How is Huntington's disease diagnosed?

Huntington's disease is characterised by a triad of symptoms: motor, psychiatric and cognitive. Symptoms, as well as their intensity and presentation, vary greatly from one patient to another. Clinical manifestations of the disease generally appear between the ages of 30 and 50, but the disease can appear at any age, from childhood onwards, for example before the age of 20 in 10% of cases. Motor symptoms are the most visible and often the first to be identified, but cognitive or psychiatric problems may already be present. In early forms, before the age of 20, the disease manifests itself mainly as behavioural and learning disorders. On average, Huntington's disease progresses over a period of 13 to 15 years after the onset of clinical symptoms, although this figure varies widely from patient to patient, towards severe dementia, an inability to walk and swallow, and eventually death.

DIAGNOSIS OF HUNTINGTON’S DISEASE

Huntington’s disease is diagnosed clinically on the basis of the symptoms presented by the patient, such as abnormal movements or behavioural problems, taking into account any family history that may help to guide the diagnosis. Brain imaging tests can help rule out other pathologies with similar symptoms.

The clinical diagnosis of the disease can be confirmed by a genetic test which identifies the expansion in the Huntingtin gene, carried out after genetic counselling involving the signing of an informed consent form and the presentation of the results during a genetic consultation.

This molecular diagnosis is carried out using DNA from blood cells and involves quantifying the number of repeats of the CAG sequence.

Because Huntington’s disease is inherited, family members of a person with Huntington’s disease may request genetic testing before symptoms appear. This genetic test enables relatives to find out whether or not they are carriers of the disease expansion and therefore whether they will develop the disease one day.

Currently, an estimated 12,000 people in France are carriers of the huntingtin gene mutation but do not yet have symptoms. The test is supervised to enable the patient to decide whether or not to undergo it at the right time. It is carried out as part of a multidisciplinary consultation involving a geneticist, neurologist, psychologist, genetic counsellor and nurse.

“When the gene and/or mutation responsible are known, the family can access genetic tests and specialist advice to find out how the disease is transmitted within the family. It’s now 30 years since Josué Feingold and Marcela Gargiulo and I set up a consultation service at the Pitié-Salpêtrière hospital for people at risk of a disease they know about. Their parents or grandparents have the disease and they know they are at risk of developing it one day. When we can detect the genetic variation responsible for the disease, we have a choice: to know or not to know before the disease starts”.

Prof. Alexandra Durr (AP-HP, Sorbonne University), medical geneticist in the functional clinical genetics unit at the Pitié-Salpêtrière hospital and co-leader of the “Fundamental and translational neurogenetics” team at the Institut du Cerveau.

Prenatal diagnosis can sometimes be requested. It is carried out in anticipation of a future pregnancy to detect the presence of the expansion in the foetus, before the end of the 3rd month. If the results are unfavourable, the pregnancy may be terminated. Preimplantation diagnosis can also be carried out. This involves looking for the presence of expansion in two- or three-day-old embryos obtained by in vitro fertilisation (with all the limitations of this technique (20% success rate). Unaffected embryos can then be implanted.

The Medical Genetics Department at the Pitié-Salpêtrière University Hospital specialises in hereditary diseases and offers consultations, from the prenatal period to adulthood, for diagnosis, follow-up and genetic counselling (including pre-symptomatic and prenatal diagnosis), for sufferers and/or their relatives.

AT THE PARIS BRAIN INSTITUTE

Identifying the factors that influence the age at which symptoms appear and the progression of the disease is at the heart of the Institut du Cerveau’s research.

Alexandra Durr’s team at the Institut du Cerveau has conducted and participated in several studies which have identified genetic variants influencing the progression of Huntington’s disease.