour.
Hallucinations and delusions may occur.
Additional symptoms
Weight loss due to involuntary movements, loss of appetite and motivation, dysphagia, and metabolic dysfunction.
Neuronal-based (hypothalamic) metabolic dysfunction suggested as weight loss is seen even when calorie intake is increased to account for dyskinesia.
Sleep disturbances due to circadian disturbances , depression and ‘break-through’ involuntary movements.
Muscle weakness due to HTT inclusions and mitochondrial dysfunction.
Chorea treatment
Used in early HD.
Antipsychotics (D2 antagonists) - olanzapine
Tetrabenazine - depletes dopamine and other monoamines
Dopamine antagonists recover some of the function of the indirect pathway as remaining neurons are not inhibited.
Benzodiazepines - clonazepam, diazepam - enhance GABA signalling → increased thalamus inhibition and less activation of the motor cortex
Other treatments
Psychiatric symptoms treated with SSRIs like citalopram.
Speech therapy
Dietician or Percutaneous endoscopic gastrostomy (PEG)
Physiotherapy
Late stage → palliative care
Future therapies
Gene therapy using siRNA or antisense oligonucleotides
The addition of these in the CSF has shown some benefits, decreasing mutated huntingtin aggregations by preventing the RNA from being translated.
Trial was halted in 2021 as some patients were actually getting worse.
