Etiology and incidence of Huntington’s disease
Huntington’s disease (MIM No. 143100) is a pan-ethnic autosomal dominant progressive neurodegenerative disease caused by mutations in the HD gene. The prevalence of Huntington’s disease ranges from 3 to 7 per 100,000 among Western Europeans to 0.1–0.38 per 100,000 among Japanese. These changes in prevalence reflect changes in the distribution of Huntington’s disease alleles and haplotypes predisposing to mutation.
Pathogenesis of Huntington’s disease
The HD gene product , the protein gungtintin, is ubiquitously expressed. The function of gungtintin remains unknown.
Disease-causing mutations in the HD gene are usually caused by the expansion of the CAG repeat sequence in exon 1, encoding the polyglutamine chain; Normally, HD alleles have 10 to 26 repeats of the CAG triplet, while mutant alleles have more than 36 repeats. Approximately 3% of patients develop Huntington’s disease as a result of a new expansion of CAG repeats; 97% inherit the HD mutant allele from an affected parent.
New mutant genes of Huntington disease arise as a result of the transition of premutation (27-35 CAG repeats) into a complete mutation. So far, all of the patients described have inherited the new complete mutation from their father.
Expansion of the polyglutamine region of gungtintin leads to the appearance of a new property in it, which is both necessary and sufficient for the induction of Huntington’s disease. In addition to severe disseminated atrophy of the neostriatum, the main symptom of Huntington’s disease, expression of mutant hengtintin causes neuronal dysfunction, general brain atrophy, changes in neurotransmitter levels, and accumulation of nuclear and cytoplasmic aggregates in neurons. As a result, expression of mutant gungtintin causes neuronal death; nevertheless, clinical symptoms and neuronal dysfunction appear to precede the development of intracellular aggregates and neuronal death. The mechanism of how the expression of an increased number of glutamine residues causes Huntington’s disease remains unclear.
Phenotype and development
The age of disease onset is inversely proportional to the number of CAG repeats in the HD gene. Adult-onset patients typically have 40–55 recurrences; in adolescence, usually more than 60 repetitions. Patients with 36-41 CAG repeats have incomplete penetrance, i.e. they may not develop the disease throughout their lives. Except for the age of onset, the number of repetitions does not affect other manifestations of Huntington’s disease.
Instability and expansion of CAG repeats often leads to the phenomenon of anticipation, i.e. an earlier age began in subsequent generations of the family. Once reaching 36, the number of repetitions increases during the spermatogenesis of the father; expansion during maternal transmission of mutation is less common. Because the number of CAG triplet repeats is inversely correlated with age of onset, individuals who inherit the mutation from the father are at increased risk of developing early-onset disease; approximately 80% of young patients inherit the mutant gene for Huntington’s disease from their father.
Approximately one third of patients have psychiatric disorders; two thirds – a combination of cognitive and motor impairments. The average age of patients at the onset of the disease is 35-44 years; In about a quarter of patients, Huntington’s disease develops after age 50 and in one-tenth before age 20. The median survival after diagnosis is 15-18 years, and the median age at death is 54-55 years.
The disease is Huntington is characterized by progressive motor, cognitive and psychiatric disorders. Movement disorders include both voluntary and unintentional movements. Initially, these movements create little interference with daily activities, but usually lead to disability as the illness progresses.
Chorea, present in more than 90% of patients , is the most common form of involuntary hyperkinesis; characterized by non-repetitive non-periodic shocks that cannot be suppressed by an effort of will. Cognitive impairments begin early in the disease and affect all aspects of cognition; speech is usually affected later than other functions.
Behavioral disorders commonly associated with illness include antisocial behavior, aggression, outbursts of anger, apathy, sexual abnormalities, and increased appetite. Psychiatric manifestations that develop at any stage of the disease include personality changes, mild psychosis, and schizophrenia.
In the end stages of Huntington disease , movement disorders are usually so pronounced that patients are completely dependent on outside care. They also lose weight, sleep disorders and mutism. As the disease progresses, behavioral disturbances decrease.
Features of the phenotypic manifestations of Huntington’s disease :
• Age of onset: from adolescence to old age
• Movement disorders
• Cognitive impairments
• Psychiatric disorders
Treatment for Huntington’s disease
To date, there is no effective treatment for Huntington’s disease. Assistance is limited to the care and pharmacological treatment of behavioral and neurological problems.
The risk of inheriting Huntington disease
Every child of a parent with Huntington disease has a 50% risk of inheriting the mutant Huntington’s disease allele. With the exception of alleles with incomplete penetrance (36-41 CAG repeats), all children who inherit the mutant allele, if they have a normal life span, develop Huntington’s disease.
Children of fathers carrying pre-mutation have an empirical approximately 3% risk of inheriting the Huntington’s disease allele, in which the pre-mutation has developed into a full mutation. However, not all males carrying a pre-mutation are equally likely to transmit a complete mutation.
Preclinical testing and prenatal diagnostics are available through analysis of the number of CAG repeats in 1 exon of the HD gene. Preclinical testing and prenatal diagnostics are prognostic techniques, therefore they are better interpreted in case of confirmation of CAG expansion in a sick family member.
An example of Huntington disease: – MP, a 44-year-old man, reported impairment of memory and attention. As his intellectual functions declined over the next year, he developed involuntary movements of the fingers and toes, as well as facial muscles such as grimacing. He understood his condition and became depressed. Prior to that, M.P. was healthy, and had no similarly sick relatives in his anamnesis; his parents died at the age of forty in a car accident. The patient has one healthy daughter.
After an in-depth examination, the neurologist diagnosed the patient’s condition as Huntington’s disease. The diagnosis of Huntington’s disease was confirmed by DNA analysis, which showed the presence of 43 repeats of the CAG triplet in one of the alleles of the HD gene (normally no more than 26). Subsequent presymptomatic examination of her daughter showed that she also inherited the mutant HD allele. Both received detailed advice.