Pharmacogenomics in diabetes: outcomes of thiamine therapy in TRMA syndrome

Abdelhadi M Habeb,Sian Ellard,Andrew T Hattersley,Renata Pomahačová,Ramlah Al Saif,Mohamed A Abdullah,Yomna Shaalan,Lesby E Colindres,Amirreza Haghighi,Thiruvengadam Vasanthi,Guillermo V Godoy,Aria Setoodeh,Alireza Haghighi,Sarah E Flanagan,Elisa De Franco,Mohamed A Zulali,Veselin Boyadzhiev

doi:10.1007/s00125-018-4554-x

Abstract

Aims/hypothesisDiabetes 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.MethodsWe studied 32 individuals with biallelic SLC19A2 mutations identified by Sanger or next generation sequencing. Clinical details were collected through a follow-up questionnaire.ResultsWe 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/interpretationIn 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 availabilitySLC19A2 mutation details have been deposited in the Decipher database (https://decipher.sanger.ac.uk/).

Highlights

Thiamine-responsive megaloblastic anaemia (TRMA) syndrome, known as Roger’s syndrome, is a rare congenital disease characterised by a triad of cardinal features: thiamineresponsive anaemia, diabetes and deafness [1,2,3,4]
Genotype Twenty-four different SLC19A2 mutations were identified in the 32 individuals from 27 families, confirming a genetic diagnosis of TRMA syndrome
Diagnosis of TRMA syndrome is important to allow targeted treatment, as more than half of the individuals with follow-up data benefited from early treatment with thiamine, with some individuals becoming insulin-independent

Summary

Introduction

Thiamine-responsive megaloblastic anaemia (TRMA) syndrome, known as Roger’s syndrome, is a rare congenital disease characterised by a triad of cardinal features: thiamineresponsive anaemia, diabetes and deafness [1,2,3,4] It is caused by recessively inherited mutations in the SLC19A2 gene encoding the high-affinity thiamine transporter 1 (THTR1) [5]. Studies in humans and animal models have shown different tissue expression patterns for the two thiamine transporters, with THTR2 being absent or minimally expressed in pancreatic endocrine cells, bone marrow and cochlear cells [7,8,9] This indicates that THTR1 is the main thiamine transporter in these three tissues and explains the presence of deafness, diabetes and anaemia in individuals with TRMA syndrome [10,11,12,13]

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