Differential diagnosis in the presence of typical clinical symptoms, especially a combination of movement disorders, dementia and personality changes
Predictive: known positive family history for HD; preceding genetic counselling is indispensable
Chorea Huntington - IT15
Huntington Disease, HD
Clinical Features
Chorea Huntington is a neurodegenerative disease with an onset around mid-life, but symptoms can manifest in any age. Motor disturbances (restlessness, hyperkinesias, jerky, choreatic movements, especially in facial muscles) occur in the early stages of the disease, along with concentration deficits and reduced physical and mental fitness. The disease course is progressive and leads to severe dyskinesias, extreme restlessness, disturbances of gait and speech; dementia is rapidly progressing; personality changes are typical (withdrawal, disturbances of impulsion, depression, but also aggressive behavior).
Genetic Information
Chorea Huntington follows an autosomal dominant pattern of inheritance and is caused by an increase of CAG triplet repeats in the huntingtin gene (IT15 gene) on chromosome 4 (4p16.3). Whilst there are 10 to 30 CAG triplet repeats in the normal population, more than 39 repeats are observed in affected individuals. In general, the age of onset is earlier with increasing repeat number, and disease progression is more rapid. However, onset of disease and the disease course cannot be predicted due to CAG triplet repeat numbers. CAG triplet repeat numbers of 36 to 39 are designated intermediate alleles (grey zone alleles), since only a part of those individuals carrying an intermediate allele develop the disease within normal life span. Patients with 40 or more CAG triplett repeats will develop Huntington disease.
From one generation to the next there may be anticipation, i.e. an earlier onset of Huntington disease symptoms. Anticipation occurs more commonly in paternal transmission of the mutated allele since the repeat number increases rather by inheritance via the male germline than via the female. Normal alleles are stably transmitted from one generation to the next.
| Repeats | |
| Normal allele | < 27 |
| Premutation allele, meiotic unstable |
27-35 |
| Pathological allele, reduced penetrance |
36-39 |
| Pathological allele | > 39 |
Prevalence
About. 1 : 5 000 to 1 : 6 000
Diagnostic
Indication
Method
The CAG repeats are detected by two independent PCR reactions. The exact repeat number (not increased or pathologically increased) is determined by subsequent fragment length analysis.
Possibly, also the number of proline repeats next to the CAG repeats is determined
Sample Requirement
2 - 4 ml of EDTA blood
Duration
approx. 2 weeks