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/ ).

Broad Institutes of Harvard and MIT Cambridge MA USA

Department of Genetics and Medicine Harvard Medical School Boston MA USA

Department of Paediatrics Charles University Medical Faculty and University Hospital Pilsen Pilsen Czech Republic

Faculty of Medicine Cairo University Cairo Egypt

Growth and Development Research Centre University of Tehran Medical Sciences Tehran Iran

Hospital María De Especialidades Pediatricas Tegucigalpa Honduras

Institute of Biomedical and Clinical Science University of Exeter Medical School Royal Devon and Exeter Hospital Barrack Road Exeter EX2 5DW UK

Kanchi Kamakoh Child Trust Hospital Chennai India

Medical University Varna Bulgaria

Paediatric Department College of Medicine Taibah University Madinah Kingdom of Saudi Arabia

Paediatric Department Khartoum University Khartoum Sudan

Paediatric Department Maternity and Children's Hospital Dammam Kingdom of Saudi Arabia

Paediatric Department Prince Mohammed bin Abdulaziz Hospital National Guard Ministry P O Box 40740 Al Madinah 41511 Kingdom of Saudi Arabia

Partners HealthCare Laboratory for Molecular Medicine Cambridge MA USA

Toronto General Hospital University of Toronto Toronto ON Canada

See more in PubMed

Diaz GA, Banikazemi M, Oishi K, Desnick RJ, Gelb BD. Mutations in a new gene encoding a thiamine transporter cause thiamine-responsive megaloblastic anaemia syndrome. Nat Genet. 1999;22:309–312. doi: 10.1038/10385. PubMed DOI

Fleming JC, Tartaglini E, Steinkamp MP, Schorderet DF, Cohen N, Neufeld EJ. The gene mutated in thiamine-responsive anaemia with diabetes and deafness (TRMA) encodes a functional thiamine transporter. Nat Genet. 1999;22:305–308. doi: 10.1038/10379. PubMed DOI

Labay V, Raz T, Baron D, et al. Mutations in SLC19A2 cause thiamine-responsive megaloblastic anaemia associated with diabetes mellitus and deafness. Nat Genet. 1999;22:300–304. doi: 10.1038/10372. PubMed DOI

Neufeld EJ, Mandel H, Raz T, et al. Localization of the gene for thiamine-responsive megaloblastic anemia syndrome, on the long arm of chromosome 1, by homozygosity mapping. Am J Hum Genet. 1997;61:1335–1341. doi: 10.1086/301642. PubMed DOI PMC

Dutta B, Huang W, Molero M, et al. Cloning of the human thiamine transporter, a member of the folate transporter family. J Biol Chem. 1999;274:31925–31929. doi: 10.1074/jbc.274.45.31925. PubMed DOI

Brown G. Defects of thiamine transport and metabolism. J Inherit Metab Dis. 2014;37:577–585. doi: 10.1007/s10545-014-9712-9. PubMed DOI

Mee L, Nabokina SM, Sekar VT, Subramanian VS, Maedler K, Said HM. Pancreatic beta cells and islets take up thiamin by a regulated carrier-mediated process: studies using mice and human pancreatic preparations. Am J Physiol Gastrointest Liver Physiol. 2009;297:G197–G206. doi: 10.1152/ajpgi.00092.2009. PubMed DOI PMC

Rajgopal A, Edmondnson A, Goldman ID, Zhao R. SLC19A3 encodes a second thiamine transporter ThTr2. Biochim Biophys Acta. 2001;1537:175–178. doi: 10.1016/S0925-4439(01)00073-4. PubMed DOI

Reidling JC, Lambrecht N, Kassir M, Said HM. Impaired intestinal vitamin B1 (thiamin) uptake in thiamin transporter-2-deficient mice. Gastroenterology. 2010;138:1802–1809. doi: 10.1053/j.gastro.2009.10.042. PubMed DOI PMC

Liberman MC, Tartaglini E, Fleming JC, Neufeld EJ. Deletion of SLC19A2, the high affinity thiamine transporter, causes selective inner hair cell loss and an auditory neuropathy phenotype. J Assoc Res Otolaryngol. 2006;7:211–217. doi: 10.1007/s10162-006-0035-x. PubMed DOI PMC

Oishi K, Hofmann S, Diaz GA, et al. Targeted disruption of Slc19a2, the gene encoding the high-affinity thiamin transporter Thtr-1, causes diabetes mellitus, sensorineural deafness and megaloblastosis in mice. Hum Mol Genet. 2002;11:2951–2960. doi: 10.1093/hmg/11.23.2951. PubMed DOI

Rathanaswami P, Pourany A, Sundaresan R. Effects of thiamine deficiency on the secretion of insulin and the metabolism of glucose in isolated rat pancreatic islets. Biochem Int. 1991;25:577–583. PubMed

Stagg AR, Fleming JC, Baker MA, Sakamoto M, Cohen N, Neufeld EJ. Defective high-affinity thiamine transporter leads to cell death in thiamine-responsive megaloblastic anemia syndrome fibroblasts. J Clin Invest. 1999;103:723–729. doi: 10.1172/JCI3895. PubMed DOI PMC

Bergmann AK, Sahai I, Falcone JF, et al. Thiamine-responsive megaloblastic anemia: identification of novel compound heterozygotes and mutation update. J Pediatr. 2009;155:888–892. doi: 10.1016/j.jpeds.2009.06.017. PubMed DOI PMC

Ricketts CJ, Minton JA, Samuel J, et al. Thiamine-responsive megaloblastic anaemia syndrome: long-term follow-up and mutation analysis of seven families. Acta Paediatr. 2006;95:99–104. doi: 10.1080/08035250500323715. PubMed DOI

Shaw-Smith C, Flanagan SE, Patch AM, et al. Recessive SLC19A2 mutations are a cause of neonatal diabetes mellitus in thiamine-responsive megaloblastic anaemia. Pediatr Diabetes. 2012;13:314–321. doi: 10.1111/j.1399-5448.2012.00855.x. PubMed DOI

Borgna-Pignatti C, Azzalli M, Pedretti S. Thiamine-responsive megaloblastic anemia syndrome: long term follow-up. J Pediatr. 2009;155:295–297. doi: 10.1016/j.jpeds.2009.01.062. PubMed DOI

Flanagan SE, De Franco E, Lango Allen H, et al. Analysis of transcription factors key for mouse pancreatic development establishes NKX2-2 and MNX1 mutations as causes of neonatal diabetes in man. Cell Metab. 2014;19:146–154. doi: 10.1016/j.cmet.2013.11.021. PubMed DOI PMC

Manimaran P, Subramanian VS, Karthi S, et al. Novel nonsense mutation (p.Ile411Metfs*12) in the SLC19A2 gene causing thiamine responsive megaloblastic anemia in an Indian patient. Clin Chim Acta Int J Clin Chem. 2016;452:44–49. doi: 10.1016/j.cca.2015.11.002. PubMed DOI

Mikstiene V, Songailiene J, Byckova J, et al. Thiamine responsive megaloblastic anemia syndrome: a novel homozygous SLC19A2 gene mutation identified. Am J Med Genet A. 2015;167:1605–1609. doi: 10.1002/ajmg.a.37015. PubMed DOI

Mozzillo E, Melis D, Falco M, et al. Thiamine responsive megaloblastic anemia: a novel SLC19A2 compound heterozygous mutation in two siblings. Pediatr Diabetes. 2013;14:384–387. doi: 10.1111/j.1399-5448.2012.00921.x. PubMed DOI

Setoodeh A, Haghighi A, Saleh-Gohari N, Ellard S, Haghighi A. Identification of a SLC19A2 nonsense mutation in Persian families with thiamine-responsive megaloblastic anemia. Gene. 2013;519:295–297. doi: 10.1016/j.gene.2013.02.008. PubMed DOI PMC

Tahir S, Leijssen LG, Sherif M, Pereira C, Morais A, Hussain K. A novel homozygous SLC19A2 mutation in a Portuguese patient with diabetes mellitus and thiamine-responsive megaloblastic anaemia. Int J Pediatr Endocrinol. 2015;2015:6. doi: 10.1186/s13633-015-0002-6. PubMed DOI PMC

De Franco E, Flanagan SE, Houghton JA, et al. The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study. Lancet. 2015;386:957–963. doi: 10.1016/S0140-6736(15)60098-8. PubMed DOI PMC

Ellard S, Lango Allen H, De Franco E, et al. Improved genetic testing for monogenic diabetes using targeted next-generation sequencing. Diabetologia. 2013;56:1958–1963. doi: 10.1007/s00125-013-2962-5. PubMed DOI PMC

Dua V, Yadav SP, Kumar V, et al. Thiamine responsive megaloblastic anemia with a novel SLC19A2 mutation presenting with myeloid maturational arrest. Pediatr Blood Cancer. 2013;60:1242–1243. doi: 10.1002/pbc.24529. PubMed DOI

Valerio G, Franzese A, Poggi V, Tenore A. Long-term follow-up of diabetes in two patients with thiamine-responsive megaloblastic anemia syndrome. Diabetes Care. 1998;21:38–41. doi: 10.2337/diacare.21.1.38. PubMed DOI