Pharmacogenomics in diabetes: outcomes of thiamine therapy in TRMA syndrome.

AIMS/HYPOTHESIS: Diabetes is one of the cardinal features of thiamine-responsive megaloblastic anaemia (TRMA) syndrome. Current knowledge of this rare monogenic diabetes subtype is limited. We investigated the genotype, phenotype and response to thiamine (vitamin B1) in a cohort of individuals with TRMA-related diabetes. METHODS: We studied 32 individuals with biallelic SLC19A2 mutations identified by Sanger or next generation sequencing. Clinical details were collected through a follow-up questionnaire. RESULTS: We identified 24 different mutations, of which nine are novel. The onset of the first TRMA symptom ranged from birth to 4 years (median 6 months [interquartile range, IQR 3-24]) and median age at diabetes onset was 10 months (IQR 5-27). At presentation, three individuals had isolated diabetes and 12 had asymptomatic hyperglycaemia. Follow-up data was available for 15 individuals treated with thiamine for a median 4.7 years (IQR 3-10). Four patients were able to stop insulin and seven achieved better glycaemic control on lower insulin doses. These 11 patients were significantly younger at diabetes diagnosis (p = 0.042), at genetic testing (p = 0.01) and when starting thiamine (p = 0.007) compared with the rest of the cohort. All patients treated with thiamine became transfusion-independent and adolescents achieved normal puberty. There were no additional benefits of thiamine doses >150 mg/day and no reported side effects up to 300 mg/day. CONCLUSIONS/INTERPRETATION: In TRMA syndrome, diabetes can be asymptomatic and present before the appearance of other features. Prompt recognition is essential as early treatment with thiamine can result in improved glycaemic control, with some individuals becoming insulin-independent. DATA AVAILABILITY: SLC19A2 mutation details have been deposited in the Decipher database ( https://decipher.sanger.ac.uk/ ).

Bone demineralization in a cohort of Egyptian pediatric liver transplant recipients: Single center pilot study.

Liver transplantation (LT) is the definitive treatment of end-stage liver disease. The long-term survival following LT spurred more interest in improving the quality of life of patients. This was a cohort study that included 23 pediatric liver transplant recipients who underwent LT due to hereditary or metabolic liver diseases. Bone health assessment was performed at their last follow up clinically (anthropometric measures), biochemically and radiologically (Dual Energy X-ray Absorptiometry [DEXA] scans). Poor bone health was defined as z-score <-1. Mean age at LT was 5.77 years (standard deviation [SD] 3.64) and 43% were males. Biliary atresia was the most common cause of end stage liver disease (35%). Mean age at follow up was 14 years (SD 5.48) and mean follow up was 8 years (SD 4.12 years). Eleven patients (48%) had poor bone health (osteopenia 22% and osteoporosis 26%). On univariate analysis, being on steroids at last follow up (odds ratio [OR] 13.2, 95% confidence interval [CI] 1.23-140.67, P = .03), weight at last follow up (OR 0.45, 95% CI 0.20-0.99, P = .04), platelets at last follow up (OR 0.98, 95% CI 0.96-s0.99, P = .02), hemoglobin at last follow up (OR 0.33, 95% CI 0.12-0.89, P = .03) were significantly associated with poor bone health. None of the variables were significant on multivariate analysis. At most recent follow up, 48% of patients demonstrated poor bone health by DEXA scans. More studies are required to evaluate predictors of poor bone health after LT in children.