Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Observational Study
. 2018 May;61(5):1027-1036.
doi: 10.1007/s00125-018-4554-x. Epub 2018 Feb 15.

Pharmacogenomics in diabetes: outcomes of thiamine therapy in TRMA syndrome

Abdelhadi M Habeb  1 , Sarah E Flanagan  2 , Mohamed A Zulali  3 , Mohamed A Abdullah  4 , Renata Pomahačová  5 , Veselin Boyadzhiev  6 , Lesby E Colindres  7 , Guillermo V Godoy  7 , Thiruvengadam Vasanthi  8 , Ramlah Al Saif  9 , Aria Setoodeh  10 , Amirreza Haghighi  11 , Alireza Haghighi  12   13   14 , Yomna Shaalan  15 ; International Neonatal Diabetes Consortium; Andrew T Hattersley  2 , Sian Ellard  2 , Elisa De Franco  16
Affiliations
Observational Study

Pharmacogenomics in diabetes: outcomes of thiamine therapy in TRMA syndrome

Abdelhadi M Habeb et al. Diabetologia. 2018 May.

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 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/ ).

Keywords: Pharmacogenomics; TRMA-related diabetes; Thiamine therapy; Vitamin B1.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Schematic representation of the SLC19A2 gene with mutations identified in our cohort. Novel mutations are highlighted in red. Compound heterozygous mutations are underlined
Fig. 2
Fig. 2
Frequency of the clinical features in the study participants
Fig. 3
Fig. 3
Kaplan–Meier plot showing the probability of developing each TRMA clinical feature. Solid line, diabetes; dotted line, deafness; dashed line, anaemia
Fig. 4
Fig. 4
HbA1c before and after starting thiamine therapy for the 15 individuals with long-term follow-up data. The horizontal black bars represent the median
See this image and copyright information in PMC

References

    1. 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. - DOI - PubMed
    1. 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. - DOI - PubMed
    1. 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. - DOI - PubMed
    1. 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. - DOI - PMC - PubMed
    1. 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. - DOI - PubMed

Publication types

MeSH terms

Supplementary concepts

LinkOut - more resources