Thiamine-responsive Megaloblastic Anemia Research Articles

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.

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.

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

Thiamine-responsive megaloblastic anaemia (TRMA) is a syndrome associated with megaloblastic anaemia, diabetes mellitus and sensorineural deafness, due to mutations in the SLC19A2 gene, 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.

Stroke as an Initial Manifestation of Thiamine-Responsive Megaloblastic Anemia.

Stroke as an Initial Manifestation of Thiamine-Responsive Megaloblastic Anemia.

Genotype/phenotype correlations of childhood-onset congenital sideroblastic anaemia in a European cohort.

Congenital sideroblastic anaemia (CSA) is a rare disease caused by germline mutations of genes involved in haem and iron-sulphur cluster formation, and mitochondrial protein biosynthesis. We performed a retrospective multicentre European study of a cohort of childhood-onset CSA patients to explore genotype/phenotype correlations. We studied 23 females and 20 males with symptoms of CSA. Among the patients, the most frequently mutated genes were ALAS2 (n=10; 23·3%) and SLC25A38 (n=8; 18·6%), causing isolated forms of microcytic anaemia of varying severity. Five patients with SLC19A2 mutations suffered from thiamine-responsive megaloblastic anaemia and three exhibited the 'anaemia, deafness and diabetes' triad. Three patients with TRNT1 mutations exhibited severe early onset microcytic anaemia associated with thrombocytosis, and two exhibited B-cell immunodeficiency, inflammatory syndrome and psychomotor delay. The prognoses of patients with TRNT1 and SLC2A38 mutations were generally dismal because of comorbidities or severe iron overload. No molecular diagnosis could be established in 14/43 cases. This study emphasizes the frequency of ALAS2 and SLC25A38 mutations and provides the largest comprehensive analysis to date of genotype/phenotype correlations in CSA. Further studies of CSA patients with data recorded in an international registry would be helpful to improve patient management and establish standardized guidelines.

PB1977 LATE DIAGNOSIS IN SYRIAN IMMIGRANT PATIENT; THIAMINE-RESPONSIVE MEGALOBLASTIC ANEMIA SYNDROME

Background: Thiamine-responsive megaloblastic anemia (TRMA) also known as Rogers syndrome was first described by Porter et al in 1969. It is characterized by diabetes mellitus, megaloblastic anemia and progressive sensorineural hearing loss. TRMA is a rare autosomal recessive disorder. Aims: This syndrome is seen especially in consanguineous marriages and isolated communities. İt has been reported in fewer than 80 families worldwide. Diagnosis relies on uncovering genetic variations (alleles) in the SLC19A2 gene, encoding for a high affinity thiamine transporter. This transporter is essentially present in hematopoietic stem cells, pancreaticc beta cells and inner ear cells, explaining the clinical manifestations of the disease. The disease is usually diagnosed in childhood period. Methods: We presented a 21-year-old patient who was diagnosed with TRMA with the findings of pancytopenia. Results: Case Report: A 21-year-old male patient was referred to our center upon the symptoms of fatigue, hearing loss and pancytopenia. He was emigrated from Syria to Turkey for years ago because of the Syrian War. Mother and father are first-degree relatives. He has hearing loss and inarticulated since hewas 1 year old. He was diagnosed as type 1 diabetes mellitus at 10 years old and treated with insulin. Erythrocyte transfusion had been performed several times due to the anemia. In laboratory tests; Wbc:2480 10^3 /μL, Hgb:4.3 g/dL Plt: 8000 10^3 /μL, MCV:81 fL, Glukoz: 345 mg/dL, Crea1nin:0,7 mg/dL, ldh:92 U/L, Ferri1n:1140 ug/L, VitB12: 702 ng/L, Folat: 5,2 ug/L were found. There was hepatomegaly and splenomegaly in abdominal ultrasonography. Megaloblastic changes were seen in peripheral blood smear, but there was no atypical cells. Bone marrow biopsy and flow cytometric evaluation were normal. Audiologic evaluation showed bilateral severe sensorineural hearing. Considering the laboratory test and clinical findings, a diagnosis of TRMA was suspected and the patient was started on thiamine hydrochloride (100 mg orally daily). An increase in leukocyte and platelet counts was observed on the 5th day of thiamine treatment. On the 10th day of treatment, an increase in hemoglobin level was observed. His pancytopenia was completely resolved. WBC: 7000 10^3 /μL, Hgb: 15 g/dL Plt: 234000 10^3 /μL, mcv: 91 were detected afer two months of treatment. At the same time genetic evaluation was initiated. Homozygous mutation in the SLC19A2 gene (c.242_243insA (p.Y81 ∗) (p.Tyr81 ∗) was detected as a result of genetic evaluation. Summary/Conclusion: Literature showed that the cases of TRMA are mostly diagnosed during childhood period. Our case was diagnosed at the age of 21. He is different from the others with this respect. Pancytopenia has been described several times in Rogers syndrome. There were serious cytopenia in our case at the time of diagnosis. Rapid improvement in cytopenia was seen afer the treatment with thiamine. In conclusion TRMA is a rare autosomal recessive disorder which typically has a clinical triad: megaloblastic anemia, diabetes mellitus and sensorineural hearing loss. Thiamine treatment should be continued for lifelong. Family screening should be done and genetic counseling should be offered when diagnosed.

TRMA syndrome (thiamine-responsive megaloblastic anemia): a case report

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

50 Years Ago in The Journal of Pediatrics: Thiamine-Responsive Megaloblastic Anemia

50 Years Ago in The Journal of Pediatrics: Thiamine-Responsive Megaloblastic Anemia

Loss-of-Function Mutation in Thiamine Transporter 1 in a Family With Autosomal Dominant Diabetes.

Solute Carrier Family 19 Member 2 (SLC19A2) encodes thiamine transporter 1 (THTR1), which facilitates thiamine transport across the cell membrane. SLC19A2 homozygous mutations have been described as a cause of thiamine-responsive megaloblastic anemia (TRMA), an autosomal recessive syndrome characterized by megaloblastic anemia, diabetes, and sensorineural deafness. Here we describe a loss-of-function SLC19A2 mutation (c.A1063C: p.Lys355Gln) in a family with early-onset diabetes and mild TRMA traits transmitted in an autosomal dominant fashion. We show that SLC19A2-deficient β-cells are characterized by impaired thiamine uptake, which is not rescued by overexpression of the p.Lys355Gln mutant protein. We further demonstrate that SLC19A2 deficit causes impaired insulin secretion in conjunction with mitochondrial dysfunction, loss of protection against oxidative stress, and cell cycle arrest. These findings link SLC19A2 mutations to autosomal dominant diabetes and suggest a role of SLC19A2 in β-cell function and survival.

L’anémie mégaloblastique thiamine dépendante ou syndrome de Rogers : une revue de la littérature

Thiamine-responsive megaloblastic anemia (TRMA), also known as Rogers syndrome, is a rare autosomal recessive disease characterized by three main components: megaloblastic anemia, diabetes mellitus and sensorineural deafness. Those features occur in infancy but may arise during adolescence. Diagnosis relies on uncovering genetic variations (alleles) in the SLC19A2 gene, encoding for a high affinity thiamine transporter. This transporter is essentially present in hematopoietic stem cells, pancreatic beta cells and inner ear cells, explaining the clinical manifestations of the disease. Based on a multidisciplinary approach, treatment resides on lifelong thiamine oral supplementation at pharmacological doses, which reverses anemia and may delay development of diabetes. However, thiamine supplementation does not alleviate already existing hearing defects.

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/).

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 – A treatable rarity

Thiamine Responsive Megaloblastic Anemia – A treatable rarity

Inborn errors of metabolism associated with hyperglycaemic ketoacidosis and diabetes mellitus: narrative review.

Inborn errors of metabolism (IEM) are heterogeneous group of disorders that might present in the clinics or emergency departments in different phenotypes, and one of these is a diabetes scenario. Diabetes is the most common endocrine disorder among children. The mechanism of how IEM could lead to diabetes is unclear; however, the postulated pathogenesis consists of three mechanisms: 1) accumulation of toxic substance in the gland, ruining structure and normal functionality, 2) disturbing energy availability required for hormone synthesis and 3) defect of complex molecules. The differential diagnosis of IEM associated with hyperglycaemic ketoacidosis and diabetes include: organic acidemias specifically propionic acidemia, methylmalonic acidemia, isovaleric acidemia, hereditary hemochromatosis, aceruloplasminemia, holocarboxylase synthetase deficiency, β-ketothiolase deficiency and finally, cystinosis, Rogers syndrome (thiamine-responsive megaloblastic anaemia) and congenital disorders of glycosylation type Ia. Clinical approach will help in ready diagnosis and treatment for IEM disorders in early detection of diabetes. In this review, we will discuss the differential diagnosis, clinical features and diagnostic approaches of IEM presenting as hyperglycaemic ketoacidosis and diabetes.

Rare case of diabetes mellitus, sensorineural hearing loss, and refractory megaloblastic anemia: SLC19A2 mutation

Reporting a rare and treatable case of thiamine responsive Megaloblastic Anemia with Sensori-neural Hearing Loss with Diabetes Mellitus in a 6 year old child due to SLC19A2 mutation. Simple thiamine treatment is cost effective and can reverse this disorder except hearing loss.

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.