Huntington Disease-Like 2

Huntington disease-like 2 (HDL2) is a severe neurodegenerative disorder considered part of the neuroacanthocytosis syndromes (see this term) characterized by a triad of movement, psychiatric, and cognitive abnormalities.

Epidemiology

Prevalence and incidence are unknown but HDL2 is very rare, with fewer than 50 families reported worldwide. The disease is most often found in patients of African descent.

Clinical description

HDL2 usually presents in young adulthood, but, as in Huntington disease (HD; see this term), the age of onset is inversely related to the size of the trinucleotide repeat expansion underlying the disorder. Patients may develop psychiatric abnormalities as the initial manifestation, with later appearance of chorea, parkinsonism and dystonia. The disease may evolve from chorea to a more bradykinetic, dystonic phenotype, or remain parkinsonian. Unlike chorea-acanthocytosis and McLeod neuroacanthocytosis syndrome (see these terms), deep tendon reflexes are usually brisk. There are no peripheral nerve or muscle abnormalities, and seizures or cardiac manifestations have not been reported.

Etiology

HDL2 is caused by expanded trinucleotide repeats of the JPH3 junctophilin 3 gene (16q24.3). Affected individuals have CTG/CAG repeat expansions of 41-59 triplets (normal population: 6-27).

Diagnostic methods

Diagnosis is based on analysis of the JPH3 gene in the presence of a clinical syndrome consistent with HDL2. Acanthocytosis is found in about 10% of patients and CK levels are normal. Neuroimaging reveals bilateral striatal atrophy, in particular of the caudate nucleus. Generalized cortical atrophy may develop during the disease course. Neuropathologically, ubiquitin-immunoreactive intranuclear neuronal inclusions, similar to those seen in HD, are found.

Differential diagnosis

Differential diagnoses include chorea-acanthocytosis, McLeod neuroacanthocytosis syndrome, Huntington disease, Huntington-like disorders, juvenile Parkinson's disease and Tourette's syndrome (see these terms).

Antenatal diagnosis

Routine methods for prenatal testing can be applied.

Genetic counseling

HDL2 follows an autosomal dominant pattern of inheritance and genetic counseling is recommended. Due to anticipation, related to expansion of the trinucleotide repeat, age of onset can be younger with successive generations. Concerning pre-symptomatic testing, the same considerations as in Huntington disease should be followed: testing is usually requested or proposed when an individual has a parent who is known to have or is suspected of having a Huntington-like disease.

Management and treatment

No curative or disease-modifying treatments are currently available and management is symptomatic.

Prognosis

HDL2 is a relentlessly progressive disorder with a poor prognosis.