Acta Paediatrica
Issue: Volume 95, Number 1 / January 2006
Pages: 99 - 104
Thiamine-responsive megaloblastic anaemia syndrome: Long-term follow-up and mutation analysis of seven families
Christopher J. Ricketts A1, Jayne A. Minton A1, Jacob Samuel A2, Indra Ariyawansa A3, Jerry K. Wales A4, Ivan F. Lo A5, Timothy G. Barrett A1
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.
 My comment:  Puberty stopping the thiamin working is interesting; one thing is the oestrogen binding the thiamin, I presume testosterone may be also?...and maybe growth hormone had some effect as well?.. expect it to from some people's reaction to growth hormone, but couldnt find anything
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1: Pflugers Arch. 2004 Feb;447(5):641-6. Epub 2003 May 6. Links
SLC19: the folate/thiamine transporter family.
Ganapathy V, Smith SB, Prasad PD.
Department of Biochemistry and Molecular Biology, Medical College of Georgia, GA 30912-2100, Augusta, USA, vganapat@mail.mcg.edu

The SLC19 gene family of solute carriers is a family of three transporter proteins with significant structural similarity, transporting, however, substrates with different structure and ionic charge. The three members of this gene family are expressed ubiquitously and mediate the transport of two important water-soluble vitamins, folate and thiamine. The concentrative transport of substrates mediated by the members of this gene family is energized by transcellular H(+)/OH(-) gradient.
SLC19A1 is expressed at highest levels in absorptive cells where it is located in a polarized manner either in the apical or basal membrane, depending on the cell type. It mediates the transport of reduced folate and its analogs, such as methotrexate, which are anionic at physiological pH.
SLC19A2 is expressed ubiquitously and mediates the transport of thiamine, a cation at physiological pH. SLC19A3 is also widely expressed and is capable of transporting thiamine.
This review summarizes the current knowledge on the structural, functional, molecular and physiological aspects of the SLC19 gene family.

BOB_sent via email.. full text and pdf, titled 'the ABC of solute carriers'. or thiamin/folate transporters

some notes of interest in article:
"SLC19A1 expression... In addition, the activity and expression of the transporter are decreased by nitric oxide and hyperglycemia [18, 31]. "
as I suspected the high blood glucose-diabetes type2 link is maybe correlated wih thiamin levels, ie higher glucose levels reduce this transporter, so reduce thiamin levels..also higher NO reduce thiamin levels.

"Role of SLC19 gene family members in the homeostasis of folate and thiamine.
The SLC19 gene family plays an important role in the transport and homeostasis of folate and thiamine in the body. Since SLC19A1 has also been shown to transport mono- and pyro-phosphate derivatives of thiamine , all three members of the SLC19 gene family may play a role in the homeostasis of thiamine. (My comment:and note above (same paper)  SLC19A1 is  decreased by hyperglycemia and NO)
It is quite evident that the role of these transporters in non-polarized cells is to mediate the influx of folate and thiamine into the cells. However, in cells that mediate the transcellular transfer of these vitamins (e.g., the absorptive cells of the intestine and kidney, the syncytiotrophoblast in the placenta, and the retinal pigment epithelium), the exact role of these transporters is dependent on their polarized distribution in the apical membrane versus the basolateral/basal membrane. The distribution of SLC19A2 and SLC19A3 in these polarized cells has not yet been investigated and therefore it is difficult to predict their exact role in the transcellular movement of thiamine and consequently in thiamine homeostasis of the whole organism. On the other hand, recent advances in the area of subcellular localization of SLC19A1 in polarized cells have enhanced our understanding of the role of this transporter in the transcellular movement of folate"
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Related:
The gene mutated in thiamine-responsive anaemia with diabetes and deafness (TRMA) encodes a functional thiamine transporter.

Novel mutation in the SLC19A2 gene in an African-American female with thiamine-responsive megaloblastic anemia syndrome.   this one mentions thyroid
"At age 19, a thiamine-responsive normocytic anemia was discovered. She was diagnosed with autoimmune thyroiditis at 20 years and she experienced a psychotic episode associated with a mood disorder at age 21. With oral thiamine therapy, her insulin requirement decreased by 30% over a 20 month period"
Interestingly, 30% is approx the amount I have had to reduce my thyroid meds by since injecting myself with 20mg daily of thiamin( I think I've settled on). but its too early to say, and it could be a coincidence or another factor (EG. I added in kelp too).
Suggestion: we usually don't have the same gene mutation or knockout.. BUT if thiamin transporters are affected, then maybe we are seeing some effects of this that may be correctable by high thiamin intake
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Polarized expression of members of the solute carrier SLC19A gene family of water-soluble multivitamin transporters: implications for physiological function
Boulware MJ, Subramanian VS, Said HM, Marchant JS.
Biochem J. 2003 Nov 15;376(Pt 1):43-8
Humans lack biochemical pathways for the synthesis of the micro-nutrients thiamine and folate. Cellular requirements are met through membrane transport activity, which is mediated by proteins of the SLC19A gene family. By using live-cell confocal imaging methods to resolve the localization of all SLC19A family members, we show that the two human thiamine transporters are differentially targeted in polarized cells, establishing a vectorial transport system. Such polarization decreases functional redundancy between transporter isoforms and allows for independent regulation of thiamine import and export pathways in cells.
www.biochemj.org/bj/376/0043/bj3760043.htm
This is where I came across targeting to apical and basolateral membranes......
full text is available
Bob
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