Comparison of the Huntington's Disease like 2 and Huntington's Disease Clinical Phenotypes

Abstract

Background Huntington's disease like 2 (HDL2) is the most common Huntington's disease (HD) phenocopy in many countries and described as the phenocopy with the greatest resemblance to HD. The current clinical description of HDL2 is based on retrospective data. It is unknown whether HDL2 has clinical features that distinguish it from HD. Objective To describe the HDL2 phenotype and compare it to HD systematically. Methods A blinded cross‐sectional design was used to compare the HDL2 (n = 15) and HD (n = 13) phenotypes. African ancestry participants underwent assessments, including the Unified Huntington's Disease Rating Scale (UHDRS). The UHDRS motor component was video recorded and evaluated by blinded experts and the inter‐rater reliability calculated. Results Both groups were homogeneous in terms of demographics and disease characteristics. However, HDL2 patients presented three years earlier with more prominent dysarthria and dystonia. Raters could not distinguish between the two diseases with a high level of agreement. No significant differences in the TMS between HDL2 and HD were found. In both disorders, disease duration correlated with motor scores, with the exception of chorea. Psychiatric and cognitive scores were not significantly different between the groups. Conclusions The HDL2 phenotype is similar to HD and is initially characterized by dementia, chorea, and oculomotor abnormalities, progressing to a rigid and bradykinetic state, suggesting the UHDRS is useful to monitor disease progression in HDL2. Although HDL2 patients scored higher on some UHDRS domains, this did not differentiate between the two diseases; it may however be emerging evidence of HDL2 having a more severe clinical phenotype.

The role of junctophilin proteins in cellular function

“…Inherited defects in JPH3 were the first junctophilin gene disorder associated with a human disease, namely Huntington Disease-Like 2 (HDL2) ( 17 ). Like Huntington Disease, HDL2 usually presents in adulthood (during the fourth decade of life) with a relentless progressive triad of movement, psychiatric, and cognitive abnormalities, which lead to death within 10 to 20 yr ( 218 ). HDL2 is clinically indistinguishable from Huntington Disease.…”

“…In addition, HDL2 patients show movement disorders including eye motion abnormalities, increased Parkinsonism, chorea, hypokinesia (rigidity, bradykinesia), dysarthria, and hyperreflexia in the later stages of the disease. There is a strong correlation between the disease duration and progression of the motor and cognitive disorder ( 218 ). Dementia is a universal feature of HDL2.…”

Huntington’s disease phenocopy syndromes revisited: a clinical comparison and next-generation sequencing exploration

“…Relatively early orolingual involvement with dysarthria, dysphagia or choking in patients with cognitive problems or hyperkinetic limb movements appears suggestive of HD. This may in part be due to the composition of our cohort, since a recent study showed that dystonia and dysarthria were more common in HDL2 than HD patients, although associations were not analysed 48 . Furthermore, different types of dysarthria in HD have been shown to vary significantly in terms of general motor dysfunction 49 .…”

Movement Disorders and Hematologic Diseases

“…HDL‐2 is caused by a CTG/CAG trinucleotide repeat expansion located within the junctophilin 3 (JPH3) gene, with expansions over 41 repeats causing disease. The age of onset is inversely related to the number of repeats, similar to HD, but anticipation has not been demonstrated; and imaging findings are similar to HD 3,4 . Junctophilin‐3 appears to be involved in calcium regulation and junctional membrane structures.…”

“…Parkinsonism and dystonia occur more frequently than in Huntington's disease (HD), and eye movements are normal or only mildly hypometric. Behavioral or psychiatric manifestations can be the presenting symptom 3,4 . Ten percent of patients have acanthocytes, however the etiology of this is unknown.…”