vitamin-b-12 and Proteinuria

Imerslund-Gräsbeck syndrome (IGS) is a rare autosomal recessive disorder characterized by vitamin B12 malabsorption. Most patients present with non-specific symptoms attributed to vitamin B12 deficiency, and proteinuria. Patients may if untreated, develop severe neurocognitive manifestations. If recognized and treated with sufficient doses of vitamin B12, patients recover completely. We provide, for the first time, an overview of all previously reported cases of IGS. In addition, we provide a complete review of IGS and describe two new patients.

Topics: Anemia, Megaloblastic; Humans; Proteinuria; Vitamin B 12; Vitamin B 12 Deficiency

Immune dysfunction, including severe combined immunodeficiency, has been described in genetic disorders affecting the metabolism of the vitamins cobalamin (vitamin B12) and folate. We have reviewed reports of clinical findings in patients with a number of inborn errors of cobalamin or folate metabolism, specifically looking for immune problems.. There is little evidence that immune function is affected in most of the disorders. Exceptions are Imerslund-Gräsbeck syndrome and hereditary folate malabsorption (affecting intestinal absorption of cobalamin and folate, respectively), transcobalamin deficiency (affecting transport of cobalamin in blood and cellular cobalamin uptake), and methylenetetrahydrofolate dehydrogenase 1 deficiency (catalyzing cytoplasmic interconversion of reduced folate coenzyme derivatives).. Although some inborn errors of cobalamin or folate can be associated with immune dysfunction, the degree and type of immune dysfunction vary with no obvious pattern.

Topics: Anemia, Megaloblastic; Folic Acid; Folic Acid Deficiency; Humans; Malabsorption Syndromes; Methylenetetrahydrofolate Dehydrogenase (NADP); Minor Histocompatibility Antigens; Nutritional Physiological Phenomena; Primary Immunodeficiency Diseases; Proteinuria; Transcobalamins; Vitamin B 12; Vitamin B 12 Deficiency

Imerslund-Gräsbeck syndrome is a rare autosomal recessive disorder, characterized by vitamin B12 deficiency due to selective malabsorption of the vitamin and usually results in megaloblastic anemia appearing in childhood. It is responsive to parenteral vitamin B12 therapy.The estimated prevalence (calculated based on Scandinavian data) is less than 6:1,000,000. However, many cases may be misdiagnosed.When there is reasonable evidence to suspect that a patient suffers from IGS, a new and straightforward approach to diagnosis is mutational analysis of the appropriate genes. We report for the first time the case of a girl of Italian ancestry with IGS genetically confirmed by the detection of a homozygous missense mutation in the AMN gene (c.208-2 A > G).

Topics: Anemia, Megaloblastic; Child, Preschool; DNA Mutational Analysis; Female; Follow-Up Studies; Genetic Predisposition to Disease; Homozygote; Humans; Italy; Malabsorption Syndromes; Membrane Proteins; Mutation, Missense; Proteins; Proteinuria; Rare Diseases; Risk Assessment; Severity of Illness Index; Treatment Outcome; Vitamin B 12; Vitamin B 12 Deficiency

In our pioneering work in 1956, two binders of vitamin B12 (B12) alias cobalamin (Cbl) were identified in gastric juice, S with slow electrophoretic mobility, a 70 kD protein with intrinsic factor (IF) activity and another rapid (R), not IF active but probable digestion product. Numerous sources contained a protein immunologically identical to R (haptocorrin, Hc). Another IF-active component (I) was found. Isoelectric focusing showed that S, I and R were assemblies of "isoproteins" with different pI's due to varying glycosidation. Isolation of S, I and R in microquantities was achieved in 1962 using a series of ion exchange chromatographies and gel filtration. Ponderable products were obtained in 1965-1966. The B12-IF complex was a dimer, contained 13% carbohydrate and showed a different absorption spectrum than B12. Using the Schilling test, B12 absorption was shown to require Ca(++), bound in vitro to the ileal receptor and IF, but most of Ca(++) could be removed with sialidase. The receptor-substrate complex contained Ca(++) and carbohydrate. The purified receptor was shown to contain two main subunits. The Imerslund-Gräsbeck syndrome was discovered 1958-1960; it is caused by mutations in either of two genes, cubilin or amnionless, which form the multiligand receptor cubam. Testicular biopsies during and after B12-treated deficiency showed remarkable improvement after therapy. Studies of the turnover of radioactive B12 revealed biliary and fecal excretion, enterohepatic circulation and allowed calculation of biological half-life and daily need. The B12 coenzymes largely behaved like B12. To study whether radiocobalt in B12 was representative of the rest of the B12 molecule, (32)P and (57)Co labeled hydroxocobalamins were biosynthesized and shown to behave identically when given simultaneously to rats. The complex metabolism of B12 explains the pathogenesis of B12 deficiencies. Some of its mechanisms are not restricted to B12, e.g. the endocytosis of B12-IF also applies to other macromolecules.

Topics: Anemia, Megaloblastic; Animals; Gastric Juice; Humans; Intrinsic Factor; Malabsorption Syndromes; Proteinuria; Vitamin B 12; Vitamin B 12 Deficiency

Imerslund-Gräsbeck syndrome (IGS) or selective vitamin B(12) (cobalamin) malabsorption with proteinuria is a rare autosomal recessive disorder characterized by vitamin B(12) deficiency commonly resulting in megaloblastic anemia, which is responsive to parenteral vitamin B(12) therapy and appears in childhood. Other manifestations include failure to thrive and grow, infections and neurological damage. Mild proteinuria (with no signs of kidney disease) is present in about half of the patients. Anatomical anomalies in the urinary tract were observed in some Norwegian patients. Vitamin B(12) absorption tests show low absorption, not corrected by administration of intrinsic factor. The symptoms appear from 4 months (not immediately after birth as in transcobalamin deficiency) up to several years after birth. The syndrome was first described in Finland and Norway where the prevalence is about 1:200,000. The cause is a defect in the receptor of the vitamin B(12)-intrinsic factor complex of the ileal enterocyte. In most cases, the molecular basis of the selective malabsorption and proteinuria involves a mutation in one of two genes, cubilin (CUBN) on chromosome 10 or amnionless (AMN) on chromosome 14. Both proteins are components of the intestinal receptor for the vitamin B(12)-intrinsic factor complex and the receptor mediating the tubular reabsorption of protein from the primary urine. Management includes life-long vitamin B(12) injections, and with this regimen, the patients stay healthy for decades. However, the proteinuria persists. In diagnosing this disease, it is important to be aware that cobalamin deficiency affects enterocyte function; therefore, all tests suggesting general and cobalamin malabsorption should be repeated after abolishment of the deficiency.

Topics: Adolescent; Anemia, Megaloblastic; Animals; Child; Child, Preschool; Diagnosis, Differential; Dogs; Finland; Humans; Infant; Malabsorption Syndromes; Models, Animal; Norway; Prevalence; Prognosis; Proteinuria; Rare Diseases; Syndrome; Vitamin B 12; Vitamin B 12 Deficiency

The disease is characterised by cobalamin (Cbl) deficiency in children 0-5 years old, causing failure to thrive, infections, megaloblastic anaemia, neuropathy, and mild general malabsorption; slight proteinuria is common. Cbl injections produce remission, but Cbl malabsorption and proteinuria persist. About 250 cases have been reported. Dogs also have it. The heredity is autosomal and recessive. The physiological and pathological absorption mechanisms are described: Cbl liberated from food by digestion is first bound to haptocorrin, but in the intestine it is transferred to intrinsic factor. In the ileum the complex attaches to a receptor on the enterocytes; this requires neutral pH and Ca2+. The receptor is a membrane-bound glycoprotein consisting of multiple subunits. The receptor-ligand complex is endocytosed and degraded in lysosomes, and the vitamin is transferred to transcobalamin which carries it to tissues. The same receptor is strongly expressed in the kidneys, but urine also contains its activity which can be assayed for diagnosis. The basic lesion is an error in the ileal receptor. In the affected dogs the synthesised receptor is retained intracellularly. Urine and ileal biopsies from human cases contained little receptor but it had conserved affinity for the ligand. Recently examined Arab patients did not excrete reduced amounts of the receptor. Apparently, the disease has subsets, such as different structural errors in the receptor and possibly faulty transport inside the enterocyte. The cause of the proteinuria is unknown but kidney damage due to severe Cbl deficiency and an error in a multiligand renal receptor are among the possibilities.

Topics: Animals; Child, Preschool; Dogs; Genes, Recessive; Humans; Infant; Infant, Newborn; Intrinsic Factor; Malabsorption Syndromes; Proteinuria; Receptors, Cell Surface; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Anemia, Macrocytic; Anemia, Pernicious; Child, Preschool; Gastric Mucosa; Humans; Ileum; Infant; Infant, Newborn; Intestinal Mucosa; Intrinsic Factor; Kidney; Malabsorption Syndromes; Proteinuria; Urogenital Abnormalities; Vitamin B 12

Topics: Achlorhydria; Anemia, Macrocytic; Anemia, Pernicious; Child, Preschool; Gastric Juice; Humans; Male; Methods; Proteinuria; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Anemia, Megaloblastic; Humans; Malabsorption Syndromes; Proteinuria; Vitamin B 12; Vitamin B 12 Deficiency

Proteinuria is an unfavorable clinical condition highly associated with a risk of renal and cardiovascular disease in chronic kidney disease (CKD). However, whether all proteinuria forms are linked to renal impairment are still unclear. Cubilin is an endocytic receptor highly expressed in renal proximal tubules mediating uptake of albumin, transferrin and α1-microglobulin.. Exome sequencing method initially identified candidate genes. With the application of exome sequencing combined with Sanger sequencing, we further focused on CUBN through bioinformatics analysis. The pathogenic effects of the potentially causative variants were verified utilizing complementary analysis of clinical data and systematic characterization of the variants' expression and function with clinical samples and in vitro experiments in HEK293T cell lines along with in vivo experiments in mice.. In this study, we identified four novel variants locating after the vitamin B12 (vitB12)-binding domain of Cubilin (encoded by CUBN, NM_001081.3: c.4397G > A (p.C1466Y), c.6796C > T (p.R2266X), c.6821 + 3A > G and c.5153_5154delCT (p.S1718X)) in two families. Moreover, the variants severely affected the expression and function of Cubilin in renal proximal tubules and caused albuminuria, increasing levels in urine transferrin and α1-microglobulin, but without progressive glomerular filtration barrier (GFB) impairment, vitB12 deficiencies or abnormal blood levels of HDL and albumin. Further mechanistic insights showed that the variants after the vitB12-binding domain of CUBN merely disrupted the association with Amnionless (AMN) that exhibited aberrant localization in cell cytoplasm rather than membrane.. Here, our findings suggested that different mutation types after the vitB12-binding domain of CUBN uncouple proteinuria from glomerular filtration barrier, that may be an unexpectedly common benign condition in humans and may not require any proteinuria-lowering treatment or renal biopsy.

Topics: Albumins; Animals; HEK293 Cells; Humans; Kidney; Mice; Proteinuria; Transferrins; Vitamin B 12

Imerslund-Gräsbeck syndrome is an autosomal recessive disorder of vitamin B12 malabsorption presenting with megaloblastic anemia and mild proteinuria in childhood. The disorder is caused by biallelic pathogenic variants in the CUBN or AMN genes, which encode proteins involved in B12 absorption. We present the case of a 17-month-old boy with failure to thrive, pancytopenia, and fevers. His megaloblastic anemia was overlooked leading to unnecessary invasive testing. Findings on bone marrow biopsy prompted investigation for genetic disorders of B12 metabolism. Exome sequencing uncovered 1 known pathogenic variant and 1 novel likely pathogenic variant in CUBN, confirming the diagnosis of Imerslund-Gräsbeck syndrome.

Topics: Anemia, Megaloblastic; Female; Humans; Infant; Malabsorption Syndromes; Male; Pancytopenia; Proteinuria; Vitamin B 12; Vitamin B 12 Deficiency

The clinical data of two children with Imerslund-Gräsbeck syndrome (IGS) who were admitted to the First Affiliated Hospital of Zhengzhou University in August 2019 was analyzed retrospectively. The two cases were siblings, aged 8 years and 8 months and 6 years and 2 months, respectively. These two boys had megaloblastic anemia, low level of vitamin B. 回顾分析郑州大学第一附属医院2019年8月收治的两例Imerslund-Gräsbeck综合征（IGS）患儿的临床资料。两例患儿为同胞兄弟，年龄分别为8岁8个月和6岁2个月，检查均示巨幼红细胞性贫血，血清维生素B

Topics: Anemia, Megaloblastic; Child; Humans; Malabsorption Syndromes; Male; Proteinuria; Retrospective Studies; Siblings; Vitamin B 12; Vitamin B 12 Deficiency

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.

Topics: Anemia, Megaloblastic; Animals; Dog Diseases; Dogs; Malabsorption Syndromes; Male; Proteinuria; Vitamin B 12; Vitamin B 12 Deficiency

Imerslund-Gräsbeck syndrome is a rare genetic disease characterised by vitamin B. A 4-year old Sri Lankan boy presented with gradually worsening difficulty in walking for two weeks duration. He was previously diagnosed and managed as having non-transfusion-dependent α-thalassaemia based on the presence of hypochromic microcytic anaemia, haemoglobin H inclusion bodies in the blood film and compound heterozygous α-thalassaemia genotype with a gene deletion. However, his transfusion requirement increased over the past three months and he gradually lost his motor developmental milestones during two weeks before admission. The neurological examination revealed generalised hypotonia, exaggerated knee jerks and extensor plantar response. His complete blood count showed pancytopenia, and bone marrow biopsy revealed megaloblastic changes. Serum vitamin B. This case report presents a rare occurrence of severe vitamin B

Topics: alpha-Thalassemia; Anemia, Megaloblastic; Child; Child, Preschool; Humans; Malabsorption Syndromes; Male; Proteinuria; Subacute Combined Degeneration; Vitamin B 12; Vitamin B 12 Deficiency

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.. 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).. 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.. 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.

Topics: Anemia, Megaloblastic; Child; Child, Preschool; Exons; Female; Frameshift Mutation; Humans; Infant; Malabsorption Syndromes; Male; Membrane Proteins; Proteinuria; Retrospective Studies; Siblings; Vitamin B 12; Vitamin B 12 Deficiency; Vitamin B Complex

Topics: Anemia, Megaloblastic; Blood Cells; Blood Transfusion; Child, Preschool; Female; Hemoglobins; Homozygote; Humans; Malabsorption Syndromes; Membrane Proteins; Mutation; Proteinuria; Vitamin B 12; Vitamin B 12 Deficiency

Efficacy of PO cobalamin (Cbl) supplementation in dogs with hereditary Cbl malabsorption (Imerslund-Gräsbeck syndrome, IGS) is unknown.. To evaluate PO Cbl supplementation in Beagles with IGS previously treated parenterally. We hypothesized that 1 mg cyano-Cbl daily PO would maintain clinical and metabolic remission.. Three client-owned Beagles with IGS and 48 healthy control dogs.. Prospective study. Daily PO cyanocobalamin (cyano-Cbl; 1 mg) supplementation was monitored for 13 (2 dogs) and 8 months (1 dog). Health status was assessed by owner observations. Methylmalonic acid (MMA)-to-creatinine concentrations were measured using an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-TMS) method on urine samples collected monthly. Concurrent measurements of serum MMA concentration (n = 7; UPLC-TMS) were available for 1 dog.. All dogs remained in excellent health during PO supplementation. Urine MMA remained consistently low in 2 dogs (median, 2.5 mmol/mol creatinine; range, 1.2-9; healthy dogs [n = 30], median, 2.9 mmol/mol creatinine; range, 1.3-76.5). Urine MMA ranged from 38.9-84.9 mmol/mol creatinine during the first 6 months in 1 dog already known to excrete comparable amounts when supplemented parenterally. Brief antibiotic treatment for an unrelated condition after 6 months resulted in low urine MMA (median, 2.8 mmol/mol creatinine; range, 1.9-4.8) for the next 7 months. All concurrent serum MMA concentrations (median, 651 nmol/L; range, 399-919) before and after month 6 were within the established reference interval (393-1476 nmol/L; n = 48).. One milligram of cyano-Cbl daily PO appears efficacious for maintaining normal clinical status and normal cellular markers of Cbl metabolism in Beagles with IGS.

Topics: Administration, Oral; Anemia, Megaloblastic; Animals; Dog Diseases; Dogs; Female; Malabsorption Syndromes; Male; Methylmalonic Acid; Proteinuria; Vitamin B 12; Vitamin B 12 Deficiency

Imerslund-Gräsbeck syndrome (IGS) is a rare autosomal recessive disorder clinically characterized by megaloblastic anemia, benign mild proteinuria, and other nonspecific symptoms. Several pathogenetic variants in the amnionless (

Topics: Anemia, Megaloblastic; Female; Genetic Variation; Humans; Infant; Infusions, Parenteral; Introns; Malabsorption Syndromes; Membrane Proteins; Proteins; Proteinuria; RNA Splicing; Sequence Analysis, DNA; Treatment Outcome; Vitamin B 12; Vitamin B 12 Deficiency

Normal red blood cells maturation depends on many different hematological factors, including vitamin (vit.) B12. Megaloblastic anemias are basically caused by vit. B12 deficiency. In childhood the deficiency of this vitamin is extremely rare. The article captures findings of observation of the patient with rare form congenital vit. B12 deficiency anemia - Imerslund-Gräsbeck syndrome. The disease is characterized with selective intestinal malabsorption of vit. B12 and permanent proteinuria, without sings of kidney disease. The diagnosis was confirmed by our team in early childhood and based on the history, clinical and paraclinical data. After two weeks of specific treatment with vit. B12 , complete clinical - hematological remission was achieved. Treatment includes lifelong vit. B12 injections once per month. Cathamnesic observation for 18 months revealed that the patient is in remission, but there was continued macrocytosis of red blood cells and mild proteinuria. The presented case is interesting as a rare case of megaloblastic anemia caused by vit. B12 deficiency in childhood. Such patients often treated under different diagnosis. In such cases early diagnosis, treatment and prevention are crucial for the good prognosis.

Topics: Anemia, Megaloblastic; Child; Child, Preschool; Humans; Malabsorption Syndromes; Proteinuria; Rare Diseases; Treatment Outcome; Vitamin B 12; Vitamin B 12 Deficiency

An 11-month-old Border collie presented collapsed and continued to deteriorate rapidly despite supportive treatment. The dog had a history of failure to thrive and recurring respiratory infection. Laboratory abnormalities included neutrophilic leucocytosis, Heinz body anaemia, hyperammonaemia, hyperbilirubinaemia, proteinuria and hypocobalaminaemia. Post-mortem examination revealed multi-focal necrosis within the heart, kidneys, pancreas, liver, meninges and cerebral cortex. Fungal hyphae in lesions were identified as Scedosporium prolificans following culture. Subsequent genotyping confirmed that the dog carried the CUBN:c.8392delC mutation in a homozygous state, verifying hereditary cobalamin deficiency (a.k.a. Imerslund-Gräsbeck syndrome). Cobalamin deficiency may have been a predisposing factor for the development of systemic fungal infection in this dog.

Topics: Anemia, Megaloblastic; Animals; Dog Diseases; Dogs; Malabsorption Syndromes; Male; Mycoses; Proteinuria; Scedosporium; Vitamin B 12; Vitamin B 12 Deficiency

Prospective studies on maintenance treatment for Beagles with hereditary selective cobalamin (Cbl) malabsorption (Imerslund-Gräsbeck syndrome, IGS) are lacking. In our experience, measurement of methylmalonic acid (MMA), a Cbl-dependent metabolite, seems more helpful to monitor Cbl status as compared with serum Cbl concentrations.. To evaluate a standardized Cbl supplementation scheme in Beagles with IGS. We hypothesized that a single parenteral dose of 1 mg hydroxocobalamin (OH-Cbl) would maintain clinical and metabolic remission for up to 2 months.. Six client-owned juvenile Beagles with genetically confirmed IGS and 28 healthy control dogs.. Prospective study. Monthly IM OH-Cbl (1 mg) supplementation was done over a median of 9 months (range, 6-13) in 6 dogs, followed by bimonthly (every 2 months) injections in 5 dogs over a median of 6 months (range, 3-10). Health status was assessed by routine clinical examinations at injection time points and owner observations. Voided urine samples were collected immediately before OH-Cbl injections for measurement of MMA-to-creatinine concentrations using a gas-liquid chromatography-tandem mass spectrometry (GC-MS) method.. All dogs were clinically healthy while receiving monthly and bimonthly OH-Cbl supplementation. Urinary MMA results in healthy dogs ranged from 1.3 to 76.5 mmol/mol creatinine (median, 2.9). Median urinary MMA concentrations did not differ between dogs with IGS receiving monthly (n = 49; 5.3 mmol/mol creatinine; range, 2.3-50.4) and bimonthly (n = 31; 5.3 mmol/mol creatinine; range, 1.6-50) injections.. A maintenance parenteral dose of 1 mg OH-Cbl monthly or bimonthly appears adequate in Beagles with IGS monitored by metabolic testing.

Topics: Anemia, Megaloblastic; Animals; Creatinine; Dog Diseases; Dogs; Drug Administration Schedule; Female; Hydroxocobalamin; Injections, Intramuscular; Malabsorption Syndromes; Male; Methylmalonic Acid; Prospective Studies; Proteinuria; Vitamin B 12; Vitamin B 12 Deficiency

The endocytic receptor cubam formed by the 460-kDa protein cubilin and the 45-kDa transmembrane protein amnionless (AMN), is essential for intestinal vitamin B

Topics: Albumins; Amino Acid Sequence; Anemia, Megaloblastic; Animals; CHO Cells; Cricetulus; Crystallography, X-Ray; Humans; Intestinal Mucosa; Kidney; Malabsorption Syndromes; Membrane Proteins; Mutation; Protein Binding; Protein Conformation; Proteins; Proteinuria; Receptors, Cell Surface; Sequence Homology, Amino Acid; Vitamin B 12; Vitamin B 12 Deficiency

Three Komondor dogs in a small family and 3 sporadic cases exhibited a constellation of signs that included juvenile-onset of failure-to-thrive, inappetence, vomiting and/or diarrhea, and weakness. In each we documented dyshematopoiesis, increased anion gap, methylmalonic acidemia/-uria, and serum cobalamin deficiency. Urine protein electrophoresis demonstrated excretion of cubam ligands. All clinical signs and metabolic abnormalities, except proteinuria, were reversed by regular parenteral cobalamin administration. The pattern of occurrence and findings in the disorder suggested an autosomal recessive inheritance of cobalamin malabsorption with proteinuria, a condition in humans called Imerslund-Gräsbeck syndrome. The purpose of this study was to determine the molecular cause of this disorder in Komondors.. Whole genome sequencing of two affected Komondor dogs of unknown relatedness and one parent and a clinically-normal littermate of an affected dog revealed a pathogenic single-base change in the CUBN intron 55 splice donor consensus sequence (NM_001003148.1: c.8746 + 1G > A) that was homozygous in affected dogs and heterozygous in the unaffected parents. Alleles of the variant co-segregated with alleles of the disease locus in the entire family and all more distantly-related sporadic cases. A population study using a simple allele-specific DNA test indicated mutant allele frequencies of 8.3 and 4.5% among North American and Hungarian Komondors, respectively.. DNA testing can be used diagnostically in Komondors when clinical signs are suggestive of cobalamin deficiency or to inform Komondor breeders prospectively and prevent occurrence of future affected dogs. This represents the third cubilin variant causing inherited selective cobalamin malabsorption in a large animal ortholog of human Imerslund-Gräsbeck syndrome.

Topics: Anemia, Megaloblastic; Animals; Breeding; Dog Diseases; Dogs; Female; Genotype; Malabsorption Syndromes; Male; Protein Isoforms; Proteinuria; Receptors, Cell Surface; United States; Vitamin B 12; Vitamin B 12 Deficiency; Whole Genome Sequencing

Homocysteine metabolism is altered in children with idiopathic nephrotic syndrome. Hyperhomocysteinemia is a risk factor of early atherosclerosis and glomerulosclerosis and may occur at time of first occurrence of idiopathic nephrotic syndrome.. Thirty children with first episode of idiopathic nephrotic syndrome (FENS) aged 1-16 years along with 30 age- and sex-matched healthy controls were enrolled in this study. Homocysteine and cysteine were measured with HPLC; vitamin B12 and folic acid were measured with electro-chemilumiscence immunoassay. Primary outcome measure was plasma homocysteine level in children with FENS and in controls. Secondary outcome measures were (1) plasma and urine homocysteine and cysteine levels in children with FENS at 12 weeks and 1 year (remission) and (2) plasma and urine levels of vitamin B12 and folic acid in children with FENS, at 12 weeks and 1 year (remission).. Plasma homocysteine and cysteine levels were comparable to controls in children with FENS, at 12 weeks and 1-year remission. Plasma levels of vitamin B12 and folic acid were significantly decreased compared to controls in FENS due to increased urinary excretion, which normalize during remission at 12 weeks and 1 year. Urinary homocysteine and cysteine levels were significantly raised in FENS compared to controls and continued to be raised even at 12-week and 1-year remission.. Homocysteine metabolism is deranged in children with FENS. Renal effects of long-term raised urinary homocysteine levels need to be studied.

Topics: Case-Control Studies; Child; Cholesterol; Cysteine; Demography; Female; Folic Acid; Homocysteine; Humans; Male; Nephrotic Syndrome; Proteinuria; Remission Induction; Serum Albumin; Vitamin B 12

Cobalamin malabsorption accompanied by selective proteinuria is an autosomal recessive disorder known as Imerslund-Gräsbeck syndrome in humans and was previously described in dogs due to amnionless (AMN) mutations. The resultant vitamin B12 deficiency causes dyshematopoiesis, lethargy, failure to thrive, and life-threatening metabolic disruption in the juvenile period. We studied 3 kindreds of border collies with cobalamin malabsorption and mapped the disease locus in affected dogs to a 2.9Mb region of homozygosity on canine chromosome 2. The region included CUBN, the locus encoding cubilin, a peripheral membrane protein that in concert with AMN forms the functional intrinsic factor-cobalamin receptor expressed in ileum and a multi-ligand receptor in renal proximal tubules. Cobalamin malabsorption and proteinuria comprising CUBN ligands were demonstrated by radiolabeled cobalamin uptake studies and SDS-PAGE, respectively. CUBN mRNA and protein expression were reduced ~10 fold and ~20 fold, respectively, in both ileum and kidney of affected dogs. DNA sequencing demonstrated a single base deletion in exon 53 predicting a translational frameshift and early termination codon likely triggering nonsense mediated mRNA decay. The mutant allele segregated with the disease in the border collie kindred. The border collie disorder indicates that a CUBN mutation far C-terminal from the intrinsic factor-cobalamin binding site can abrogate receptor expression and cause Imerslund-Gräsbeck syndrome.

Topics: Anemia, Megaloblastic; Animals; Dogs; Exons; Female; Frameshift Mutation; Gene Expression Regulation; Humans; Ileum; Kidney; Malabsorption Syndromes; Male; Protein Binding; Proteinuria; Receptors, Cell Surface; RNA Stability; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Anemia, Megaloblastic; Child, Preschool; Female; Foot; Hand; Humans; Hyperpigmentation; Malabsorption Syndromes; Proteinuria; Vitamin B 12; Vitamin B 12 Deficiency

The Imersland-Gräsbeck Syndrome (IGS) is a rare inherited disorder characterized by megaloblastic anemia due to a selective Vitamin B₁₂ malabsorption in association with mild proteinuria. This syndrome can be diagnosed and treated easily. Herein, we describe an infant with IGS as a rare etiology of growth retardation with diarrhea, vomiting and therapy-resistant proteinuria.

Topics: Anemia, Megaloblastic; Diarrhea, Infantile; Growth Disorders; Humans; Infant; Malabsorption Syndromes; Male; Proteinuria; Recurrence; Respiratory Tract Infections; Treatment Outcome; Vitamin B 12; Vitamin B 12 Deficiency; Vitamin B Complex; Vomiting

Inborn errors of cobalamin (Cbl, vitamin B(12)) absorption include hereditary intrinsic factor deficiency (HIFD) and Imerslund-Gräsbeck disease (IGD). HIFD is secondary to mutations in the HIF gene while IGD is due to mutations in one of the 2 subunits of the intrinsic factor receptor that is cubilin (CUBN) or amnionless (AMN). These disorders lead to intracellular Cbl depletion which in turn causes megaloblastic bone marrow failure, accumulation of homocysteine and methylmalonic acid (MMA), and methionine depletion. The clinical presentation reflects Cbl deficiency, with gastrointestinal symptoms, pancytopenia, and megaloblastic anemia. Mixed proteinuria, when it is present is strongly suggestive of IGD. Accurate diagnosis is always an emergency because early detection and treatment with life-long parenteral pharmacological doses of hydroxocobalamin are life saving and prevent further deterioration. However, the optimal frequency for cobalamin injections as a maintenance therapy is poorly reported. In order to evaluate the optimal maintenance schedule of cobalamin injections, we retrospectively collected clinical, biological, molecular and treatment data on 7 patients affected with congenital Cbl malabsorption. Unlike previous recommendations, we showed that a maintenance dosage of 1 mg cobalamin twice a year was enough to ensure a normal clinical status and keep the hematological and metabolic parameters in the normal range. These data suggest that patients affected with inborn errors of cobalamin absorption may be safely long-term treated with cobalamin injections every 6 months with careful follow-up of hematological and metabolic parameters. This maintenance regime is beneficial because the patients' quality of life improves.

Topics: Anemia, Megaloblastic; Child; Child, Preschool; Female; Genotype; Humans; Infant; Injections; Malabsorption Syndromes; Male; Membrane Proteins; Mutation; Proteins; Proteinuria; Treatment Outcome; Vitamin B 12; Vitamin B 12 Deficiency

Inherited malabsorption of cobalamin (Cbl) causes hematological and neurological abnormalities that can be fatal. Three genes have been implicated in Cbl malabsorption; yet, only about 10% of ~400-500 reported cases have been molecularly studied to date. Recessive mutations in CUBN or AMN cause Imerslund-Gräsbeck Syndrome (IGS), while recessive mutations in GIF cause Intrinsic Factor Deficiency (IFD). IGS and IFD differ in that IGS usually presents with proteinuria, which is not observed in IFD. The genetic heterogeneity and numerous differential diagnoses make clinical assessment difficult.. We present a large genetic screening study of 154 families or patients with suspected hereditary Cbl malabsorption. Patients and their families have been accrued over a period spanning >12  years. Systematic genetic testing of the three genes CUBN, AMN, and GIF was accomplished using a combination of single strand conformation polymorphism and DNA and RNA sequencing. In addition, six genes that were contenders for a role in inherited Cbl malabsorption were studied in a subset of these patients.. Our results revealed population-specific mutations, mutational hotspots, and functionally distinct regions in the three causal genes. We identified mutations in 126/154 unrelated cases (82%). Fifty-three of 126 cases (42%) were mutated in CUBN, 45/126 (36%) were mutated in AMN, and 28/126 (22%) had mutations in GIF. We found 26 undescribed mutations in CUBN, 19 in AMN, and 7 in GIF for a total of 52 novel defects described herein. We excluded six other candidate genes as culprits and concluded that additional genes might be involved.. Cbl malabsorption is found worldwide and genetically complex. However, our results indicate that population-specific founder mutations are quite common. Consequently, targeted genetic testing has become feasible if ethnic ancestry is considered. These results will facilitate clinical and molecular genetic testing of Cbl malabsorption. Early diagnosis improves the lifelong care required by these patients and prevents potential neurological long-term complications. This study provides the first comprehensive overview of the genetics that underlies the inherited Cbl malabsorption phenotype.

Topics: Anemia, Megaloblastic; Ethnicity; Female; Founder Effect; Genetic Association Studies; Genetic Heterogeneity; Genetic Testing; Humans; Intrinsic Factor; Malabsorption Syndromes; Male; Membrane Proteins; Mutation; Proteins; Proteinuria; Vitamin B 12; Vitamin B 12 Deficiency

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.. 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.. 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).. 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.

Topics: Anemia, Megaloblastic; Humans; Malabsorption Syndromes; Male; Membrane Proteins; Middle Aged; Mutation; Proteins; Proteinuria; Treatment Outcome; Vitamin B 12; Vitamin B 12 Deficiency

Derivatives of cobalamin (vitamin B(12)) are required for activity of two enzymes in humans. Adenosylcobalamin is required for activity of mitochondrial methylmalonylCoA mutase and methylcobalamin is required for activity of cytoplasmic methionine synthase. Deficiency in cobalamin, or inability to absorb cobalamin normally, can result in accumulation of methylmalonic acid and homocysteine in blood and urine. Methylmalonic acidemia can result in metabolic acidosis which in severe cases may be fatal. Hyperhomocysteinemia along with hypomethioninemia can result in hematologic (megaloblastic anemia, neutropenia, thrombocytopenia) and neurologic (subacute combined degeneration of the cord, dementia, psychosis) defects. Inborn errors affecting cobalamin absorption (inherited intrinsic factor deficiency, Imerslund–Gra¨ sbeck syndrome) and transport (transcobalamin deficiency) have been described. A series of inborn errors of intracellular cobalamin metabolism, designated cblA-cblG, have been differentiated by complementation analysis. These can give rise to isolated methylmalonic acidemia (cblA, cblB, cblD variant 2), isolated hyperhomocysteinemia (cblD variant 1, cblE, cblG) or combined methylmalonic acidemia and hyperhomocysteinemia (cblC, classic cblD, cblF). All these disorders are inherited as autosomal recessive traits. The genes underlying each of these disorders have been identified. Two other disorders, haptocorrin deficiency and transcobalamin receptor deficiency, have been described, but it is not clear that they have any consistent clinical phenotype.

Topics: Amino Acid Metabolism, Inborn Errors; Anemia, Megaloblastic; Cobamides; Homocysteine; Humans; Hyperhomocysteinemia; Infant, Newborn; Malabsorption Syndromes; Metabolism, Inborn Errors; Methylmalonic Acid; Methylmalonyl-CoA Mutase; Neonatal Screening; Proteinuria; Vitamin B 12; Vitamin B 12 Deficiency

Receptor-mediated endocytosis is responsible for protein reabsorption in the proximal tubule. This process involves two interacting receptors, megalin and cubilin, which form a complex with amnionless. Whether these proteins function in parallel or as part of an integrated system is not well understood. Here, we report the renal effects of genetic ablation of cubilin, with or without concomitant ablation of megalin, using a conditional Cre-loxP system. We observed that proximal tubule cells did not localize amnionless to the plasma membrane in the absence of cubilin, indicating a mutual dependency of cubilin and amnionless to form a functional membrane receptor complex. The cubilin-amnionless complex mediated internalization of intrinsic factor-vitamin B12 complexes, but megalin considerably increased the uptake. Furthermore, cubilin-deficient mice exhibited markedly decreased uptake of albumin by proximal tubule cells and resultant albuminuria. Inactivation of both megalin and cubilin did not increase albuminuria, indicating that the main role of megalin in albumin reabsorption is to drive the internalization of cubilin-albumin complexes. In contrast, cubulin deficiency did not affect urinary tubular uptake or excretion of vitamin D-binding protein (DBP), which binds cubilin and megalin. In addition, we observed cubilin-independent reabsorption of the "specific" cubilin ligands transferrin, CC16, and apoA-I, suggesting a role for megalin and perhaps other receptors in their reabsorption. In summary, with regard to albumin, cubilin is essential for its reabsorption by proximal tubule cells, and megalin drives internalization of cubilin-albumin complexes. These genetic models will allow further analysis of protein trafficking in the progression of proteinuric renal diseases.

Topics: Absorption; Albumins; Animals; Disease Models, Animal; DNA-Binding Proteins; Integrases; Kidney Tubules, Proximal; Low Density Lipoprotein Receptor-Related Protein-2; Mice; Mice, Inbred C57BL; Mice, Knockout; Proteinuria; Receptors, Cell Surface; Transcription Factors; Vitamin B 12

cblC disease is a cause of hemolytic uremic syndrome (HUS), which has been primarily described in neonates and infants with severe renal and neurological lesions.. Two sisters aged 6 and 8.5 years presented with a latent hemolytic process characterized by undetectable or low plasma haptoglobin, respectively, associated with renal failure and gross proteinuria. Renal biopsies performed in both patients found typical findings of thrombotic microangiopathy suggesting the diagnosis of HUS. Both patients were free of neurologic signs.. Biochemical investigations found a cobalamin processing deficiency of the cblC type. Search for additional factors susceptible to worsen endothelial damage revealed homozygosity 677C--> T mutation in the methylenetetrahydrofolate reductase gene as well as heterozygosity for a 3254T--> C mutation in factor H in the patient with the most severe clinical presentation. Long-term subcutaneous administration of hydroxocobalamin in combination with oral betaine and folic acid resulted in clinical and biological improvement in both patients.. cblC disease may be a cause of chronic HUS with delayed onset in childhood. Superimposed mutation of factor H gene might influence clinical severity.

Topics: Anemia; Betaine; Child; Combined Modality Therapy; Complement Factor H; Drug Therapy, Combination; Endothelium, Vascular; Female; Folic Acid; Genetic Predisposition to Disease; Genotype; Haptoglobins; Hemolytic-Uremic Syndrome; Humans; Hydroxocobalamin; Hypertension; Kidney; Methylenetetrahydrofolate Reductase (NADPH2); Mutation, Missense; Nephrotic Syndrome; Plasma Exchange; Point Mutation; Proteinuria; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-cbl; Renal Dialysis; Vitamin B 12

Patients with diabetic nephropathy are at elevated cardiovascular risk. C-reactive protein (CRP) has been used to successfully predict cardiovascular events.. We identified clinical and biochemical characteristics that correlate with CRP levels in diabetic nephropathy patients.. Baseline data obtained from 722 patients in the Irbesartan Diabetic Nephropathy Trial included age, sex, body mass index (BMI), systolic blood pressure (BP), serum creatinine, plasma low- and high-density cholesterol, triacylglycerol, serum albumin, hemoglobin A1C, 24h urinary protein excretion, plasma total homocysteine (tHcy), folate, B12, pyridoxal 5'-phosphate (PLP, active form of Vitamin B(6)), and plasma CRP levels.. In univariate analyses CRP was positively associated with female sex (r=0.08; P=0.04), BMI (r=0.34; P<0.01), serum creatinine (r=0.21; P<0.01), hemoglobin A1C (r=0.08; 0.04), and inversely associated with PLP (r=-0.17; P<0.01) and folate (r=-0.09; P=0.02). A stepwise multiple regression model found CRP directly correlated with BMI (P<0.01) and serum creatinine (P<0.01), and inversely correlated with PLP (P<0.01). The final model explained 16% of the total variance of CRP.. These results extend previous findings of an inverse relationship between Vitamin B(6) and CRP. The lack of association between CRP and certain established or emerging cardiovascular risk factors offers novel information regarding cardiovascular risk in this population.

Topics: Adult; Aged; Blood Pressure; Body Mass Index; C-Reactive Protein; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Creatinine; Depsipeptides; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Folic Acid; Glycated Hemoglobin; Humans; Male; Middle Aged; Peptides, Cyclic; Proteinuria; Pyridoxal Phosphate; Risk Factors; Serum Albumin; Triglycerides; Vitamin B 12

Conflicting data have been reported concerning the independent association between proteinuria and plasma total homocysteine (tHcy) levels, particularly among chronic renal disease (CRD) patients with a normal range serum creatinine. Studies of this potential relationship have been limited by failure to assess true GFR, failure to assess proteinuria in a quantitative manner, or arbitrary restriction of the range of proteinuria examined. We examined the potential independent relationship between plasma tHcy levels and a wide range of quantitatively determined proteinuria (i.e., 0.000-8.340 g/day), among 109 CRD patients with a normal range serum creatinine (range; 0.8-1.5 mg/dl; median=1.2 mg/dl). Glomerular filtration rate (GFR) was directly assessed by iohexol clearance, and plasma status of folate, pyridoxal 5'-phosphate, and B12, along with serum albumin, were also determined. Linear modeling with ANCOVA revealed that proteinuria was not independently associated with tHcy levels (partial R=0.127; P=0.201), after adjustment for potential confounding by GFR (partial R=0.408; P<0.001), age, sex, plasma B-vitamin status, and serum albumin. Moreover, descending across quartiles (Q) [from Q4 to Q1] of GFR, ANCOVA-adjusted (i.e., for age, sex, and folate status) geometric mean tHcy levels (micromol/l) were significantly increased: tHcy Q4 GFR=9.6; tHcy Q3 GFR=10.5; tHcy Q2 GFR=11.9; tHcy Q4 GFR=14.5; P<0.001 for overall Q difference. We conclude that across a broad spectrum of quantitatively determined proteinuria, after adjustment for true GFR, in particular, there is no independent relationship between proteinuria and tHcy levels among CRD patients with a normal range serum creatinine.

Topics: Adult; Aged; Chronic Disease; Creatinine; Female; Folic Acid; Glomerular Filtration Rate; Homocysteine; Humans; Kidney; Kidney Diseases; Male; Middle Aged; Proteinuria; Pyridoxal Phosphate; Serum Albumin; Vitamin B 12

Cubilin is a high molecular weight multiligand receptor that mediates intestinal absorption of intrinsic factor-cobalamin and selective protein reabsorption in renal tubules. The genetic basis of selective intestinal cobalamin malabsorption with proteinuria was investigated in a canine model closely resembling human Imerslund-Gräsbeck syndrome caused by cubilin mutations. Canine CUBN cDNA was cloned and sequenced, showing high identity with human and rat CUBN cDNAs. An intragenic CUBN marker was identified in the canine family and used to test the hypothesis of genetic linkage of the disease and CUBN loci. Linkage was rejected, indicating that the canine disorder resembling Imerslund-Gräsbeck syndrome is caused by defect of a gene product other than cubilin. These results imply that there may be locus heterogeneity among human kindreds with selective intestinal cobalamin malabsorption and proteinuria and that normal brush-border expression of cubilin requires the activity of an accessory protein.

Topics: Amino Acid Sequence; Animals; DNA, Complementary; Dogs; Female; Genetic Predisposition to Disease; Humans; Intestinal Absorption; Intrinsic Factor; Male; Microvilli; Molecular Sequence Data; Proteinuria; Receptors, Cell Surface; Vitamin B 12

Gräsbeck-Imerslund disease (congenital familial selective vitamin B12-malabsorption with proteinuria, MGA1, MIM No. 261100) is a rare disorder displaying autosomal recessive inheritance. This study was designed to investigate the usefulness of measuring the activity of the urinary receptor for the intrinsic factor-cobalamin complex as a tool to diagnose this disease.. The receptor activity was measured by a radioisotope-binding assay, using phenyl-Sepharose gel as the adsorbant solid phase of the receptor.. In 10 Finnish patients, urinary receptor activity was on the average 640 times (15-1400 times) lower than that in 13 healthy control subjects: mean values of 0.1 nmol/mol (range, 0.01-0.32 nmol/mol) and 6.4 nmol/mol (range, 3.8-12.4 nmol/mol) creatinine, respectively. The mean value of urinary receptor activity in 11 first-degree, healthy relatives of the patients was 4.6 nmol/mol (range, 1.1-10.4 nmol/mol) creatinine, a difference from levels in control subjects that is not statistically significant. When the first-degree relatives were divided into heterozygotes (parents and siblings heterozygous for the haplotype of genetic markers associated with the disease gene) and wild-type homozygotes (siblings not displaying the disease haplotype), no difference was seen.. Determination of receptor activity in the urine is a highly accurate method for diagnosis of Gräsbeck-Imerslund disease at an early stage, but it does not detect carriers of the disorder.

Topics: Absorption; Adult; Aged; Anemia, Megaloblastic; Finland; Heterozygote; Humans; Middle Aged; Proteinuria; Radioligand Assay; Receptors, Cell Surface; Vitamin B 12; Vitamin B 12 Deficiency

Imerslund syndrome, a recessive autosomal disease, initially described by Imerslund and Grasbeck in 1960, associates megaloblastic anemia and proteinuria.. We report on six cases, studied in five different families. All patients (mean age: 3.5 years) had clinical symptoms of anemia, three had malabsorption, proteinuria was present in five, at the time of diagnosis. Hemogram and decreased serum vitamin B12 levels were consistent with the diagnosis in all cases. Intra-muscular injections of cyanocobalamine was instituted on a life-time basis and the long term prognosis is good.. The diagnosis should be evoked when the three typical features are present: macrocytic anemia, decreased serum B12 level and proteinuria. It will be confirmed by the bone marrow megaloblastic aspects and the Schilling test findings.

Topics: Anemia, Megaloblastic; Child; Child, Preschool; Hematinics; Humans; Infant; Proteinuria; Vitamin B 12

Two brothers in a Chinese family with selective malabsorption of vitamin B12 associated with proteinuria (Imerslund-Grasbeck syndrome) presented with widespread mottled skin pigmentation, termed poikiloderma. In contrast to anaemia, this pigmentary disturbance remained unresponsive to vitamin B12 replacement. This is different from the reported hyperpigmentation sometimes seen in vitamin B12 deficiency which is reversible following treatment. As far as is known, an irreversible and persistent skin disorder has not been reported in this syndrome before.

Topics: Adult; Humans; Malabsorption Syndromes; Male; Pigmentation Disorders; Proteinuria; Skin Pigmentation; Syndrome; Vitamin B 12

The Imerslund-Gräsbeck syndrome (IGS) is a rare inherited disorder characterized by a megaloblastic anemia due to a selective vitamin B12 malabsorption in association with a mild proteinuria. Usually recurrent infections, gastrointestinal complaints, and pallor are presenting symptoms. We report two cases of IGS with an unusual presentation.. Two girls are described with the Imerslund-Gräsbeck syndrome who had a failure to thrive as a presenting symptom without infections or gastrointestinal complaints. The diagnosis of IGS was based on marked macrocytic anemia, very low serum vitamin B12 levels, abnormal Schilling urinary excretion test results, and mild proteinuria. When parenteral vitamin B12 was started, a rapid catch-up growth was seen in both girls.. The absence of well-known causes of failure to thrive, such as recurrent infections and gastrointestinal complaints, favors the concept that the metabolic disturbances caused by an isolated cobalamin deficiency as seen in IGS causes a failure to thrive.

Topics: Anemia, Megaloblastic; Failure to Thrive; Female; Humans; Infant; Proteinuria; Syndrome; Vitamin B 12; Vitamin B 12 Deficiency

Imerslund-Najman-Grasbeck disease is a rare inherited megaloblastic anaemia secondary to a selective malabsorption of vitamin B12 by ileal enterocytes. The authors report on a 4 year-old tunisian girl who presented as visceral infantile leishmaniasis because of huge splenomegaly and major anaemia. The diagnosis of Imerslund disease was performed on the basis of the association of typical megaloblastic cells in the marrow, permanent proteinuria and favourable outcome under parenteral B12 administration. In addition, ther were no folate deficiency, no anti-intrinsic factor antibodies and no intrinsic factor deficiency. The outcome of the disease is always favourable if parenteral administration of vitamin B12 maintained.

Topics: Anemia, Megaloblastic; Child, Preschool; Female; Humans; Malabsorption Syndromes; Proteinuria; Vitamin B 12; Vitamin B 12 Deficiency

The authors present a case of Imerslund-Gräsbeck syndrome, i. e. a familial megaloblastic anemia with proteinuria. The disease is due to congenital, selective malabsorption of vitamin B12. The subnormal absorption of vitamin B12 is not altered by orally given intrinsic factor, but parenteral vitamin B12 therapy results in complete recovery. Approximately 150 cases have been described in literature, the authors' case is the first in Hungary.

Topics: Anemia, Megaloblastic; Child, Preschool; Female; Humans; Malabsorption Syndromes; Proteinuria; Syndrome; Vitamin B 12

Vitamin B12 malabsorption in the ileum has been postulated as the underlying cause of the Imerslund-Grasbeck syndrome comprising megaloblastic anemia, proteinuria, and multiple neurological abnormalities. A young Saudi child with spasticity, truncal ataxia, cerebral atrophy, megaloblastic anaemia and proteinuria is described. Replacement therapy with parenteral vitamin B12 resulted in the complete resolution of his neurological findings and brain atrophy.

Topics: Anemia, Megaloblastic; Atrophy; Brain Diseases; Cerebral Cortex; Child, Preschool; Humans; Male; Proteinuria; Syndrome; Tomography, X-Ray Computed; Vitamin B 12; Vitamin B 12 Deficiency

Imerslund syndrome is a rare autosomal recessive disorder of megaloblastic anemia as a result of selective vitamin B12 malabsorption associated with proteinuria. An Arabic Muslim family is described, with three children who had inherited selective vitamin B12 malabsorption with proteinuria. Dolichocephaly was noted in all the male children of this family in association with congenital megaloblastic anemia and proteinuria. The findings of this anemia are compatible with Imerslund-Gräsbeck syndrome, and coexistence of this syndrome with dolichocephaly in a single family has not been previously reported.

Topics: Anemia, Megaloblastic; Consanguinity; Ethnicity; Female; Humans; Hypophosphatemia, Familial; Infant; Israel; Malabsorption Syndromes; Male; Proteinuria; Skull; Vitamin B 12; Vitamin B 12 Deficiency

Immerslund-Grasbeck syndrome is an uncommon disease, characterized by megaloblastic anaemia and persistent proteinuria. A Libyan boy with the characteristic findings is presented. He received intramuscular vitamin B12 injections and there followed a remarkable clinical and haematological improvement.

Topics: Anemia, Macrocytic; Anemia, Megaloblastic; Child; Humans; Libya; Male; Proteinuria; Syndrome; Vitamin B 12

Topics: Adolescent; Anemia, Macrocytic; Follow-Up Studies; Humans; Intestinal Absorption; Intrinsic Factor; Lymphangiectasis, Intestinal; Malabsorption Syndromes; Male; Protein-Losing Enteropathies; Proteinuria; Vitamin B 12; Vitamin B 12 Deficiency

A Syrian family is described with three children who had inherited selective vitamin B12 malabsorption associated with proteinuria. (Imerslund-Grasbeck syndrome). Although inherited the defect was apparently not present at birth. A third child had less severe vitamin B12 malabsorption, was not vitamin B12 deficient and had no proteinuria. Studies on two of the affected children with subcellular fractionation of the uptake of radioactive vitamin B12 by ileal tissue in vivo indicate a defect in the ileal receptors for IF-bound vitamin B12. These findings are different from the single in vitro experiment on a patient with this condition that has been previously reported.

Topics: Adolescent; Adult; Anemia, Megaloblastic; Child; Child, Preschool; Humans; Ileum; Infant; Malabsorption Syndromes; Male; Proteinuria; Subcellular Fractions; Syndrome; Vitamin B 12

A 7-month-old boy presented with vomiting and failure to thrive associated with proteinuria, methylmalonic aciduria and macrocytosis, but without anaemia. Plasma vitamin B12 levels were normal by a radio-dilution method. He was treated as an inborn error of metabolism with intramuscular cyanocobalamin and a low protein diet. However when treatment was withdrawn he remained well for 11 months before relapsing with vomiting and weight loss. Re-investigation again showed methylmalonic aciduria, but the haemoglobin was low and plasma vitamin B12 levels by a specific method showed them to be reduced. Studies of vitamin B12 absorption showed the picture of selective malabsorption. He was started on regular cyanocobalamin injections.

Topics: Child, Preschool; Dietary Proteins; Humans; Infant; Malabsorption Syndromes; Male; Methylmalonic Acid; Proteinuria; Vitamin B 12

A follow-up study has been performed on 14 patients, now aged 6-46 years, with Imerslund-Gräsbeck anemia (congenital, hereditary selective malasorption of vitamin B12). On intramuscular vitamin B12 therapy, the patients are clinically and hematologically normal. Those who had constant proteinuria in childhood continue to excrete protein in the urine. Our patients excrete an average of 750 mg of protein per 24 hours (range 13-1460 mg). The proteinuria is predominantly of glomerular origin, but some is also of tubular origin. Renal biopsies of the two oldest patients were normal on light microscopy. Electron microscopy revealed moderate signs of chronic glomerulopathy of mesangioproliferative type in both patients. The renal lesions do not seem to be progressive.

Topics: Adolescent; Adult; Anemia, Macrocytic; Child; Chronic Disease; Female; Follow-Up Studies; Humans; Kidney; Kidney Function Tests; Male; Middle Aged; Prognosis; Proteinuria; Recurrence; Syndrome; Vitamin B 12

Topics: Anemia, Megaloblastic; Child, Preschool; Female; Humans; Malabsorption Syndromes; Proteinuria; Vitamin B 12

We examined the effect of methyl-B12 on the immune system. As a result, it was revealed that methyl-B12 enhanced antibody production in the in vitro system and that this activity was the strongest with methyl-B12 among the homologues of B12 examined, being nearly as strong as that of Levamisole. It was also revealed that methyl-B12 can exert an enhancing activity on the induction of suppressor T cells Con A. These facts suggest that methyl-B12 has a therapeutic effect against spontaneous incidence of diseases in NZA/W mice. These immunomodulative activities of methyl-B12 and their therapeutic significance against immune disorders were discussed.

Topics: Animals; Antibody Formation; Antibody-Producing Cells; Cell Survival; Concanavalin A; Female; Hemolytic Plaque Technique; Levamisole; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Inbred NZB; Proteinuria; Sheep; Spleen; T-Lymphocytes, Regulatory; Vitamin B 12

Topics: Anemia, Macrocytic; Anemia, Megaloblastic; Child, Preschool; Female; Humans; Infant; Malabsorption Syndromes; Male; Proteinuria; Vitamin B 12

Topics: Anemia, Macrocytic; Anemia, Megaloblastic; Child; Child, Preschool; Female; Humans; Infant; Malabsorption Syndromes; Proteinuria; Syndrome; Vitamin B 12; Vitamin B 12 Deficiency

Renal biopsy material obtained from a 6 year old girl suffering from an Imerslund-Najman-Gräsbeck-syndrome was examined by light- and electron-microscopy. Clinically the patient presented the characteristic intrinsic factor independent vitamin B12 malabsorption with severe megaloblastic anemia and a benign nephropathy with non-selective proteinuria. Electron microscopic examination of the prenal glomeruli showed no obvious alterations of the Electron microscopic examination of the renal glomeruli showed no obvious alterations of the capillary basement membranes but revealed a considerable diffuse dilatation of the rough endoplasmic reticulum in the podocytes with accumulation of a finely fibrillar material within the widened cisternae. This finding is interpreted as an indication that the synthesis and/or secretory activities of the podocytes, as far as the basement membrane is concerned, and thus the basement membranes themselves, may be altered with the consequence of an increased permeability of the filtration barrier. Because proteinurie contrary to anemia did not respond to parenteral vitamin B12 therapy and therefore is obviously not vitamin B12 dependent, it is assumed that both vitamin B12 malabsorption and glomerulopathy in this hereditary disease are established by a pleiotropic gene or two closely associated genes.

Topics: Anemia, Macrocytic; Anemia, Megaloblastic; Child; Female; Humans; Kidney Glomerulus; Malabsorption Syndromes; Microscopy, Electron; Proteinuria; Syndrome; Vitamin B 12

Topics: Anemia, Macrocytic; Anemia, Megaloblastic; Child; Child, Preschool; Female; Humans; Infant; Male; Proteinuria; Syndrome; Vitamin B 12

Topics: Adrenal Gland Neoplasms; Adult; Binding Sites; Cells, Cultured; Centrifugation; Cobalt Radioisotopes; Dialysis; Female; Granulocytes; Hodgkin Disease; Humans; Leukemia, Lymphoid; Leukemia, Myeloid; Leukocytes; Lung Neoplasms; Male; Melanoma; Multiple Myeloma; Protein Binding; Proteinuria; Pyelonephritis; Time Factors; Vitamin B 12

Topics: Alanine; Amino Acids; Anemia, Macrocytic; Child; Chromatography, Gas; Glycine; Hemoglobins; Histidine; Humans; Isoleucine; Leucine; Malabsorption Syndromes; Male; Malonates; Methionine; Proteinuria; Renal Tubular Transport, Inborn Errors; Reticulocytes; Serine; Taurine; Threonine; Tyrosine; Valine; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Alkaline Phosphatase; Bile; Blood Proteins; Carcinoma; Cerebrospinal Fluid Proteins; Chemistry, Clinical; Gastric Juice; Humans; Immunoglobulins; Intrinsic Factor; Isoelectric Focusing; Isoenzymes; Kidney Cortex; Kidney Medulla; Kidney Neoplasms; Methods; Multiple Sclerosis; Nephrotic Syndrome; Nerve Tissue Proteins; Proteinuria; Vitamin B 12

Topics: Adult; Anemia, Sideroblastic; Bone Marrow Cells; Bone Marrow Examination; Erythropoiesis; Erythropoietin; Exchange Transfusion, Whole Blood; Folic Acid; Humans; Iron; Isoniazid; Lupus Erythematosus, Systemic; Male; Megakaryocytes; Prednisone; Proteinuria; Pyridoxine; Vitamin B 12

Topics: Adolescent; Anemia, Macrocytic; Humans; Immunologic Deficiency Syndromes; Intrinsic Factor; Malabsorption Syndromes; Male; Proteinuria; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Adolescent; Anemia, Pernicious; Binding Sites; Biopsy; Child; Gastric Juice; Humans; Ileum; Intestinal Absorption; Intestinal Mucosa; Intrinsic Factor; Malabsorption Syndromes; Male; Microscopy, Electron; Proteinuria; Vitamin B 12

Topics: Anemia, Macrocytic; Humans; Infant; Infant Nutrition Disorders; Malabsorption Syndromes; Male; Proteinuria; Syndrome; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Adolescent; Anemia, Macrocytic; Bone Marrow Examination; Female; Gastric Juice; Humans; Hydrochloric Acid; Infant; Intrinsic Factor; Kidney Function Tests; Malabsorption Syndromes; Male; Proteinuria; Schilling Test; Vitamin B 12

Topics: Albuminuria; Anemia, Macrocytic; Body Height; Body Weight; Child, Preschool; Female; Humans; Intestinal Absorption; Proteinuria; Schilling Test; Thrombocytopenia; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Adult; Anemia, Pernicious; Autoantibodies; Biological Assay; Gastric Juice; Humans; Intestinal Absorption; Intrinsic Factor; Male; Proteinuria; Schilling Test; Vitamin B 12

Topics: Anemia, Macrocytic; Blood Transfusion; Child; Child, Preschool; Cobalt Isotopes; Folic Acid; Humans; Leukopenia; Malabsorption Syndromes; Male; Myelitis; Proteinuria; Schilling Test; Thrombocytopenia; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Adolescent; Adult; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Male; Metabolism, Inborn Errors; Proteinuria; Vitamin B 12

Topics: Adolescent; Adult; Anemia, Macrocytic; Child, Preschool; Female; Humans; Intestinal Absorption; Male; Proteinuria; Schilling Test; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Adult; Anemia, Pernicious; Child; Child, Preschool; Chromosome Aberrations; Chromosome Disorders; Diagnosis, Differential; Female; Humans; Ileum; Intestinal Absorption; Intrinsic Factor; Jejunum; Kidney; Male; Proteinuria; Urogenital Abnormalities; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Anemia, Macrocytic; Humans; Infant; Malabsorption Syndromes; Male; Peptide Hydrolases; Proteinuria; Schilling Test; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Anemia; Anemia, Pernicious; Diagnosis, Differential; Humans; Intestinal Absorption; Intrinsic Factor; Metabolism; Proteinuria; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Anemia, Pernicious; Child; Child, Preschool; Female; Humans; Infant; Male; Metabolic Diseases; Proteinuria; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Anemia; Anemia, Macrocytic; Child; Cobalt Isotopes; Genetics, Medical; Hematinics; Humans; Infant; Metabolism; Prednisone; Proteinuria; Tetracycline; Urine; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Anemia; Anemia, Megaloblastic; Child; Humans; Infant; Proteinuria; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Anemia, Pernicious; Corrinoids; Humans; Malabsorption Syndromes; Proteinuria; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Corrinoids; Humans; Malabsorption Syndromes; Proteinuria; Vitamin B 12; Vitamin B 12 Deficiency