Huntington’s disease (HD) is an inherited condition affecting the brain function in a progressive manner. This means that it can be transmitted from parents to children and that its onset may start quite unobserved, with slow and steady development affecting the patient.
Most commonly, Huntington’s symptoms appear in adults aged 35-44. If it develops before the age of 20, it is classified as juvenile Huntington’s disease. An early-onset implies slightly different symptoms and can progress faster than the standard HD.
People affected by Huntington’s disease usually live on for about 15-18 years after the onset, in the case of the common form of the disease, and about 10-15 years for the juvenile HD. However, in some cases symptoms are not present until their 50s or 70s.
For European populations, the average prevalence of Huntington’s disease is around 9-17:100,000. The disease is less common in other populations, with values ranging from 0.1 to 2 in 100,000 within indigenous African populations in South Africa, for example.
Huntington’s disease is caused by mutations in the HTT gene. This gene provides instructions for making huntingtin, a protein that appears to play a crucial role in neurons in the brain. It was the first disease-associated gene to be molecularly mapped to a human chromosome in 1983.
Specifically, the mutation that causes Huntington’s disease is a CAG trinucleotide repeat i.e., a sequence of cytosine, adenine and guanine that is repeated several times. In general, we expect to see 10-35 repetitions of these trinucleotides in the HTT gene. However, in people with Huntington’s disease, the CAG segment is repeated 36 to 120 times or more.
The CAG repeat size will determine the phenotype:
– 26 or fewer CAG repeats: normal
– 27-35 repeats: there is no risk of developing the symptoms of the disease, however, it is possible that their children will develop the disease because of instability of the CAG trinucleotide that may increase in the next generations.
– 36 or more repeats: these individuals are considered to have a lifetime risk of developing Huntington disease, but they are also classified into:
o 36-39 repeats: considered to have a reduced penetrance allele. This means that the individuals are at risk of developing the disease but may not develop symptoms of the disease, it is common that with this number of repeats people are asymptomatic.
o 40 or more repeats: they are considered to have a full penetrance allele. That is, all persons having this number of repeats will develop symptoms of the disease. It has been shown that the higher the number of trinucleotide repeats, the more severe and wider the range of symptoms such as motor, cognitive and functional impairment can be.
There is a correlation between the number of repeats and the age of onset: 36-55 repeats usually appear in the adult form, while over 60 repeats are present in people with the juvenile form of the disease.
The alteration in the gene, causes an abnormally long huntingtin protein, which is cut into smaller, toxic fragments that bind together, translocate within the nucleus, alters gene transcription, mitochondrial function, disrupting their normal function, leading to cell death. The dysfunction and, eventually, death of these neurons in certain parts of the brain lead to the onset of symptoms of Huntington’s disease.
How can Huntington’s disease be identified and what symptoms should alert to this condition? Bearing in mind that symptoms become more severe as the disease progresses, we can split them into categories based on the timeline of their occurrence.
Symptoms in the early stages
● Olfactory dysfunction
Mid-disease Huntington’s symptoms
● Chorea, twisting movements, jerking, staggering, unconnected gait
● Problems with activities requiring manual dexterity
● Slow voluntary movements; difficulty initiating movement
● General weakness
● Weight loss
● Speech difficulties
End of disease symptoms:
● Severe chorea (less common)
● Inability to walk and/or talk
● Trouble swallowing, which may be a choking hazard
● Inability to care for themselves
Common psychiatric disorders associated with Huntington’s disease include:
Most of these are also present in persons with juvenile Huntington’s disease, such as movement, mental and emotional problems. Additionally, juvenile affected persons will experience slow movements, clumsiness, frequent falls, stiffness, slurred speech and drooling.
While there is no known cure for Huntington’s disease, persons affected can receive treatment specific to their symptoms as they appear.
For example, for chorea movements, drugs may be prescribed, and anti-parkinsonian agents are also effective in improving conditions of hypokinesia and rigidity. For those experiencing psychotic symptoms, antidepressants can prove effective. Depending on each patient, there are a range of medications that can act on specific symptoms. Specialists will advise on these on a case-by-case basis.
Psychotherapeutic consultations can be very beneficial once the disease has been diagnosed, since they can address several symptoms including behaviour problems. With a doctor, patients can develop future coping strategies and they can also manage expectations of the disease for the patient and their family.
Another important area for treatment in Huntington’s disease is managing difficulties with the muscles necessary for swallowing.
Finally, physical therapy can work to learn exercises developing strength and flexibility, as well as coordination and balance in affected persons. This will help them retain mobility and an independent lifestyle for as long as possible while living with the disease.
Huntington’s disease is inherited in an autosomal dominant manner, meaning that if only one copy of the gene is altered, the disease will appear. Therefore, a person affected by Huntington’s disease has a 50% chance of transmitting it to their children. Studies have shown that individuals with the two copies of the gene affected have a similar age of onset than individuals with just one copy but may show an accelerated rate of disease progression.
When the altered HTT gene is passed on across generations the number of these repeats increases. This leads to an increase in disease severity and/or decrease in age of onset in successive generations – a phenomenon known as anticipation. The expansion of the CAG trinucleotide in the HTT gene can be identified through genetic testing.
Veritas has an expert medical team of genetic counsellors that can help understand your risk for certain genetic diseases. Don’t hesitate to contact us in case you need more information.
Maria Moreno - Medical Science Liaison Manager
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9 August, 2022 12:46 am
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