全周 (9AM - 6PM)

我们和你在一起

Extra info thumb
IMERSLUND-GRASBECK SYNDROME 2; IGS2

IMERSLUND-GRASBECK SYNDROME 2; IGS2

Alternative titles; symbolsMEGALOBLASTIC ANEMIA, NORWEGIAN TYPE▼ DescriptionImerslund-Grasbeck syndrome-2 (IGS2) is an autosomal recessive disorder characterized...

Alternative titles; symbols

  • MEGALOBLASTIC ANEMIA, NORWEGIAN TYPE

▼ Description
Imerslund-Grasbeck syndrome-2 (IGS2) 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 usually 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. Treatment with vitamin B12 results in sustained clinical improvement of the anemia. 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/CUBN (602997) 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, De Filippo et al., 2013, and Storm et al., 2013).

For a discussion of genetic heterogeneity of Imerslund-Grasbeck syndrome, see 261100.

▼ Nomenclature
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 (602997) and is here designated IGS1 (261100); the disorder in the Norwegian cases was found to be due to mutations in the AMN gene and is designated IGS2.

▼ Clinical Features
Imerslund (1960), Lamy et al. (1961), and Imerslund and Bjornstad (1963) reported on a syndrome of chronic relapsing megaloblastic anemia and permanent proteinuria.

Broch et al. (1984) described long-term follow-up on 14 Norwegian patients, aged 6 to 46 years, with IGS2. All were diagnosed with megaloblastic anemia in the first few years of life. Proteinuria was present in most at the same time, but occurred later in a few patients. All were treated with vitamin B12, which resulted in normalization of the anemia and normal neurologic development. Those with proteinuria in childhood continued to excrete protein (an average of 750 mg/24 hrs), and the creatinine clearance was slightly decreased in some patients, but the glomerular filtration rate (GFR) was essentially normal and there was no significant progression of renal disease overall. None of the patients had hypertension.

Levin-Iaina et al. (2011) reported 2 adult Israeli Jewish males of Tunisian and Algerian descent who presented in their fifties with nephrology with proteinuria. Both patients had normal kidney function and normal serum B12 levels. However, detailed history revealed that both had anemia from early childhood and had been continuously treated with vitamin B12. One patient had a family history of megaloblastic anemia. Genetic analysis confirmed that both patients were homozygous for a common Mediterranean/Middle Eastern founder splice site mutation in the AMN gene (c.208-2A-G; 605799.0003), consistent with IGS2. Levin-Iaina et al. (2011) emphasized that the proteinuria is mild, stable, and nonprogressive, and that kidney function in these patients does not deteriorate.

Storm et al. (2013) reported 6 children from 4 unrelated families (families 1-4) with IGS2. The families were of Turkish, Tunisian, Moroccan, and Italian descent; 3 families were consanguineous. The patients had B12-dependent megaloblastic anemia and proteinuria. Detailed urinary analysis showed excretion of the low molecular weight proteins transferrin (TF; 190000), apo A-I (APOA1; 107680), albumin (ALB; 103600), VDBP (139200), and A1M (176870), which are all cubilin ligands. Storm et al. (2013) noted that the AMN mutations identified in these patients (see MOLECULAR GENETICS) resulted in the secondary abrogation of cubulin expression at the cell surface.

De Filippo et al. (2013) reported an Italian girl, born of consanguineous parents, with IGS2. She presented at 25 months of age with failure to thrive associated with megaloblastic anemia. Other features included loss of appetite, frequent vomiting, and weight loss. Laboratory studies showed decreased serum Cbl and normal folate; urinary excretion of total protein and albumin were normal. Treatment with parenteral vitamin B12 resulted in rapid and sustained clinical improvement with normal psychomotor development.

Montgomery et al. (2015) reported a Caucasian English family in which 2 half sisters had a clinical diagnosis of IGS. In the first years of life, the patients developed pernicious anemia and were treated successfully with vitamin B12. Both were noted to have mild proteinuria in the teenage years and later developed sub-nephrotic-range proteinuria during pregnancy that persisted after delivery, but was nonprogressive. Other features included recurrent urinary tract infections and episodes of lethargy and tiredness associated with anemia. The sisters had normal growth and development, no hypertension, and no neurologic abnormalities.

▼ Inheritance
The transmission pattern of IGS2 in the families reported by Storm et al. (2013) was consistent with autosomal recessive inheritance.

▼ Mapping
By genomewide linkage analysis of the Norwegian families with IGS reported by Imerslund (1960) and Broch et al. (1984), Tanner et al. (2003) established linkage to chromosome 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.

▼ Molecular Genetics
In affected members of 4 Norwegian families with IGS2, including the original Norwegian family reported by Imerslund (1960) and the family reported by Broch et al. (1984), Tanner et al. (2003) identified 2 different homozygous mutations in the AMN gene (c.14delG, 605799.0001 and T41I, 605799.0002). Affected members in a family of Tunisian Jewish descent were homozygous for a splice site mutation (c.208-2A-G, 605799.0003) in the AMN gene. The mutations, which were found by a combination of linkage analysis and candidate gene sequencing, segregated with the disorder in the families from whom parental DNA was available. Because all mutations occurred toward the N-terminal end of the gene, Tanner et al. (2003) suggested that the 5-prime part of the gene might not be essential for embryonic development, but might be essential for vitamin B12 uptake.

Tanner et al. (2004) studied 42 sibships with IGS, 24 of which were from Scandinavia and 15 from the Middle East. Several of the families had previously been reported. Tanner et al. (2004) found that all cases in Finland were caused by mutation in the CUBN gene (3 different mutations were identified), consistent with IGS1, whereas all cases in Norway were caused by mutation in the AMN gene (2 different mutations were identified), consistent with IGS2. Among Middle Eastern families from Turkey, Israel, and Saudi Arabia, there were 2 different AMN mutations and 3 different CUBN mutations. 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.

In a girl, born of consanguineous Tunisian parents (family MA2), with IGS2, Bouchlaka et al. (2007) identified homozygosity for the c.208-2A-G splice site mutation in the AMN gene (605799.0003) that had previously been reported in Tunisian and Turkish families, suggesting a founder effect.

In 6 patients from 4 unrelated families (families 1-4) with IGS2, Storm et al. (2013) identified homozygous or compound heterozygous mutations in the AMN gene (605799.0003-605799.0005). Two families of Middle Eastern descent were homozygous for the founder c.208-2A-G mutation, whereas 2 Italian sibs were compound heterozygous for this founder mutation and a frameshift mutation occurring in a more distal region of the gene. The last patient was homozygous for a frameshift mutation that also occurred in a more distal region of the gene. Functional studies of the variants were not performed, but all were predicted to affect the extracellular domain of AMN, which would most likely result in secondary adverse effects on cell surface expression of CUBN. Storm et al. (2013) noted that the novel AMN mutations extended beyond the 5-prime region of the AMN gene.

In an Italian girl, born of consanguineous parents, with IGS2, De Filippo et al. (2013) identified homozygosity for the founder c.208-2A-G mutation. The mutation, which was found by direct mutation analysis, segregated with the disorder in the family and was not found in 600 unrelated individuals from the same geographic region. Analysis of paternal lymphocytes showed presence of the normal transcript and an abnormally spliced transcript. Additional functional studies were not performed.

In 2 Caucasian half sisters with IGS2, Montgomery et al. (2015) identified compound heterozygous mutations in the AMN gene (c.35delA, 605799.0006 and M69K, 605799.0007). Although parental DNA was not available, the mutations were demonstrated to occur in compound heterozygous state, implying inheritance from the parents. Neither variant was found in the ExAC database. Functional studies of the variants and studies of patient cells were not performed.

▼ Pathogenesis
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.

▼ Population Genetics
Grasbeck (2006) estimated the prevalence of both forms of IGS in Finland and Norway at about 1 in 200,000.

▼ Animal Model
He 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.

Tags: 14q32.32