Thiamine-responsive Megaloblastic Anemia Research Articles

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.

Abstract 13543: Novel Genes That Regulate QT Interval in Taiwanese Cohort

Introduction: QT interval denoted repolarization of the ventricule. QT intervals prolongation or shortening would lead patients prone to sudden cardiac death, i.e. Long QT or Short QT syndrome. There are many genes that have been reported to be related to QT interval changes. In this study, we used Genome wide association study(GWAS) to search for genes that regulate QT interval in a large Taiwanese cohort. Methods: We collected 13020 samples and did GWAS study. We collect ECG and analyze QTc interval by standard method. We search for genes and SNP have correlation with QT interval and used Taiwan Biobank as control. The QTc was measured as continuous variables. A P<10 -8 was considered significant variants. Results: In this study, we found many variants that regulate QT interval. (Figure 1). The variants included rs36092684 encoding C1orf132 which was long none coding RNA (never reported before), rs846111 that influences QT interval, 1:162021296:A:ATTG (a novel variants non reported yet), rs12143965, encoding NME7 ( ATP1B1 was a strong functional candidate, although NME7 could not be excluded without functional validation), rs10490255 encoding SLC8A1 Na + -Ca ++ exchanger that wound prolonged QT, rs16862199, encoded SLC19A2 genes that was associated with Thiamine-responsive megaloblastic anemia (TRMA), in such patients, their QT prolonged, rs2277923, encoding NKS2-5 that would cause dilated cardiomyopathy, conduction disorder, long QT, tetralogy of Fallot, rs144500919 (a novel SNP), rs12665409 encoding SLC35F1 that affects QT interval, and rs3778873(KCNH2), rs2074239 (KCNQ1). Conclusion: In this large Taiwanese QT study, we identified variants that would regulate QT interval. Some were reported before, such in QTGEN or QTSCD studies, and others were novel. The novel variants warrant further functional studies.

A long-term follow-up of a case of Rogers syndrome, Thiamine responsive megaloblastic anemia

Thiamine-responsive megaloblastic anemia (TRMA) also known as Rogers syndrome is a rare autosomal recessive disorder characterized by megaloblastic anemia, diabetes mellitus, and progressive sensorineural deafness. The disease can be manifested anytime between infancy and adolescence, and all the cardinal findings may not be present at the time of the diagnosis. The main defect lies in the active thiamine uptake into cells which is disturbed. Not many cases have been reported about the long-term follow-up of children with this disorder and their associated complications. We hereby report a 14 years follow-up of a girl with Rogers syndrome diagnosed at toddler age with nonresponsive anemia and diabetes and further progressed to have sensorineural hearing loss. Her clinical exome study showed a mutation in the SLC19A2 gene. This experience illustrates the relevance of a detailed evaluation and regular follow-up to assess the progression of the syndrome till her pubertal age.

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.

Endoplasmic Reticulum Stress in the Pathogenesis of Hyperglycemia Induced by Thiamine-Responsive Megaloblastic Anemia.

Thiamine responsive megaloblastic anemia (TRMA) is a genetic disease caused by SLC19A2 gene mutation. This study aimed to preliminarily explore the relationship between endoplasmic reticulum stress (ERS)-PERK signaling pathway and the pathogenesis of hyperglycemia induced by TRMA. Islet β (INS.1 and β-TC-6) and HEK293T cell line models with stable overexpression of SLC19A2 and SLC19A2 (c.1409insT) were established. The cells were divided into empty virus group (control), wild-type group (overexpressed SLC19A2), and mutation group (overexpressed SLC19A2 (c.1409insT)). Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and western blotting were used to detect the expression levels of ERS-PERK signaling pathway-related proteins, including glucose-regulated protein 78 (GRP78), protein kinase R-like ER kinase (PERK), and eukaryotic initiation factor 2 (eIF2α), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP) in islet β cells. Protein localization was assessed by immunofluorescence staining. Compared with the control group, the mRNA expression levels of SLC19A2 in wild-type and mutant islet β cells (INS.1 and β-TC-6) and HEK293T cells were significantly upregulated (all p < 0.05). Compared with the control group and the wild-type group, the mRNA expression levels of GRP78, PERK, eIF2α, ATF4, and CHOP were increased (all p < 0.05) in the mutant islet β cells; the protein expression levels of PERK, GRP78, and eIF2α were elevated (all p < 0.05). In addition, the results of immunofluorescence staining showed that SLC19A2 (c.1409insT) mutation changed the localization of the proteins in the cells. Thus, they were not located on the cell surface, but in the cytoplasm and nuclei, and protein aggregation occurred in the cytoplasm. 1. Islet β and HEK293Tcell lines, stably overexpressing SLC19A2 and SLC19A2 (c.1409insT) mutations, were successfully constructed. 2. SLC19A2 (c.1409insT) mutation could raise the expression levels of ERS-PERK signaling pathway-related proteins (GRP78, PERK, eIF2α, ATF4, and CHOP), and activate apoptosis pathway. 3. SLC19A2 (c.1409insT) mutation could change the localization of proteins and produce protein aggregation in cells. It could lead to protein misfolding and ERS, which would participate in the pathological mechanism of hyperglycemia induced by TRMA.

An extremely rare case of Rogers syndrome or thiamine responsive megaloblastic anemia.

Rogers syndrome is an extremely rare autosomal recessive syndrome of which only 100 cases are known worldwide. It is characterized by thiamine-responsive megaloblastic anaemia, diabetes mellitus and sensorineural deafness. It results from the deficiency of a thiamine transporter protein. We herein report a 16-year-old Indian male referred to our centre with complaints of refractory anaemia, deafness, diabetes pulmonary arterial hypertension and tricuspid regurgitation. Based on the clinical features and haematologic picture and dramatic response of anaemia to thiamine therapy the possibility of a TRMA was considered. Sequencing analysis for TRMA revealed a homozygous c.242dup (p.Tyr81Ter) mutation of the SLC19A2 gene.

Diabetes Out-of-the-Box: Diabetes Mellitus and Impairment in Hearing and Vision.

This review aims to provide an update on the etiologies of diabetes that are due to genetic disorders and that co-occur with impaired hearing or vision and to compare them. The potential mechanisms, including novel treatments, will be detailed. Wolfram syndrome, Kearns-Sayre syndrome, thiamine-responsive megaloblastic anemia, and maternally inherited diabetes and deafness are genetic disorders characterized by diabetes, impaired hearing, and vision. They differ in mode of inheritance, age at presentation, and the involvement of other organs; they are often misdiagnosed as type 1 or type 2 diabetes. Suspicion of a genetic diabetes syndrome should be raised when pancreatic autoantibodies are negative, other organs are involved, and family history includes diabetes. Correct diagnosis of the various syndromes is important for tailoring the most advanced treatment, preventing disease progression, and enabling proper genetic counseling.

ROGERS SYNDROME-THIAMINE RESPONSIVE MEGALOBLASTIC ANEMIA SYNDROME: CASE REPORT

Thiamine responsive megaloblastic anemia (TRMA) encompasses a complex syndrome of anemia, sensorineural hearing loss and Diabetes Mellitus. We report a 06 years old male child with pallor, bilateral sensorineural hearing loss, Diabetes Mellitus, megaloblastic anemia, retinitis pigmentosa and a normal response to water deprivation test. Child responded well to high doses of thiamine treatment. Rogers Syndrome, a spectrum disease, should be kept in mind in differential diagnosis of Diabetes Mellitus and megaloblastic anemia in population with frequent consanguinity. Thorough medical and family history and physical examination are vital for diagnosis. Prompt diagnosis, use of careful clinical monitoring and supportive care can relieve the debilitating symptoms. Key Words: Diabetes Mellitus, Megaloblastic anemia, Sensorineural hearing loss, Rogers syndrome.

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.

High-risk proliferative retinopathy and macular oedema in an adolescent boy with thiamine-responsive megaloblastic anaemia

High-risk proliferative retinopathy and macular oedema in an adolescent boy with thiamine-responsive megaloblastic anaemia

Monogenic diabetes in Pakistani infants and children: challenges in a resource poor country.

To review the data of infants and children with suspected monogenic diabetes who underwent genetic testing. Monogenic diabetes is a rare form of diabetes resulting from mutations in a single gene. It can be caused by dominant as well as recessive modes of inheritance. In a country like Pakistan where interfamily marriages are common the incidence of genetic disorders is increased. As Pakistan a resource-poor country, the diagnosis of insulin-dependent diabetes is often delayed and a genetic diagnosis of monogenic diabetes is extremely difficult. Children with clinical diagnosis of monogenic and syndromic diabates were recruited and blood samples were sent for genetic analysis. One thousand sixty four new cases diagnosed with type 1 diabetes were registered at the National Institute of Child Health, Karachi, in the last 10 years. Of these 39 patients were selected for genetic testing who were diagnosed with diabetes/had a sibling diagnosed with diabetes before the age of nine months (n = 27) or had extra pancreatic features ( n= 12). We identified mutations in 18/27 cases diagnosed with diabetes before nine months of age. The most common genetic subtype was WolcottRallison syndrome caused by EIF2AK3 mutations (seven cases). KCNJ11 mutations were identified in two cases, ABCC8mutations were identified in four cases from three families, GCK and INS mutations were each identified in two cases, and one SLC2A2 mutation was identified in one case. A genetic diagnosis was made in 12/12 children from six families with diabetes diagnosed after the age of nine months who had extrapancreatic features. Six patients had genetically confirmed Wolfram syndrome (WFS1), three had thiamine-responsive megaloblastic anemia (SLC19A2) and three were diagnosed with histocytosis lymphadenopathy plus syndrome (SLC29A3). Genetic testing is essential to confirm a diagnosis of monogenic diabetes which guides clinical management and future counselling. Our study highlights the importance of diagnosing monogenic diabetes in the largely consanguineously-married population of Pakistan.

Identification of novel compound heterozygous variants in SLC19A2 and the genotype-phenotype associations in thiamine-responsive megaloblastic anemia

Background and aimsThiamine-responsive megaloblastic anemia (TRMA), caused by SLC19A2 loss-of-function variants, is characterized by the triad of megaloblastic anemia, progressive sensorineural deafness, and non-type 1 diabetes mellitus. Here, we present the case of a Chinese infant with two novel variants segregating in compound heterozygous form in SLC19A2 and reviewed genotype–phenotype associations (GPAs) in patients with TRMA. Materials and methodsWhole-exome sequencing was performed to establish a genetic diagnosis. The clinical manifestations and genetic variants were collected by performing a literature review. The bioinformatics software SIFT, PolyPhen2, and Mutation Taster was applied to predict variant effects and analyze GPAs. ResultsTwo novel variants segregating in compound heterozygous form in SLC19A2 (NM_006996.2: exon2:c.336_363del:p.W112fs; exon2:c.358G>T:p.G120X) was identified. Thiamine supplementation corrected anemia and diabetes mellitus but did not improve the hearing defect. In the literature, 183 patients with TRMA with 74 variants in SLC19A2 have been reported, with high incidence in the Middle East, South Asia, and the northern Mediterranean. Patients with biallelic premature termination codon variants presented with more severe phenotypes, and truncating sites on extracellular domains was a protective factor for the hemoglobin level at diagnosis. ConclusionTwo novel compound heterozygous variants (NM_006996.2: exon2:c.336_363del:p.W112fs; exon2:c.358G>T:p.G120X) were identified, and GPAs in TRMA indicated the predictability of clinical manifestations.

Thiamine-Responsive Megaloblastic Anemia-Related Diabetes: Long-Term Clinical Outcomes in 23 Pediatric Patients From the DPV and SWEET Registries

ObjectivesTo describe clinical presentation and long-term outcomes in a large cohort of children diagnosed with thiamine-responsive megaloblastic anemia (TRMA)-related diabetes. MethodsData from the Diabetes Patienten Verlaufsdokumentation (DPV) and Better control in Pediatric and Adolescent diabeteS: Working to crEate CEnTers of Reference (SWEET) registries were used to identify cases. Complementary information was collected through a chart review of each case. Descriptive analyses with medians and interquartile ranges and numbers (proportions) were tabulated. ResultsWe identified 23 cases (52% male) in the 2 registries. Eighteen (78%) had genetic confirmation of TRMA. Median age at diabetes onset was 1.4 (quartiles 0.8 to 3.6) years and median age at initiation of thiamine treatment was 5.9 (2.4 to 12.4) years. At their most recent visit, patients’ median age was 14.3 (8.1 to 17.5) years, glycated hemoglobin level was 6.9% (6.1% to 7.9%), insulin dose was 0.9 (0.4 to 1.2) units/kg per day and thiamine dose was 200 (100 to 300) mg/day. Three patients were not treated with insulin or antidiabetic drugs. There was no difference in diabetes outcomes in patients with initiation of thiamine ≤1 year after diabetes onset compared to patients with initiation of thiamine >1 year after diabetes onset. ConclusionsThis is the longest case series of pediatric TRMA-related diabetes reported to date. Diabetes onset often occurs several years before initiation of thiamine supplementation. Early initiation of thiamine (within 1 year of diabetes onset) was not linked to improved diabetes outcome. However, the role of thiamine in pancreatic function needs further assessment. Patients with TRMA-related diabetes maintained good glycemic control even after 9 years (median) of follow up.

Understanding Sideroblastic Anemia: An Overview of Genetics, Epidemiology, Pathophysiology and Current Therapeutic Options.

Sideroblastic anemia (SA) consists of a group of inherited and acquired anemias of ineffective erythropoiesis characterized by the accumulation of ring sideroblasts in the bone marrow due to disrupted heme biosynthesis. Congenital sideroblastic anemia (CSA) is rare and has three modes of inheritance: X-linked (XLSA), autosomal recessive (ARCSA), and maternal. Acquired SA is more common and can be a result of myelodysplastic syndromes (MDS) or other, generally reversible causes. The diagnostic approach to SA includes a work-up for reversible causes and genetic testing for CSA based on clinical suspicion, family history and genetic pedigree. The treatment of SA depends on the underlying etiology but remains primarily supportive with vitamin B6 supplementation for select cases of XLSA, thiamine for thiamine-responsive megaloblastic anemia subtype, red blood cell transfusions for symptomatic patients and iron chelation therapy for iron overload. The management of anemia in MDS subtypes with ring sideroblasts remains unique and includes the recently approved erythroid maturation agent, Luspatercept. Although there is currently no curative therapy for CSA, anecdotal reports of hematopoietic stem cell transplant demonstrate remissions in selective, non-syndromic cases. This review summarizes the genetics, pathophysiology, diagnosis and treatment of SA for general practitioners and clinical hematologists.

Thiamine-responsive megaloblastic anemia syndrome with dysrhythmia

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

Relapse of rare diseases during COVID-19 pandemic: bicytopenia in an adult patient with thiamine-responsive megaloblastic anaemia.

Thiamine-responsive megaloblastic anaemia (TRMA) is a syndrome associated with megaloblastic anaemia, diabetes mellitus and sensorineural deafness, due to mutations in the SLC19A2gene, which codes for a thiamine carrier protein. Oral thiamine supplementation is the main treatment. We report the case of a 19-year-old man known for TRMA, who presented in the emergency department with bicytopenia (haemoglobin 5,4 g/dL, thrombocytes 38×109/L) revealed by dyspnea and chest pain. Investigations excluded bleeding, hemolysis, coagulopathy and iron deficiencies. A recent infection and an acute coronary syndrome have also been eliminated. We later found out that thiamine treatment had been discontinued three months before, due to general confinement in Tunisia during the COVID-19 pandemic. Parenteral administration of 100 mg of thiamine daily resulted in the recovery of haematopoiesis within three weeks.

Monogenic diabetes: A single center experience from South India

Monogenic forms of diabetes in children are frequently misclassified as either type 1 diabetes or young-onset type 2 diabetes. There is a paucity of literature regarding pediatric monogenic diabetes in the Indian population. A retrospective analysis of case records of 37 children with monogenic diabetes who were diagnosed between 2008 and 2019 in a South Indian tertiary care center was performed. The write-up describes the clinical, biochemical, and genetic characterization of these patients with the diagnoses of neonatal diabetes mellitus (15 patients), MODY (five patients), and various forms of syndromic diabetes (13 with Wolfram syndrome, two with H syndrome, one with mitochondrial diabetes, and one with thiamine responsive megaloblastic anemia).

Incidence and characteristics of childhood- and youth-onset diabetes in the Qalandarabad area in northern Pakistan

ObjectivesDetermine the types, incidence, mortality rate, and clinical status of youth diabetes at Bach Christian Hospital (BCH), Qalandarabad, Pakistan. MethodsAnalysis of incidence and mortality data of all patients (<25 year (y)) diagnosed from January 2014-June 2019, and also analysis of clinical status of patients < 25y seen in 2018/2019. ResultsNinety-three patients were seen over the study period. Eighty-eight were type 1 diabetes (T1D), 51.1% female. Age of diagnosis was 0.8–24.5 years (y) (mean = 11.4 y, SD = 6.2y). 15.1% were 0–4y, 31.4% 5–9 y, 24.4% 10–14y, 19.8% 15–19y, and 9.3% 20–24y. Minimum incidence for the Mansehra tehsil administrative district was calculated as 1.0 per 100,000 population <15y/y, 1.2 per 100,000 < 20y/y and 1.1 per 100,000 < 25y/y; the degree of ascertainment could not be assessed.A further four patients were diagnosed with thiamine-responsive megaloblastic anaemia (TRMA), all male, three from the same consanguineous family, and were treated with high-dose thiamine. One other patient was diagnosed with type 2 diabetes.Three T1D and one TRMA patient died during the study period. The standardised mortality rate for T1D was 9.4, but vital status was unknown for 13 patients.The mean/median HbA1c of T1D patients seen in 2018/2019 was 9.1%/9.2% (76/77 mmol/mol). ConclusionsMinimum T1D incidence in Mansehra tehsil is double the previously reported value for Pakistan (from 1990 to 1999), although is still low compared to most other countries. Considering the limited resources available, patients attending BCH are achieving fair glycemic control. The TRMA cases show the importance of genetic testing in atypical cases.

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.