Thiamine-responsive Megaloblastic Anemia Research Articles

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.

Novel nonsense mutation (p.Ile411Metfs*12) in the SLC19A2 gene causing Thiamine Responsive Megaloblastic Anemia in an Indian patient

Thiamine-responsive megaloblastic anemia (TRMA), an autosomal recessive disorder, is caused by mutations in SLC19A2 gene encodes a high affinity thiamine transporter (THTR-1). The occurrence of TRMA is diagnosed by megaloblastic anemia, diabetes mellitus, and sensorineural deafness. Here, we report a female TRMA patient of Indian descent born to 4th degree consanguineous parents presented with retinitis pigmentosa and vision impairment, who had a novel homozygous mutation (c.1232delT/ter422; p.Ile411Metfs*12) in 5th exon of SLC19A2 gene that causes premature termination of hTHTR-1. PROSITE analysis predicted to abrogate GPCRs family-1 signature motif in the variant by this mutation c.1232delT/ter422, suggesting uncharacteristic rhodopsin function leading to cause RP clinically. Thiamine transport activity by the clinical variant was severely inhibited than wild-type THTR-1. Confocal imaging had shown that the variant p.I411Mfs*12 is targeted to the cell membrane and showed no discrepancy in membrane expression than wild-type. Our findings are the first report, to the best of our knowledge, on this novel nonsense mutation of hTHTR-1 causing TRMA in an Indian patient through functionally impaired thiamine transporter activity.

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

English

Thiamine responsive megaloblastic anemia (TRMA) is an autosomal recessive disorder, which is caused by loss of function mutations in the SLC19A2 gene. TRMA is characterized by anemia, deafness, and diabetes mellitus. We now report two sisters, the eldest of which presented to a different hospital during childhood with sensorineural deafness, which was treated with a hearing prosthesis, insulin requiring diabetes, megaloblastic anemia. The younger sister is also affected with sensorineural deafness along with diabetes and megaloblastic anemia. Because a diagnosis of TRMA was suspected, therapy with insulin and thiamine was started to which the child is responding. Diabetes associated with deafness and megaloblastic anemia, suggests a diagnosis of TRMA.

Defects of thiamine transport and metabolism.

Thiamine, in the form of thiamine pyrophosphate, is a cofactor for a number of enzymes which play important roles in energy metabolism. Although dietary thiamine deficiency states have long been recognised, it is only relatively recently that inherited defects in thiamine uptake, activation and the attachment of the active cofactor to target enzymes have been described, and the underlying genetic defects identified. Thiamine is transported into cells by two carriers, THTR1 and THTR2, and deficiency of these results in thiamine-responsive megaloblastic anaemia and biotin-responsive basal ganglia disease respectively. Defective synthesis of thiamine pyrophosphate has been found in a small number of patients with episodic ataxia, delayed development and dystonia, while impaired transport of thiamine pyrophosphate into the mitochondrion is associated with Amish lethal microcephaly in most cases. In addition to defects in thiamine uptake and metabolism, patients with pyruvate dehydrogenase deficiency and maple syrup urine disease have been described who have a significant clinical and/or biochemical response to thiamine supplementation. In these patients, an intrinsic structural defect in the target enzymes reduces binding of the cofactor and this can be overcome at high concentrations. In most cases, the clinical and biochemical abnormalities in these conditions are relatively non-specific, and the range of recognised presentations is increasing rapidly at present as new patients are identified, often by genome sequencing. These conditions highlight the value of a trial of thiamine supplementation in patients whose clinical presentation falls within the spectrum of documented cases.

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.

Thiamine-responsive megaloblastic anemia syndrome with Ebstein anomaly: a case report

Thiamine-responsive megaloblastic anemia (TRMA) or Roger syndrome is a rare autosomal recessive disorder characterized by the occurrence of multiple clinical manifestations including megaloblastic anemia, diabetes mellitus, and sensorineural deafness. A few patients have been also described with congenital cardiac malformations. The patients usually respond to treatment with pharmacological doses of thiamine. Mutations in the SLC19A2 gene, located at chromosome 1q24.2, are responsible for this syndrome. Here, we present two new Iranian TRMA patients who were homozygous for c.697C > T mutation in the SLC19A2 gene. On follow-up, one of the patients showed Ebstein anomaly. The present study confirms the variability of the clinical manifestations caused by the same mutation within patients with TRMA syndrome. Therefore, follow-up of the affected children should be considered.

Identification of four SLC19A2 mutations in four Chinese thiamine responsive megaloblastic anemia patients without diabetes

Identification of four SLC19A2 mutations in four Chinese thiamine responsive megaloblastic anemia patients without diabetes

Thiamine responsive megaloblastic anemia: The puzzling phenotype

Thiamine responsive megaloblastic anemia (TRMA) is characterized by a triad of megaloblastic anemia, non-type 1 diabetes mellitus and sensorineural deafness. Other clinical findings have been described in few cases. The SLC19A2 gene on chromosome 1q 23.3 is implicated in all cases with TRMA. Our aim is to discuss the clinical manifestations of all Omani children diagnosed with TRMA and determine genotype-phenotype relationship. Clinical and laboratory data of all patients diagnosed in Oman were retrospectively collected. Mutation analysis of affected families was conducted using two Microsatellite markers. Genotyping was performed with fluorescent-labeled PCR primers. To define the deletion breakpoint region, PCR reactions were carried out using different primer pairs located at the introns 3 and 3'-untranslated region with Expand Long Template PCR kit. A total of six children have been diagnosed with this syndrome. They were five females and one male. They all presented with sensorineural deafness at birth while the age of anemia presentation ranged between 6 weeks to 19 months. They all belong to same family with complex interfamilial marriages and presented with the typical triad. Of interest is the very rare presentation of one patient with Uhl cardiac anomaly (total absence of right ventricular myocardium with apposition of endocardium and pericardium) that has never been described before in patients with TRMA. All patients have a novel large deletion of 5,224 bp involving exons 4, 5, and 6 of SLC19A2. TRMA is a disease of expanding phenotypic spectrum with poor genotype-phenotype correlation.

Novel Mutation in the SLC19A2 Gene in an Iranian Family with Thiamine-Responsive Megaloblastic Anemia: A Series of Three Cases

Thiamine-responsive megaloblastic anemia (TRMA) is a clinical triad characterized by megaloblastic anemia, non-autoimmune diabetes mellitus, and sensory-neural hearing loss. Mutations in the thiamine transporter gene, solute carrier family 19, member 2 (SLC19A2), have been associated with TRMA. Three pediatric patients from a large consanguineous Iranian family with hyperglycemia, anemia, and hearing loss were clinically diagnosed with TRMA. In all three patients, TRMA was confirmed by direct sequencing of the SLC19A2 gene that revealed a novel missense homozygous mutation c.382 G>A (p.E128K). This mutation results in the substitution of glutamic acid to lysine at position 128 in exon 2 and was not detected in 200 control chromosomes. Thiamine therapy reversed the anemia and alleviated the hyperglycemia in all three patients. We recommend sequence analysis of the SLC19A2 gene in individuals with a clinical triad of diabetes mellitus, hearing loss, and anemia. The administration of thiamine ameliorates the megaloblastic anemia and the hyperglycemia in patients with TRMA.Conflict of interest:None declared.

Thiamine responsive megaloblastic anemia with a novel SLC19A2 mutation presenting with myeloid maturational arrest

Thiamine responsive megaloblastic anemia with a novel SLC19A2 mutation presenting with myeloid maturational arrest

Identification of a SLC19A2 nonsense mutation in Persian families with thiamine-responsive megaloblastic anemia

Thiamine-responsive megaloblastic anemia (TRMA) is an autosomal recessive syndrome characterized by early-onset anemia, diabetes, and hearing loss caused by mutations in the SLC19A2 gene. We studied the genetic cause and clinical features of this condition in patients from the Persian population. A clinical and molecular investigation was performed in four patients from three families and their healthy family members. All had the typical diagnostic criteria. The onset of hearing loss in three patients was at birth and one patient also had a stroke and seizure disorder. Thiamine treatment effectively corrected the anemia in all of our patients but did not prevent hearing loss. Diabetes was improved in one patient who presented at the age of 8months with anemia and diabetes after 2months of starting thiamine. The coding regions of SLC19A2 were sequenced in all patients. The identified mutation was tested in all members of the families. Molecular analyses identified a homozygous nonsense mutation c.697C>T (p.Gln233*) as the cause of the disease in all families. This mutation was previously reported in a Turkish patient with TRMA and is likely to be a founder mutation in the Persian population.

Thiamine responsive megaloblastic anemia: a novelSLC19A2compound heterozygous mutation in two siblings

Thiamine responsive megaloblastic anemia (TRMA) is an autosomal recessive disease caused by loss of function mutations in the SLC19A2 gene. TRMA is characterized by anemia, deafness, and diabetes. In some cases, optic atrophy or more rarely retinitis pigmentosa is noted. We now report two sisters, the eldest of which presented to a different hospital during childhood with sensorineural deafness, which was treated with a hearing prosthesis, insulin requiring diabetes, retinitis pigmentosa, optic atrophy, and macrocytic anemia. These features initially suggested a clinical diagnosis of Wolfram syndrome (WS). Therapy with thiamine was initiated which resulted in the resolution of the anemia. The younger sister, who was affected with sensorineural deafness, was referred to our hospital for non-autoimmune diabetes. She was found to have macrocytosis and ocular abnormalities. Because a diagnosis of TRMA was suspected, therapy with insulin and thiamine was started. Sequencing analysis of the SLC19A2 gene identified a compound heterozygous mutation p.Y81X/p.L457X (c.242insA/c.1370delT) in both sisters. Non-autoimmune diabetes associated with deafness and macrocytosis, without anemia, suggests a diagnosis of TRMA. Patients clinically diagnosed with WS with anemia and/or macrocytosis should be reevaluated for TRMA.

Heart failure after transvenous closure of atrial septal defect associated with atrial standstill and thiamine-responsive megaloblastic anemia

Despite advances in device closure for atrial septal defect, post-closure heart failure remains a clinical problem in adult patients but is seen only rarely in children. An eight-year-old boy, who had been followed by a local pediatrician with the diagnosis of diabetes mellitus and congenital heart disease, was consulted to us for cardiac re-evaluation. Electrocardiography demonstrated absent P waves, and echocardiography revealed enlargement of the right ventricle and both atria and secundum atrial septal defect. With the diagnosis of atrial standstill, secundum atrial septal defect and thiamine-responsive megaloblastic anemia, acute heart failure developed after transvenous closure of the atrial septal defect, which improved dramatically with thiamine and supportive treatment.

Thiamine-responsive megaloblastic anemia (TRMA) in an Austrian boy with compound heterozygous SLC19A2 mutations

Thiamine-responsive megaloblastic anemia (TRMA) is a rare disorder typically characterized by megaloblastic anemia, non-type I diabetes and sensorineural deafness. It is caused by various mutations in the SLC19A2 gene that impair the encoded thiamine transporter. So far, only 70 affected individuals mainly from consanguineous families of Middle and Far Eastern origin with a wide spectrum of signs and symptoms, variable onset of disease, and primarily homozygote mutations in SLC19A2 have been reported. We present the first genuine central European descendent with combined heterozygote mutations in SLC19A2, an Austrian boy suffering from pancytopenia and non-type I diabetes. Both manifestations resolved completely under continuous oral thiamine supplementation. Our observation underlines that despite its rarity, TRMA must be considered as an important differential diagnosis in native central European patients with suggestive signs and symptoms. An early molecular genetic verification of the diagnosis provides a sound basis for a successful and simple treatment that helps to prevent severe sequelae.

NOVEL MUTATION IN THE SLC19A2 GENE IN THIAMINE-RESPONSIVE MEGALOBLASTIC ANEMIA (ROGERS’ SYNDROME)

Introduction: The Thiamine Transporter gene SLC19A2 is the only gene known to be associated with TRMA. This syndrome is a trial clinical characterized by megaloblastic anemia, nonautoimmune diabetes mellitus and sensory-neural hearing loss. Methods: Described here are three children from consanguineous Iranian families with thiamine – responsive megaloblastic anemia (TRMA) or Rogers' syndrome. Case one and two were siblings of healthy first-cousin parents and case three from a healthy second-cousin couple. These cases presented with hyperglycemia, anemia, and hearing loss. Thiamine reversed the anemia and there was a satisfactory response for the hyperglycemia as well. Results: In all three patients, direct sequencing revealed a homozygous mutation c.38 G>A (P.E.128K) resulting in the substitution of glutamic acid to lysine at position 128 in exon 2 of the SLC19A2 gene on chromosome 1q23.3. This novel mutation was confirmed by the PCR RFLP assay of more than 100 control alleles. Conclusion: TRMA or Rogers' syndrome should be considered for patients with diabetes (DM) and other symptoms, including hearing loss and anemia. Early diagnosis can assist families in planning future pregnancies. The administration of thiamine ameliorates the megaloblastic anemic condition and produces a better response in DM.

Recessive SLC19A2 mutations are a cause of neonatal diabetes mellitus in thiamine-responsive megaloblastic anaemia

Permanent neonatal diabetes mellitus (PNDM) is diagnosed within the first 6 months of life, and is usually monogenic in origin. Heterozygous mutations in ABCC8, KCNJ11, and INS genes account for around half of cases of PNDM; mutations in 10 further genes account for a further 10%, and the remaining 40% of cases are currently without a molecular genetic diagnosis. Thiamine-responsive megaloblastic anaemia (TRMA), due to mutations in the thiamine transporter SLC19A2, is associated with the classical clinical triad of diabetes, deafness, and megaloblastic anaemia. Diabetes in this condition is well described in infancy but has only very rarely been reported in association with neonatal diabetes. We used a combination of homozygosity mapping and evaluation of clinical information to identify cases of TRMA from our cohort of patients with PNDM. Homozygous mutations in SLC19A2 were identified in three cases in which diabetes presented in the first 6 months of life, and a further two cases in which diabetes presented between 6 and 12 months of age. We noted the presence of a significant neurological disorder in four of the five cases in our series, prompting us to examine the incidence of these and other non-classical clinical features in TRMA. From 30 cases reported in the literature, we found significant neurological deficit (stroke, focal, or generalized epilepsy) in 27%, visual system disturbance in 43%, and cardiac abnormalities in 27% of cases. TRMA should be considered in the differential diagnosis of diabetes presenting in the neonatal period.