NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Thiamine-Responsive Megaloblastic Anemia Syndrome

Synonyms: Rogers Syndrome, TRMA

, MD and , MD, PhD.

Author Information

Initial Posting: ; Last Update: May 4, 2017.

Summary

Clinical characteristics.

Thiamine-responsive megaloblastic anemia syndrome (TRMA) is characterized by megaloblastic anemia, progressive sensorineural hearing loss, and diabetes mellitus. Onset of megaloblastic anemia occurs between infancy and adolescence. The anemia is corrected with thiamine treatment, but the red cells remain macrocytic, and anemia can recur when treatment is withdrawn.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. Thiamine treatment may delay onset of diabetes in some individuals.

Diagnosis/testing.

The diagnosis of TRMA is established in a proband (with or without diabetes or hearing loss):

  • With megaloblastic anemia and normal vitamin B12/folic acid levels in whom there is a response to oral thiamine; and/or
  • By identification of biallelic pathogenic variants in SLC19A2 by molecular genetic testing.

Management.

Treatment of manifestations: Lifelong use of pharmacologic doses (50-100 mg/day) of oral thiamine (vitamin B1) in affected individuals regardless of age. Red blood cell transfusion for severe anemia.

Prevention of secondary complications: Complications secondary to poor glycemic control for diabetes or chronic anemia may occur. Ongoing management of the primary disease is essential.

Surveillance: At least yearly monitoring of the efficacy of the oral thiamine therapy and of disease progression, including: hematologic tests (CBC, reticulocyte count); assessment for glucose intolerance (fasting serum glucose concentration, OGTT, urine analysis); and hearing, ophthalmologic, and cardiac evaluations.

Pregnancy management: Good diabetic control prior to and during pregnancy is recommended.

Genetic counseling.

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. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible for families in which the SLC19A2 pathogenic variants have been identified in the affected family member.

Diagnosis

Suggestive Findings

Thiamine-responsive megaloblastic anemia syndrome (TRMA) should be suspected in individuals with the following triad of clinical features:

  • Megaloblastic anemia occurring between infancy and adolescence:
    • Examination of the bone marrow reveals megaloblastic changes with erythroblasts often containing iron-filled mitochondria (ringed sideroblasts).
    • Vitamin B12/folic acid levels are normal
    • The anemia is corrected with pharmacologic doses of thiamine (vitamin B1) (50-100 mg/day). However, the red cells remain macrocytic, suggesting a persistent erythropoietic abnormality [Haworth et al 1982, Neufeld et al 1997]; anemia can recur when thiamine is withdrawn.
    • Even without thiamine supplementation, serum thiamine concentrations are normal; there is no evidence of acidosis or aciduria.
  • Progressive sensorineural deafness. Hearing loss is generally early and has been detected in toddlers. Whether hearing loss is congenital (prelingual) is unknown. Some affected individuals have signs of megaloblastic anemia and diabetes at an early age, but no hearing loss.
  • Diabetes mellitus that is non-type I in nature, with age of onset from infancy to adolescence. Insulin secretion is present but defective [Valerio et al 1998].

Establishing the Diagnosis

The diagnosis of TRMA is established in a proband with megaloblastic anemia with normal vitamin B12/folic acid levels, with or without diabetes or hearing loss in whom there is a response to oral thiamine and/or identification of biallelic pathogenic variants in SLC19A2 by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include single-gene testing, use of a multi-gene panel, and more comprehensive genomic testing:

  • Single-gene testing. Sequence analysis of SLC19A2 is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
  • A multi-gene panel that includes SLC19A2 and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene varies by laboratory and over time. (2) Some multi-gene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multi-gene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost while limiting secondary findings. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing based tests.
    For more information on multi-gene panels click here.
  • More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For more information on comprehensive genomic testing click here.

Table 1.

Molecular Genetic Testing Used in Thiamine-Responsive Megaloblastic Anemia Syndrome

Gene 1Test MethodProportion of Probands with Pathogenic Variants 2 Detectable by This Method
SLC19A2Sequence analysis 3Nearly 100% 4
Gene-targeted deletion/duplication analysis 5Very rare; observed in 1 family to date 6
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Nearly all individuals with the diagnostic phenotypic triad evaluated by sequence analysis have identifiable pathogenic variants in SLC19A2. To date, more than 40 families with 33 distinct pathogenic variants have been identified [Diaz et al 1999, Raz et al 2000, Scharfe et al 2000, Gritli et al 2001, Neufeld et al 2001, Ozdemir et al 2002, Lagarde et al 2004, Ricketts et al 2006, Bergmann et al 2009, Onal et al 2009, Pichler et al 2012, Shaw-Smith et al 2012, Yilmaz Agladioglu et al 2012]. Homozygosity by descent has been the most common finding. Seven individuals from six families were compound heterozygotes with distinct pathogenic variants from each parent [Bergmann et al 2009, Pichler et al 2012, Shaw-Smith et al 2012].

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Clinical Characteristics

Clinical Description

Thiamine-responsive megaloblastic anemia syndrome (TRMA) is characterized by megaloblastic anemia, progressive sensorineural hearing loss, and diabetes mellitus.

  • The earliest findings of significant bone marrow problems (see Suggestive Findings) have been in the first year of life and the latest in teenage years.
    • Peripheral blood count shows a pattern of macrocytic anemia with low hemoglobin and high mean corpuscular volume (MCV) in the absence of deficiencies of folate or vitamin B12.
    • Bone marrow shows dysplastic hematopoiesis with numerous megaloblasts.
  • Hearing defects may be present at an early age and in some families may even be present at birth [Setoodeh et al 2013]. Progressive sensorineural hearing loss is irreversible and may not be prevented by thiamine treatment. The basis of the sensorineural deafness is obscure; it is not known if the deafness is caused by abnormalities of the cochlea or of the auditory nerve. However, animal studies suggest that selective inner hair cell loss in the cochlea could be the cause of hearing defects in TRMA [Liberman et al 2006].
  • Non-type I diabetes mellitus has appeared before school age in many (though not all) individuals with glycosuria and hyperglycemia. Diabetic ketoacidosis has been reported in a few cases [Kurtoğlu et al 2008, Pomahačová et al 2016]. Initially, patients respond to oral hypoglycemic agents but most become insulin dependent in the long term.

In addition to the triad of clinical features that characterize TRMA, other findings have been observed, each in only a subset of individuals:

Genotype-Phenotype Correlations

No genotype-phenotype correlation has been discerned.

Nomenclature

The synonym “Rogers syndrome” derives from the first report of the disease in a child with diabetes mellitus, sensorineural deafness, and megaloblastic anemia who responded to thiamine (vitamin B1) treatment.

One case report suggests “thiamine-responsive myelodysplasia” as an alternative name for the syndrome [Bazarbachi et al 1998].

Prevalence

Approximately 50 pedigrees are known.

TRMA is exceedingly rare outside of consanguineous families or isolated populations. Cases have been observed in various ethnicities including Israeli Arab and Lebanese populations, an Alaskan kindred of native and ethnic Russian descent, and kindreds from Brazil, Japan, Oman, Tunisia, Italy (Venetian and other), Iran, India, and Pakistan, as well as Kashmiri families in Great Britain, ethnic Kurds, persons of northern European heritage, and African Americans [Raz et al 2000, Neufeld et al 2001, Lagarde et al 2004, Bergmann et al 2009, Pichler et al 2012, Shaw-Smith et al 2012, Yilmaz Agladioglu et al 2012].

Differential Diagnosis

The combination of megaloblastic red cell changes and ringed sideroblasts in individuals with thiamine-responsive megaloblastic anemia syndrome (TRMA) is unique among anemias influenced by metabolic or nutritional causes. Among acquired anemias, this combination is most suggestive of myelodysplastic syndromes in which megaloblastosis and sideroblasts are often noted. TRMA should not be confused with myelodysplastic disorders of premalignant potential.

Phenotypic overlap exists between TRMA and Wolfram syndrome, or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), including diabetes mellitus, optic atrophy, and deafness. Notably missing in Wolfram syndrome are megaloblastic anemia and thiamine responsiveness. Wolfram syndrome is caused by pathogenic variants in WFS1. The encoded protein is a novel transmembrane glycoprotein of 100 kd located in the endoplasmic reticulum, where it is thought to play a role in membrane trafficking, protein processing, or regulation of calcium homeostasis.

The combination of diabetes mellitus and deafness calls to mind mitochondrial disorders [Fischel-Ghodsian 1999], but the macrocytic anemia, megaloblastic bone marrow, and response to thiamine distinguish TRMA from these disorders (see book-part://mt-overview/). Inheritance in TRMA is unequivocally autosomal recessive, which sets it apart from disorders with apparent maternal transmission and mitochondrial inheritance.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with thiamine-responsive megaloblastic anemia syndrome (TRMA), the following evaluations are recommended if they have not already been completed:

  • Peripheral blood count and bone marrow analysis for evidence of megaloblastic anemia
  • Serum folate concentration, serum vitamin B12 concentration, and serum iron studies to exclude other entities
  • Hearing test
  • Fasting serum glucose concentration, oral glucose tolerance test (OGTT), and urinalysis to diagnose diabetes mellitus
  • Ophthalmologic evaluation
  • Cardiac evaluation, including echocardiography
  • Neuroimaging including brain MRI when clinically indicated
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Thiamine

Management focuses on lifelong use of pharmacologic doses (50-100 mg/day) of oral thiamine (vitamin B1) in affected individuals regardless of age.

High-dose thiamine supplementation:

  • Invariably improves the hematologic picture;
  • Did not prevent the development of hearing loss in infants with TRMA in some studies [Borgna-Pignatti et al 2009, Akın et al 2011]. The efficacy of high-dose thiamine in improving hearing or delaying hearing loss has been difficult to study and remains unclear.
  • May delay onset of diabetes mellitus, and may ameliorate diabetes mellitus in the short term and perhaps even for decades [Valerio et al 1998]. Insulin requirements are reduced with thiamine therapy in some cases [Neufeld et al 1997].
  • Has not been evaluated as a treatment for optic atrophy, cardiovascular abnormalities, or neurologic abnormalities associated with TRMA.

Additional Treatment

Red blood cell transfusion for severe anemia is indicated.

See Deafness and Hereditary Hearing Loss Overview for treatment strategies for hearing loss. Treatment has included cochlear implant [Hagr 2014].

Diabetes, cardiovascular abnormalities, and neurologic disorders should be treated in the standard manner.

Prevention of Primary Manifestations

See Treatment of Manifestations.

Prevention of Secondary Complications

Complications secondary to poor glycemic control for diabetes or chronic anemia may occur. Ongoing management of the primary disease is essential.

Surveillance

The following are recommended at least yearly to monitor the efficacy of the oral thiamine therapy as well as disease progression:

  • Hematologic tests (CBC, reticulocyte count)
  • Hearing test
  • Assessment for glucose intolerance (fasting serum glucose concentration, OGTT, urinalysis)
  • Ophthalmologic evaluation
  • Cardiac evaluation
  • Neurologic evaluation

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of sibs of an affected individual by molecular genetic testing of the SLC19A2 pathogenic variants in the family in order to identify those who would benefit from prompt initiation of treatment and preventive measures.

Supplementation with pharmacologic doses of thiamine (vitamin B1) (25-75 mg/day compared to US RDA of 1.5 mg/day) is recommended as early as possible for at-risk sibs until their genetic status can be determined.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

While there are no published studies evaluating pregnancy outcome in affected women, good diabetic control prior to and during pregnancy is recommended.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Thiamine-responsive megaloblastic anemia syndrome (TRMA) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one SLC19A2 pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • 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.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with TRMA are obligate heterozygotes (carriers) for a pathogenic variant in SLC19A2.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an SLC19A2 pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the SLC19A2 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the SLC19A2 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for TRMA are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Alexander Graham Bell Association for the Deaf and Hard of Hearing
    3417 Volta Place Northwest
    Washington DC 20007
    Phone: 866-337-5220 (toll-free); 202-337-5220; 202-337-5221 (TTY)
    Fax: 202-337-8314
    Email: info@agbell.org
  • American Diabetes Association (ADA)
    Phone: 1-800-DIABETES (800-342-2383)
    Email: AskADA@diabetes.org
  • American Society for Deaf Children (ASDC)
    800 Florida Avenue Northeast
    Suite 2047
    Washington DC 20002-3695
    Phone: 800-942-2732 (Toll-free Parent Hotline); 866-895-4206 (toll free voice/TTY)
    Fax: 410-795-0965
    Email: info@deafchildren.org; asdc@deafchildren.org
  • my baby's hearing
    This site, developed with support from the National Institute on Deafness and Other Communication Disorders, provides information about newborn hearing screening and hearing loss.
  • National Association of the Deaf (NAD)
    8630 Fenton Street
    Suite 820
    Silver Spring MD 20910
    Phone: 301-587-1788; 301-587-1789 (TTY)
    Fax: 301-587-1791
    Email: nad.info@nad.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Thiamine-Responsive Megaloblastic Anemia Syndrome: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
SLC19A21q24​.2Thiamine transporter 1SLC19A2 databaseSLC19A2SLC19A2

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Thiamine-Responsive Megaloblastic Anemia Syndrome (View All in OMIM)

249270THIAMINE-RESPONSIVE MEGALOBLASTIC ANEMIA SYNDROME; TRMA
603941SOLUTE CARRIER FAMILY 19 (THIAMINE TRANSPORTER), MEMBER 2; SLC19A2

Molecular Genetic Pathogenesis

Defect of a high-affinity thiamine transporter, SLC19A2, causes TRMA; however, it is still unclear how the absence of SLC19A2 expression results in the seemingly divergent disorders of megaloblastic anemia, diabetes mellitus, and deafness. Biochemical studies on fibroblasts or erythrocytes from individuals with TRMA showed that absence of the high-affinity component of thiamine transport results in low intracellular thiamine concentrations [Rindi et al 1992, Stagg et al 1999]. Defective RNA ribose synthesis caused by intracellular thiamine deficiency is thought to be the cause of megaloblastic changes in TRMA [Boros et al 2003]. Slc19a2 knockout mouse models have been developed [Oishi et al 2002, Fleming et al 2003]; the animal models manifest megaloblastic changes, diabetes mellitus, and sensorineural deafness (the main features of TRMA) when dietary thiamine levels are decreased [Oishi et al 2002]. While the mechanism of megaloblastic changes is still to be elucidated, these models showed defects in insulin secretion and selective loss of inner hair cells in cochlea [Oishi et al 2002, Liberman et al 2006].

Questions regarding TRMA disease pathogenesis that still require explanation include why individuals with TRMA do not have manifestations seen in dietary thiamine deficiency [Mandel et al 1984, Poggi et al 1984, Abboud et al 1985] and why the findings in TRMA are organ specific.

Studies showed that a second high-affinity thiamine transporter, encoded by SLC19A3, has major roles in intestinal thiamine uptake in mouse, accounting for the absence of overt thiamine deficiency in persons with TRMA [Reidling et al 2010]. In support of this, two Japanese brothers with a Wernicke’s-like encephalopathy were reported to have compound heterozygous pathogenic variants in SLC19A3 [Kono et al 2009]. In addition, the difference in distribution of expression of the two thiamine transporters is critical in TRMA: in pancreatic endocrine cells, the expression of SLC19A2 is much higher than that of SLC19A3 and TRMA-associated SLC19A2 mutated alleles disrupt thiamine uptake significantly [Mee et al 2009]. Similarly, it is hypothesized that in TRMA, the other affected tissues (namely, bone marrow and cochlea) do not express or minimally express SLC19A3 [Eudy et al 2000, Rajgopal et al 2001].

Gene structure. SLC19A2 spans approximately 22.5 kb and has six exons with a 237-bp 5' UTR and a 1,620-bp 3' UTR [Diaz et al 1999, Dutta et al 1999]. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. SLC19A2 pathogenic variants are distributed throughout the gene with no apparent clustering or mutation hot spots. The majority of SLC19A2 pathogenic variants known to date are predicted to be null for protein because of pathogenic nonsense or frameshift variants and missense variants which would likely severely disrupt the folding and membrane targeting of the transporter. Additionally, some splicing variants and small deletion/duplication variants have been reported. Consistently, Balamurugan & Said [2002] showed that introducing several of these pathogenic variants into transfected HeLa cells resulted in impaired thiamine uptake.

Normal gene product. The 497-amino acid protein, the high-affinity thiamine transporter 1, is predicted to have 12 transmembrane domains.

Abnormal gene product. Pathogenic variants result in either a truncated protein from a premature stop codon or aberrantly folded protein caused by missense variants in transmembrane domains.

References

Literature Cited

  • Abboud MR, Alexander D, Najjar SS. Diabetes mellitus, thiamine-dependent megaloblastic anemia, and sensorineural deafness associated with deficient alpha-ketoglutarate dehydrogenase activity. J Pediatr. 1985;107:537–41. [PubMed: 4045602]
  • Akın L, Kurtoğlu S, Kendirci M, Akın MA, Karakükçü M. Does early treatment prevent deafness in thiamine-responsive megaloblastic anaemia syndrome? J Clin Res Pediatr Endocrinol. 2011;3:36–9. [PMC free article: PMC3065315] [PubMed: 21448333]
  • Aycan Z, Baş VN, Cetinkaya S, Ağladioğlu SY, Kendirci HN, Senocak F. Thiamine-responsive megaloblastic anemia syndrome with atrial standstill: a case report. J Pediatr Hematol Oncol. 2011;33:144–7. [PubMed: 21285901]
  • Balamurugan K, Said HM. Functional role of specific amino acid residues in human thiamine transporter SLC19A2: mutational analysis. Am J Physiol Gastrointest Liver Physiol. 2002;283:G37–43. [PubMed: 12065289]
  • Bazarbachi A, Muakkit S, Ayas M, Taher A, Salem Z, Solh H, Haidar JH. Thiamine-responsive myelodysplasia. Br J Haematol. 1998;102:1098–100. [PubMed: 9734663]
  • Bergmann AK, Sahai I, Falcone JF, Fleming J, Bagg A, Borgna-Pignati C, Casey R, Fabris L, Hexner E, Mathews L, Ribeiro ML, Wierenga KJ, Neufeld EJ. Thiamine-responsive megaloblastic anemia: identification of novel compound heterozygotes and mutation update. J Pediatr. 2009;155:888–92.e1. [PMC free article: PMC2858590] [PubMed: 19643445]
  • Borgna-Pignatti C, Azzalli M, Pedretti S. Thiamine-responsive megaloblastic anemia syndrome: long term follow-up. J Pediatr. 2009;155:295–7. [PubMed: 19619756]
  • Borgna-Pignatti C, Marradi P, Pinelli L, Monetti N, Patrini C. Thiamine-responsive anemia in DIDMOAD syndrome. J Pediatr. 1989;114:405–10. [PubMed: 2537896]
  • Beshlawi I, Al Zadjali S, Bashir W, Elshinawy M, Alrawas A, Wali Y. Thiamine responsive megaloblastic anemia: the puzzling phenotype. Pediatr Blood Cancer. 2014;61:528–31. [PubMed: 24249281]
  • Boros LG, Steinkamp MP, Fleming JC, Lee WN, Cascante M, Neufeld EJ. Defective RNA ribose synthesis in fibroblasts from patients with thiamine-responsive megaloblastic anemia (TRMA). Blood. 2003;102:3556–61. [PubMed: 12893755]
  • Diaz GA, Banikazemi M, Oishi K, Desnick RJ, Gelb BD. Mutations in a new gene encoding a thiamine transporter cause thiamine-responsive megaloblastic anaemia syndrome. Nat Genet. 1999;22:309–12. [PubMed: 10391223]
  • Dutta B, Huang W, Molero M, Kekuda R, Leibach FH, Devoe LD, Ganapathy V, Prasad PD. Cloning of the human thiamine transporter, a member of the folate transporter family. J Biol Chem. 1999;274:31925–9. [PubMed: 10542220]
  • Eudy JD, Spiegelstein O, Barber RC, Wlodarczyk BJ, Talbot J, Finnell RH. Identification and characterization of the human and mouse SLC19A3 gene: a novel member of the reduced folate family of micronutrient transporter genes. Mol Genet Metab. 2000;71:581–90. [PubMed: 11136550]
  • Fischel-Ghodsian N. Mitochondrial deafness mutations reviewed. Hum Mutat. 1999;13:261–70. [PubMed: 10220138]
  • Fleming JC, Tartaglini E, Kawatsuji R, Yao D, Fujiwara Y, Bednarski JJ, Fleming MD, Neufeld EJ. Male infertility and thiamine-dependent erythroid hypoplasia in mice lacking thiamine transporter Slc19a2. Mol Genet Metab. 2003;80:234–41. [PubMed: 14567973]
  • Gritli S, Omar S, Tartaglini E, Guannouni S, Fleming JC, Steinkamp MP, Berul CI, Hafsia R, Jilani SB, Belhani A, Hamdi M, Neufeld EJ. A novel mutation in the SLC19A2 gene in a Tunisian family with thiamine-responsive megaloblastic anaemia, diabetes and deafness syndrome. Br J Haematol. 2001;113:508–13. [PubMed: 11380424]
  • Hagr AA. Cochlear implant and thiamine-responsive megaloblastic anemia syndrome. Ann Saudi Med. 2014;34:78–80. [PubMed: 24658560]
  • Haworth C, Evans DI, Mitra J, Wickramasinghe SN. Thiamine responsive anaemia: a study of two further cases. Br J Haematol. 1982;50:549–61. [PubMed: 6175336]
  • Kipioti A, George ND, Hoffbrand AV, Sheridan E. Cone-rod dystrophy in thiamine-responsive megaloblastic anemia. J Pediatr Ophthalmol Strabismus. 2003;40:105–7. [PubMed: 12691235]
  • Kono S, Miyajima H, Yoshida K, Togawa A, Shirakawa K, Suzuki H. Mutations in a thiamine-transporter gene and Wernicke's-like encephalopathy. N Engl J Med. 2009;360:1792–4. [PubMed: 19387023]
  • Kurtoğlu S, Hatipoglu N, Keskin M, Kendirci M, Akcakus M. Thiamine withdrawal can lead to diabetic ketoacidosis in thiamine responsive megaloblastic anemia: report of two siblings. J Pediatr Endocrinol Metab. 2008;21:393–7. [PubMed: 18556972]
  • Lagarde WH, Underwood LE, Moats-Staats BM, Calikoglu AS. Novel mutation in the SLC19A2 gene in an African-American female with thiamine-responsive megaloblastic anemia syndrome. Am J Med Genet A. 2004;125A:299–305. [PubMed: 14994241]
  • Liberman MC, Tartaglini E, Fleming JC, Neufeld EJ. Deletion of SLC19A2, the high affinity thiamine transporter, causes selective inner hair cell loss and an auditory neuropathy phenotype. J Assoc Res Otolaryngol. 2006;7:211–7. [PMC free article: PMC1805778] [PubMed: 16642288]
  • Lorber A, Gazit AZ, Khoury A, Schwartz Y, Mandel H. Cardiac manifestations in thiamine-responsive megaloblastic anemia syndrome. Pediatr Cardiol. 2003;24:476–81. [PubMed: 14627317]
  • Mandel H, Berant M, Hazani A, Naveh Y. Thiamine-dependent beriberi in the "thiamine-responsive anemia syndrome.". N Engl J Med. 1984;311:836–8. [PubMed: 6472386]
  • Mee L, Nabokina SM, Sekar VT, Subramanian VS, Maedler K, Said HM. Pancreatic beta cells and islets take up thiamin by a regulated carrier-mediated process: studies using mice and human pancreatic preparations. Am J Physiol Gastrointest Liver Physiol. 2009;297:G197–206. [PMC free article: PMC2711754] [PubMed: 19423748]
  • Meire FM, Van Genderen MM, Lemmens K, Ens-Dokkum MH. Thiamine-responsive megaloblastic anemia syndrome (TRMA) with cone-rod dystrophy. Ophthalmic Genet. 2000;21:243–50. [PubMed: 11135496]
  • Neufeld EJ, Fleming JC, Tartaglini E, Steinkamp MP. Thiamine-responsive megaloblastic anemia syndrome: a disorder of high-affinity thiamine transport. Blood Cells Mol Dis. 2001;27:135–8. [PubMed: 11358373]
  • Neufeld EJ, Mandel H, Raz T, Szargel R, Yandava CN, Stagg A, Faure S, Barrett T, Buist N, Cohen N. Localization of the gene for thiamine-responsive megaloblastic anemia syndrome, on the long arm of chromosome 1, by homozygosity mapping. Am J Hum Genet. 1997;61:1335–41. [PMC free article: PMC1716091] [PubMed: 9399900]
  • Oishi K, Hofmann S, Diaz GA, Brown T, Manwani D, Ng L, Young R, Vlassara H, Ioannou YA, Forrest D, Gelb BD. Targeted disruption of Slc19a2, the gene encoding the high-affinity thiamin transporter Thtr-1, causes diabetes mellitus, sensorineural deafness and megaloblastosis in mice. Hum Mol Genet. 2002;11:2951–60. [PubMed: 12393806]
  • Onal H, Bariş S, Ozdil M, Yeşil G, Altun G, Ozyilmaz I, Aydin A, Celkan T. Thiamine-responsive megaloblastic anemia: early diagnosis may be effective in preventing deafness. Turk J Pediatr. 2009;51:301–4. [PubMed: 19817279]
  • Ozdemir MA, Akcakus M, Kurtoglu S, Gunes T, Torun YA. TRMA syndrome (thiamine-responsive megaloblastic anemia): a case report and review of the literature. Pediatr Diabetes. 2002;3:205–9. [PubMed: 15016149]
  • Pichler H, Zeitlhofer P, Dworzak MN, Diakos C, Haas OA, Kager L. Thiamine-responsive megaloblastic anemia (TRMA) in an Austrian boy with compound heterozygous SLC19A2 mutations. Eur J Pediatr. 2012;171:1711–5. [PubMed: 22576805]
  • Poggi V, Longo G, DeVizia B, Andria G, Rindi G, Patrini C, Cassandro E. Thiamin-responsive megaloblastic anaemia: a disorder of thiamin transport? J Inherit Metab Dis. 1984;7 Suppl 2:153–4. [PubMed: 6090807]
  • Pomahačová R, Zamboryová J, Sýkora J, Paterová P, Fiklík K, Votava T, Černá Z, Jehlička P, Lád V, Šubrt I, Dort J, Dortová E. 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. Pediatr Diabetes. 2016 Dec 22; Epub ahead of print. [PubMed: 28004468]
  • Rajgopal A, Edmondnson A, Goldman ID, Zhao R. SLC19A3 encodes a second thiamine transporter ThTr2. Biochim Biophys Acta. 2001;1537:175–8. [PubMed: 11731220]
  • Raz T, Labay V, Baron D, Szargel R, Anbinder Y, Barrett T, Rabl W, Viana MB, Mandel H, Baruchel A, Cayuela JM, Cohen N. The spectrum of mutations, including four novel ones, in the thiamine-responsive megaloblastic anemia gene SLC19A2 of eight families. Hum Mutat. 2000;16:37–42. [PubMed: 10874303]
  • Reidling JC, Lambrecht N, Kassir M, Said HM. Impaired intestinal vitamin B(1) (thiamin) uptake in thiamin transporter-2-deficient mice. Gastroenterology. 2010;138:1802–9. [PMC free article: PMC4916904] [PubMed: 19879271]
  • Ricketts CJ, Minton JA, Samuel J, Ariyawansa I, Wales JK, Lo IF, Barrett TG. Thiamine-responsive megaloblastic anaemia syndrome: long-term follow-up and mutation analysis of seven families. Acta Paediatr. 2006;95:99–104. [PubMed: 16373304]
  • Rindi G, Casirola D, Poggi V, De Vizia B, Patrini C, Laforenza U. Thiamine transport by erythrocytes and ghosts in thiamine-responsive megaloblastic anaemia. J Inherit Metab Dis. 1992;15:231–42. [PubMed: 1326679]
  • Scharfe C, Hauschild M, Klopstock T, Janssen AJ, Heidemann PH, Meitinger T, Jaksch M. A novel mutation in the thiamine responsive megaloblastic anaemia gene SLC19A2 in a patient with deficiency of respiratory chain complex I. J Med Genet. 2000;37:669–73. [PMC free article: PMC1734685] [PubMed: 10978358]
  • Setoodeh A, Haghighi A, Saleh-Gohari N, Ellard S, Haghighi A. Identification of a SLC19A2 nonsense mutation in Persian families with thiamine-responsive megaloblastic anemia. Gene. 2013;519:295–7. [PMC free article: PMC3725413] [PubMed: 23454484]
  • Shaw-Smith C, Flanagan SE, Patch AM, Grulich-Henn J, Habeb AM, Hussain K, Pomahacova R, Matyka K, Abdullah M, Hattersley AT, Ellard S. Recessive SLC19A2 mutations are a cause of neonatal diabetes mellitus in thiamine-responsive megaloblastic anaemia. Pediatr Diabetes. 2012;13:314–21. [PubMed: 22369132]
  • Stagg AR, Fleming JC, Baker MA, Sakamoto M, Cohen N, Neufeld EJ. Defective high-affinity thiamine transporter leads to cell death in thiamine-responsive megaloblastic anemia syndrome fibroblasts. J Clin Invest. 1999;103:723–9. [PMC free article: PMC408117] [PubMed: 10074490]
  • Valerio G, Franzese A, Poggi V, Tenore A. Long-term follow-up of diabetes in two patients with thiamine-responsive megaloblastic anemia syndrome. Diabetes Care. 1998;21:38–41. [PubMed: 9538968]
  • Villa V, Rivellese A, Di Salle F, Iovine C, Poggi V, Capaldo B. Acute ischemic stroke in a young woman with the thiamine-responsive megaloblastic anemia syndrome. J Clin Endocrinol Metab. 2000;85:947–9. [PubMed: 10720020]
  • Yilmaz Agladioglu S, Aycan Z, Bas VN, Peltek Kendirci HN, Onder A. Thiamine-responsive megaloblastic anemia syndrome: a novel mutation. Genet Couns. 2012;23:149–56. [PubMed: 22876572]

Chapter Notes

Author History

George A Diaz, MD, PhD (2006-present)
Judith C Fleming, PhD; Children's Hospital and Harvard Medical School (2003-2006)
Ellis J Neufeld, MD, PhD; Children's Hospital and Harvard Medical School (2003-2006)
Kimihiko Oishi, MD (2006-present)

Revision History

  • 4 May 2017 (ha) Comprehensive update posted live
  • 20 November 2014 (me) Comprehensive update posted live
  • 20 September 2012 (me) Comprehensive update posted live
  • 8 April 2010 (me) Comprehensive update posted live
  • 19 November 2007 (cd) Revision: sequence analysis and prenatal diagnosis available clinically for SCL19A2
  • 22 June 2006 (ca) Comprehensive update posted to live Web site
  • 24 October 2003 (me) Review posted to live Web site
  • 25 August 2003 (ejn) Original submission
Copyright © 1993-2018, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2018 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK1282PMID: 20301459

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...