Thiamine-responsive megaloblastic anaemia syndrome: long-term follow-up and mutation analysis of seven families.
OBJECTIVE
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.


CONCLUSIONS
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.
Ricketts
Christopher J
CJ
Medical and Molecular Genetics, Medical School, University of Birmingham, Birmingham, UK.
Minton
Jayne A
JA
Samuel
Jacob
J
Ariyawansa
Indra
I
Wales
Jerry K
JK
Lo
Ivan F
IF
Barrett
Timothy G
TG
D000293:Adolescent; D000328:Adult; D000749:Anemia, Megaloblastic / Q000209:etiology*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D003638:Deafness / Q000209:etiology; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000209:etiology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007194:India / Q000208:ethnology; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D013577:Syndrome; D013831:Thiamine / Q000627:therapeutic use; D013832:Thiamine Deficiency / Q000150:complications / Q000235:genetics*
D026901:Membrane Transport Proteins; C120043:SLC19A2 protein, human; D013831:Thiamine