Objective: To investigate the occurrence of phenocopy mutations in a cohort of black South African individuals referred to the National Health Laboratory Service (NHLS) for Huntington disease confirmatory molecular testing.

Background: Huntington disease (HD) is a disabling neurodegenerative disorder caused by an unstable expanded trinucleotide (CAG) repeat in the huntingtin (HTT) gene. The condition characteristically presents with a triad of symptoms: behavioural problems, movement disorder and cognitive decline. Internationally, between 1 and 7% of individuals clinically diagnosed with HD do not carry the mutation and are said to have an HD phenocopy (Wild et al. 2008); a term used to describe any syndrome that manifests HD-like symptoms in the absence of an HTT expansion. In South Africa, direct mutation testing for HD is performed in the public sector by the NHLS. A significant proportion (30-40%) of patients referred for molecular diagnostic confirmation does not carry an expansion in the HTT gene and may therefore have a phenocopy. Up to one third of these patients have been found to carry a repeat expansion in the junctophilin-3 (JPH3) gene underlying Huntington disease-like 2 (HDL2), an African specific phenocopy (Krause et al 2015). As a result, HDL2 has been incorporated into routine diagnostic testing for HD referrals. However, many patients test negative for both mutations and therefore have no molecular diagnosis.

Methods: Record review identified 105 black South Africans referred to the NHLS who had previously tested negative for both the HTT and JPH3 expansions. Molecular laboratory testing protocols were undertaken for selected HD phenocopies including Spinocerebellar ataxia (SCA) subtypes: 1, 2, 7, 17; Dentatorubral-palidolluysian atrophy (DRPLA) and the recently identified C9orf72 hexanucleotide expansions.

Results: A systematic screen for each of the above-named disorders was undertaken. SCA2 has been confirmed in one individual and results are anticipated for the DRPLA and C9orf72 mutation screen. No mutations have been identified for SCA 1, 7 and 17.

Conclusions: This is the first systematic investigation of a South African cohort for the presence of mutations underlying HD phenocopies. Initial results suggest that misdiagnosis may be commonly encountered in the South African setting.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/huntington-disease-phenocopies-or-misdiagnosis-a-black-south-african-cohort/