Pharmacogenomics in diabetes: outcomes of thiamine therapy in TRMA syndrome

Autor: Mohamed A. Zulali, Elisa De Franco, Thiruvengadam Vasanthi, Guillermo V. Godoy, Lesby E. Colindres, Sarah E. Flanagan, Andrew T. Hattersley, Ramlah Al Saif, Mohamed A. Abdullah, Abdelhadi M. Habeb, Yomna Shaalan, Alireza Haghighi, Sian Ellard, Aria Setoodeh, Renata Pomahačová, Veselin Boyadzhiev, Amirreza Haghighi
Rok vydání: 2018
Předmět:
Male
0301 basic medicine
Anemia
Megaloblastic
Endocrinology
Diabetes and Metabolism
medicine.medical_treatment
TRMA-related diabetes
Cohort Studies
0302 clinical medicine
Interquartile range
Surveys and Questionnaires
Thiamine
medicine.diagnostic_test
biology
Thiamine Deficiency
food and beverages
3. Good health
Phenotype
Child
Preschool
Thiamine therapy
Cohort
SLC19A2
Female
medicine.symptom
medicine.medical_specialty
Genotype
Hearing Loss
Sensorineural
030209 endocrinology & metabolism
Asymptomatic
Article
03 medical and health sciences
Internal medicine
Diabetes mellitus
Diabetes Mellitus
Internal Medicine
medicine
Humans
Genetic Testing
Alleles
Genetic testing
business.industry
Insulin
Infant
Membrane Transport Proteins
medicine.disease
030104 developmental biology
Pharmacogenetics
Mutation
biology.protein
Pharmacogenomics
business
Vitamin B1
Zdroj: Diabetologia
ISSN: 1432-0428
0012-186X
DOI: 10.1007/s00125-018-4554-x
Popis: 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/). Electronic supplementary material The online version of this article (10.1007/s00125-018-4554-x) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Databáze: OpenAIRE
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