ESPE Abstracts (2018) 89 P-P2-102

A Novel Missense Variant, p.(Thr405Arg), in the SLC19A2 Gene in an Infant with Thiamine Responsive Megaloblastic Anemia Syndrome Presenting with Anemia and Diabetes but with Normal Hearing

Anita Spehar Uroica, Dragan Milenkovica, Ellisa De Francob, Natasa Rojnic Putareka & Nevena Krnicc


aUniversity Hospital Centre Zagreb, Departmant of Pediatrics, Zagreb, Croatia; 2University of Exeter Medical School, Molecular Genetics, Exeter, UK; 3University Hospital Centre Zagreb, Departmant of Pediatrics, School of Medicine, University of Zagreb, Zagreb, Croatia


Objectives: Thiamine responsive megaloblastic anemia syndrome (TRMA) is characterized by the clinical triad of megaloblastic anemia, non-immune diabetes mellitus and sensorineural deafness. It is a very rare autosomal recessive disease with an increased frequency in consanguineous marriages and isolated communities. The syndrome is due to intracellular thiamine deficiency which is the result of a defective high affinity low performance thiamine transporter protein (THTR1) encoded by the SLC19A2 gene. Treatment with pharmacological doses of thiamine leads to an increase in intracellular thiamine concentrations and resolution of anemia and better glycemic control, but apparently does not affect hearing loss. To date approximately 50 different mutations in 80 patients have been described.

Patients and Methods: We present a 4 months old boy born to non-consanguineous parents who presented with failure to thrive, profound anemia (Hgb 58, Hct 0.170, MCV 92.4 fL), diabetes mellitus (blood glucose 24.4 mmol/L, HbA1c 7.1%) and preserved hearing. After initial red blood cell transfusion and insulin treatment (0.66 IU/kg/day) a diagnosis of TRMA syndrome was suspected and the patient was started empirically on oral thiamine (100 mg/day). Insulin treatment could be stopped on the second day of thiamine treatment and his hemoglobin level improved.

Results: Analysis of all coding regions and exon/intron boundaries of the SLC19A2 gene (NM_006996.2) by Sanger sequencing was performed and revealed that our patient is a compound heterozygote for a nonsense, c.373C>T; p.(Gln125Ter), and a novel missense variant, c.1214C>G; p.(Thr405Arg), in the SLC19A2 gene. Both variants are predicted to be pathogenic and this result confirms the TRMA diagnosis

Conclusion: Of about 80 patients with TRMA that have been reported to date, only a few presented with neonatal diabetes mellitus, and even fewer with preserved hearing. Only a couple of patients started thiamine treatment at age 4 month or earlier, and this could be crucial for the preservation of hearing, or at least for postponing hearing loss. Also it is possible that compound heterozygotes may have less severe phenotype regarding hearing loss but further data is needed. Follow- up is needed to evaluate effect of novel gene variant and therapy on hearing in our patient.

Keywords: Thiamine responsive megaloblastic anemia; neonatal diabetes mellitus; hearing loss; novel SLC19A2 gene variant.

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