Huntington disease-like 2

Huntington disease-like 2 (HDL2) is a rare trinucleotide repeat expansion disorder that closely resembles Huntington disease. It is considered as one of the core neuroacanthocytosis syndromes (NAS).

Epidemiology

HDL2 occurs at a median age of 41 years, range 12 to 66 years, and typically affects those of Southern African ethnicity . The highest reported number of affected individuals is 69, making HDL2 incredibly rare .

Clinical presentation

Presentation is similar to Huntington disease. Chorea and dystonia are present in the majority of cases . Bradykinesia, tremor and rigidity may also occur . Dementia and psychiatric disturbance, namely depression and aggression, are considered universal . Acanthocytosis is present in a small proportion patients affected by HDL2; due to the low prevalence of acanthocytosis, there is some debate as to whether HDL2 should be considered a neuroacanthocytosis syndrome .

Pathology

Etiology

A diagnosis of HLD2 is based on genetic profiling. Specifically, the absence of genetic alteration in the huntingtin gene and the presence of repeat expansions in the junctophilin 3 (JPH3) gene. JPH3 is a structural membrane protein that is highly expressed in the brain and has a role in cross-talk between ion channels and the cell surface . The exact pathogenesis of JPH3 alteration is unclear, but preliminary data suggest that loss of JPH3 causes a movement-disorder-like phenotype .

Radiographic features

Magnetic resonance imaging demonstrates bilateral atrophy of the caudate, putamen and globus pallidus . This is particularly apparent in the caudate nucleus, which is most frequently affected. HDL2 differs from the other neuroacanthocytosis syndromes due to the occurrence of generalized cortical atropy .

Treatment and prognosis

Supportive treatment is at the center of patient care. HDL2 is often aggressive, rapidly progressing to death in 10-20 years .