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Objective: Transcobalamin II deficiency is one of the rare causes of inherited vitamin B12 disorders in which the patients have characteristically normal or high vitamin B12 levels related to the transport defect of vitamin B12 into the cell, ending up with intracellular cobalamin depletion and high homocysteine and methylmalonic acid levels., Materials and Methods: Herein, we describe the findings at presentation of four patients who were diagnosed to have transcobalamin II deficiency with novel mutations., Results: These patients with transcobalamin II deficiency were found to have novel mutations, of whom 2 had the same large deletion (homozygous c.1106+1516-1222+1231del)., Conclusion: Transcobalamin II deficiency should be considered in differential diagnosis of any infant with pancytopenia, failure to thrive, diarrhea, and vomiting.

In the folate cycle MTHFD1, encoded by MTHFD1, is a trifunctional enzyme containing 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase activity. To date, only one patient with MTHFD1 deficiency, presenting with hyperhomocysteinemia, megaloblastic anaemia, hemolytic uremic syndrome (HUS) and severe combined immunodeficiency, has been identified (Watkins et al J Med Genet 48:590-2, 2011). We now describe four additional patients from two different families. The second patient presented with hyperhomocysteinemia, megaloblastic anaemia, HUS, microangiopathy and retinopathy; all except the retinopathy resolved after treatment with hydroxocobalamin, betaine and folinic acid. The third patient developed megaloblastic anaemia, infection, autoimmune disease and moderate liver fibrosis but not hyperhomocysteinemia, and was successfully treated with a regime that included and was eventually reduced to folic acid. The other two, elder siblings of the third patient, died at 9 weeks of age with megaloblastic anaemia, infection and severe acidosis and had MTFHD1 deficiency diagnosed retrospectively. We identified a missense mutation (c.806C > T, p.Thr296Ile) and a splice site mutation (c.1674G > A) leading to exon skipping in the second patient, while the other three harboured a missense mutation (c.146C > T, p.Ser49Phe) and a premature stop mutation (c.673G > T, p.Glu225*), all of which were novel. Patient fibroblast studies revealed severely reduced methionine formation from [(14)C]-formate, which did not increase in cobalamin supplemented culture medium but was responsive to folic and folinic acid. These additional cases increase the clinical spectrum of this intriguing defect, provide in vitro evidence of disturbed methionine synthesis and substantiate the effectiveness of folic or folinic acid treatment.

Unlabelled: Improvement in the quality of life in Europe and North America in last decades caused that economical and social aspects of living conditions of the population have less effect and genetic defects of malabsorption of vitamin B12 became the main reason for cobalamin deficiency in children. Imerslund-Grasbeck syndrome (IGS) is characterized by vitamin B12 deficiency that leads usually to megaloblastic anemia and mild proteinuria. We described two pairs of siblings in two families with IGS. The diagnosis in first family (two brothers) was established at 33 and 22 months of age. The reason for diagnostic tests were proteinuria and anemia. Apart from respiratory tract infections, they didn't present other symptoms of cobalamin deficiency. In the second family IGS was diagnosed in children at 5 and 8 years of age. Diagnostic evaluation procedures wereperformedbecause ofneurologicalsigns, including weakness, loss of appetite, dysmorphia, psychomotor retardation. Laboratory tests revealed megaloblastic anemia, low concentration of vitamin B12 in serum and mild proteinuria. In the first pair low concentration of vitamin B12 was validated by the Schilling test, in the second pair methylomalonate acid was detected in the urinary metabolic test. All children were successfully treated with vitamin B12 and anemia and neurological signs disappeared. Long-term follow up showed failure to thrive in the girl and physical and mental retardation, microcephaly in her brother. Proteinuria in the range: 0.3-1.2 g/24 h was detected in each child, and the other laboratory tests were normal. Clinical symptoms, laboratory tests and good reaction to parenteral treatment with vitamin B12 allowed us to diagnose Imerslund-Grasbeck syndrome, even without genetic tests., Conclusion: A delayed diagnosis of congenital malabsorption of cobalamin can lead to physical and mental retardation in children. Children with megaloblastic anemia and proteinuria resistant to classical treatment should be tested for congenital malabsorbtion of cobalamin.

Thiamine responsive megaloblastic anemia syndrome (TRMAS) is a rare autosomal recessive disorder especially in countries where consanguinity is uncommon. Three main features are characteristic of the disease - megaloblastic anemia, early onset deafness, and non-type I diabetes. TRMAS is a Mendelian disorder; a gene SLC19A2 coding high affinity thiamine transporter mediating vitamin B1 uptake through cell membrane has been identified. We present the first patient with TRMAS in Lithuania - a 3-year-old boy born to a non-consanguineous family with a novel homozygous SLC19A2 gene mutation. The patient had insulin dependent diabetes (onset 11 months), respiratory illness (onset 11 months), bilateral profound hearing loss (onset at 7 months, verified at 20 months), refractory anemia (onset 2 years), and decreased vision acuity and photophobia (onset 2.5 years). The psychomotor abilities developed according to age. Phenotypic evaluation did not reveal any dysmorphic features. The clinical diagnosis of TRMAS was suspected and daily supplementation with thiamine 100 mg was started. The condition of the patient markedly improved several days after the initiation of treatment. The results of SLC19A2 gene molecular testing confirmed the clinical diagnosis - novel homozygous c.[205G>T], p.[(Val69Phe)] mutation changing conserved amino acid residue or even interfering the mRNA splicing. Clinical heterogeneity, diverse dynamics, and wide spectrum of symptoms are aggravating factors in the diagnosis. The possibility of treatment demands early recognition of disorder to facilitate the improvement of the patient's condition., (© 2015 Wiley Periodicals, Inc.)

Background: To report ophthalmologic fundus autofluorescence and spectral domain optical coherence tomography findings in a patient with thiamine responsive megaloblastic anemia (TRMA)., Methods: A 13-year-old girl with genetically proven TRMA was ophthalmologically (visual acuity, funduscopy, perimetry, electroretinogram) followed up over >5 years. Fundus imaging also included autofluorescence and spectral domain optical coherence tomography., Results: During a 5-year follow-up, visual acuity and visual field decreased, despite a special TRMA diet. Funduscopy revealed bull's eye appearance, whereas fundus autofluorescence showed central and peripheral hyperfluorescence and perifoveal hypofluorescence. Spectral domain optical coherence tomography revealed affected inner segment ellipsoid band and irregularities in the retinal pigment epithelium and choroidea., Conclusion: Autofluorescence and spectral domain optical coherence tomography findings in a patient with TRMA show retinitis pigmentosa-like retina, retinal pigment epithelium, and choroid alterations. These findings might progress even under special TRMA diet, indispensable to life. Ophthalmologist should consider TRMA in patients with deafness and ophthalmologic disorders.

Introduction: Although vitamin B12 deficiency is a well-known cause of hematological and neuropsychiatric illness, the presentation of combined severe pancytopenia, demyelination and prominent psychiatric impairment is rare., Case Presentation: We present a case of a previously healthy 55-year-old East African man with severe vitamin B12 deficiency (serum vitamin B12 22pmol/L) secondary to pernicious anemia. He had a severe hypoproliferative megaloblastic anemia with hemolysis (hemoglobin 61g/L, mean corpuscular volume 99fL, reticulocytes 0.8%, haptoglobin undetectable), leukopenia (2.7×109/L), thrombocytopenia (96×109/L), ataxia with central demyelination, and megaloblastic madness. The patient's anemia, myelopathy and psychiatric condition responded well to parenteral vitamin B12 replacement therapy, with significant improvement seen within weeks., Conclusion: Hematological manifestations of vitamin B12 deficiency are typically inversely correlated with the presence and severity of neuropsychiatric impairment. Although uncommon, a presentation with severe hematological and neuropsychiatric disease can occur, as illustrated by this case. Its presence may help guide diagnosis as well as provide clinically important prognostic information.

Background: 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., Procedure: 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., Results: 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., Conclusions: TRMA is a disease of expanding phenotypic spectrum with poor genotype-phenotype correlation., (© 2013 Wiley Periodicals, Inc.)

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) 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.

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., (© 2012 John Wiley & Sons A/S.)

Background: The cblE disorder is an inherited disorder of vitamin B12 metabolism that results in elevated levels of homocysteine and decreased methionine in body fluids. Renal complications have been reported in patients with cblC disease, but not in those with cblE disease. The renal complications of cblC disease include thrombotic microangiopathy (TMA), neonatal hemolytic uremic syndrome, chronic renal failure, tubulointerstitial nephritis and proximal renal tubular acidosis. Previously, we reported a patient with cblC disease who had an atypical glomerulopathy that manifested with proteinuria and progressive renal insufficiency., Case-Diagnosis/treatment: Studies were done on cultured fibroblasts. Renal biopsy tissue was examined by light and electron microscopy. There was decreased incorporation of labeled methyltetrahydrofolate and decreased synthesis of methylcobalamin. Complementation analysis placed the patient into the cblE complementation group. The findings from the histological and ultrastructural studies of renal biopsy were similar, but not identical, to those of idiopathic membranoproliferative glomerulonephritis (MPGN) and overlapped with those of TMA., Conclusions: We describe a patient with cblE disease who had an atypical glomerulopathy similar to MPGN. Additional findings included migraine headaches, hypothyroidism and livedo reticularis.

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., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Folate and vitamin B(12) metabolism are essential for de novo purine synthesis, and several defects in these pathways have been associated with immunodeficiency. Here we describe the occurrence of severe combined immunodeficiency (SCID) with megaloblastic anemia, leukopenia, atypical hemolytic uremic syndrome, and neurologic abnormalities in which hydroxocobalamin and folate therapy provided partial immune reconstitution. Whole exome sequencing identified compound heterozygous mutations in the MTHFD1 gene, which encodes a trifunctional protein essential for processing of single-carbon folate derivatives. We now report the immunologic details of this novel genetic cause of SCID and the response to targeted metabolic supplementation therapies. This finding expands the known metabolic causes of SCID and presents an important diagnostic consideration given the positive impact of therapy.

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., (© 2012 John Wiley & Sons A/S.)

Leukocytosis, splenomegaly, and an increased vitamin B(12) level are characteristic findings of chronic myelogenous leukemia in the chronic phase (CML-CP). Here, we report a patient with CML-CP accompanied by megaloblastic anemia. A 61-year-old man consulted our hospital because of anemia and thrombocytopenia. On physical examination, there were no remarkable findings; there was no hepatosplenomegaly. Laboratory findings were: hemoglobin 6.0 g/dl; MCV 113.6 fl; platelet count 100×10(9)/l; white cell count 8.66×10(9)/l; and LDH 1,236 IU/l. Peripheral blood smear demonstrated hypersegmented neutrophils and megalocytes with emergence of myeloblasts, giant metamyelocytes, and nucleated red cells. Vitamin B(12) and folic acid levels were low. Bone marrow examination showed megaloblastic change in the erythroblasts and myeloid hyperplasia. Following vitamin B(12) and folic acid administration, anemia and thrombocytopenia rapidly improved; thereafter, marked leukocytosis became evident. Based on the presence of t(9;22)(q34;q11) on cytogenetic study and a positive result for Major bcr/abl fusion gene, a diagnosis of CML-CP was established. This case illustrates that ineffective erythropoiesis results in anemia and thrombocytopenia in CML with vitamin B12 and/or folic acid deficiency.

Vitamin B12 deficiency in infants often presents with nonspecific hematological, gastrointestinal, and neurological manifestations. It is usually caused by inadequate intake, abnormal absorption, or congenital disorders of vitamin B12 metabolism, including transport disorders. We describe a vitamin B12-deficient infant with severe anemia who was breastfed. His mother had undiagnosed vitamin B12 deficiency having undergone total gastrectomy 18 years earlier. The infant developed normally after taking vitamin B12. It is important to suspect vitamin B12 deficiency in mothers who have undergone gastrectomy. Early diagnosis and treatment of vitamin B12 deficiency in infants is important and will help improve long-term prognosis.

Vitamin B12 deficiency is an uncommon cause of pyrexia. We report the case of a patient who presented with pyrexia and anaemia, which after exclusion of infective, inflammatory or endocrine causes was attributed to megaloblastic anaemia secondary to vitamin B12 deficiency. The patient's fever responded to treatment of vitamin B12 deficiency.

Dihydrofolate reductase (DHFR) is a critical enzyme in folate metabolism and an important target of antineoplastic, antimicrobial, and antiinflammatory drugs. We describe three individuals from two families with a recessive inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency due to a germline missense mutation in DHFR, resulting in profound enzyme deficiency. We show that cerebral folate levels, anemia, and pancytopenia of DHFR deficiency can be corrected by treatment with folinic acid. The characterization of this disorder provides evidence for the link between DHFR and metabolism of cerebral tetrahydrobiopterin, which is required for the formation of dopamine, serotonin, and norepinephrine and for the hydroxylation of aromatic amino acids. Moreover, this relationship provides insight into the role of folates in neurological conditions, including depression, Alzheimer disease, and Parkinson disease., (Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

We report the case of a 7-month-old breast fed infant who presented with a nose bleed and bruises. Investigation showed severe nutritional B12 deficiency anemia with a pancytopenia. It is important to take the nutritional history of both the infant and the mother for early prevention and treatment.

Background/aims: Current consensus supports the notion that proteinuria is a marker of renal disease with prognostic implications. Whereas most chronic kidney disease patients with proteinuria would often require antiproteinuric agents, there are some exceptions. Megaloblastic anemia type 1 (MGA1) is characterized by megaloblastic anemia due to congenital selective vitamin B(12) malabsorption and proteinuria. In the present study, we describe 2 Israeli Jewish patients with MGA1 and isolated proteinuria., Methods: Because of their origin, the patients were screened for the presence of the already studied Tunisian AMN mutation, by direct sequencing the corresponding region from genomic DNA. PCR products were purified and sequenced., Results: Genomic DNA sequencing of the AMN gene of both patients confirmed that the acceptor splice site in intron 3 was changed from CAG to CGG (208-2A→G)., Conclusion: We determined the molecular basis of MGA1 in both patients and discuss the involvement of the cubilin/AMN complex in this pathology and its role in the development of the proteinuria. We also discuss the questionable significance of antiproteinuric treatment for these patients., (Copyright © 2010 S. Karger AG, Basel.)

Thiamine-responsive megaloblastic anaemia (TRMA; OMIM 249270) syndrome is an autosomal recessive disorder characterized by diabetes mellitus, megaloblastic anaemia, and sensorineural deafness. Progressive hearing loss is one of the cardinal findings of the syndrome and is known to be irreversible. Whether the deafness in TRMA syndrome can be prevented is not yet known. Here, we report a four-month-old female infant diagnosed with TRMA syndrome at an early age. There was no hearing loss at the time of diagnosis. The patient's initial auditory evoked brainstem response measurements were normal. Although she was given thiamine supplementation regularly following the diagnosis, the patient developed moderate sensorineural hearing loss at 20 months of age, indicating that early diagnosis and treatment with oral thiamine (100 mg/day) could not prevent deafness in TRMA syndrome. It would be premature to draw general conclusions from one case, but we believe that further patient-based observations can shed light on the pathophysiology of this rare syndrome as well as prediction of its prognosis., (©Journal of Clinical Research in Pediatric Endocrinology, Published by Galenos Publishing.)

We report herein our interesting case series of 15 infants admitting with neurological symptoms who were found to have vitamin B12 deficiency. Infants who were admitted to our hospital between 2004 and 2007 with neurological symptoms and were found to have vitamin B12 deficiency were included in this study. Data regarding clinical and laboratory features were obtained. Of 15 infants, 9 were boys (60%) and 6 were girls (40%). The mean age was 11.7 months. Anorexia, pallor, hypotonia, and neurodevelopmental retardation were present in all infants. Seizures and tremor were observed in 46.6% (7/15) and 33% (5/15) of patients, respectively. Seizures were generalized tonic-clonic in 4 patients, generalized tonic in 1 patient and focal in 2 patients. Four patients had tremor on admission and 1 patient had occurrence after vitamin B12 treatment. Vitamin B12 deficiency may lead to serious neurological deficits in addition to megaloblastic anemia. Persistent neurological damage can be prevented with early diagnosis and treatment. We believe that a thorough clinical and neurological assessment might prevent failure to notice rare but possible vitamin B12 deficiency in infants with neurological deficits and neurodevelopmental retardation.

Objective: To determine causative mutations and clinical status of 7 previously unreported kindreds with TRMA syndrome, (thiamine-responsive megaloblastic anemia, online Mendelian inheritance in man, no. 249270), a recessive disorder of thiamine transporter Slc19A2., Study Design: Genomic DNA was purified from blood, and SLC19A2 mutations were characterized by sequencing polymerase chain reaction-amplified coding regions and intron-exon boundaries of all probands. Compound heterozygotes were further analyzed by sequencing parents, or cloning patient genomic DNA, to ascertain that mutations were in trans., Results: We detected 9 novel SLC19A2 mutations. Of these, 5 were missense, 3 were nonsense, and 1 was insertion. Five patients from 4 kindreds were compound heterozygotes, a finding not reported previously for this disorder, which has mostly been found in consanguineous kindreds., Conclusion: SLC19A2 mutation sites in TRMA are heterogeneous; with no regional "hot spots." TRMA can be caused by heterozygous compound mutations; in these cases, the disorder is found in outbred populations. To the extent that heterozygous patients were ascertained at older ages, a plausible explanation is that if one or more allele(s) is not null, partial function might be preserved. Phenotypic variability may lead to underdiagnosis or diagnostic delay, as the average time between the onset of symptoms and diagnosis was 8 years in this cohort.

Anemia is a very common symptom encountered in numerous clinical situations in pediatrics. Etiologies range from classic iron-deficiency anemia to the more particular etiologies. We report on a clinical history where usual symptoms such as asthenia, drowsiness and proteinuria provided a rare diagnosis: Imerslund-Gräsbeck syndrome. We discuss the exams to be done with aregenerative macrocytic anemia so as not to underestimate these diagnoses, which each require adapted treatments.

Thiamine-responsive megaloblastic anemia (TRMA) is a rare autosomal recessive disorder characterized by megaloblastic anemia, diabetes mellitus and progressive sensorineural deafness. We report the cases of two infants, aged 4 and 5 months, hospitalized for diabetic ketoacidosis requiring insulin therapy. Laboratory tests revealed megaloblasic anemia, thrombocytopenia and normal thiamine level. Neurosensorial investigations showed bilateral deafness and ophthalmic involvement. Treatment with oral thiamine normalized hematological disorders and controlled diabetes; however, thiamine therapy had no impact on neurosensorial disorders.

Pregnant women with low B12 levels are unable to provide the necessary amount of this vitamin to their fetuses. The mothers are usually not anemic, and failure to thrive and neurologic deficits are more common in their infants than in megaloblastic anemia. We report the case of a newborn that was born to a vegetarian mother and presented with the symptoms of megaloblastic anemia at birth; we also discuss vitamin B12 metabolism during pregnancy and lactation. An interesting feature of the present case is that it is the only reported case of a newborn that was treated by supplementation of the mother.

Megaloblastic anemias are a subgroup of macrocytic anemias, in which distinctive morphologic abnormalities occur in red cell precursors in bone marrow, namely megaloblastic erythropoiesis. Of the many causes of megaloblastic anemia, the most common are disorders resulting from cobalamin or folate deficiency. The clinical symptoms are weakness, fatigue, shortness of breath and neurologic abnormalities. The presence of oral signs and symptoms, including glossitis, angular cheilitis, recurrent oral ulcer, oral candidiasis, diffuse erythematous mucositis and pale oral mucosa offer the dentist an opportunity to participate in the diagnosis of this condition. Early diagnosis is important to prevent neurologic signs, which could be irreversible. The aim of this paper is to describe the oral changes in a patient with megaloblastic anemia caused by a dietary deficiency of cobalamin.

Thiamine-responsive megaloblastic anemia is a rare autosomal recessive disorder whose main symptoms are anemia, diabetes mellitus, and sensorineural deafness. We describe a 20-year follow-up of 2 previously reported patients and of 1 patient diagnosed before onset of symptoms and treated with thiamine since the first sign of disease.

Megaloblastic anemias are basically caused by vitamin B(12) and/or folic acid deficiency. Childhood vitamin B(12) deficiency is extremely rare. There are congenital and acquired forms of vitamin B(12)-deficiency anemias. The article captures findings of 10 year observation of 3 patients with Imerslund-Gräsbeck Syndrome (congenital chronic megaloblastic anemia with proteinuria), in which the diagnosis was established by us in early childhood and due to correct treatment and prevention complete clinical-laboratory remission is kept so far. We have also observed rare case of acquired megaloblastic anemia - 14 years old vegetarian patient, who was diagnosed with vitamin B(12)-deficiency anemia based on history, clinical and para-clinical data. It was caused by strict vegetarianism of the patient. Therefore first of all the diet was corrected. In 5 days of specific treatment with vitamin B(12) "reticulocyte crisis" was manifested (proving the correctness of diagnosis and treatment) and complete clinical-hematological remission was achieved in 2 weeks. The given cases are interesting as megaloblastic anemias in childhood are both rare and difficult to diagnose. In such cases timely diagnosis, treatment and prevention tactics should be based on cause-and-effect relation of disease.

Thiamine-responsive megaloblastic anemia syndrome is an autosomal recessive disorder characterized by diabetes mellitus, megaloblastic anemia and sensorineural hearing loss. Mutations in the SLC19A2 gene, encoding a high-affinity thiamine transporter protein, THTR-1, are responsible for the clinical features associated with thiamine-responsive megaloblastic anemia syndrome in which treatment with pharmacological doses of thiamine correct the megaloblastic anemia and diabetes mellitus. The anemia can recur when thiamine is withdrawn. Thiamine may be effective in preventing deafness if started before two months. Our patient was found homozygous for a mutation, 242insA, in the nucleic acid sequence of exon B, with insertion of an adenine introducing a stop codon at codon 52 in the high-affinity thiamine transporter gene, SLC19A2, on chromosome 1q23.3.

Thiamine responsive megaloblastic anemia syndrome (TRMA) is a clinical triad characterized by thiamine-responsive anemia, diabetes mellitus and sensorineural deafness. We report a 4-year-old girl with TRMA whose anemia improved following administration of thiamine and this case report sensitizes the early diagnosis and treatment with thiamine in children presenting with anemia, diabetes and deafness.

This report describes a female child with thiamine responsive megaloblastic anemia syndrome (Rogers syndrome), presenting with anemia and diabetes mellitus responding to thiamine. She also had retinitis pigmentosa. The anemia improved and blood sugar was controlled with daily oral thiamine. Previously unreported olfactory abnormalities, as described in Wolfram syndrome, were also present in our patient.

Background: Thiamine-responsive megaloblastic anemia syndrome is a rare autosomal recessive disorder defined by the occurrence of megaloblastic anemia, diabetes mellitus, and neurosensoriel deafness, responding in varying degrees to thiamine treatment., Aim: Report an unusual case of this rare disorder, Case Report: We report the case of a four-year-old boy who presented unusual features of thiamine-responsive megaloblastic anemia. In addition to the typical triad of the syndrome, he presented leuconeutropenia, hepatosplenomegalia, cardiac abnormalities including absent P waves, mitral and tricuspid insufficiency, retinitis pigmentosa, nystagmus, developmental delay and a brain Magnetic resonance imaging ischemic lesion. Lactate levels in serum and the lactate/pyruvate ratio were increased. The mitochondrial mutation m.3243A > G located in MTTL1 gene encoding for transfer RNA leucine (tRNALeu(UUR)) was not found. Treatment with thiamine resulted in normalisation of the haemoglobin level, white cell count, and glucose and lactate levels. On three years follow up, the patient did not need insulinotherapy., Conclusion: These data sign the crucial role that thiamine plays for many cells and tissues and its importance in the activity of the respiratory chain.

A 55-year-old female with a history of psychosis and rheumatoid arthritis was admitted to the hospital for fatigue and dizziness. At admission, macrocytic anemia, high serum lactic acid dehydrogenase (LDH) and gastrin concentrations, decreased serum vitamin B12 concentration, with macroovalocytes and poikilocytes in peripheral blood smear suggested the diagnosis of pernicious anemia. Indirect antiglobulin test (IAT) was negative. Surprisingly, treatment by vitamin B12 and folic acid administered for two weeks was ineffective and followed by transitory worsening of hemoglobin concentration on day 8. Repeat direct antiglobulin test (DAT) and IAT were positive. This immunotransfusion conversion, suggesting the presence of autoimmune hemolytic anemia, could be explained by change in the macroblastic erythrocyte population, i.e. emerging red cells with completely exposed membrane antigens due to vitamin B12 treatment and/or higher degree of dysregulation of the lymphocyte clone secreting erythrocyte autoantibodies. We proposed the coexistence of pernicious and autoimmune hemolytic anemia; therefore, methylprednisolone was added to vitamin B12 treatment. This therapy successfully improved hemoglobin and erythrocyte concentration. Although megaloblastic-pernicious anemia is a common disease, association of pernicious and autoimmune hemolytic anemia with two mechanisms of hemolysis (ineffective erythropoiesis and immune mechanism) is a rare condition, with only several dozens of cases described so far.

A 70-year-old man was diagnosed as having rheumatoid arthritis (RA) in 2005. He was treated with 1 g salazosulfapyridine (SASP) daily for two years. Hematological investigations conducted since 2005 demonstrated hemoglobin concentrations of 8 approximately 9 g/dl, which then dropped to 4.9 g/dl on November 21, 2007, following which he was admitted to our hospital. Megaloblastic anemia associated with SASP treatment and anemia of chronic disorders were diagnosed on the basis of folate deficiency and bone marrow examination. This report describes a case of megaloblastic anemia, which developed two years after starting SASP and promptly recovered after its withdrawal and treatment with folic acid and prednisolone. The doses of SASP prescribed for RA in Japan are less than those prescribed abroad. Megaloblastic anemia associated with SASP treatment for RA is not usually detected in Japan. Currently, SASP is widely used and one of the key drugs in the treatment of RA. This case suggests that SASP therapy in RA might result in megaloblastic anemia.

A three year old boy presented with sensory neural hearing loss since birth, Diabetes mellitus and anaemia. On investigation he was found to be suffering from thiamine responsive megaloblastic anaemia (TRMA) a very rare condition diagnosed in our settings.

Nutritional B12 deficiency in childhood is an uncommon disorder. Most cases are due to maternal insufficiency, resulting from deficient stores and intake, and is generally seen in exclusively breast fed infants. This report describes a breast-fed infant with megaloblastic anemia secondary to maternal vitamin B12 deficiency. We describe this patient to remind readers that B12 deficiency may cause severe pancytopenia and regression of motor functions. These patients can present with unexpected signs and symptoms, such as developmental delay and regression as in our patient. It is also important to take the nutritional history of both the child and the mother of early prevention and treatment. With early awareness and appropriate measures potentially irreversible neurologic damage can be prevented in the infant.