Rare Genetic Diseases: Huntington’s disease
Although Huntington’s disease is a rare form of genetic disorder, you might have already heard of it. On average, it affects 5–7 individuals in 100,000. But how much do we really know about Huntington’s disease?
Huntington’s disease is an autosomal-dominant, progressive neurodegenerative disorder. Typically, the onset of the symptoms, which include chorea as well as dystonia, starts in the middle-age, after the affected individual has already had children. However, the individuals can become symptomatic from the age of 1 till 80. Due to the late presentation of the disease, it is important for the family to undergo counseling, as well as genetic testing of the children.
It is often the family members or close relatives who notice that something has gone wrong, as the patient experiences changes in personality (depression and suicidal thoughts, or aggression), cognition as well as motor control. This is known as the prediagnostic stage. The cognitive dysfunction impairs the executive functions such as planning and organising. The poor motor control tends to develop into motor impersistence, when the affected individual is unable to maintain a voluntary muscle contraction at a constant level. As the disease progresses, patients might develop dementia due to progressive cerebral atrophy. It is also very common for the patients to develop disarthria (unclear speech). The disease is incurable, and the treatment is purely symptomatic.
MRI is used as the most common diagnostic tool, however, other examinations are included such as the fine motor skill test, which consists of finger-tapping rhythm and rate. The gross motor skills examination incorporates holding the right posture of the body. Due to the deterioration of the motor and cognitive skills, individuals affected by Huntington’s disease die from complications of falls, inanition (lack of nourishment), dysphagia (difficulty/pain while swallowing), or aspiration pneumonia within 20 years from the diagnosis.
Even though the principles behind Huntington’s disease are poorly understood, it is known that the mutant protein Huntington, which is the main cause, is produced from CAG repeat. This expanded repeat leads to a polyglutamine strand, that varies in length from patient to patient, at the N-terminus.
The length of the CAG sequence influences the age at which the onset of the disease starts. Furthermore, the length of the polyglutamine repeat affects the severity of the disease irrespective of the gene affected. If the trinucleotide repeat of CAG is longer than 41 repeats, the disease is fully penetrated. At the length between 36 and 40 repeats there is an incomplete penetrance, and if the number of repeats is 35 and less, the patient does not suffer from Huntington’s disease.
The gene for Huntington protein is located on the short arm of the 4th chromosome. Huntington’s disease (HD) gene is present in all mammalian and animal cells with the highest concentration in the brain and testes. The results of a study carried out on mice suggest that the gene confers a toxic gain of function. The research on transgenic animal models is providing an insight into causative factors and future of the treatments.
