Megaloblastic Anemia 1
A number sign (#) is used with this entry because of evidence that hereditary megaloblastic anemia-1 can be caused by mutation in the gene encoding cubilin (CUBN; 602997) or the AMN (605799) gene.
The CUBN and AMN gene products form a complex that acts as a receptor for vitamin B12 and gastric intrinsic factor (GIF; 609342).
Imerslund-Grasbeck syndrome was described by Imerslund (1960) in Norway and Grasbeck et al. (1960) in Finland; the Finnish cases were found to be due to mutations in cubilin, whereas the Norwegian cases were found to be due to mutations in AMN.
DescriptionImerslund-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.
Clinical FeaturesWaters 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.
MappingLinkage to Chromosome 10
Working with Ralph Grasbeck, an original discoverer of this disorder (Grasbeck and Kantero, 1959; Grasbeck, 1960; Grasbeck, 1972), Aminoff et al. (1995) reported linkage of a recessive gene locus for malabsorption of vitamin B12 to chromosome 10 in multiplex families from Finland and Norway. The locus was assigned to the 6-cM interval between markers D10S548 and D10S466, with a multipoint maximum lod score of 5.36 near marker D10S1477. By haplotype analysis, the healthy sibs in these families did not appear to constitute examples of nonpenetrance, i.e., they appeared not to be homozygotes. A phenomenon awaiting explanation had been the observation that in Finland and Norway, within a few years of the initial description of the condition in 1959 and 1960, many cases were diagnosed, but 30 years later almost no new cases were recognized. Aminoff et al. (1995) hypothesized that the paucity of new cases in these populations was due either to a dietary effect on the gene penetrance that changed with time, or to a drop in the birth rate in subpopulations showing enrichment of the mutation, or to both of these causes. They symbolized the disease locus MGA1 (megaloblastic anemia-1) and localized it to 10p12.1.
Kozyraki et al. (1998) used fluorescence in situ hybridization, radiation hybrid mapping, and screening of YAC clones to map the human cubilin gene (602997) to the same region where the MGA1 locus maps. Thus, cubilin was a strong candidate for the molecule whose impaired synthesis, processing, or ligand binding is the basis of this hereditary form of megaloblastic anemia.
Linkage to Chromosome 14
Aminoff et al. (1999) demonstrated that most cases of this disorder in Finland, where it is relatively frequent, are the result of homozygosity for a missense mutation in the gene encoding cubilin. Unexpectedly, however, Norwegian individuals showing the MGA1 phenotype, as described by Imerslund (1960) (the Norwegian partner in the double eponym), did not have mutations in CUBN. Tanner et al. (2003) used these families to carry out a genomewide search for linkage and established linkage to 14q. They reasoned that candidate genes might have an expression pattern similar to that of CUBN, and previous work indicated high expression in the kidney and small intestine. In searching the database for ESTs, amnionless (AMN; 605799) emerged as a strong candidate.
CytogeneticsCelep et al. (1996) described Imerslund-Grasbeck syndrome in 3 Turkish sibs with first-cousin parents. One of the sibs was found to have a deletion of the 2 terminal bands of chromosome 21, q22.2 and q22.3. No other members of the family had a cytogenetic abnormality; 2 affected sibs had previously died. The authors stated that 'the syndrome has not been mapped to a particular chromosome,' and suggested that there might be an etiologic connection between the chromosome deletion and IGS in this case. In fact, it was probably coincidence.
PathogenesisFyfe et al. (2004) showed that cubilin and AMN colocalize in the endocytic apparatus of polarized epithelial cells and form a tightly bound complex early in the biosynthetic pathway that is essential for apical membrane localization and endocytic functions previously ascribed to cubilin alone. Therefore, mutations affecting either of the 2 proteins may abrogate function of the cubilin/AMN (cubam) complex and cause Imerslund-Grasbeck syndrome.
DiagnosisIn 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.
Molecular GeneticsTanner 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.
Animal ModelHe et al. (2003) demonstrated that Imerslund-Grasbeck syndrome in the dog maps to a region that is orthologous to human 14q and contains the AMN gene, and is presumably caused by mutation in that gene.