SLC19A2 – Thiamine-Responsive Megaloblastic Anemia Syndrome

SLC19A2 encodes the high-affinity thiamine transporter THTR-1 and biallelic loss-of-function variants cause thiamine-responsive megaloblastic anemia (TRMA) syndrome, an autosomal recessive disorder characterized by early-onset megaloblastic anemia, sensorineural hearing loss and diabetes mellitus. In TRMA, defective cellular uptake of vitamin B₁ leads to impaired erythropoiesis and β-cell function, while high-dose thiamine supplementation rescues anemia and glycemic control if initiated early.

Genetic evidence includes identification of homozygous or compound heterozygous SLC19A2 mutations in six independent TRMA families (PMID:10391221) and numerous subsequent case reports totaling over 100 affected individuals. The variant spectrum comprises missense, nonsense, splice-site and frameshift alleles. A recurrent missense change, c.152C>T (p.Pro51Leu), was reported in an African-American patient with the full TRMA triad (PMID:14994241). Segregation analysis across these families demonstrates strict co-segregation of biallelic variants with disease.

Functional studies confirm that pathogenic SLC19A2 alleles abolish thiamine transport. Site-directed mutants p.Ser143Phe and p.Gly172Asp exhibit severely reduced thiamine uptake in transfected cells (PMID:12065289), and the D93H substitution eliminates transporter activity despite normal glycosylation and membrane targeting (PMID:14622275). These data support a loss-of-function mechanism.

Clinically, TRMA presents within the first year of life with transfusion-dependent anemia and insulin-requiring diabetes; progressive sensorineural deafness is irreversible if thiamine is delayed. Additional features may include cardiac arrhythmias and visual impairment as described in ophthalmic and cardiology case series (PMID:23638917; PMID:30511554). High-dose thiamine (100–300 mg/day) leads to sustained correction of anemia and partial improvement of glycemic control, highlighting the importance of early genetic diagnosis.

References

• Nature Genetics • 1999 • Mutations in SLC19A2 cause thiamine-responsive megaloblastic anaemia associated with diabetes mellitus and deafness. PMID:10391221
• American Journal of Physiology Gastrointestinal and Liver Physiology • 2002 • Functional role of specific amino acid residues in human thiamine transporter SLC19A2: mutational analysis. PMID:12065289
• European Journal of Biochemistry • 2003 • Disruption of transport activity in a D93H mutant thiamine transporter 1, from a Rogers Syndrome family. PMID:14622275
• American Journal of Medical Genetics Part A • 2004 • Novel mutation in the SLC19A2 gene in an African-American female with thiamine-responsive megaloblastic anemia syndrome. PMID:14994241
• Ophthalmic Genetics • 2014 • Leber's congenital amaurosis as the retinal degenerative phenotype in thiamine responsive megaloblastic anemia: a case report. PMID:23638917
• The Turkish Journal of Pediatrics • 2018 • Arrhythmia in thiamine responsive megaloblastic anemia syndrome. PMID:30511554

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