HUNTINGTON’S DISEASE (HD)

HD is a dominantly inherited disorder characterized by the gradual onset of motor incoordination and cognitive decline in midlife. Symptoms develop insidiously, either as a movement disorder manifest by brief, jerk like movements of the extremities, trunk, face, and neck (chorea) or as personality changes or both. Fine motor incoordination and impairment of rapid eye movements are early features. Occasionally, especially when the onset of symptoms occurs before age 20, choric movements are less prominent; instead, bradykinesia and dystonia predominate.

As the disorder progresses, the involuntary movements become more severe, dysarthria and dysphagia develop, and balance is impaired. The cognitive disorder manifests first as slowness of mental processing and difficulty in organizing complex tasks. Memory is affected, but affected persons rarely lose their memory of family, friends, and the immediate situation. Such persons often become irritable, anxious, and depressed. Less frequently, paranoia and delusional states are manifest. The outcome of HD is invariably fatal; over a course of 15 to 30 years, the affected person becomes totally disabled and unable to communicate, requiring full-time care; death ensues from the complications of immobility.

HD is characterized by prominent neuronal loss in the striatum (caudate/putamen) of the brain. Atrophy of these structures proceeds in an orderly fashion, first affecting the tail of the caudate nucleus and then proceeding anteriorly from mediodorsal to ventrolateral. Other areas of the brain also are affected, although much less severely; morphometric analyses indicates that there are fewer neurons in cerebral cortex, hypothalamus, and thalamus. Even within the striatum, the neuronal degeneration of HD is selective. Interneurons and afferent terminals are largely spared, whereas the striatal projection neurons (the medium spiny neurons) are severely affected. This leads to large decreases in striatal GABA concentrations, whereas somatisation and dopamine concentrations are relatively preserved.

Selective vulnerability also appears to underlie the most conspicuous clinical feature of HD, the development of chorea. In most adult-onset cases, the medium spiny neurons that project to the GPi and SNpr (the indirect pathway) appear to be affected earlier than those projecting to the GPe (the direct pathway).The disproportionate impairment of the indirect pathway increases excitatory drive to the neocortex, producing involuntary choreiform movements. In some individuals, rigidity rather than chorea is the predominant clinical feature; this is especially common in juvenile-onset cases. In these cases the striatal neurons giving rise to both the direct and indirect pathways are impaired to a comparable degree.

The HD gene is expressed widely throughout the body. High levels of expression are present in brain, pancreas, intestine, muscle, liver, adrenals, and testes. In brain, expression of IT15 does not correlate with neuron vulnerability: Although the striatum is most severely affected, neurons in all regions of the brain express similar levels of IT15 mRNA.

The ability of the HD mutation to produce selective neural degeneration despite nearly universal expression of the gene among neurons may be related to metabolic or excitotoxic mechanisms. For many years it has been noted that HD patients are thin, suggesting the presence of a systemic disturbance of energy metabolism. In animal models, agonists for the NMDA subtype of excitatory amino acid receptor can cause pathology similar to that seen in HD when they are injected into the striatum. Interestingly, inhibitors of complex II of the mitochondrial respiratory chain also can produce HD-like striatal lesions¾even when given systemically.

Furthermore, this pathology can be diminished by NMDA-receptor antagonists, suggesting that this is an example of a metabolic impairment giving rise to excitotoxic neuronal injury. Thus the link between the widespread expression of the gene for the abnormal IT15 protein in HD and the selective vulnerability of neurons in the disease may arise from the interaction of a widespread defect in energy metabolism with the intrinsic properties of striatal neurons, including their capacity and need for oxidative metabolism, as well as the types of glutamate receptors present.

An alternative mechanism for the neurodegeneration observed in HD has arisen from studies of effects of the disease on gene expression. In both the human disease and animal models there are striking and selective alterations in patterns of gene expression. This has led to the “transcriptional hypothesis” that suggests that the abnormal function of mutant Huntington may be an ability to alter or interfere with mechanisms of gene transcription.

These two hypotheses have given rise to trials of several different types of therapies in animal models and patients with HD, addressing on the one hand, metabolic defects and energy defects through treatment with agents such as coenzyme Q10 and, on the other hand, drugs that alter gene transcription. None of these approaches is yet established to be effective in altering the course of the disease.

Practical treatment for symptomatic HD emphasizes the selective use of medications. No current medication slows the progression of the disease, and many medications can impair function because of side effects. Treatment is needed for patients who are depressed, irritable, paranoid, excessively anxious, or psychotic. Depression can be treated effectively with standard antidepressant drugs with the caveat that drugs with substantial anticholinergic profiles can exacerbate chorea. Fluoxetine is effective treatment for both the depression and the irritability manifest in symptomatic HD.

Carbamazepine also has been found to be effective for depression. Paranoia, delusional states, and psychosis usually require treatment with antipsychotic drugs, but the doses required often are lower than those usually used in primary psychiatric disorders. These agents also reduce cognitive function and impair mobility and thus should be used in the lowest doses possible and should be discontinued when the psychiatric symptoms resolve. In individuals with predominantly rigid HD, clozapine, quetiapine or carbamazepine may be more effective for treatment of paranoia and psychosis.

The movement disorder of HD per se only rarely justifies pharmacological therapy. For those with large-amplitude chorea causing frequent falls and injury, dopamine-depleting agents such as tetrabenazine and reserpine can be tried, although patients must be monitored for hypotension and depression. Antipsychotic agents also can be used, but these often do not improve overall function because they decrease fine motor coordination and increase rigidity.

Many HD patients show worst of involuntary movements as a result of anxiety or stress. In these situations, judicious use of sedative or anxiolytic benzodiazepines can be very helpful. In juvenile-onset cases where rigidity rather than chorea predominates, dopamine agonists have had variable success in the improvement of rigidity. These individuals also occasionally develop myoclonus and seizures that can be responsive to clonazepam, valproic acid, and other anticonvulsants.

By: Ammarah Khan

    

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