Alternative titles; symbols
SNOMEDCT: 234363001; ICD10CM: D51.1; ORPHA: 35858; DO: 13382;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 10p13 | Imerslund-Grasbeck syndrome 1 | 261100 | Autosomal recessive | 3 | CUBN | 602997 |
A number sign (#) is used with this entry because of evidence that Imerslund-Grasbeck syndrome-1 (IGS1) is caused by homozygous or compound heterozygous mutation in the CUBN gene (602997) on chromosome 10p13.
Biallelic mutation in the CUBN gene can also cause isolated chronic benign proteinuria (PROCHOB; 618884).
Imerslund-Grasbeck syndrome-1 (IGS1) is an autosomal recessive disorder characterized by onset of megaloblastic anemia associated with decreased serum vitamin B12 (cobalamin, Cbl) in infancy or early childhood. Low molecular weight (LMW) proteinuria is frequently present, but sometimes occurs later and is usually mild or subclinical. Patients often present with vague symptoms, including failure to thrive, loss of appetite, fatigue, lethargy, and/or recurrent infections. Some patients may present later in childhood with neurologic abnormalities related to B12 deficiency, such as sensorimotor neuropathy and/or cognitive disturbances. Treatment with vitamin B12 results in sustained clinical improvement of the anemia and resolution of the neurologic symptoms, if present. The proteinuria is nonprogressive, and affected individuals do not have deterioration of kidney function; correct diagnosis is important to prevent unnecessary treatment. The disorder results from a combination of vitamin B12 deficiency due to selective malabsorption of the vitamin, and impaired reabsorption of LMW proteins in the proximal renal tubule. These defects are caused by disruption of the AMN (605799)/CUBN complex that forms the 'cubam' receptor responsible for intestinal uptake of B12/GIF (CBLIF; 609342). In the kidney, AMN/CUBN interacts with the endocytic receptor megalin (LRP2; 600073), which is important for the reabsorption of plasma proteins (summary by Grasbeck, 2006, Storm et al., 2011, Storm et al., 2013).
Genetic Heterogeneity of Imerslund-Grasbeck Syndrome
See also IGS2 (618882), caused by mutation in the AMN gene (605799) on chromosome 14q32.
Congenital pernicious anemia (261000), a distinct disorder with overlapping features, is caused by mutation in the GIF (CBLIF) gene (609342). Adult pernicious anemia (170900) is another distinct autoimmune disorder associated with plasma autoantibodies to gastric parietal cells or gastric intrinsic factor.
Imerslund-Grasbeck syndrome was first described by Grasbeck et al. (1960) in Finland and by Imerslund (1960) in Norway. The disorder in the Finnish cases was found to be due to mutations in the CUBN gene and is here designated IGS1; the disorder in the Norwegian cases was found to be due to mutations in the AMN gene and is designated IGS2 (618882).
In Finnish patients, Grasbeck (1960) described pernicious anemia in association with proteinuria and malformation of the urinary tract. Grasbeck (1960) favored a selective defect in intestinal absorption of vitamin B12 in this disorder, which was uninfluenced by administration of intrinsic factor.
Grasbeck (1972) 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.
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.
Lin et al. (1994) described 2 affected brothers with IGS 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 sensorimotor deficits leading to 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.
Hauck et al. (2008) reported a 15-year-old German girl with chronic spondylolisthesis who presented acutely with ataxia and sensorimotor deficiencies of the lower limbs. Laboratory investigations showed a demyelinating sensorimotor neuropathy, macrocytic anemia, and decreased serum Cbl with normal serum folate levels. She also had proteinuria with increased urinary excretion of total protein, albumin, transferrin, and IgG. Creatine clearance was mildly increased and the kidneys were different sizes, but there were no severe malformations. Vitamin D levels were not altered. Genetic analysis was consistent with IGS1, and she was successfully treated with vitamin B12, which normalized the hematologic parameters and resolved the neurologic symptoms. Renal function did not decline over time, although proteinuria was persistent.
Ciancio et al. (2019) reported 4 sibs, born of unrelated parents of Ashkenazi Jewish descent, with IGS1. The 2 older sibs presented in infancy with lethargy, failure to thrive, mouth ulcerations, and megaloblastic anemia. They were found to be deficient in vitamin B12 and also had proteinuria. Treatment with cobalamin resulted in clinical improvement, although the proteinuria persisted. Genetic analysis identified a homozygous frameshift mutation in the CUBN gene (602997.0006), and the 2 younger sibs were found to be affected. Treatment in the younger sibs was successful in preventing manifestations. In addition, all patients had profound vitamin D deficiency requiring supplementation. Ciancio et al. (2019) concluded that null CUBN mutations may affect the DBP protein (139200), resulting in vitamin D deficiency; this suggested a possible genotype/phenotype correlation. Functional studies of the variant and studies of patient cells were not performed.
The transmission pattern of IGS1 in the families reported by Aminoff et al. (1999) was consistent with autosomal recessive inheritance.
In the oldest known patient with IGS, 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.
Fyfe 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.
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 locus for recessive 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. They symbolized the disease locus MGA1 (megaloblastic anemia-1) and localized it to chromosome 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.
In affected members of 15 of 17 Finnish families with IGS, Aminoff et al. (1999) identified a homozygous missense mutation in the CUBN gene (P1297L; 602997.0001). The mutation, which was found by a combination of linkage analysis and candidate gene sequencing, segregated with the disorder in the families. It was present in 1 of 316 Finnish controls, yielding a carrier rate of 0.3% in that population. Western blot analysis of patient urine samples showed normal expression of the mutant protein; additional functional studies were not performed. The findings were consistent with a founder effect. Affected members of another Finnish family with the disorder were homozygous for a splice site mutation in the CUBN gene (602997.0002); Western blot analysis of patient urine samples did not detect any CUBN protein, consistent with a loss of function.
In a patient with IGS1, Storm et al. (2011) identified a homozygous splice site mutation in the CUBN gene (602997.0003). This patient showed no immunogenic reaction to cubilin, and renal biopsy showed abnormal cytoplasmic and vesicular distribution of AMN, the partner of CUBN. The findings indicated that AMN depends on cubilin for correct localization in the human proximal tubule.
In a 15-year-old German girl, born of unrelated parents, with IGS1, Hauck et al. (2008) identified compound heterozygosity for a missense variant in the CUBN gene (P337L; 602997.0004), inherited from her unaffected father, and a heterozygous large deletion encompassing the entire CUBN gene as well as about 150-kb up- and downstream from the gene boundaries. The deletion was presumably inherited from the mother, although DNA from the mother was not available. Functional studies of the variant and studies of the variant in patient cells were not performed.
Nykjaer et al. (2001) found that a patient with IGS1 who was homozygous for the CUBN splice site mutation (602997.0002) showed urinary loss of vitamin D-binding protein (DBP; 139200) and 25(OH)D3. On the other hand, patients with the missense mutation P1297L (602997.0001) reabsorbed DBP normally, suggesting that the binding site for 25(OH)D3-DBP is distinct from the binding site for IF-B12.
Storm et al. (2013) reported 3 patients from 2 unrelated families with IGS1. Family 5 was a consanguineous Tunisian family with a homozygous G1112E mutation in the CUBN gene (602997.0005), and family 6 was a nonconsanguineous Finnish family with the homozygous founder Finnish mutation (P1297L; 602997.0001). Clinical details were limited, but all patients had megaloblastic anemia unrelated to intrinsic factor. However, only the Tunisian patients had LMW proteinuria with significantly increased excretion of cubulin ligands, including transferrin (TF; 190000), apo A-I (APOA1; 107680), albumin (ALB; 103600), VDBP (139200), and A1M (176870). In vitro functional expression studies in transfected CHO cells showed that the G1112E mutation in the CUB6 domain resulted in the absence of CUBN expression at the cell surface. In contrast, the P1297L mutation in the CUB8 domain was predicted not to affect CUBN cell surface expression (Kristiansen et al., 2000). Storm et al. (2013) concluded that different mutations may have different functional effects on CUBN receptor function, resulting in phenotypic differences.
In individuals from 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 (CBLIF) gene (609342.0002-609342.0007). Tanner et al. (2005) proposed that mutation analysis of the CUBN, AMN, and GIF genes, rather than radiocobalamin absorption tests, should be the diagnostic method of choice for cobalamin absorption disorders.
Grasbeck (2006) estimated the prevalence of both forms of IGS in Finland and Norway at about 1 in 200,000.
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).
Spurling et al. (1964) described 2 Baltimore sisters, born of consanguineous parents, with juvenile pernicious anemia associated with 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 appeared to be an integral part of the syndrome.
Celep 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.
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