Knowledge on rare diseases and orphan drugs

Huntington disease-like 2 (HDL2) has been exclusively reported in patients of African descent. Although the prevalence and incidence are unknown it is the most common HD phenocopy in African populations with the highest frequency of HDL2 reported in Johannesburg, South Africa.

HDL2 usually presents in adulthood, but, as in Huntington disease (HD), the age of onset is inversely related to the size of the trinucleotide repeat expansion underlying the disorder. HDL2 manifests with chorea, and oculomotor abnormalities. This then progresses to parkinsonism with rigidity, bradykinesia and dystonia with dysphagia and weight loss finally dominating the clinical features. HDL2 has a heterogeneous neuropsychological profile characterized by early cognitive decline that progresses to a subcortical-like dementia in a heterogeneous fashion. The neuropsychiatric presentation is also variable but the most prominent symptoms include sadness, irritability and anxiety. Over the duration of the disease, the HDL2 and HD phenotypes are indistinguishable when comparing the cognitive, psychiatric and motor features. This makes HDL2 the disease which most closely resembles the HD phenotype.

HDL2 is caused by expanded trinucleotide repeats of the JPH3 junctophilin 3 gene (16q24.3). Affected individuals have CTG/CAG repeat expansions of 41-60 triplets (normal range of repeats: 6-27).

Diagnosis is based on analysis of the JPH3 gene in the presence of a clinical syndrome consistent with HDL2. Acanthocytosis was found in three cases but subsequently, this has not been found in other patients. Neuroimaging reveals bilateral striatal atrophy, in particular of the caudate nucleus. Generalized cortical atrophy may develop during the disease course. Neuropathologically, ubiquitin-immunoreactive intracellular neuronal inclusions are found in both HD and HDL2, however these only extend and become intranuclear inclusions in HD.

Differential diagnoses include Huntington disease, Huntington-like disorders, McLeod neuroacanthocytosis syndrome, Parkinson disease, neuroferritinopathy, dentarubralpallidoluysian atrophy, chorea-acanthocytosis, benign hereditary chorea, spinocerebellar ataxia types 2,3,17, familial Creutzfeldt-Jakob disease, Wilson disease, aceruloplasminemia, pantothenate kinase-associated neurodegeneration, mitochondrial disorders, polycythemia rubra vera, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementia, familial Alzheimer, and Tourette syndrome.

Routine methods for prenatal genetic testing can be applied.

HDL2 follows an autosomal dominant pattern of inheritance and genetic counseling is recommended. Anticipation has not been established yet in HDL2. 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.

No curative or disease-modifying treatments are currently available and management is symptomatic and is similar to that of HD.

HDL2 is a relentlessly progressive disorder with a poor prognosis.

Last update: April 2022 - Expert reviewer(s): Dr David ANDERSON - Aline FERREIRA-CORREIA