Pharmacogenomics in diabetes: outcomes of thiamine therapy in TRMA syndrome

Abstract

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 B 1 ) 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 . At presentation, three individuals had isolated diabetes and 12 had asymptomatic hyperglycaemia. Followup 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 A list of the members of the International Neonatal Diabetes Consortium is included in the electronic supplementary material (ESM).Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-018-4554-x) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

ISPAD Clinical Practice Consensus Guidelines 2018: The diagnosis and management of monogenic diabetes in children and adolescents

“…Pancreatic scanning is unreliable in neonates and so it is best to use functional tests of exocrine pancreatic function (fecal elastase and fecal fats) when assessing if pancreatic aplasia is present . Apart from KATP‐NDM and some patients with SLC19A2 mutations causing thiamine‐responsive megaloblastic anemia (TRMA) syndrome, all other causes need to be treated with subcutaneous insulin. Patients with pancreatic aplasia/hypoplasia will also require exocrine pancreatic supplements.…”

Type 1 diabetes genetic risk score discriminates between monogenic and Type 1 diabetes in children diagnosed at the age of <5 years in the Iranian population

“…The mutations in SLC29A3 have also been detected in children with mild manifestations and our findings in this child indicate that the prevalence of H syndrome is likely to be underestimated as a result of undiagnosed mild cases . The child with a mutation in SLC19A2 had developed other features of thiamine‐responsive megaloblastic anaemia syndrome, also known as Roger's syndrome, including anaemia, cardiac defects and deafness; however, studies of other cases suggest diabetes can be isolated and present before the appearance of other features . Prompt diagnosis is essential as more than half of the individuals with follow‐up data benefitted from early treatment with thiamine, with some individuals becoming insulin‐independent .…”

Whole exome sequencing identifies a new mutation in the SLC19A2 gene leading to thiamine‐responsive megaloblastic anemia in an Egyptian family

“…Our patient is the second Egyptian with a pathogenic mutation in the SLC19A2 gene. The first one was identified by direct sequencing of known genes involved in diabetes (Habeb et al, ). As for our proband, the first Egyptian patient identified in the study of Habeb and collaborators was from consanguineous parents.…”