Thiamine-Responsive Megaloblastic Anemia: Identification of Novel Compound Heterozygotes and Mutation Update

Abstract

Objective-To determine causative mutations and clinical status of seven previously unreported kindreds with TRMA syndrome, (Thiamine Responsive Megaloblastic Anemia, OMIM #249270), a recessive disorder of thiamine transporter Slc19A2.Study design-Genomic DNA was purified from blood, and SLC19A2 mutations were characterized by sequencing PCR-amplified coding regions and intron-exon boundaries of all probands. Compound heterozygotes were further analyzed by sequencing parents, or cloning patient genomic DNA, to ascertain that mutations were in trans.Results-We detected 9 novel SLC19A2 mutations. Of these, five were missense, three nonsense, and one insertion. Five patients from four kindreds were compound heterozygotes, a finding not reported previously for this disorder, which has mostly been found in consanguineous kindreds.Conclusion-SLC19A2 mutation sites in TRMA are heterogeneous; with no regional "hot spots". TRMA can be caused by heterozygous compound mutations; in these cases, the disorder is found in outbred populations. To the extent that heterozygous patients were ascertained at older ages, a plausible explanation is that if one or more allele(s) is not null, partial function might be preserved. Phenotypic variability may lead to underdiagnosis or diagnostic delay, as the average time between the onset of symptoms and diagnosis was 8 years in this cohort.

Congenital Sideroblastic Anemias: Iron and Heme Lost in Mitochondrial Translation

“…Mutations in the high-affinity thiamine transporter SLC19A2 are the basis of the disorder and explain the hallmark of the disease, clinical response of the anemia, and to a lesser extent the other clinical signs, to supraphysiological doses of thiamine. 41,42 The link between thiamine-responsive megaloblastic anemia (TRMA) and mitochondrial protein synthesis has not been experimentally validated. Impairment of the thiamine-dependent generation of succinyl-CoA, which is required for heme biosynthesis, has been suggested as the cause of the ringed sideroblast abnormality, but thiamine is also an essential cofactor in the de novo synthesis of ribose, which is essential for protein production.…”

Pharmacogenomics in diabetes: outcomes of thiamine therapy in TRMA syndrome

“…In some individuals additional features such as thrombocytopenia, neurological symptoms, cardiac anomalies, visual disturbances and short stature have also been reported [14][15][16][17].…”

Infantile-onset thiamine responsive megaloblastic anemia syndrome with SLC19A2 mutation: a case report

“…Although most common mutations are in exon 2, mutations in the exons 1, 3, and 4 are also known. 16 In our case report, sequencing analysis of the SLC19A2 gene identified a known homozygous mutation c.242_243insA (p.Y81*) in exon 2.…”