Pyruvate dehydrogenase complex (PDHC) deficiencies are a group of mainly infantile onset disorders stemming from defects in pyruvate catabolism. They are characterised by severe lactic acidosis and progressive neurodegeneration.Although the PDHA1 gene is implicated in most cases of PDHC deficiency worldwide, no pathogenic variants have been reported in South African patients to date, despite availability of PDHA1 sequencing in the state diagnostic setting.METHODS:DNA from five patients with low to absent PDHC activity in fibroblasts were subjected to PDHC deficiency gene panel analysis. Included in the panel were: PDHA1, PDHB, DLAT, DLD, PDHX, BOLA3, GLRX5, IBA57, LIAS, LIPT1, LIPT2, NFU1, PDP1, PDP2, SLC19A2, SLC19A3, SLC25A19, SLC25A26, TPK1 and FBXL4.RESULTS:No pathogenic variants were identified in 4 out of 5 cases investigated. A homozygous frame-shift mutation was detected in the BOLA3 gene in one patient, supporting a diagnosis of multiple mitochondrial dysfunction syndrome type 2.DISCUSSION:A single, novel, homozygous BOLA3 frame-shift mutation was detected in a black South African child with severe neurodegenerative disease and very low to absent PDHC enzyme activity. This finding of a homozygous mutation in a patient from a non-consanguineous background may indicate a need for further investigation in clinically similar cases as well as heterozygous carrier rates in unaffected individuals from the same ethnic background.The paucity of identifiable mutations in 4 out of 5 South African patients with confirmed PDHC deficiency highlights the dangers in relying on Western population based genetic panels for diagnosing rare metabolic disease in genetically understudied populations.

BackgroundLiver dysfunction is common and often unrecognized. Liver biopsy is the gold standard in the assessment of liver fibrosis, but has disadvantages. We assessed the diagnostic accuracy of serum prolidase enzyme activity (SPA) in predicting the presence and degree of liver fibrosis, as compared with liver biopsy. Further, we evaluated the effect of hemolysis on measured SPA levels.MethodsWe undertook a prospective case control study. Thirty eight outpatients without apparent liver illness and 20 patients with liver pathology scheduled to undergo liver biopsy had their SPA levels measured.ResultsPatients undergoing liver biopsy had higher SPA levels (361 (268) IU/l [median (interquartile range)]) compared with controls (169 (160) (P < 0.001)). A SPA cutoff value of 200 IU/l yielded a sensitivity of 89%, specificity of 59%, an odds ratio of 11.5, negative predictive value of 92%, and a positive predictive value of 50%. Hemolysis causes an apparent increase in SPA levels.ConclusionHigher SPA levels in patients undergoing liver biopsies compared with controls may reflect the presence of liver fibrosis. SPA levels could not be used to stage the degree of fibrosis. SPA measurement may be useful in the diagnostic workup of suspected liver disease.

We present a 23-year-old man with a history of advanced multi-bacillary leprosy treated with dapsone, clofazimine, rifampicin and isoniazid.

Glutaric Aciduria type 1 (GA 1) is an inherited disorder of lysine and tryptophan catabolism that typically manifests in infants with acute cerebral injury associated with intercurrent illness. We investigated the clinical, biochemical and molecular features in 14 known GA 1 patients in South Africa, most of whom were recently confirmed following the implementation of sensitive urine organic acid screening at our laboratory. Age at diagnosis ranged from 3days to 5years and poor clinical outcome reflected the delay in diagnosis in all but one patient. Twelve patients were unrelated black South Africans of whom all those tested (n=11) were found homozygous for the same A293T mutation in the glutaryl-CoA dehydrogenase (GCDH) gene. Excretion of 3-hydroxyglutarate (3-OHGA) was >30.1μmol/mmol creatinine (reference range <2.5) in all cases but glutarate excretion varied with 5 patients considered low excretors (glutarate <50μmol/mmol creatinine). Fibroblast GCDH activity was very low or absent in all of five cases tested. Heterozygosity for the A293T mutation was found 1 in 36 (95% CI; 1/54 - 1/24) unrelated black South African newborns (n=750) giving a predicted prevalence rate for GA 1 of 1 in 5184 (95% CI; 1/11664 - 1/2304) in this population. GA 1 is a treatable but often missed inherited disorder with a previously unrecognised high carrier frequency of a single mutation in the South African black population.

The objective of the study was to examine the association between a functional 4 bp proinsulin gene insertion polymorphism (IVS‐69), fasting insulin concentrations, and body composition in black South African women. Body composition, body fat distribution, fasting glucose and insulin concentrations, and IVS‐69 genotype were measured in 115 normal‐weight (BMI <25 kg/m2) and 138 obese (BMI ≥30 kg/m2) premenopausal women. The frequency of the insertion allele was significantly higher in the class 2 obese (BMI ≥35kg/m2) compared with the normal‐weight group (P = 0.029). Obese subjects with the insertion allele had greater fat mass (42.3 ± 0.9 vs. 38.9 ± 0.9 kg, P = 0.034) and fat‐free soft tissue mass (47.4 ± 0.6 vs. 45.1 ± 0.6 kg, P = 0.014), and more abdominal subcutaneous adipose tissue (SAT, 595 ± 17 vs. 531 ± 17 cm2, P = 0.025) but not visceral fat (P = 0.739), than obese homozygotes for the wild‐type allele. Only SAT was greater in normal‐weight subjects with the insertion allele (P = 0.048). There were no differences in fasting insulin or glucose levels between subjects with the insertion allele or homozygotes for the wild‐type allele in the normal‐weight or obese groups. In conclusion, the 4 bp proinsulin gene insertion allele is associated with extreme obesity, reflected by greater fat‐free soft tissue mass and fat mass, particularly SAT, in obese black South African women.

A 32-year-old female patient presented complaining of increased flushing, perspiration and heat intolerance of 3 months’ duration. Medical history included idiopathic thrombocytopenic purpura of 4 years’ duration, which had been treated by splenectomy after failed immunosuppression with prednisone and azathioprine and was currently in remission. On examination, she was found to be clinically euthyroid without a goiter. She had also developed a diffuse erythematous papular rash on the face and back, with bullous lesions on the chest. Immunofluorescent antibody studies performed on a punch biopsy of skin were positive for several autoantibodies, leading to a diagnosis of subacute cutaneous lupus erythematosus. This diagnosis was further characterized by positive titers of nuclear and double-stranded DNA autoantibodies in the serum. Thyroid function testing on an Advia Centaur® Immunoassay System (Siemens Medical Solutions Diagnostics) revealed an increased concentration of serum free thyroxine (FT4)1 of 90.1 pmol/L (6.97 ng/dL) (reference range 11.5–22.7 pmol/L), a nonsuppressed thyroid-stimulating hormone (TSH) concentration of 1.8 mIU/L (1.8 μIU/mL) (reference range 0.35–5.5 mIU/L), and normal free triiodothyronine (FT3) concentration of 4.2 pmol/L (0.33 ng/dL) (reference range 3.5–6.5 pmol/L). Repeat investigation 1 and 2 months later revealed a progressive increase in FT4 to 125.3 pmol/L (9.7 ng/dL) and ≥155 pmol/L (≥12.0 ng/dL), respectively. TSH and FT3 remained within reference intervals, as did total T4 by RIA, at 155 nmol/L (12 μg/dL) (reference range 58–161 nmol/L). Furthermore, she tested positive for antithyroperoxidase antibodies at 110 IU/L (reference range <37 IU/L) and antithyroglobulin antibodies at 149 IU/L (reference range <98.1 IU/L). An investigation of her disconcordant thyroid function tests was initiated. Increased serum FT4 concentrations, with a nonsuppressed TSH, are most often seen with erratic thyroxine replacement therapy. Other less common causes include antibody interference in the FT4 assay causing falsely increased …

Megaloblastic anaemia in childhood usually occurs as a result of dietary folate deficiency or, rarely, congenital disorders of vitamin B-12 metabolism.We present a 2-year-old girl with megaloblastic anaemia and insulin-dependent diabetes mellitus, both of which proved responsive to pharmacological doses of thiamine. She was also found to have sensorineural hearing loss.Also known as Rogers' syndrome, thiamine-responsive megaloblastic anaemia is the result of inactivating mutations in a gene encoding a thiamine transporter.A clinical diagnosis is supported by characteristic bone marrow findings and can be confirmed by demonstrating apoptosis in skin fibroblasts cultured in thiamine-depleted medium. Where available, DNA sequencing is definitive.There is rapid reticulocytosis after thiamine administration. We recommend a trial of therapy for megaloblastic anaemia not responding to folate and vitamin B-12, especially in a deaf and/or diabetic child.

As a marker of tubular disruption, urine CST3 concentrations can be measured in hospitalized patients as well as in emergency situations in which acute renal failure is suspected.In the latter cases, collection of 24-h urine is impossible because physicians need rapid laboratory results for immediate patient staging.The absence of a circadian rhythm for CST3 allows its quantification in a single urine sample.As its automatic measurement allows a result in less than 1 h, both plasma/serum and urine CST3 could be used as standard markers for assessment of renal function.

A patient with cholestatic jaundice and normal serum alkaline phosphatase was found to have low levels of the enzyme before and after this illness. It is suggested that this patient has hypophosphatasia because of the low serum alkaline phosphatase, a leukocyte alkaline phosphatase value of zero, and increased excretion of urinary phosphoethanolamine to 12 times normal. There were no bony abnormalities except for osteoporosis compatible with his age and some old rib fractures that followed trauma. His serum magnesium, B12, and thyroid function tests were normal.