Knowledge on rare diseases and orphan drugs

Prevalence in the Caucasian population is estimated at 1/20, 000-1/10,000.

Mean age at onset of symptoms is 30-50 years. In some cases symptoms start before the age of 20 years with behavior disturbances and learning difficulties at school (Juvenile Huntington disease, JHD; see this term). The classic sign is chorea that gradually spreads to all muscles. Other unwanted movements include tics, comparable to those seen in Tourette syndrome (see this term), but these are fairly rare. Cerebellar signs can appear sporadically, similar to the presence of hypo- and hypermetria. Dystonia (e.g. torticollis) can be the first motor sign in Huntington disease. Other less well-known, but prevalent and often debilitating features of HD include unintended weight loss, sleep- and circadian rhythm disturbances and autonomic nervous system dysfunction. Dysarthria and dysphagia become very prominent during the course of the disease. Talking and swallowing gradually become more problematic leading to choking at any time in some patients. All patients develop hypokinesia and rigidity leading to bradykinesia and severe akinesia. All psychomotor processes become severely impaired. Patients also experience cognitive decline. Psychiatric symptoms are very common in the early stage of the disease, often prior to onset of motor symptoms. The percentage of patients with psychiatric signs, such as low self-esteem, feelings of guilt, anxiety and apathy, varies between 33% and 76%. Suicide occurs more frequently in early symptomatic patients and also in premanifest gene carriers. The most risky periods for suicide are around the time of the gene test and when independence starts to diminish.

HD is caused by an elongated CAG repeat (36 repeats or more) on the short arm of chromosome 4 (4p16.3) in the huntingtin gene, HTT. The longer the CAG repeat, the earlier the onset of disease. In cases of JHD, the repeat often exceeds 55.

Diagnosis is based on clinical symptoms and signs in an individual with a parent with proven HD and is confirmed by DNA determination Premanifest diagnosis should only be performed by multidisciplinary teams in healthy at-risk adult individuals who want to know whether they carry the mutation or not.

Differential diagnoses include other causes of chorea including general internal disorders or iatrogenic disorders. Phenocopies (clinically diagnosed cases of HD without the genetic mutation) are observed.

Prenatal diagnosis is possible by chorionic villus sampling or amniocentesis. Pre-implantation diagnosis with in vitro fertilization is offered in several countries.

HD is transmitted in an autosomal dominant manner.

To date, no cure is available. Management should be multidisciplinary and is based on treating symptoms with a view to improving quality of life. Chorea is treated with dopamine receptor blocking or depleting agents. Medication and non-medical care for depression and aggressive behavior may be required.

The progression of the disease leads to complete dependency in daily life, which results in patients requiring full-time care, and finally death. The most common cause of death is pneumonia, followed by suicide.

Last update: January 2011 - Expert reviewer(s): Pr R.A.C. [Raymund] ROOS