The Frequency of Huntington Disease and Huntington Disease-Like 2 in the South African Population.

BACKGROUND: Huntington disease (HD) has most recently been estimated to affect between 10.6 and 13.7 per 100,000 individuals in European populations. However, prevalence is known to differ geographically. In South Africa, the only published estimates are from a survey performed in the 1970s, an era when the disease was believed to be rare or absent in black individuals and molecular confirmation was absent. The disease phenotype in South Africa is currently attributable to mutations in both the huntington and junctophilin-3 genes, which underlie the well-known HD and the rarer HD-like 2 (HDL2) respectively. This study aimed at providing improved minimum estimates of disease frequency in South Africa, based on molecular genetic testing data. METHODS: A review of all testing records for HD and HDL2 over a 20-year period was undertaken. HDL2 is virtually indistinguishable on clinical features, thus necessitating its inclusion. RESULTS: Based on molecular diagnostic records, minimum estimates of disease frequency are: 5.1, 2.1 and 0.25 (per 100,000 individuals) for the white, mixed ancestry and black population groups respectively. CONCLUSION: Although ascertainment remains incomplete, these minimum estimates suggest that disease frequencies are significantly higher than those previously reported in South Africa.

A study of Huntington disease-like syndromes in black South African patients reveals a single SCA2 mutation and a unique distribution of normal alleles across five repeat loci.

Huntington disease (HD) is a progressive neurodegenerative disease, characterised by a triad of movement disorder, emotional and behavioural disturbances and cognitive impairment. The underlying cause is an expanded CAG repeat in the huntingtin gene. For a small proportion of patients presenting with HD-like symptoms, the mutation in this gene is not identified and they are said to have a HD "phenocopy". South Africa has the highest number of recorded cases of an African-specific phenocopy, Huntington disease-like 2 (HDL2), caused by a repeat expansion in the junctophilin-3 gene. However, a significant proportion of black patients with clinical symptoms suggestive of HD still test negative for HD and HDL2. This study thus aimed to investigate five other loci associated with HD phenocopy syndromes - ATN1, ATXN2, ATXN7, TBP and C9orf72. In a sample of patients in whom HD and HDL2 had been excluded, a single expansion was identified in the ATXN2 gene, confirming a diagnosis of Spinocerebellar ataxia 2. The results indicate that common repeat expansion disorders do not contribute significantly to the HD-like phenotype in black South African patients. Importantly, allele sizing reveals unique distributions of normal repeat lengths across the associated loci in the African population studied.

Huntington disease in the South African population occurs on diverse and ethnically distinct genetic haplotypes.

Huntington disease (HD) is a neurodegenerative disorder resulting from the expansion of a CAG trinucleotide repeat in the huntingtin (HTT) gene. Worldwide prevalence varies geographically with the highest figures reported in populations of European ancestry. HD in South Africa has been reported in Caucasian, black and mixed subpopulations, with similar estimated prevalence in the Caucasian and mixed groups and a lower estimate in the black subpopulation. Recent studies have associated specific HTT haplotypes with HD in distinct populations. Expanded HD alleles in Europe occur predominantly on haplogroup A (specifically high-risk variants A1/A2), whereas in East Asian populations, HD alleles are associated with haplogroup C. Whether specific HTT haplotypes associate with HD in black Africans and how these compare with haplotypes found in European and East Asian populations remains unknown. The current study genotyped the HTT region in unaffected individuals and HD patients from each of the South African subpopulations, and haplotypes were constructed. CAG repeat sizes were determined and phased to haplotype. Results indicate that HD alleles from Caucasian and mixed patients are predominantly associated with haplogroup A, signifying a similar European origin for HD. However, in black patients, HD occurs predominantly on haplogroup B, suggesting several distinct origins of the mutation in South Africa. The absence of high-risk variants (A1/A2) in the black subpopulation may also explain the reported low prevalence of HD. Identification of haplotypes associated with HD-expanded alleles is particularly relevant to the development of population-specific therapeutic targets for selective suppression of the expanded HTT transcript.