Thiamine-responsive megaloblastic anaemia syndrome: long-term follow-up and mutation analysis of seven families |
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Authors: | Ricketts Christopher J Minton Jayne A Samuel Jacob Ariyawansa Indra Wales Jerry K Lo Ivan F Barrett Timothy G |
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Institution: |
a Medical and Molecular Genetics, Medical School, University of Birmingham, Birmingham, UK
b Queen's Hospital, Staffordshire, UK
c Department of Paediatrics, Rochdale Infirmary, Lancashire, Rochdale, UK
d Sheffield Children's Hospital, South Yorkshire, Sheffield, UK
e Clinical Genetic Service, Department of Health, Hong Kong Special Administrative Region, China |
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Abstract: | Aim: Thiamine-responsive megaloblastic anaemia syndrome (TRMA) is the association of diabetes mellitus, anaemia and deafness, due to mutations in SLC19A2, encoding a thiamine transporter protein. This is a unique monogenic form of vitamin-dependent diabetes for which there is limited long-term data. We aimed to study genotype-phenotype relationships and long-term follow-up in our cohort. Methods: We have studied 13 patients from seven families and have follow-up data for a median of 9 y (2-30 y). Results: All patients originated from Kashmir or Punjab, and presented with non-immune, insulin-deficient diabetes mellitus, sensorineural deafness and a variable anaemia in the first 5 y of life, the anaemia progressing to megaloblastic and sideroblastic changes in the bone marrow. The anaemia and diabetes mellitus responded to oral thiamine hydrochloride 25?mg/d, but during puberty thiamine supplements became ineffective, and almost all patients require insulin therapy and regular blood transfusions in adulthood. All patients are homozygous for mutations in the SLC19A2 gene. We have identified a novel missense mutation (T158R) that was excluded in 100 control alleles.
Conclusion: Diabetes in this syndrome is due to an insulin insufficiency that initially responds to thiamine supplements; however, most patients become fully insulin dependent after puberty. A mutation screening strategy is feasible and likely to identify mutations in almost all cases. |
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Keywords: | Diabetes SLC19A2 thiamine |
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