Thiamine-responsive megaloblastic anemia syndrome
General Information (adopted from Orphanet):
Synonyms, Signs: |
THIAMINE METABOLISM DYSFUNCTION SYNDROME 1 (MEGALOBLASTIC ANEMIA, DIABETES MELLITUS, AND DEAFNESS TYPE) MEGALOBLASTIC ANEMIA, THIAMINE-RESPONSIVE, WITH DIABETES MELLITUS AND SENSORINEURAL DEAFNESS THIAMINE-RESPONSIVE MYELODYSPLASIA THIAMINE-RESPONSIVE ANEMIA SYNDROME THMD1 TRMA Thiamine-responsive megaloblastic anemia with diabetes mellitus and sensorineural deafness rogers syndrome |
Number of Symptoms | 60 |
OrphanetNr: | 49827 |
OMIM Id: |
249270
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ICD-10: |
D53.1 |
UMLs: |
C0342287 |
MeSH: |
C536510 |
MedDRA: |
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Snomed: |
237617006 |
Prevalence, inheritance and age of onset:
Prevalence: | < 80 cases [Orphanet] |
Inheritance: |
Autosomal recessive [Orphanet] |
Age of onset: |
Childhood [Orphanet] |
Disease classification (adopted from Orphanet):
Parent Diseases: |
AARSKOG SYNDROME, AUTOSOMAL DOMINANT
-AARSKOG SYNDROME, AUTOSOMAL DOMINANT Constitutional sideroblastic anemia -Rare genetic disease -Rare hematologic disease Disorder of thiamin metabolism and transport -Rare genetic disease Other rare diabetes mellitus -Rare endocrine disease Rare genetic diabetes mellitus -Rare genetic disease Syndromic genetic deafness -Rare developmental defect during embryogenesis -Rare genetic disease -Rare otorhinolaryngologic disease Vitamin B12- and folate-independent constitutional megaloblastic anemia -Rare genetic disease -Rare hematologic disease |
Comment:
Monogenic form of diabetes caused by mutations in SLC19A2 (PMID:21127150) |
Symptom Information:
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(HPO:0008689) | Bilateral cryptorchidism | 38 / 7739 | ||||
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(HPO:0003355) | Aminoaciduria | 65 / 7739 | ||||
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(HPO:0000028) | Cryptorchidism | 347 / 7739 | ||||
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(HPO:0007703) | Abnormality of retinal pigmentation | Occasional [Orphanet] | 21 / 7739 | |||
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(HPO:0000510) | Rod-cone dystrophy | Occasional [Orphanet] | 266 / 7739 | |||
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(HPO:0000646) | Amblyopia | Occasional [Orphanet] | 42 / 7739 | |||
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(HPO:0000546) | Retinal degeneration | 61 / 7739 | ||||
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(HPO:0007754) | Macular dystrophy | 26 / 7739 | ||||
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(HPO:0000639) | Nystagmus | 555 / 7739 | ||||
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(HPO:0000618) | Blindness | Occasional [Orphanet] | 124 / 7739 | |||
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(HPO:0000648) | Optic atrophy | Frequent [Orphanet] | 238 / 7739 | |||
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(HPO:0001085) | Papilledema | Frequent [Orphanet] | 31 / 7739 | |||
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(HPO:0000505) | Visual impairment | Occasional [Orphanet] | 297 / 7739 | |||
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(HPO:0000572) | Visual loss | Occasional [Orphanet] | 272 / 7739 | |||
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(HPO:0000548) | Cone/cone-rod dystrophy | 47 / 7739 | ||||
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(HPO:0000608) | Macular degeneration | 36 / 7739 | ||||
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(HPO:0000407) | Sensorineural hearing impairment | Very frequent [Orphanet] | 524 / 7739 | |||
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(HPO:0008625) | Severe sensorineural hearing impairment | Very frequent [Orphanet] hallmark [HPO] | 150 / 7739 | |||
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(HPO:0008527) | Congenital sensorineural hearing impairment | Very frequent [Orphanet] hallmark [HPO] | 165 / 7739 | |||
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(HPO:0002066) | Gait ataxia | 327 / 7739 | ||||
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(HPO:0001249) | Intellectual disability | 1089 / 7739 | ||||
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(HPO:0001263) | Global developmental delay | 853 / 7739 | ||||
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(HPO:0001270) | Motor delay | 322 / 7739 | ||||
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(HPO:0001250) | Seizures | 1245 / 7739 | ||||
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(HPO:0001327) | Photomyoclonic seizures | 125 / 7739 | ||||
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(HPO:0001251) | Ataxia | 413 / 7739 | ||||
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(HPO:0002311) | Incoordination | 84 / 7739 | ||||
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(HPO:0000819) | Diabetes mellitus | 131 / 7739 | ||||
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(HPO:0100651) | Type I diabetes mellitus | Very frequent [Orphanet] | 44 / 7739 | |||
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(HPO:0002020) | Gastroesophageal reflux | 101 / 7739 | ||||
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(HPO:0003363) | Abdominal situs inversus | 19 / 7739 | ||||
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(HPO:0001696) | Situs inversus totalis | 44 / 7739 | ||||
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(HPO:0004322) | Short stature | Occasional [Orphanet] | 1232 / 7739 | |||
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(HPO:0003510) | Severe short stature | Occasional [Orphanet] | 90 / 7739 | |||
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(HPO:0011354) | Generalized abnormality of skin | 7 / 7739 | ||||
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(HPO:0000951) | Abnormality of the skin | 147 / 7739 | ||||
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(HPO:0002140) | Ischemic stroke | Occasional [Orphanet] rare [HPO] | 70 / 7739 | |||
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(HPO:0004760) | Congenital septal defect | 69 / 7739 | ||||
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(HPO:0001678) | Atrioventricular block | 59 / 7739 | ||||
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(HPO:0002637) | Cerebral ischemia | Occasional [Orphanet] | 17 / 7739 | |||
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(HPO:0001629) | Ventricular septal defect | 316 / 7739 | ||||
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(HPO:0001695) | Cardiac arrest | Occasional [Orphanet] | 87 / 7739 | |||
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(HPO:0001637) | Abnormality of the myocardium | 76 / 7739 | ||||
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(HPO:0001297) | Stroke | Occasional [Orphanet] rare [HPO] | 44 / 7739 | |||
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(HPO:0001671) | Abnormality of the cardiac septa | 55 / 7739 | ||||
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(HPO:0001638) | Cardiomyopathy | 192 / 7739 | ||||
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(HPO:0002326) | Transient ischemic attack | Occasional [Orphanet] | 13 / 7739 | |||
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(HPO:0030680) | Abnormality of cardiovascular system morphology | Occasional [Orphanet] | 355 / 7739 | |||
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(HPO:0001635) | Congestive heart failure | Occasional [Orphanet] | 232 / 7739 | |||
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(HPO:0011675) | Arrhythmia | Occasional [Orphanet] | 226 / 7739 | |||
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(HPO:0001631) | Atria septal defect | 274 / 7739 | ||||
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(HPO:0001645) | Sudden cardiac death | Occasional [Orphanet] | 84 / 7739 | |||
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(HPO:0001889) | Megaloblastic anemia | 28 / 7739 | ||||
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(HPO:0001972) | Macrocytic anemia | Very frequent [Orphanet] | 26 / 7739 | |||
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(HPO:0001924) | Sideroblastic anemia | 12 / 7739 | ||||
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(HPO:0001873) | Thrombocytopenia | Frequent [Orphanet] | 224 / 7739 | |||
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(HPO:0004860) | Thiamine-responsive megaloblastic anemia | 1 / 7739 | ||||
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(HPO:0001609) | Hoarse voice | 34 / 7739 | ||||
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(HPO:0006543) | Cardiorespiratory arrest | Occasional [Orphanet] | 11 / 7739 | |||
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(OMIM) | Serum thiamine is normal | 1 / 7739 |
Associated genes:
SLC19A2 |
ClinVar (via SNiPA)
Gene symbol | Variation | Clinical significance | Reference |
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Additional Information:
Description: (OMIM) |
Thiamine-responsive megaloblastic anemia syndrome comprises megaloblastic anemia, diabetes mellitus, and sensorineural deafness. Onset is typically between infancy and adolescence, but all of the cardinal findings are often not present initially. The anemia, and sometimes the diabetes, improves with high ... |
Clinical Description OMIM |
Rogers et al. (1969) described an 11-year-old girl with megaloblastic anemia responsive only to thiamine. She also had diabetes mellitus, amino aciduria, and sensorineural deafness. Viana and Carvalho (1978) described a 6-year-old girl with congenital megaloblastic anemia that responded ... |
Molecular genetics OMIM |
By positional cloning, Labay et al. (1999) identified the SLC19A2 gene, which they called THTR1, within the critical TRMA locus region. In all affected members of 6 families segregating TRMA, they identified homozygous mutations in the SLC19A2 gene, which ... |
Diagnosis GeneReviews | The diagnosis of thiamine-responsive megaloblastic anemia syndrome (TRMA) is based on an obligate triad of clinical features:... Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilitySLC19A2Sequence analysis of coding region | Sequence variants 2100% 3Clinical 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. All individuals with the diagnostic phenotypic triad evaluated by sequence analysis have identifiable mutations in SLC19A2. To date, over 40 families with 33 distinct mutations 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 mutations from each parent [Bergmann et al 2009, Pichler et al 2012, Shaw-Smith et al 2012]. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases. and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a probandA clinical diagnosis of TRMA should be considered in individuals with megaloblastic anemia with normal vitamin B12/folic acid levels, with or without diabetes or hearing loss; response to oral thiamine makes the diagnosis highly likely. Identification of two SLC19A2 mutations by sequence analysis confirms the diagnosis. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in SLC19A2.
Clinical Description GeneReviews | TRMA is characterized by megaloblastic anemia, sensorineural hearing loss, and diabetes mellitus.... |
Genotype-Phenotype Correlations GeneReviews | No genotype-phenotype correlation has been discerned. Homozygous null mutations in SLC19A2, regardless of position within the gene sequence, result in TRMA, as do all of the reported missense mutations (however, bias of ascertainment may have occurred). ... |
Differential Diagnosis GeneReviews |
Table 2. Thiamine-Responsive Dysfunction Syndrome: OMIM Phenotypic Series ... PhenotypePhenotype MIM NumberGene/LocusGene/Locus MIM NumberMicrocephaly, Amish type | 607196 SLC25A19, DNC, MUP1, MCPHA, THMD3, THMD4 606521 Thiamine-responsive megaloblastic anemia syndrome 249270 SLC19A2, THTR1, TRMA, THMD1 603941 Thiamine metabolism dysfunction syndrome 2 (biotin- or thiamine-responsive encephalopathy type 2) 607483 SLC19A3, THMD2, BBGD 606152 Thiamine metabolism dysfunction syndrome 4 (progressive polyneuropathy type) 613710 SLC25A19, DNC, MUP1, MCPHA, THMD3, THMD4 606521 Thiamine metabolism dysfunction syndrome 5 (episodic encephalopathy type) 614458 TPK1, THMD5 606370 Data from Online Mendelian Inheritance in ManThe 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 is megaloblastic anemia and thiamine responsiveness. Wolfram syndrome; is caused by mutations 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 Mitochondrial Disorders Overview). Inheritance in TRMA is unequivocally autosomal recessive, which sets it apart from disorders with apparent maternal transmission and mitochondrial inheritance.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
Management GeneReviews | To establish the extent of disease in an individual diagnosed with thiamine-responsive megaloblastic anemia syndrome (TRMA), the following evaluations are recommended:... |
Molecular genetics GeneReviews |
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.... Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSLC19A21q24 | Thiamine transporter 1SLC19A2 homepage - Mendelian genesSLC19A2Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Thiamine-Responsive Megaloblastic Anemia Syndrome (View All in OMIM) View in own window 249270THIAMINE-RESPONSIVE MEGALOBLASTIC ANEMIA SYNDROME; TRMA 603941SOLUTE CARRIER FAMILY 19 (THIAMINE TRANSPORTER), MEMBER 2; SLC19A2Molecular Genetic PathogenesisDefect 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. Recent studies showed that a second high-affinity thiamine transporter, encoded by SLC19A3, has major roles in intestinal thiamine uptake using mouse models, 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 mutations 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 mutants 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].Normal allelic variants. SLC19A2 is encoded by six exons spanning approximately 22.5 kb. Pathologic allelic variants. SLC19A2 mutations are distributed throughout the gene with no apparent clustering or mutation hot spots. The majority of SLC19A2 mutations known to date are predicted to be null for protein because of nonsense or frameshift mutations. Ten missense mutations have been reported. Such mutations would likely severely disrupt the folding and membrane targeting of the transporter. Consistently, Balamurugan & Said [2002] showed that introducing several of these mutations into transfected HeLa cells resulted in impaired thiamine uptake [Balamurugan & Said 2002]. Normal gene product. The 497-amino acid protein, the high-affinity thiamine transporter 1, is predicted to have 12 transmembrane domains. Abnormal gene product. Mutations result in either a truncated protein from a premature stop codon or aberrantly folded protein caused by missense mutations in transmembrane domains.