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Aims Acute intermittent porphyria (AIP) is a disorder of the haem biosynthetic pathway caused by mutations in the hydroxymethylbilane synthase ( HMBS ) gene. Knowledge of the spectrum of mutations present in South Africa is limited. This study presents the molecular profile of 20 South African patients with AIP, and the kinetic analysis of one novel expressed mutated HMBS enzyme and a previously identified mutation at the same position. Methods Genomic DNA was isolated from affected probands and selected family members, the HMBS gene amplified and mutations characterised by direct sequencing and restriction enzyme analysis. One of the novel mutations (p.Lys98Glu), a previously characterised mutation at the same position (p.Lys98Arg), and the wild-type enzyme were expressed, purified and subjected to partial kinetic characterisation. Results Four new mutations, p.Lys98Glu, p.Asp230Aspfs * 20, c.161-1G>A and c.422+3_6delAAGT, are described. Seven previously described mutations were found, while four patients revealed no mutations. Mutation analysis of five offspring of one of the probands carrying the p.Trp283X mutation revealed two asymptomatic carriers. Kinetic analysis showed that the p.Lys98Glu mutation results in loss of substrate affinity, whereas the previously described p.Lys98Arg mutation causes the loss of binding between the enzyme and its dipyrromethane cofactor, rendering the enzyme inactive. Conclusions This study comprises the most comprehensive characterisation of HMBS gene mutations in patients with AIP in South Africa. The biochemical characterisation of expressed HMBS mutants reveals insight into the mechanism of catalytic activity loss, which may inspire investigation into individualised therapy based on the molecular lesion identified.

Globally, hepatitis B virus (HBV) remains a significant yet preventable health issue. In South Africa, seroprevalence prior to the vaccine introduction in 1995 ranged between 0.3and 15% with differences observed in ethnic groups, provinces and rural versus urban areas.1 Vaccination has reduced incidence although with no catch-up schedule, those born before vaccination or incompletely vaccinated, remain at risk.2 Chronic HBV infection elevates the risk of cirrhosis, end-stage liver disease and hepatocellular carcinoma (HCC). Acute HBV carries low mortality but potentially significant morbidity for a professional sportsperson. We report a professional rugby player, incidentally found to have chronic HBV infection. Born before 1995, his HBV acquisition was likely in childhood before age 5, in keeping with HBV epidemiology in sub-Saharan Africa. He used no alcohol, illicit substances or performance enhancing drugs. Table 1 lists his workup identifying the immune clearance/active phase of chronic HBV infection with HBeAg positive, alanine transaminase >5X elevated and a markedly elevated viral load of >log 9 IU/mL. Examination was normal and …