Thiamine-responsive megaloblastic anemia (TRMA) in an Austrian boy with compound heterozygous SLC19A2 mutations

Pichler, Herbert; Zeitlhofer, Petra; Dworzak, Michael; Diakos, Christopher; Haas, Oskar A.; Kager, Leo

doi:10.1007/s00431-012-1730-8

Cited by 26 publications

(16 citation statements)

References 11 publications

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“…Both patients presented with comparatively mild phenotype. 1,17 The genotypes of our cases are consistent with the diagnosis of TRMA based on SLC19A2 mutations resulting in loss or decrease in THTR-1 function.…”

Section: Case Reportsupporting

confidence: 82%

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First 2 cases with thiamine-responsive megaloblastic anemia in the Czech Republic, a rare form of monogenic diabetes mellitus: a novel mutation in the thiamine transporter SLC19A2 gene-intron 1 mutation c.204+2T>G

et al. 2016

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Thiamine-responsive megaloblastic anemia (TRMA) is a rare autosomal recessive disorder caused by mutations in the SLC19A2 gene. To date at least 43 mutations have been reported for the gene encoding a plasma membrane thiamine transporter protein (THTR-1). TRMA has been reported in less than 80 cases worldwide. Here, we illustrate 2 female patients with TRMA first diagnosed in the Czech Republic and in central Europe being confirmed by sequencing of the THTR-1 gene SLC19A2. Both subjects are compound heterozygotes with 3 different mutations in the SLC19A2 gene. In case 2, the SLC19A2 intron 1 mutation c.204+2T>G has never been reported before. TRMA subjects are at risk of diabetic ketoacidosis during intercurrent disease and arrythmias. Thiamine supplementation has prevented hematological disorders over a few years in both pediatric subjects, and improved glycaemic control of diabetes mellitus. Patient 1 was suffering from hearing loss and rod-cone dystrophy at the time of diagnosis, however, she was unresponsive to thiamine substitution. Our patient 2 developed the hearing loss despite the early thiamine substitution, however no visual disorder had developed. The novel mutation described here extends the list of SLC19A2 mutations causing TRMA.

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Section: Case Reportsupporting

confidence: 82%

“…This mutation was reported previously in at least 2 compound heterozygous patients of Italian and Austrian descent. Both patients presented with comparatively mild phenotype . The genotypes of our cases are consistent with the diagnosis of TRMA based on SLC19A2 mutations resulting in loss or decrease in THTR‐1 function.…”

Section: Discussionmentioning

confidence: 99%

First 2 cases with thiamine-responsive megaloblastic anemia in the Czech Republic, a rare form of monogenic diabetes mellitus: a novel mutation in the thiamine transporter SLC19A2 gene-intron 1 mutation c.204+2T>G

et al. 2016

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“…Our patient’s medical history and initial presentation were similar to other case reports: Turkish origin, classic triad of manifestations (megaloblastic anaemia, diabetes mellitus and sensorineural deafness), diagnosis made during childhood. Although most cases have been reported in consanguineous families of Middle and Far Eastern origins,13 our patient did not have a family history of consanguinity.…”

Section: Discussionmentioning

confidence: 70%

Pancytopenia in an adult patient with thiamine-responsive megaloblastic anaemia

et al. 2018

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Thiamine-responsive megaloblastic anaemia (TRMA) is a syndrome associated with megaloblastic anaemia, diabetes mellitus and sensorineural deafness, due to mutations in the gene, which codes for a thiamine carrier protein. Oral thiamine supplementation is the main treatment. We report the case of a 25-year-old woman known for TRMA, who presented with pancytopenia (haemoglobin 7.6 g/dL, leucocytes 2.9×10/L, thrombocytes 6×10/L) revealed by dyspnoea. Investigations excluded coagulopathy, a recent viral infection, vitamin and iron deficiencies, and a malignant process. We later found out that thiamine treatment had been discontinued 5 weeks before, due to prescription error. Parenteral thiamine administration resulted in the recovery of haematopoiesis within 3 weeks. Pancytopenia is uncommon in patients with TRMA. Pre-existing medullary impairment caused by the patient's daily antipsychotic medications or the natural course of the syndrome may explain the severity of the laboratory findings in our patient.

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“…Thus, if any of the pathological effects of FeLV-A infection result from such disruption, it may be possible to reverse the pathology by raising the thiamine concentration in extracellular fluids. Indeed, the anemia, pancytopenia, and, to some extent, diabetes observed in humans with defective THTR1 function can be effectively treated, without adverse effects, by oral or parenteral administration of 20 to 100 mg thiamine per day (15,43,44). Likewise, these same diseases, which are observed in THTR1 knockout mice given a low thiamine diet, can be reversed by feeding the mice a standard mouse chow that contains a high level of thiamine (45).…”

Section: Discussionmentioning

confidence: 99%

Disruption of Thiamine Uptake and Growth of Cells by Feline Leukemia Virus Subgroup A

Mendoza

Miller

Overbaugh

2013

J Virol

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Feline leukemia virus (FeLV) is still a major cause of morbidity and mortality in domestic cats and some wild cats despite the availability of relatively effective vaccines against the virus. FeLV subgroup A (FeLV-A) is transmitted in natural infections, and FeLV subgroups B, C, and T can evolve directly from FeLV-A by mutation and/or recombination with endogenous retroviruses in domestic cats, resulting in a variety of pathogenic outcomes. The cell surface entry receptor for FeLV-A is a putative thiamine transporter (THTR1). Here, we have addressed whether FeLV-A infection might disrupt thiamine uptake into cells and, because thiamine is an essential nutrient, whether this disruption might have pathological consequences. First, we cloned the cat ortholog of the other of the two known thiamine transporters in mammals, THTR2, and we show that feline THTR1 (feTHTR1) and feTHTR2 both mediate thiamine uptake, but feTHTR2 does not function as a receptor for FeLV-A. We found that feTHTR1 is widely expressed in cat tissues and in cell lines, while expression of feTHTR2 is restricted. Thiamine uptake mediated by feTHTR1 was indeed blocked by FeLV-A infection, and in feline fibroblasts that naturally express feTHTR1 and not feTHTR2, this blockade resulted in a growth arrest at physiological concentrations of extracellular thiamine. The growth arrest was reversed at high extracellular concentrations of thiamine. Our results show that FeLV-A infection can indeed disrupt thiamine uptake with pathological consequences. A prediction of these experiments is that raising the plasma levels of thiamine in FeLVinfected cats may ameliorate the pathogenic effects of infection.

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Thiamine-responsive megaloblastic anemia (TRMA) in an Austrian boy with compound heterozygous SLC19A2 mutations

Cited by 26 publications

References 11 publications

First 2 cases with thiamine-responsive megaloblastic anemia in the Czech Republic, a rare form of monogenic diabetes mellitus: a novel mutation in the thiamine transporter SLC19A2 gene-intron 1 mutation c.204+2T>G

First 2 cases with thiamine-responsive megaloblastic anemia in the Czech Republic, a rare form of monogenic diabetes mellitus: a novel mutation in the thiamine transporter SLC19A2 gene-intron 1 mutation c.204+2T>G

Pancytopenia in an adult patient with thiamine-responsive megaloblastic anaemia

Disruption of Thiamine Uptake and Growth of Cells by Feline Leukemia Virus Subgroup A

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