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

BACKGROUND: Individuals 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 PRESENTATION: Our 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. CONCLUSIONS: Early 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.

Clinico-laboratory Profile and Outcomes of Megaloblastic Anemia presenting as Severe Pyrexial Illness mimicking Tropical Infection.

BACKGROUND: Anemia-causing fever has been described in patients with megaloblastic anemia. Although the exact mechanism of this is unknown, high-grade fever is relatively less reported. MATERIALS AND METHODS: This prospective observational study included all new cases of megaloblastic anemia presenting with febrile illness (>101°F) during a 3-year period. Patients with existing anemia, comorbidities, and other causes of macrocytosis were excluded. A detailed evaluation for megaloblastic anemia and workup for excluding tropical infections was done. The patients were treated with parenteral vitamin B12, folic acid, and other hematinics. RESULTS: Around 24 cases of megaloblastic anemia presenting with high-grade fever were included, with 14 (58.3%) males, mean duration of fever 7.7 days (4-18 days), and 09 (37.5%) having temperature >103°F. The mean hemoglobin (Hb) was 8.15 g/dL (3.7-11.1 g/dL), the mean corpuscular volume (MCV) was 111 ± 7.8 fL, 18 (75%) had unconjugated hyperbilirubinemia, the mean lactate dehydrogenase (LDH) was 814 ± 24 IU/L, and 21 (87.5%) had low B12 or folate levels. Most showed good therapeutic response to B12 or folic acid with defervescence in 1-5 days (mean 2.6 days) and improvement in lab parameters in 1 week. The study population was divided into those with temperature ≥103°F, and temperature <103°F it was seen that there was a significant association (p < 0.05) with leucocyte count of ≤3000/cumm, and MCV ≥110 fL, in patients with temperature ≥103°F Conclusion: Megaloblastic anemia should be considered in the differentials of a patient presenting with a febrile illness with no clinical localization and a negative initial fever workup. Early identification and prompt therapy of this easily treatable disorder are very essential.

Thiamine responsive megaloblastic anaemia complicated with acute Parvovirus infection: A case report.

Thiamine responsive megaloblastic anaemia syndrome also known as Rogers syndrome is a very rare autosomal recessive disorder. The hallmark of the disease is the presence of the classic triad of anaemia, diabetes mellitus, and sensorineural deafness. We report the case of a 14-year-old boy who presented to us with severe megaloblastic anaemia, diabetes mellitus, and sensorineural deafness. The anaemia was further complicated by acute parvovirus infection. He was put on high doses of thiamine (vitamin B1) which led to an improvement.

Vitamina B12: ¿para algo más que el tratamiento de la anemia megaloblástica? / Vitamin B12: For more than just the treatment of megaloblastic anemia?

Vitamin B12, or cobalamin, belongs to the group of water-soluble vitamins and is ingested through food of animal origin such as eggs, milk, red meat and poultry, fish, and shellfish. Its clinical indication is the treatment of hypovitaminosis B12 administered orally or intramuscularly in the form of hydroxocobalamin. Hypovitaminosis B12 is mainly caused by deficient dietary intake (individuals with malnutrition, vegetarians or vegans, older adults, pregnant people, individuals with alcohol use disorder); when intestinal absorption is reduced (atrophic gastritis, malabsorption syndrome, gastrointestinal surgery); and for causes associated with the intake of drugs (antacids, metformin). Hypervitaminosis B12 has been associated with renal failure; liver diseases such as cirrhosis and acute-phase hepatitis; alcohol use disorder with or without liver involvement; solid tumors of the lung, liver, esophagus, pancreas, and colorectum; and in hematological malignancies such as leukemia and bone marrow dysplasia (AU)

La vitamina B12 o cobalamina pertenece al grupo de vitaminas hidrosolubles y su aporte se realiza a través de la ingesta de alimentos de origen animal como huevo; leche; carnes rojas y de aves; pescados y mariscos. Su indicación clínica es el tratamiento de la hipovitaminosis B12 administrada por vía oral o intramuscular en forma de hidroxicobalamina. La hipovitaminosis B12 se origina, principalmente, por un déficit de aporte en la dieta (malnutrición, sujetos vegetarianos o veganos, ancianos, embarazo, alcoholismo); cuando está disminuida su absorción intestinal (gastritis atrófica, síndrome de malabsorción intestinal, cirugía gastro-intestinal) y asociada a ingesta de fármacos (antiácidos, metformina). La hipervitaminosis B12 se ha relacionado con la insuficiencia renal; hepatopatías como cirrosis y hepatitis en fase aguda; alcoholismo con o sin afectación hepática; tumores sólidos de pulmón, hígado, esófago, páncreas y colorrectal y en neoplasias hematológicas como leucemia y la displasia medular (AU)

Vitamin B12: For more than just the treatment of megaloblastic anemia?

Vitamin B12, or cobalamin, belongs to the group of water-soluble vitamins and is ingested through food of animal origin such as eggs, milk, red meat and poultry, fish, and shellfish. Its clinical indication is the treatment of hypovitaminosis B12 administered orally or intramuscularly in the form of hydroxocobalamin. Hypovitaminosis B12 is mainly caused by deficient dietary intake (individuals with malnutrition, vegetarians or vegans, older adults, pregnant people, individuals with alcohol use disorder); when intestinal absorption is reduced (atrophic gastritis, malabsorption syndrome, gastrointestinal surgery); and for causes associated with the intake of drugs (antacids, metformin). Hypervitaminosis B12 has been associated with renal failure; liver diseases such as cirrhosis and acute-phase hepatitis; alcohol use disorder with or without liver involvement; solid tumors of the lung, liver, esophagus, pancreas, and colorectum; and in hematological malignancies such as leukemia and bone marrow dysplasia.

Thiamine-Responsive Megaloblastic Anaemia With Hypothyroidism, A Puzzling Association.

Background: Thiamine-responsive megaloblastic anaemia (TRMA) is characterized by the classic trio of diabetes mellitus, sensorineural hearing loss, and megaloblastic anaemia, typically emerging subtly between infancy and adolescence. Administration of high-dose thiamine often yields improvements in anaemia and occasionally in diabetes. Uncommon manifestations include optic atrophy, congenital heart defects, short stature, and stroke. In this specific case, a 5-year-old diagnosed with insulin-dependent diabetes mellitus (IDDM) since the age of one presented with symptoms such as polyuria, fever, and vomiting, revealing an HbA1c of 10.64. Further examinations disclosed compromised hearing and vision. A negative antibody workup and a thyroid profile indicating hypothyroidism prompted additional investigations, including Brainstem Evoked Response Audiometry (BERA) and retinal examination, confirming bilateral sensorineural hearing loss and maculopathy, respectively. A comprehensive blood count unveiled megaloblastic anaemia. Genetic profiling confirmed a homozygous mutation in the SLC19A2 gene, thus diagnosing TRMA. An early diagnosis, coupled with genetic confirmation, enables timely intervention, with patients responding positively to high-dose thiamine. Genetic counselling plays a pivotal role in enlightening families about the disease and its inheritance patterns, fostering awareness and understanding.

[Vitamin B12 deficiency in an infant child of a mother with pernicious anemia]. / Déficit de vitamina B12 en un lactante hijo de madre portadora de anemia perniciosa.

INTRODUCTION: In infants, vitamin B12 deficiency is mainly due to nutritional deficiencies related to maternal deficit. Most cases of maternal deficiencies are associated with vegetarian diets. Pernicious anemia is an au toimmune disease that affects the absorption of this vitamin. Although it is less common than nutri tional deficiency, is also an important cause of maternal deficiency. OBJECTIVE: to report a case of an infant with vitB12 deficiency, secondary to pernicious anemia in his mother, and to review the most important aspects of this disease in childhood. CLINICAL CASE: Nine months-old male infant, without pathological perinatal history, exclusively breastfed, with persistent rejection of solid food from 6 months of age. One month before hospitalization, he progressively presented hyporesponsiveness, with fluctuating state of alertness, regression of motor development milestones, and vomiting. The blood count showed macrocytic anemia and neutropenia. Vitamin B12 deficiency was confirmed in the patient. He received treatment with intramuscular vitamin B12 with good clinical and laboratory response. Maternal B12 deficiency was confirmed as the cause of the infant's deficiency. Since the mother reported no dietary restrictions, anti-intrinsic factor and anti-parietal cell antibodies were measured, leading to the diagnosis of pernicious anemia. CONCLUSIONS: Early recognition is essential to prevent the development of potentially irreversible neurological damage. Maternal pernicious ane mia should be considered in children with megaloblastic anemia, especially in those whose mothers do not follow vegetarian diets.

Parenteral vs Oral Vitamin B12 in Children With Nutritional Macrocytic Anemia: A Randomized Controlled Trial.

BACKGROUND: There is limited literature in children on efficacy of different routes of vitamin B12 administration for vitamin B12 deficiency macrocytic-megaloblastic anemia. OBJECTIVE: To compare parenteral with oral vitamin B12 therapy in children with macrocytic-megaloblastic anemia. STUDY DESIGN: Single-center, open-label randomized controlled trial. PARTICIPANT: 80 children aged 2 month-18 year with clinical and laboratory features of nutritional macrocytic anemia. INTERVENTION: All children received an initial single parenteral dose of 1000 µg vitamin B12 followed by randomization to either parenteral or oral vitamin B12 for subsequent doses. Group A was given 1000 µg intramuscular (IM) vitamin B12 (3 doses on alternate days for those aged <10 year, five doses for age >10 year), followed by monthly 1000 µg IM for the subsequent two doses. Group B was given daily oral vitamin B12 1500 µg (500 µg in <2 years age) for three months. Folic acid and iron supple-mentation, and relevant dietary advice were given to both groups in a similar fashion. OUTCOME: Improvement in serum vitamin B12 levels and total hemoglobin was compared three months post-treatment. RESULT: The median(IQR) increase in serum vitamin B12 level was significantly higher in group A [600 (389,775) vs 399 (313, 606) pg/mL; P= 0.016]. The median (IQR) rise of hemoglobin was also more in group A [2.7 (0.4,4.6) vs 0.5 (-0.1,1.2) g/dL; P=0.001]. CONCLUSION: Increase in serum vitamin B12 levels and hemoglobin was better in children with nutritional macrocytic anemia receiving parenteral as compared to oral vitamin B12.

Leber congenital amaurosis as an initial manifestation in a Chinese patient with thiamine-responsive megaloblastic anemia syndrome.

Thiamine-responsive megaloblastic anemia syndrome (TRMA) is an autosomal recessive disorder, inherited by the defective SLC19A2 gene that encodes a high-affinity thiamine transporter (THTR-1). TRMA is characterized by the occurrence of classical triad manifestations including megaloblastic anemia, diabetes mellitus, and sensorineural deafness. In addition to the systemic manifestations, ophthalmic features can be present and include retinitis pigmentosa, optic atrophy, cone-rod dystrophy, maculopathy, and Leber congenital amaurosis. Here we report a 6-year-old boy presenting severe early-onset retinal dystrophy with the initial diagnosis of Leber congenital amaurosis, which followed for 12 years. Diabetes mellitus occurred 3 years after vision problem. Eosinophilic granuloma of the left scapula was confirmed at 13 years old. Whole-exome sequencing was performed to identify two novel compound heterozygous variants c.725dupC (p.Ala243Serfs*3) and c.121G>A (p.Gly41Ser) in SLC19A2 gene (NM_006996.3). Oral thiamine supplementation treatment was initiated at 13 years. This case demonstrates Leber congenital amaurosis can present as the first clinical feature before systemic manifestations. Phenotypic variety should be aware and multidisciplinary teamwork and regular follow-up are important for TRMA patient care.

Megaloblastic anemia-related iron overload and erythroid regulators: a case report.

BACKGROUND: In ineffective erythropoiesis, hepcidin synthesis is suppressed by erythroid regulators, namely erythroferrone and growth differentiation factor-15. For the first time, the hypothesis that iron overload in megaloblastic anemia may be related to ineffective erythropoiesis is explored by describing the kinetics of hepcidin, erythroferrone, and growth differentiation factor-15 levels in a patient diagnosed with megaloblastic anemia associated with iron overload. CASE PRESENTATION: An 81-year-old Caucasian male was admitted for fatigue. He had type-2 diabetes previously treated with metformin, ischemic cardiac insufficiency, and stage-3 chronic kidney disease. Vitiligo was observed on both hands. Biological tests revealed normocytic non-regenerative anemia associated with hemolysis, thrombocytopenia, and elevated sideremia, ferritin, and transferrin saturation levels. Megaloblastic anemia was confirmed with undetectable blood vitamin B12 and typical cytological findings like hyper-segmented neutrophils in blood and megaloblasts in bone marrow. The patient received vitamin B12 supplementation. At 3 months, biological parameters reached normal values. Hepcidin kinetics from diagnosis to 3 months inversely correlated with those of erythroferrone and growth differentiation factor-15. CONCLUSIONS: This case suggests that iron-overload mechanisms of dyserythropoietic anemias may apply to megaloblastic anemias.

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

BACKGROUND AND AIMS: Thiamine-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 METHODS: Whole-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. RESULTS: Two 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. CONCLUSION: Two 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.

Clinical and molecular characteristics of imerslund-gräsbeck syndrome: First report of a novel Frameshift variant in Exon 11 of AMN gene.

INTRODUCTION: Imerslund-Gräsbeck syndrome (IGS) is a rare autosomal-recessive disorder characterized by selective vitamin B12 malabsorption, megaloblastic anemia, and proteinuria. The precise incidence of this disorder is unknown in the Middle East and Arab countries. The disease is caused by a homozygous variant in either AMN or CUBN genes. In addition, some compound heterozygous variants are reported. METHODS: Clinical and laboratory data of patients diagnosed with IGS in Oman were retrospectively collected. Mutation analysis for all genes involved in vitamin B12/folic acid metabolism and megaloblastic anemia was conducted using next-generation sequencing (NGS). RESULTS: Three siblings (2 girls and a boy) have been diagnosed with the condition. They exhibit a phenotypic variability with different age of presentation and different spectrum of disease. All patients harbor a novel biallelic frameshift mutation in exon 11 of AMN gene (p.Pro409Glyfs*), which was not reported previously in the literature. Both parents are heterozygotes for the same variant. All patients responded well to vitamin B12 parenteral therapy, but proteinuria persisted. CONCLUSION: In communities with high incidence of consanguinity, cases of early-onset vitamin B12 deficiency should be thoroughly investigated to explore the possibility of Imerslund-Gräsbeck syndrome and other vitamin B12-related hereditary disorders. Further local and regional studies are highly recommended.

Vitamin B12 Deficiency Resembling Acute Leukemia: A Case Report.

Vitamin B12 deficiency in children can cause megaloblastic anemia, poor growth, and increased chances of infections. It is an important reversible cause of bone marrow suppression which at the time of presentation can mimic hematological malignancy. Therefore, it should be considered as a differential diagnosis in cases suspected of acute leukemia. We report a case of 14 months old child who had atypical presentation of vitamin B12 deficiency. He had chronic fever, decreased feeding and increased paleness for one year. Pancytopenia with severe anemia was present along with 19% reactive/atypical cells in peripheral blood smear suggesting acute leukemia. However, bone marrow aspiration and biopsy showed features of megaloblastic anemia. Vitamin B12 level measured was very low and treatment with cyanocobalamin caused drastic improvement in the child's condition.

Imerslund-Grasbeck syndrome in a cross-breed dog.

Imerslund-Gräsbeck syndrome is an autosomal recessive disease reported only in certain pure-breed dogs. An 18-month-old, male neutered beagle cross-breed was presented for evaluation of severe lethargy, progressive weakness and anorexia. Main clinicopathological findings included low body condition score (2.5/9), severe muscle atrophy, several neurological abnormalities, mild normochromic, normocytic, non-regenerative anaemia, severe hypocobalaminemia and mild proteinuria. Extensive diagnostic tests ruled out most of differential diagnoses for the aforementioned clinicopathological abnormalities and genetic evaluation showed that the dog was heterozygous for two previously described mutations affecting the CUBN gene, the beagle and the border collie variants. The dog showed an excellent clinical response to oral cobalamin supplementation with no relapse after 4 months. In conclusion, this case creates awareness that Imerslund-Gräsbeck syndrome should be considered even in mixed-breed dogs with compatible clinical signs and that two different pathogenic CUBN mutations in compound heterozygosity can lead to a typical Imerslund-Gräsbeck syndrome phenotype.