What is Huntington's disease?
Huntington’s disease (HD) is a rare, hereditary disease of the brain. It causes a progressive breakdown of nerve cells in certain regions of the brain, the so-called striatum, which can lead to significant disorders of movement, mental abilities and behavior. Increasing weight loss is also common.
Frequency and age
In Western Europe, around 4 to 15 in 100,000 people are affected; in Switzerland there are around 900-1400 sufferers. The number of carriers in whom the disease has not yet broken out is estimated to be up to ten times higher. HD is the most common autosomal-dominantly inherited neurodegenerative disease. Men and women are equally affected. The first symptoms typically appear between the ages of 30 and 50, less frequently in adolescence or later in life.
Causes of Huntington's disease
Huntington’s disease is caused by a mutation in a specific gene, the so-called huntingtin gene(HTT).
Genes consist of chains of DNA (deoxyribonucleic acid), which function as building instructions and contain information for the production of proteins (proteins). DNA is organized in the cell nucleus in the form of chromosomes. Each human cell contains a double set of chromosomes, so there are two copies (alleles) of each gene. During reproduction, the father and mother each pass on one allele at random to their offspring.
The protein produced by the mutated HTT gene is called mutant huntingtin protein (mHTT). Both mutated and normal (“wild-type”) huntingtin are produced in the cells. Wild-type HTT is essential for the functioning of cell metabolism.
The mode of inheritance of HD is described as autosomal dominant: Both sexes can inherit the predisposition equally, as the genetic defect is located on chromosome 4 and not on one of the sex chromosomes (X and Y). In addition, the defective copy will always “prevail”; it is therefore sufficient to inherit the genetic defect from one parent.
If one parent has the disease-causing gene mutation, each child has a 50% chance of inheriting it. It should be noted that this risk is the same for every offspring. This can be compared to repeatedly tossing a coin: Each toss has a 50% chance of coming up heads or tails, regardless of the previous result.
CAG repeat expansion
CAG repeats are short sections in the genetic code in which the three nucleic bases – the building blocks of DNA – cytosine (C), adenine (A) and guanine (G) are repeated several times in the same sequence. When the gene is read, each CAG is translated into a specific amino acid: Glutamine.
The genetic change that causes HD is a so-called CAG repeat expansion at the start of the HTT gene – the CAG pattern repeats too frequently.
The number of CAG repeats in the huntingtin gene is the factor that determines whether and when Huntington’s disease will develop: The longer the CAG repeat expansion, the higher the probability of an earlier onset of the disease and a more severe manifestation of symptoms.
Healthy individuals usually have between 10 and 26 CAG repeats in the huntingtin gene.
From 40 CAG repeats onwards, Huntington’s disease is fully penetrant: any person with this number or higher will certainly develop symptoms in the course of their life.
Most sufferers have between 40 and 46 repeats, which typically means a manifestation between the ages of 30 and 50.
Between 36 and 39 CAG repeats there is a so-called reduced penetrance: The disease does not necessarily occur in all people, but there is already a significantly higher risk of developing the disease than in the general population.
With 27 to 35 CAG repeats, those affected do not show any symptoms themselves, but have an increased probability that the number of repeats will increase when passed on to their offspring.
Somatic expansion
The CAG repeat expansion in the huntingtin gene is unstable. It continues to increase in length in the course of life, as more and more CAG repeats are incorporated due to faulty DNA repair mechanisms. This process takes place in all cells of the body. However, certain nerve cells in the striatum, an area of the brain that is mainly responsible for controlling movement, are particularly susceptible.
The increase in length occurs gradually over decades, but accelerates as the length of the repeat increases. But it is only when a critical threshold (approx. 150 CAG repeats) is exceeded that a cascade of profound changes in gene expression and cell metabolism is triggered, which ultimately leads to the death of the nerve cell. Not all cells reach this stage at the same time, and it is only when a large number of nerve cells have died that the symptoms of the disease become visible.
The role of the huntingtin protein
Until now, it was assumed that a gradual accumulation and clumping (“aggregation”) of the mHTT protein or one of its variants over a person’s lifetime was the trigger for the disease. However, recent research suggests that this only occurs as a function of the length of the CAG repeat and therefore somatic expansion is probably the decisive factor in the development of the disease, and the aggregation of huntingtin is one of the harmful consequences for the nerve cells.
Anticipation
When the gene is passed on to the offspring, the length of the repeat may increase, thus increasing the probability of an earlier onset of symptoms. This phenomenon is very rare and is known as “anticipation”. It occurs almost exclusively in paternal inheritance.
Symptoms of Huntington's disease
The symptoms of Huntington’s disease affect motor, mental and cognitive functions.
- Uncontrollable, jerky muscle twitching(chorea)
- Deteriorated coordination and balance
- Unsteady, staggering gait
Mental impairments:
- Declining action planning, attention and concentration
- Late stage: dementia / severe impairment of higher brain functions
- Anosognosia: lack of awareness of one’s own deficits
Mental abnormalities:
- Mood swings, depression, irritability
- Increasing listlessness
Other common symptoms:
- Unintentional weight loss despite a normal diet
Diagnosis with us
The diagnosis is made when there is a corresponding clinical picture with characteristic motor symptoms and a positive family history of the disease. A genetic test clearly confirms the diagnosis and is therefore an essential part of the clarification.
To the consultation
It is also possible to carry out genetic testing for the presence of CAG repeat expansion years or decades before the onset of the disease.
More information
Treatment of Huntington's disease
Unfortunately, a course-modifying treatment or even a cure for Huntington’s disease is not yet possible. Therapy therefore aims to alleviate the symptoms and maintain the quality of life of those affected for as long as possible. Various medications can, for example, weaken the uncontrolled movements and treat depression or other psychological complaints. Physiotherapy, occupational therapy and speech therapy are also used to maintain the mobility, independence and communication skills of those affected for as long as possible.
Intensive research is being carried out worldwide into therapies that are intended to reduce the defective huntingtin protein or directly influence the genetic cause, the somatic expansion. Some of these approaches are already in clinical trials, while many others are still being investigated in the laboratory. The hope is to be able to slow down or even stop the disease in the future.
Progression and prognosis of Huntington's disease
The progression of HD is gradual. In most cases, the symptoms worsen over 10 to 25 years, which can ultimately lead to a need for care.
The course of the disease is divided into a premanifest stage and a manifest stage. The transition to manifest (outbreak) disease is determined by the first occurrence of functional deficits relevant to everyday life.
