Thiamine Responsive Megaloblastic Anemia (TRMA) is an autosomal recessive disorder, characterized by the triad of megaloblastic anemia, sensorineural deafness, and diabetes mellitus. The anemia may be accompanied by mild thrombocytopenia, and/or leucopenia. In addition, some patients may also demonstrate congenital heart defects, stroke-like episodes and/or arrhythmias, and optic atrophy.
TRMA is caused due to mutations in the SLC19A2 (Solute Carrier Family 19, Member 2) gene. The product of this gene is a thiamine transporter, and mutations in this gene disrupt the active uptake of thiamine into cells. This deficiency of thiamine in the cells, in turn, leads to a loss of ribose synthesis within the cells, resulting in anemia.
Bappal et al. (2001) reported two female children of consanguineous parents (third degree relatives) diagnosed with thiamine responsive megaloblastic anemia, diabetes mellitus, and sensorineural deafness. Their eldest sibling was a deaf-mute, who died at the age of two-years of severe transfusion anemia and diabetic ketacidosis. The first sibling presented at the age of 18 months with pancytopenia (Hb of 2.7g/dl, MCV of 94, WBC of 2.9 with 10% neutrophils and platelets of 42) and diabetic ketoacidosis (blood sugar of 28.5 mmol/l, bicarbonate of 12 mmol/l, and 2+ urine ketones). Absent islet cell antibodies and low C-peptide levels (<265pmol/l) were detected. Peripheral blood smear revealed hypochromia, anisopoikilocytosis, and moderate macrocytosis, while the bone marrow had ring sideroblasts with megaloblastic changes. The levels of serum cyanocobalamin and folate were found to be normal. Bilateral sensorineural deafness was detected on brain stem auditory evoked potential (BAEP), while her optic fundi were found to be normal. Accordingly, she was diagnosed with thiamine responsive megaloblastic anemia and diabetes mellitus, and was managed by blood transfusion, intravenous fluids and insulin along with thiamine (100 mg/day). She continued to be hyperglycemic and needed insulin, despite improvement of her blood counts. The diabetes worsened with an occasional interruption of the thiamine therapy. As her insulin requirement increased over the period of three years with few episodes of ketoacidosis, thiamine dose was increased to 200 mg/day, which controlled her hyperglycemia with complete discontinuation of insulin within three weeks. Over a period of five years she remained healthy, with normal OGTT and normal glycosylated hemoglobin. Her sibling presented at the age of five months with atrial septal defect and heart failure, sensorineural deafness, diabetes mellitus, and low hemtological parameters along with megaloblasts and ring sideroblasts in her bone marrow. All investigations were almost similar to the above patient. She responded to decongestive therapy, thiamine (200 mg/day) and crystal-line insulin which was discontinued after four days, and her blood counts normalized within a week. She was maintained on thiamine and anti-failure drugs and her cardiac anomaly was repaired at the age of four years. She remained healthy during the follow up period of five years with normal glycosylated hemoglobin and OGTT. Bappal et al. (2001) suggested that increasing the thiamine dose might overcome the thiamine transport protein deficiency in such cases and should be tried before declaring its ineffectiveness in controlling diabetes.
Neufeld et al. (1997) performed homozygosity mapping and linkage mapping in 4 large kindreds of native Alaskan and Italian origin with TRMA. Strong evidence for linkage was found to a single marker on 1q23.2-q23.3; maximum lod = 3.7 for D1S1679. Sixteen markers spanning the region were examined in the Alaskan kindred, plus 2 additional kindreds from two unrelated consanguineous Arab families. These results confirmed the putative disease gene interval, suggesting genetic homogeneity. Linkage analysis generated the highest combined lod score, 8.1 at theta = 0.0, with marker D1S2779. The Italian and Alaskan patients shared no haplotypes with each other nor with the Arab families, suggesting that the disease arose independently on three different genetic backgrounds. Noticeably, Arab kindreds exhibited closely related haplotypes. Several heterozygous parents had diabetes mellitus, deafness, or megaloblastic anemia, raising the possibility that mutations at this locus predispose carriers to these manifestations.