Huntington’s disease

What it is

Huntington’s disease is a neurodegenerative disorder, meaning one in which nerve cells progressively stop working and die^1,3.

Symptoms usually start between the ages of 30 and 50, but can begin at any age; a rare juvenile form begins in childhood or adolescence^1,2. The condition worsens slowly over many years².

SideFrontAbove

StriatumCerebral cortex

The striatum (caudate and putamen) is particularly vulnerable, and its gradual loss contributes to chorea and to changes in thinking and mood^1,3. MRI can measure shrinkage of the caudate years before diagnosis^1,9.

As the disease progresses, other brain regions, including the cortex, are also affected, and scans may show shrinkage¹.

Signs and symptoms

Early symptoms vary between people and may include mild clumsiness, difficulty concentrating or planning, and mood changes^1,2. Changes in thinking and behaviour can begin years before obvious movement symptoms; measurable brain and behavioural changes have been detected up to 15 years before diagnosis¹.

• Chorea: involuntary, jerky or dance-like movements of the face, fingers, feet or body^1,2
• Dystonia (sustained muscle contractions causing abnormal postures), stiffness and slowness¹
• Problems with balance, walking and falls¹
• Difficulty with attention, planning and flexible thinking, progressing in some people to dementia^1,2
• Irritability, apathy, depression, anxiety and, in some people, thoughts of suicide or psychosis¹
• Slurred speech, difficulty swallowing and weight loss in later stages^1,2

Causes and risk factors

Huntington’s disease has a single genetic cause: an expanded stretch of repeated DNA in the HTT gene^3,5. It is inherited in an autosomal dominant pattern, which means one altered copy of the gene, from either parent, is enough to cause the condition³. A person who does not inherit the altered gene will not develop the disease and cannot pass it on¹.

• Having a parent with Huntington’s disease: each child has a 1 in 2 chance of inheriting the altered gene^1,2
• The number of CAG repeats in HTT: 36 or more repeats are associated with the disease¹
• Repeats in an intermediate range (27 to 35) are unlikely to cause the disease in that person, but the condition could still be passed on to their children¹
• Geographic and ancestral background: prevalence is markedly lower in Asian populations than in European, North American and Australian ones, largely explained by differences in HTT gene haplotypes (inherited blocks of DNA)⁶

Genetics

The gene responsible, now called HTT, was identified in 1993 on chromosome 4. It contains a repeated sequence of three DNA letters, CAG, that is expanded and unstable in people with the disease⁵. HTT provides instructions for making a large protein called huntingtin³.

Longer repeats are associated with earlier onset, but repeat length does not fully predict when symptoms begin³. Genome-wide studies of genetic modifiers showed that the length of the uninterrupted CAG sequence, rather than the length of the resulting protein segment, best predicts the age of onset, and that variants in DNA repair genes alter the timing⁷.

These findings suggest that the CAG repeat keeps expanding within vulnerable brain cells during life, a process called somatic expansion, which may help drive the onset and speed of the disease^4,7. Predictive genetic testing is available to adults at risk, ideally with genetic counselling².

What happens in the brain

The expanded CAG repeat produces huntingtin with an abnormally long stretch of the amino acid glutamine. This mutant protein gains toxic properties, tends to break into fragments and to form clumps, and leads to nerve cell dysfunction and death³.

Mutant huntingtin disrupts many cell processes, including the control of gene activity, mitochondrial energy production and immune function, and the mutant RNA (the gene’s working copy) may itself be harmful⁴.

The striatum, a deep brain region involved in controlling movement and behaviour, is particularly vulnerable, and its gradual loss contributes to chorea and to changes in thinking and mood^1,3. As the disease progresses, other brain regions are also affected, and brain scans may show shrinkage¹.

How it is diagnosed

Diagnosis is based on symptoms, neurological examination, family history and a genetic test¹. Testing a person with symptoms confirms the diagnosis, while predictive testing in a person without symptoms is a personal choice with major implications, usually offered from age 18 with specialist counselling².

• Neurological assessment of movement, balance, reflexes, thinking, memory and mood¹
• A genetic blood test that counts the CAG repeats in HTT, the most accurate way to confirm the diagnosis¹
• Predictive testing for adults at risk who choose it, after genetic counselling²
• Prenatal testing options for people with a family history who are planning a family¹
• MRI or CT brain scans, which may show shrinkage of certain areas but can be normal early on¹

How scientists study it

Current treatments

Research frontiers

Living with the condition and seeking help

Huntington’s disease affects whole families, and decisions about genetic testing, work, driving and having children can be difficult. Genetic counselling and specialist Huntington’s disease services can help people make informed choices at their own pace².

Most people live for many years after symptoms begin and will eventually need support with daily living². National Huntington’s disease associations provide information and support for patients and carers.

Thoughts of suicide can occur in Huntington’s disease¹; anyone with such thoughts, or with choking, chest infections or sudden severe changes in behaviour, should seek urgent medical help. In India, emergency help is available on 112¹⁶, and Tele-MANAS, the national tele-mental health service, offers free support at all hours on 14416¹⁷.