Thiamine-responsive Megaloblastic Anemia Syndrome Research Articles

Novel Homozygous Variant in the SLC19A2 Gene Causing Thiamine Responsive Megaloblastic Anemia Syndrome: A Disease to Be Considered in Diabetes Clinics

Novel Homozygous Variant in the SLC19A2 Gene Causing Thiamine Responsive Megaloblastic Anemia Syndrome: A Disease to Be Considered in Diabetes Clinics

Bibliometric visualization analysis of thiamine-responsive megaloblastic anemia syndrome

Visual analysis of the current status, research hotspots, evolving trends, and future prospects in the field of thiamine-responsive megaloblastic anemia syndrome (TRMA), providing new insights and directions for subsequent research on the pathogenic mechanisms and prevention strategies of TRMA. Taking the core database of Web of Science as the literature source, selecting TRMA-related literature records published from 1997 to 2023 as the research object, and using R software and Citexs database to conduct visual analysis and discussion of the research content. The results showed that a total of 89 publications related to the topic were published from 1997 to 2023, with an average annual publication volume of 3 papers. Classified by country, it was found that the United States, and Israel among other countries and institutions, published a significant number of papers. Through keyword frequency analysis, high frequencies of keywords such as diabetes, deafness, thiamine-responsive megaloblastic anemia, and mutations in the solute carrier family 19 member 2 (SLC19A2) gene were observed, indicating that to date, these keywords have been the main research directions, highlighting a gradually reached consensus on the mechanism exploration of TRMA. In conclusion, TRMA research focuses on the mechanisms of hot topics such as diabetes, deafness, and thiamine-responsive megaloblastic anemia, and the core gene SLC19A2 research may currently become a new breakthrough point for future molecular studies.

An Italian case series' description of thiamine responsive megaloblastic anemia syndrome: importance of early diagnosis and treatment

BackgroundIndividuals with thiamine-responsive megaloblastic anemia (TRMA) mainly manifest macrocytic anemia, sensorineural deafness, ocular complications, and nonautoimmune diabetes. Macrocytic anemia and diabetes may be responsive to high-dosage thiamine treatment, in contrast to sensorineural deafness. Little is known about the efficacy of thiamine treatment on ocular manifestations.Cases presentationOur objective is to report data from four Italian TRMA patients: in Cases 1, 2 and 3, the diagnosis of TRMA was made at 9, 14 and 27 months. In 3 out of 4 subjects, thiamine therapy allowed both normalization of hyperglycemia, with consequent insulin suspension, and macrocytic anemia. In all Cases, thiamine therapy did not resolve the clinical manifestation of deafness. In Cases 2 and 3, follow-up showed no blindness, unlike Case 4, in which treatment was started for megaloblastic anemia at age 7 but was increased to high doses only at age 25, when the genetic diagnosis of TRMA was performed.ConclusionsEarly institution of high-dose thiamine supplementation seems to prevent the development of retinal changes and optic atrophy in TRMA patients. The spectrum of clinical manifestations is broad, and it is important to describe known Cases to gain a better understanding of this rare disease.

Thiamine-Responsive Megaloblastic Anemia Syndrome Combined with Thalassemia Trait: A Rare Association

Abstract Introduction Thiamine-responsive megaloblastic anemia syndrome (TRMA, OMIM reference 249270), also known as Rogers' syndrome, is a rare type of anemia characterized by the triad megaloblastic anemia, sensorineural hearing loss, and diabetes mellitus (DM). Disturbance of thiamine transport into cells results from homozygous or compound heterozygous mutations in the SLC19A2 gene. Case Report We report the case of an 8-year-old girl who presented at age 4 years with anemia. She had a combined hematological profile of microcytic and macrocytic anemia. The parents refused bone marrow aspiration and genetic diagnosis. Hemoglobin electrophoresis established the thalassemia trait. She was later confirmed to have sensorineural deafness and monogenic DM. A tentative TRMA diagnosis was based on megaloblastic anemia, sensorineural deafness, and monogenic DM triad. The patient was treated empirically with a daily dose of thiamine 200 mg; her hemoglobin level normalized, but the deafness and DM did not improve. Conclusion In routine practice, patients with TRMA must be evaluated thoroughly for other causes of megaloblastic anemia, including therapeutic thiamine trials in the presence of sensorineural deafness or DM. These patients should be followed throughout their life span both for DM and to control their response to thiamine therapy for megaloblastic anemia.

Thiamine-responsive megaloblastic anaemia syndrome – A case report

Thiamine is a water-soluble vitamin which is helpful for tissue growth and development. Thiamine-responsive megaloblastic anaemia (TRMA), also known as Rogers syndrome, is caused by the mutation of a gene SLC19A2 which encodes for a thiamine transporter protein. TRMA is characterised by the triad of megaloblastic anaemia, progressive sensorineural hearing loss and diabetes mellitus. The onset of megaloblastic anaemia is between the extremes of infancy and adolescence, which can be corrected with pharmacological doses of thiamine. Progressive sensorineural hearing loss is generally early in onset, irreversible and may not be prevented by thiamine treatment.

Whole-Exome Sequencing Revealed a Pathogenic Nonsense Variant in the SLC19A2 Gene in an Iranian Family with Thiamine-Responsive Megaloblastic Anemia.

Solute carrier family 19 member 2 (SLC19A2, OMIM *603941) encodes thiamine human transporter 1 (THTR-1), which contributes to bringing thiamine (vitamin B1) into cells. Mutations in SLC19A2 lead to a rare recessive genetic disorder termed thiamine-responsive megaloblastic anemia (TRMA) syndrome. An Iranian family with TRMA was investigated by whole-exome sequencing (WES) to determine the genetic cause(s) of the disease. Accordingly, SLC19A2 genetic variants were gathered through literature analysis. WES recognized a known pathogenic variant, c.697C > T (p. Q233X), within exon 2 of SLC19A2 (NM_006996). Subsequently, the proband's parents and sister were confirmed as heterozygous carriers of the identified variant. The diagnostic utility and affordability of WES were confirmed as the first approach for the genetic testing of TRMA to verify the diagnosis. This analysis can be used to guide future prenatal diagnoses and determine the consequences in the other family members.

Thiamine-responsive megaloblastic anemia syndrome with dysrhythmia

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Frameshift variance in SLC19A2 gene causing thiamine responsive megaloblastic anemia (TRMA): a case report from Pakistan

Thiamine responsive megaloblastic anemia syndrome is a rare genetic disorder usually associated with sensorineural deafness, megaloblastic anemia, and/or diabetes mellitus due to mutations in SLC19A2, encoding a thiamine transporter protein. In this case, we report a 2.5-year-old baby boy born to consanguineous parents. He was noted to be deaf and mute during his first year of life. He was diagnosed with anemia at the age of 15 months and required blood transfusion twice. The cause of anemia was not established and it was attributed secondary to some viral infection. At the age of 2 years, he was diagnosed with DM. The diagnosis of TRMA had been made during his evaluations for uncontrolled blood glucose, sensorineural deafness, and anemia. After few weeks of thiamine replacement, his hemoglobin increased to normal values; his sugars improved but had no changes in his deafness. Analysis of all coding regions and exon/intron boundaries of the SLC19A2 gene by Sanger sequencing. A p,Leu208fs homozygous frame shift variant is identified in the SLC19A2 gene, located on the Exon 2 and DNA description is c.623dup. This variant is predicted to be pathogenic and diagnosis of TRMA syndrome is confirmed. The diagnosis of TRMA should be kept in mind in differential diagnosis of DM with anemia and or sensorineural hearing loss. Particularly in the populations where the consanguinity is frequent as diagnosis has great impact on management.

Thiamine-responsive megaloblastic anemia syndrome: A case report

Thiamine-responsive megaloblastic anemia (TRMA) syndrome is a rare autosomal recessive disorder characterized by a cardinal triad consisting of megaloblastic anemia, sensorineural deafness, and diabetes mellitus. TRMA is caused by mutations in the gene SLC19A2 encoding a high-affinity thiamine transporter, which disturbs the active thiamine uptake into cells. We report here on a 1-year and 9-month-old female baby with megaloblastic anemia, thrombocytopenia, and diabetes mellitus. Our patient had significant sensorineural hearing loss that was late to appear. Diagnosis was based on clinical features and dramatic response of anemia, thrombocytopenia, and glycemic control to thiamine therapy. In view of the clinical history of the patient, targeted gene sequencing of genes causing monogenic diabetes was performed. The genes selected comprised 40 gene loci and were sequenced by Illumina sequencing platform. We found a novel homozygous deletion mutation of complete exon 2 of the SLC19A2 gene (ENS0236137), which we believe has not been described to be associated with TRMA. Exon 2 of SLC19A2 gene includes amino acid from 69 to 269. Thiamine resulted in rapid normalization of the hemoglobin level with improvement in glycemic control. TRMA syndrome should be kept in mind in the differential diagnosis of megaloblastic anemia, deafness, and diabetes mellitus. Early introduction of high-dose thiamine can reverse anemia and allow more glycemic control for diabetes. We conclude that genetic analysis confirms the diagnosis of TRMA. As exogenous thiamine is shown to reverse some of the clinical features of the disease, a genetic diagnosis of TRMA syndrome is extremely important.

Pharmacogenomics in diabetes: outcomes of thiamine therapy in TRMA syndrome

Aims/hypothesisDiabetes is one of the cardinal features of thiamine-responsive megaloblastic anaemia (TRMA) syndrome. Current knowledge of this rare monogenic diabetes subtype is limited. We investigated the genotype, phenotype and response to thiamine (vitamin B1) in a cohort of individuals with TRMA-related diabetes.MethodsWe studied 32 individuals with biallelic SLC19A2 mutations identified by Sanger or next generation sequencing. Clinical details were collected through a follow-up questionnaire.ResultsWe identified 24 different mutations, of which nine are novel. The onset of the first TRMA symptom ranged from birth to 4 years (median 6 months [interquartile range, IQR 3–24]) and median age at diabetes onset was 10 months (IQR 5–27). At presentation, three individuals had isolated diabetes and 12 had asymptomatic hyperglycaemia. Follow-up data was available for 15 individuals treated with thiamine for a median 4.7 years (IQR 3–10). Four patients were able to stop insulin and seven achieved better glycaemic control on lower insulin doses. These 11 patients were significantly younger at diabetes diagnosis (p = 0.042), at genetic testing (p = 0.01) and when starting thiamine (p = 0.007) compared with the rest of the cohort. All patients treated with thiamine became transfusion-independent and adolescents achieved normal puberty. There were no additional benefits of thiamine doses >150 mg/day and no reported side effects up to 300 mg/day.Conclusions/interpretationIn TRMA syndrome, diabetes can be asymptomatic and present before the appearance of other features. Prompt recognition is essential as early treatment with thiamine can result in improved glycaemic control, with some individuals becoming insulin-independent.Data availabilitySLC19A2 mutation details have been deposited in the Decipher database (https://decipher.sanger.ac.uk/).

Recurrent Stroke in a Child with TRMA Syndrome and SLC19A2 Gene Mutation.

Here we report a 5-month-old boy with thiamine Responsive Megaloblastic Anemia syndrome (TRMA syndrome) with several attacks of stroke, admitted to Mofid Children's Hospital, Tehran, Iran, in 2016. In addition to the cardinal clinical manifestations of the syndrome, other manifestations comprise thiamine-responsive megaloblastic anemia, diabetes mellitus, and sensor neural hearing loss. The patient showed the ischemic attack of stroke. Megaloblastic anemia and diabetes were diagnosed at 8 months and was successfully treated with vitamin and insulin prescription. After treatment of thiamine, diabetes was controlled and insulin was discontinued. In spite of the thiamine administration, the second stroke as hemorrhagic stroke occurred in the patient after a few months. TRAMA is inherited in an autosomal recessive manner. TRMA was confirmed by mutation in SLC19A2. A homozygous splice site variant was detected in SLC19A2 gene. Stroke was not reported in this syndrome (only in one report about one attack in an adult patient) but in this patient, several attacks of stroke were reported before and after thiamin administration.

A Novel Mutation of SLC19A2 in a Chinese Zhuang Ethnic Family with Thiamine-Responsive Megaloblastic Anemia

Background/Aims: Thiamine-responsive megaloblastic anemia syndrome is a rare autosomal recessive disorder resulting from mutations in SLC19A2, and is mainly characterized by megaloblastic anemia, diabetes, and progressive sensorineural hearing loss. Methods: We study a Chinese Zhuang ethnicity family with thiamine-responsive megaloblastic anemia. The proband of the study presented with anemia and diabetes, similar to his late brother, as well as visual impairment. All clinical manifestations were corrected with thiamine (30 mg/d) supplementation for 1–3 months, except for visual impairment, which was irreversible. The presence of mutations in all exons and the flanking sequences of the SLC19A2 gene were analyzed in this family based on the proband’s and his brother’s clinical data. Computer analysis and prediction of the protein conformation of mutant THTR-1. The relative concentration of thiamine pyrophosphate in the proband’s whole blood before and after initiation of thiamine supplement was measured by high performance liquid chromatography (HPLC). Results: Gene sequencing showed a homozygous mutation in exon 6 of the SLC19A2 gene (c.1409insT) in the proband. His parents and sister were diagnosed as heterozygous carriers of the c.1409insT mutation. Computer simulation showed that the mutations caused a change in protein conformation. HPLC results suggested that the relative concentration of thiamine pyrophosphate in the proband’s whole blood after thiamine supplement was significantly different (P=0.016) from that at baseline. Conclusions: This novel homozygous mutation (c.1409insT) caused the onset of thiamine-responsive megaloblastic anemia in the proband.

THIAMINE-RESPONSIVE MEGALOBLASTIC ANEMIA WITH EPILEPSY: A CASE REPORT

Abstract Background: Thiamine-responsive megaloblastic anemia (TRMA) syndrome is a rare autosomal recessive disorder characterized by cardinal triad features of megaloblastic anemia, sensorineural deafness and diabetes mellitus. TRMA manifestation is caused by mutations in the gene SLC19A2 encoding a high-affinity thiamine transporter, which disturbs the active thiamine uptake into cells. Case presentation: We herein report a 16-year-old Egyptian male with megaloblastic anemia, deafness and diabetes in addition he had epilepsy and hepatosplenomegaly. Diagnosis was based on clinical features and dramatic response of anemia to thiamine therapy. Thiamine in a dose of 250 mg/day resulted in rapid normalization of the hemoglobin level; which lasted for the whole 12-month follow up period; with partial improvement in glycemic control as reflected by decrease in glycosylated hemoglobin and regression of hepatosplenomegaly. Deafness and seizures showed no response to thiamin. Conclusions: TRMA syndrome should be ...

A Thiamine Responsive Megaloblastic Anemia Presented with Hypertriglyceridemia and Auto-immune Diabetes

Background: Thiamine responsive megaloblastic anemia syndrome (TRMA) is an autosomal recessive disorder characterized by non type 1 diabetes mellitus (DM), sensorineural hearing loss and megaloblastic anemia and caused by mutations in SLC19A2 gene, encoding a thiamine transporter protein. Case: A 3-month-old male infant presented with megaloblastic anemia, DM, patent ductus arteriosus and hypertriglyceridemia. His autoimmune markers for DM were positive but with the additional finding of sensorineural deafness he was diagnosed with TRMA and thiamine therapy was started. His anemia was improved and insulin needs decreased and his genetic studies revealed a homozygous frameshift mutation, c.641del within coding region of SLC19A2 gene. Conclusion: Clinical presentation of TRMA could be highly variable and some co-existence could perplex physicians, but this diagnosis should be considered in all patients with DM and anemia and further assessment should be done.

Clinical and genetic features of Argentinian children with diabetes-onset before 12 months of age: Successful transfer from insulin to oral sulfonylurea

AimsNeonatal diabetes mellitus (NDM) is a rare monogenic disorder, reported to affect less than 2 cases per 100,000 infants. There are two types, permanent (PNDM) and transient (TNDM). We describe our clinical experience in determining and comparing the genetic basis of diabetes in children with onset before 6months versus those diagnosed between 6 and 12months of age. MethodsWe reviewed medical records of children with diabetes diagnosed before 12months of age. Genetic testing was performed in all cases. Results12 patients were diagnosed with diabetes before 6months of age (PNDM=6; TNDM=6), and 11 patients between 6 and 12months (all with permanent diabetes). Among children with PNDM, we identified three different KCNJ11 mutations in 5 patients, and one novel ABCC8 mutation in a single patient. Among children with TNDM, we detected a KCNJ11 and ABCC8 mutation each in a single patient and methylation abnormalities at chromosome 6q24 in 4 patients.Among children with diabetes diagnosed between 6 and 12months, 1 patient had an INS mutation and one patient was homozygous for an SLC19A2 mutation which confirmed a diagnosis of thiamine-responsive megaloblastic anaemia syndrome. Five of the patients with an ABCC8 or KCNJ11 mutation have successfully transferred from insulin to glibenclamide whist 1 child demonstrated a partial response to sulfonylurea treatment. ConclusionsInvestigating the underlying genetic basis of diabetes in children with onset before 1year is useful for choosing the most efficient treatment, the basis of Personalized Medicine.

TRMA syndrome (thiamine-responsive megaloblastic anaemia): An example of rare monogenic diabetes: is thiamine a magic pill for anaemia and diabetes?

Thiamine-responsive megaloblastic anaemia (TRMA) is a rare syndrome presenting with early onset non-autoimmune diabetes mellitus, megaloblastic anaemia and sensorineural deafness. We report a 16-month-old male, a youngest case of genetically confirmed TRMA syndrome in Indian phenotype, born to consanguineous parents. We found a homozygous pathogenic variant in exon 2 of the SLC19A2 gene, c.314G>A (p.Gly105Glu). The anaemia showed a good response to daily thiamine doses and was able to avoid unwanted blood transfusion. There was no benefit with regard to insulin requirement. Early detection of hearing impairment and referral to audiological treatment was possible. The report indicates that TRMA should be considered as a differential diagnosis for patients presenting with suggestive clinical symptoms which would have tremendous impact on patient management if identified early.

G407(P) Macrocytosis – a rare but serious problem!

Aims A case report to highlight the importance of macrocytosis. Methods A 7½ year old boy was referred with macrocytosis (MCV 108). He was fit and thriving child (weight, height 50th centile). History and examination was unremarkable. Bloods done 5 years ago also showed high MCV (95). Routine tests for evaluation of macrocytosis were normal. Later FBC showed thrombocytopenia, leucopenia and neutropenia. He was finally diagnosed to have Fanconi anaemia. He has been put on register for bone marrow transplant, and whole family is being tested for gene mutations. Fanconi anaemia is an autosomal recessive or X-linked form of inherited aplastic anaemia. Sixteen mutations (FA-A to FA-Q) have been identified. Hematologic findings evolve over months to years, with 70% of children developing bone marrow failure by age 10. They are at high risk for developing myelodysplastic syndrome, acute myeloid leukaemia, and squamous cell carcinoma. Characteristic congenital malformations are present in up to 70% of affected children (short stature, cafe-au-lait spots, hypopigmented spots, thumb abnormality, microcephaly, hydrocephaly, hypogonadism, developmental delay). Diagnosis is made by presence of increased chromosomal breakage in lymphocytes cultured in the presence of DNA cross-linking agents (mitomycin C or diepoxybutane). Bone marrow transplant is the only available curative treatment. Other treatment options include androgens, hematopoietic growth factors, and blood product transfusions with supportive care. Results Hb 122, WCC 8.6, Platelets 164, MCV 102 in 2011. Hb 118, WCC 5.4, Neutrophils 1.34, Platelets 130, MCV 108 in 2014. U&E, LFT, immunoglobulins, B12, Folate, Ferritin, and TFT were normal. Bone marrow biopsy revealed mild aplasia, and no myelodysplastic syndrome or leukaemia. HIV, Hepatitis screen and viral serology were negative. Fanconi Anaemia test came back positive. Conclusions Children presenting with macrocytosis should be carefully evaluated and referred to a haematologist, as it could be the first manifestation of a serious underlying bone marrow problem. Macrocytosis in age range of six months to 12 years age is MCV >90. Causes of macrocytosis include disorders of folate/B12 metabolism, liver disease, congenital heart disease, Down’s syndrome, hypothyroidism, drugs (anticonvulsants, zidovudine, hydroxyurea, immunosuppresants), myelodysplastic syndromes, bone marrow failure, and rare genetic syndromes (eg, Fanconi anaemia, thiamine-responsive megaloblastic anaemia syndrome).

Erken Başlangıçlı Tiamin Yanıtlı Megaloblastik Anemi Sendromu Olgusu

Erken Başlangıçlı Tiamin Yanıtlı Megaloblastik Anemi Sendromu Olgusu

Recurrent psychiatric manifestations in thiamine‐responsive megaloblastic anemia syndrome due to a novel mutation c.63_71 delACCGCTC in the gene SLC19A2

Thiamine-responsive megaloblastic anemia syndrome (TRMA) is a recessive condition that mainly manifests as megaloblastic anemia, hearing loss, and diabetes.1, 2 It is caused by mutations in the gene SLC19A2, which codes for a high-affinity thiamine transporter.3 Our male proband had sensorineural deafness diagnosed at 4 years of age and insulin-dependent diabetes diagnosed at 5 years. At 19 he was found to have myopia, astigmatism and decreased peripheral visual fields, as well as megaloblastic anemia with low serum thiamine level. He was started on 100 mg thiamine daily, which was later decreased to 50 mg. The proband's brother had similar features. He died at 18 years, reportedly from a heart problem. The proband had a history of inappropriate sexual behavior since the age of 13 and a long history of explosive/aggressive/assaulting behavior and transient paranoid ideations. Aggressive behavior was triggered by frustration around food items and by misperceptions and beliefs that others were ‘bad-mouthing’ him. He communicated through sign language and a few spontaneous verbalizations and was oriented x3. Irritable mood, impulsivity, and paranoid ideations were noted. Insight was impaired and judgment was fair for his mental age. A gradual decline from low–normal to mild intellectual disability was noted. Thiamine treatment during 18 months substantially decreased the frequency and severity of his explosive/aggressive episodes but did not affect his transient paranoid ideations. Multiple psychotropic medications were previously ineffective at controlling these episodes. Testing for mutations in SLC19A2 revealed homozygosity for the c.63_71delACCGCTC mutation, resulting in a frameshift and truncated protein. This mutation was not previously reported.2 To our knowledge, one other patient with TRMA and a psychotic episode was previously reported.4 This female patient had only one documented psychotic episode with mood changes. Neuropsychological manifestations related to thiamine deficiency have been well established in alcoholic populations known for nutrient deficits.5 Thiamine administration controlled the progressive encephalopathy and the explosive/aggressive behavior in our patient, but his recurrent mood disorder with paranoid ideations did not resolve with thiamine supplementation. In addition to the thiamine deficiency, the novel SLC19A2 mutation reported here may have contributed to the patient's psychotic manifestations by an unknown mechanism. No conflict of interest is reported for any of the authors. This report was partially supported by The Office of People with Developmental Disabilities of New York State. The sponsor did not have any role in the conducting or the reporting of the study. Consent was obtained from the patient's legal guardian.

Cochlear implant and thiamine-responsive megaloblastic anemia syndrome

Thiamine-responsive megaloblastic anemia syndrome is a rare autosomal recessive disorder defined by the occurrence of megaloblastic anemia, diabetes mellitus, and bilateral sensorineural deafness, responding in varying degrees to thiamine treatment. We report a precedence case for the treatment of deafness associated with the typical triad of thiamine-responsive megaloblastic anemia in a 4-year-old boy who showed a poor use of preoperative hearing aids but demonstrated significant improvements in hearing ability 1 year after receiving a cochlear implant.