Thiamine-responsive megaloblastic anemia syndrome (TRMA) is characterized by megaloblastic anemia, sensorineural hearing loss, and diabetes mellitus. Onset of megaloblastic anemia is between infancy and adolescence. The anemia is corrected with pharmacologic doses of thiamine (vitamin B1) (25-75 mg/day compared to US RDA of 1.5 mg/day). However, the red cells remain macrocytic. The anemia can recur when thiamine is withdrawn. Progressive sensorineural hearing loss has generally been early and can be detected in toddlers; hearing loss is irreversible and may not be prevented by thiamine treatment. The diabetes mellitus is non-type I in nature, with age of onset from infancy to adolescence.
The diagnosis of TRMA requires the presence of the phenotypic triad of megaloblastic anemia, sensorineural hearing loss, and diabetes mellitus. Examination of the bone marrow reveals megaloblastic anemia with erythroblasts often containing iron-filled mitochondria (ringed sideroblasts). SLC19A2, which encodes the high-affinity thiamine transporter, is the only gene in which mutations are known to cause TRMA. All individuals with the diagnostic phenotypic triad evaluated by sequence analysis have identifiable mutations in SLC19A2.
TRMA is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible for families in which the disease-causing mutations have been identified.