Learn about the evolution of Huntington’s disease and how to treat it

Huntington’s disease (HD) is a rare movement disorder. It is inherited and is characterized by involuntary movements (chorea), psychiatric disorders and cognitive impairment.

Causes of Huntington’s disease

Huntington’s disease is caused by a defect in a gene (IT15), which encodes a protein called huntingtin. The genetic defect results in the production of an abnormally elongated protein (mutant huntingtin), which is responsible for the neuronal degeneration that occurs in the disease. In the brain there is neuronal loss, as well as deposits of huntingtin and other proteins in the form of nuclear and cytoplasmic inclusions in the surviving neurons.

There is no relationship between Huntington’s disease and Parkinson’s disease, although in both there is a process of neurodegeneration and deposition of abnormal proteins in the brain: hungtintin in HD and synuclein in Parkinson’s disease. In Parkinson’s, unlike HD, the patient’s movements are characteristically slowed. In Huntington’s disease there is an excess of mobility (hyperkinesias).

There is also a significant clinical overlap between HD and other hereditary neurological diseases.

When and how Huntington’s disease appears

The average age of symptom onset is 38 years, with variable limits between the second and seventh decades of life. The established clinical picture consists of three cardinal manifestations: choreic hyperkinesias, neuropsychiatric disorders and cognitive impairment. Chorea affects the axial musculature but also the limbs. There is also dysarthria and sometimes dysphagia, as a result of dysfunction of the pharyngeal and upper esophageal musculature. The range of neuropsychiatric disorders is highly variable, from subtle personality changes and depression to severe psychotic disorders. There is a high incidence of suicide in families with Huntington’s disease.

Differential diagnosis of Huntington’s disease

Diagnosis is based on clinical data and evidence of vertical transmission of autosomal dominant inheritance. Neuroimaging tests (CT and MRI) reveal typical alterations. Confirmation of HD, as well as presymptomatic diagnosis, can be made by molecular genetic techniques demonstrating pathological expansion of the CAG triplet in the IT15 gene.

We know that 1 to 7% of patients clinically diagnosed with HD do not have a mutation of the IT15 gene. These subjects with a clinical diagnosis of Huntington’s disease but negative IT15 have come to be referred to as Huntington disease-like (HDL).

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In addition to genetic causes, there are numerous acquired chorea that should be considered in the differential diagnosis of HD chorea. These include Sydenham’s chorea, Wilson’s disease, hyperthyroidism, drug-induced choreic dyskinesias (tardive dyskinesia) or Gilles de la Tourette’s disease.

Histology shows in addition to significant loss of medium spiny neurons in the basal ganglia, intranuclear accumulation of CAG repeats, as seen by immunohistochemistry with antibodies against polyglutamine expansions (left panel, polyQ). Compact intranuclear inclusions are visible using anti-ubiquitin or anti-p62 immunostains (right panel, p62).

Prognosis of Huntington’s disease

Huntington’s disease follows an invariably progressive clinical course that is more rapid in the juvenile-onset forms. The average duration of HD is 19 years, with limits between 10 and 25 years.

Treatment of Huntington’s disease

Treatment relieves some manifestations, but does not delay either the onset or progression of symptoms. Treatment should be multidisciplinary and should support not only the patient, but also his or her relatives, so it is advisable to involve, in addition to neurology experts, social workers, psychologists and other professionals who are familiar with the problems of these patients.

The only drugs that have been shown to be effective in the control of chorea are dopamine receptor antagonists in the striatum (neuroleptics) and inhibitors of dopamine storage or release (tetrabenazine and reserpine). There is no effective treatment for dementia, which is the most disabling aspect of the disease, but antipsychotic and antidepressant drugs are useful in the treatment of other neuropsychiatric manifestations.

In addition, appropriate genetic counseling is essential in Huntington’s disease. The detection of carriers of the disease, in pre-symptomatic phases, is possible thanks to new molecular biology techniques. Since the application of these techniques is not free of legal and ethical problems, many hospitals have set up committees involving patients, physicians, lawyers and experts in medical ethics to advise, on a case-by-case basis, on the appropriateness of implementing them.