Constitutional megaloblastic anemia due to vitamin B12 metabolism disorder
-Rare genetic disease
-Rare hematologic disease
Disorder of cobalamin metabolism and transport
-Rare genetic disease
Intestinal disease due to vitamin absorption anomaly
-Rare gastroenterologic disease
-Rare genetic disease
Nephropathy secondary to a storage or other metabolic disease
-Rare genetic disease
-Rare renal disease
Imerslund-Grasbeck syndrome is a form of congenital megaloblastic anemia due to vitamin B12 deficiency caused by a defect in the vitamin B12/intrinsic factor receptor. See also congenital pernicious anemia due to a defect in intrinsic factor (261000). ... Imerslund-Grasbeck syndrome is a form of congenital megaloblastic anemia due to vitamin B12 deficiency caused by a defect in the vitamin B12/intrinsic factor receptor. See also congenital pernicious anemia due to a defect in intrinsic factor (261000). Adult pernicious anemia (170900) is a distinct autoimmune disorder associated with plasma autoantibodies to gastric parietal cells or gastric intrinsic factor. In these cases, there is gastric atrophy and a relatively high frequency of associated thyroiditis and myxedema.
In 7 families previously diagnosed with Imerslund-Grasbeck syndrome due to inconclusive results on radiocobalamin absorption tests, but who were negative for mutations in the CUBN or the AMN gene, Tanner et al. (2005) identified homozygosity for 6 different ... In 7 families previously diagnosed with Imerslund-Grasbeck syndrome due to inconclusive results on radiocobalamin absorption tests, but who were negative for mutations in the CUBN or the AMN gene, Tanner et al. (2005) identified homozygosity for 6 different mutations in the GIF gene (609342.0002-609342.0007). Tanner et al. (2005) proposed that rather than radiocobalamin absorption tests, mutation analysis of the CUBN, AMN, and GIF genes may be the diagnostic method of choice for cobalamin absorption disorders.
Waters and Murphy (1963) reported 3 affected brothers. Both parents and 5 other sibs had subnormal or borderline vitamin B12 absorption. See also Lambert et al. (1961). Mollin et al. (1955) reported juvenile pernicious anemia in the offspring ... Waters and Murphy (1963) reported 3 affected brothers. Both parents and 5 other sibs had subnormal or borderline vitamin B12 absorption. See also Lambert et al. (1961). Mollin et al. (1955) reported juvenile pernicious anemia in the offspring of a first-cousin marriage. The father developed classic pernicious anemia in middle age. These may have been cases of congenital pernicious anemia due to a defect in intrinsic factor (261000). Grasbeck (1960) described pernicious anemia in association with proteinuria. Whereas a defect in production of intrinsic factor was postulated by the authors cited above, Grasbeck (1960) favored a selective defect in intestinal absorption of vitamin B12 in this disorder which was uninfluenced by administration of intrinsic factor. Proteinuria and malformation of the urinary tract were also present. Imerslund and Bjornstad (1963) and Lamy et al. (1961) reported on the syndrome of chronic relapsing megaloblastic anemia and permanent proteinuria. Mohamed et al. (1966) reported sisters with selective malabsorption of vitamin B12 with adequate gastric secretion of functionally competent intrinsic factor and hydrochloric acid. Persistent proteinuria appears to be an integral part of the syndrome (Mohamed et al., 1966). The latter authors gave a genetic analysis of published cases. In the oldest known patient, Goldberg and Fudenberg (1968) found normal amounts of biologically active intrinsic factor in the gastric juice and found neither antibodies to intrinsic factor nor inhibitors of intrinsic factor. The mechanism of defective absorption was unknown. MacKenzie et al. (1972) studied 3 brothers and found no morphologic abnormality of the ileal mucosa. There seems to be no defect in ileal receptors for the complex between intrinsic factor and B12; the defect appears to be located between the attachment of B12 to the surface of the ileal cell and the binding to transcobalamin II. On the other hand, Burman et al. (1985) described absence of functional receptor. It was inferred that there may be more than one nonallelic form of this disorder--a not surprising finding in light of the complexity of cobalamin absorption. In 1972 Grasbeck stated that 47 cases were known, of which 21 had been diagnosed in Finland. Nevanlinna (1980) stated that in Finland 27 cases in 17 sibships had been identified. Spurling et al. (1964) described 2 Baltimore sisters with this syndrome who had proteinuria. Their parents were fourth cousins. Urban et al. (1981) described 3 cases from 2 families with congenital B12 malabsorption without proteinuria. The defect in intestinal absorption may have been partial. Broch et al. (1984) described a long-term follow-up on 14 patients, aged 6 to 46 years at the time of report. Those with proteinuria in childhood continued to excrete protein (an average of 750 mg/24 hrs), but it seemed that no progression of the renal lesion had occurred. Lin et al. (1994) described 2 affected brothers in a Chinese family. An unusual feature was widespread mottled skin pigmentation, termed poikiloderma, which, unlike the hyperpigmentation sometimes seen with vitamin B12 deficiency, did not respond to treatment. The skin changes in these young adults had been present since the age of 3 or 4 years. Al Essa et al. (1998) described 2 Saudi sisters with this disorder. In children, early anemia usually leads to the diagnosis. In this case, however, the presence of hemoglobinopathy that required frequent transfusions masked the usual macrocytosis, and the older sister was not diagnosed until the age of 12 years when neurologic changes became apparent. Dementia and paralysis responded remarkably to treatment, despite the late diagnosis. Rossler et al. (2003) reported a Lebanese family in which 2 sisters and their 2 first cousins all had Imerslund-Grasbeck syndrome without proteinuria. All presented with classic symptoms of anemia between age 6 and 11 years, and all responded well to treatment with cobalamin. In 2 patients, Schilling test showed 18 to 27% ileal uptake of intrinsic factor/cobalamin, consistent with partial function. Partial function of cobalamin uptake may explain the absence of proteinuria in affected members of this family.
Tanner et al. (2003) identified 3 different mutations in the AMN gene in homozygosity among 11 affected individuals from 5 families, with heterozygosity found in the 5 parents available for study.
Tanner et al. (2004) studied ... Tanner et al. (2003) identified 3 different mutations in the AMN gene in homozygosity among 11 affected individuals from 5 families, with heterozygosity found in the 5 parents available for study. Tanner et al. (2004) studied 42 sibships with MGA1, 24 of which were from Scandinavia and 15 from the Middle East. They found that all cases in Finland were caused by mutation in the CUBN gene (3 different mutations were identified), and all cases in Norway were caused by mutation in the AMN gene (2 different mutations were identified); in Turkey, Israel, and Saudi Arabia, there were 2 different AMN mutations and 3 different CUBN mutations. Haplotype evidence excluded both CUBN and AMN conclusively in 5 families and tentatively in 3 families, suggesting the presence of at least 1 more gene locus that can cause MGA1. Tanner et al. (2004) concluded that the Scandinavian cases were typical examples of enrichment by founder effects, whereas in the Mediterranean region, high degrees of consanguinity exposed rare mutations in both genes. They suggested that in both regions, physicians' awareness of this disease causes it to be more readily diagnosed than elsewhere. Bouchlaka et al. (2007) reported 9 patients with MGA1 from 6 unrelated consanguineous Tunisian families. Linkage analysis and homozygosity mapping showed that 4 of the families likely had mutations in the CUBN gene, although screening for known mutations in the CUBN gene was negative. Affected members of 1 of the other families had a mutation in the AMN gene (605799.0003) that had been previously reported in a Jewish Israeli family of Tunisian origin and in Turkish families, suggesting a founder effect. The sixth family was excluded from both loci, suggesting further genetic heterogeneity.