Imerslund-Grasbeck Syndrome Type 1

Mendelian MONDO:0100156 Pathograph 30 Show in embeddings browser Inherited cobalamin malabsorption Megaloblastic anemia

Imerslund-Grasbeck syndrome type 1 is an autosomal recessive disorder in which biallelic CUBN variants disable cubilin, the ligand-binding subunit of the cubam receptor. Cubam is a heterodimeric endocytic receptor that sits in the brush border of two epithelia only: the ileal enterocyte, where it takes up the intrinsic factor-cobalamin complex, and the renal proximal tubule cell, where it reabsorbs filtered low-molecular-weight proteins. One receptor lesion therefore produces a two-organ disease, and the two organ effects are independent of each other. The intestinal arm is the one that makes the patient ill. Cobalamin absorption fails at the final receptor step while intrinsic factor secretion and gastric acid output are normal, so children present between a few months and several years of age, once maternal stores are exhausted, with megaloblastic anemia, failure to thrive, recurrent infections and, less often, neurological signs. It is fully correctable: lifelong parenteral cobalamin restores and maintains health. The renal arm is not correctable and does not need to be. Proteinuria persists unchanged on treatment because cobalamin replacement bypasses the gut but does nothing for the tubular receptor, and it does not progress to renal failure. Reading that proteinuria as glomerular disease is the characteristic clinical error, and it has led to renal biopsies and proteinuria-lowering treatment in patients whose kidneys were never going to fail. Where in cubilin the lesion falls decides which arm is affected. Variants affecting the N-terminal third, which carries the CUB 5-8 intrinsic factor-cobalamin binding site and the amnionless-association helix, give the full IGS picture. Variants after the vitamin B12-binding domain leave cobalamin uptake intact and produce isolated benign albuminuria, a phenotype common enough to appear as an association in population cohorts.

Ask OpenScientist

Ask a research question about Imerslund-Grasbeck Syndrome Type 1. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
9
Pathophys.
14
Phenotypes
2
Gaps
30
Pathograph
1
Genes
1
Variants
3
Medical Actions
3
Differentials
2
Models
19
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Homozygous or compound heterozygous CUBN variants. Heterozygous carriers are clinically unaffected for the cobalamin phenotype.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:37710296 SUPPORT Human Clinical
"Homozygous or compound heterozygous mutations in either CUBN or AMN lead to IGS"
States the recessive requirement for two damaged alleles, and that CUBN is one of the two genes that produce this phenotype.
PMID:10080186 SUPPORT Human Clinical
"Megaloblastic anaemia 1 (MGA1, OMIM 261100) is a rare, autosomal recessive disorder characterized by juvenile megaloblastic anaemia, as well as neurological symptoms that may be the only manifestations."
The original gene-mapping paper's own statement of the inheritance mode, and a reminder that a purely neurological presentation is possible.
?

Discussions and Knowledge Gaps

2
Why is proteinuria near-universal in most reported IGS populations and rare in Finnish patients, when the same cubam receptor is lost in every case?
KNOWLEDGE GAP igs1_proteinuria_penetrance
Attached to
pathophysiology#Loss of Proximal Tubular Reabsorption of Filtered Protein phenotypes#Proteinuria
The intestinal arm of the disease is essentially fully penetrant and the renal arm is not, from one lesion in one receptor. The 2023 systematic review changes the shape of this question rather than answering it: at 89% of patients with documented urinalysis, the renal arm is close to universal in most of the world, and the striking number is the Finnish 20%. So the gap is now geographic and, plausibly, allelic rather than a generic half-penetrance. Candidate explanations have not been separated: residual cubilin function at the tubule for alleles that abolish it in the gut, which the Finnish founder missense allele is a specific candidate for; compensation by megalin; an unrecognised threshold effect; or ascertainment, since the review itself argues that patients without proteinuria are less likely to be tested for IGS and that its 89% is therefore an overestimate. Resolving it would also settle whether absent proteinuria is genuinely uninformative for the diagnosis or only appears so.
Can high-dose oral cobalamin replace lifelong injections in human Imerslund-Grasbeck syndrome?
KNOWLEDGE GAP igs1_oral_cobalamin_in_humans
Attached to
treatments#High-dose oral cobalamin
The only direct evidence in this disease is three dogs. Receptor-independent passive diffusion is well established as a route and oral replacement has been adopted in other malabsorptive cobalamin deficiencies, but no human IGS trial has been done. The question matters because the alternative is intramuscular injection from childhood for life.
Proposed experiments
Non-inferiority trial of daily oral versus parenteral cobalamin in genetically confirmed IGS
igs1_oral_vs_parenteral_noninferiority
Randomise genetically confirmed IGS patients in metabolic remission to continue parenteral dosing or switch to daily high-dose oral cyanocobalamin, with serum cobalamin, plasma homocysteine and urinary methylmalonate as the maintenance endpoints.
Readouts
Urinary methylmalonic acid
pathophysiology#Systemic Cobalamin Deficiency
Direction: UNCHANGED
Interpretation: Remaining within the reference interval on the oral arm would indicate maintained cobalamin sufficiency.
⚙

Pathophysiology

9
Biallelic CUBN Loss-of-Function Variants
Nonsense, frameshift, splice and missense variants on both CUBN alleles. Cubilin is a 460 kDa protein built from an N-terminal alpha helix, eight EGF domains and 27 CUB domains; the intrinsic factor-cobalamin binding site is CUB domains 5-8 and the amnionless-binding region is the N-terminal helix. Both lie in the N-terminal third, which is where IGS-causing alleles fall.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
Downstream
Failure of Cubam Receptor Assembly at the Brush Border
Show evidence (2 references)
PMID:10080186 SUPPORT Human Clinical
"We have now refined the MGA1 region by linkage disequilibrium (LD) mapping, fine-mapped CUBN and identified two independent disease-specific CUBN mutations in 17 Finnish MGA1 families."
The genetic evidence that CUBN variants are the lesion in this disease.
PMID:23746554 SUPPORT Model Organism
"CUB domains 5-8 comprise the essential IF-Cbl binding site ... and the N-terminal alpha helical region mediates association with AMN"
Locates the two functional sites within cubilin that an IGS-causing allele has to damage. Quoted in the ellipsis form the snippet auditor supports, because the source's inline citation markers sit between the two clauses.
Failure of Cubam Receptor Assembly at the Brush Border
Cubilin has no transmembrane domain and no endocytic motif of its own. Amnionless supplies both, binding the N-terminal third of cubilin and carrying it to the apical surface; neither subunit endocytoses ligand alone. A cubilin that cannot bind amnionless, or cannot bind intrinsic factor-cobalamin, leaves a brush border without a working receptor. Cubam is not the whole endocytic machine. Megalin (LRP2) is required for efficient internalization of cubilin and its ligands, so apical uptake depends on a three-protein system in which CUBN supplies ligand recognition and the other two supply membrane anchoring and internalization. The same cubilin regions bind intrinsic factor-cobalamin and albumin, which is why one receptor lesion produces both the intestinal and the renal arm of this disease rather than one or the other.
intrinsic factor-cobalamin binding by cubilin GO:0031419 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased intrinsic factor-cobalamin binding by cubilin, annotated with cobalamin binding (GO:0031419). GO:0031419 is a molecular function from the Gene Ontology. ↓ DECREASED
apical brush border membrane GO:0016324 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves apical brush border membrane, annotated with apical plasma membrane (GO:0016324). GO:0016324 is a cellular component from the Gene Ontology.
Animal models
Border Collie CUBN exon 53 frameshift Dog recapitulates A spontaneous biallelic CUBN lesion in an outbred animal, producing cobalamin malabsorption with selective proteinuria, the same two-organ pattern as the human disease and from the same gene.
Downstream
Loss of Ileal Intrinsic Factor-Cobalamin Endocytosis
Loss of Proximal Tubular Reabsorption of Filtered Protein
Show evidence (6 references)
PMID:14576052 SUPPORT In Vitro
"In transfected cells expressing either AMN or a truncated IF-cobalamin-binding cubilin construct, neither protein alone conferred ligand endocytosis."
The transfection experiment establishing that a lone cubilin subunit cannot endocytose ligand, which is why a CUBN lesion abolishes receptor function rather than merely reducing it.
PMID:14576052 SUPPORT In Vitro
"These data indicate that cubilin and AMN are subunits of a novel cubilin/AMN (cubam) complex, where AMN binds to the amino-terminal third of cubilin and directs subcellular localization and endocytosis of cubilin with its ligand."
Defines the cubam complex and the division of labour between its two subunits that this node depends on.
PMID:20237569 SUPPORT INDIRECT In Vitro
"This occurs by the combined action of the gastric intrinsic factor (IF) and the ileal endocytic cubam receptor formed by the 460-kilodalton (kDa) protein cubilin and the 45-kDa transmembrane protein amnionless."
Names the two cubam subunits and their masses, and places the complex at the ileal apical surface where this node locates the failure. Graded INDIRECT because this is the paper's statement of normal physiology, from which the consequence of losing the receptor follows by inference.
+ 3 more references
Loss of Ileal Intrinsic Factor-Cobalamin Endocytosis
Every upstream step of cobalamin handling is normal: gastric acid, intrinsic factor secretion, haptocorrin release and pancreatic proteolysis. The block is at the single receptor-mediated uptake step in the distal ileum, which is why the malabsorption is selective for cobalamin rather than general, and why giving intrinsic factor with the test dose does not correct it.
ileal enterocyte CL:1000334 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves ileal enterocyte, annotated with enterocyte of epithelium of small intestine (CL:1000334). CL:1000334 is a cell type from the Cell Ontology.
receptor-mediated uptake of the intrinsic factor-cobalamin complex GO:0006898 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased receptor-mediated uptake of the intrinsic factor-cobalamin complex, annotated with receptor-mediated endocytosis (GO:0006898). GO:0006898 is a biological process from the Gene Ontology. ↓ DECREASED intestinal cobalamin transport GO:0015889 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased intestinal cobalamin transport, annotated with cobalamin transport (GO:0015889). GO:0015889 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Systemic Cobalamin Deficiency
Show evidence (2 references)
PMID:16722557 SUPPORT Human Clinical
"The cause is a defect in the receptor of the vitamin B(12)-intrinsic factor complex of the ileal enterocyte."
Names the cell and the receptor step at which absorption fails.
PMID:16722557 SUPPORT Human Clinical
"Vitamin B(12) absorption tests show low absorption, not corrected by administration of intrinsic factor."
The observation that localises the block distal to intrinsic factor, which is what distinguishes this node from pernicious anemia.
Loss of Proximal Tubular Reabsorption of Filtered Protein
The same receptor operates in the proximal tubule, where it retrieves albumin, vitamin D binding protein, transferrin, apolipoprotein A1 and other filtered proteins from the primary urine. Cubam loss there produces persistent proteinuria with a high albumin fraction. This arm runs in parallel with the intestinal arm from the same lesion; it is not a consequence of the cobalamin deficiency, which is why replacing cobalamin does not touch it.
renal proximal tubule epithelial cell CL:0002306 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves renal proximal tubule epithelial cell, annotated with epithelial cell of proximal tubule (CL:0002306). CL:0002306 is a cell type from the Cell Ontology.
receptor-mediated retrieval of filtered protein GO:0006898 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased receptor-mediated retrieval of filtered protein, annotated with receptor-mediated endocytosis (GO:0006898). GO:0006898 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Persistent Non-Progressive Proteinuria
Show evidence (4 references)
PMID:23746554 SUPPORT Model Organism
"Cubam is a multi-ligand, endocytic receptor expressed in epithelial brush borders of distal small intestine and renal proximal tubules."
Places the same receptor in the proximal tubule, which is what makes the renal arm a direct consequence of the same lesion.
PMID:31613795 SUPPORT Human Clinical
"Collectively, our data suggest an important role for the C-terminal half of cubilin in renal albumin reabsorption."
Human genetic evidence that cubilin function is what performs the tubular albumin retrieval this node describes.
PMID:24156255 SUPPORT Human Clinical
"Analysis of urinary protein excretion in the patients and 20 healthy controls revealed increased urinary excretion of cubilin ligands including apolipoprotein A-I, transferrin, vitamin D-binding protein, and albumin."
Measures the lost reabsorption directly in IGS patients, and names the ligands, which is what makes this a cubilin-ligand leak rather than generic tubular injury.
+ 1 more reference
Systemic Cobalamin Deficiency
Body cobalamin stores are large relative to daily need, so the deficiency declares itself only after maternal stores run down, from about four months of age and sometimes not for years. Both cobalamin-dependent enzymes fail: methionine synthase, giving hyperhomocysteinemia and the functional folate trap that blocks thymidylate synthesis, and methylmalonyl-CoA mutase, giving methylmalonic acidemia and aciduria.
Animal models
Beagle hereditary cobalamin malabsorption Dog measures Used as a treatment-response model rather than a mechanism model: urinary methylmalonate is read as the metabolic index of cobalamin sufficiency under an oral regimen.
Downstream
Megaloblastic Erythropoiesis
Cobalamin-Dependent Enzyme Block
Decreased circulating vitamin B12 concentration The measurement of this node rather than a consequence of it. Drawn as an edge because the serum level is what a clinician sees, and the node is the systemic state it reports.
Failure to thrive Growth failure in an infant with untreated deficiency. The intermediate steps between the cofactor loss and the growth curve are not established here, so the edge is typed as indirect.
Abnormal oral mucosa morphology Oral mucosal lesions follow the same impaired DNA synthesis that produces the megaloblastic marrow, in another rapidly dividing epithelium. Typed indirect because no source cited here demonstrates that route in IGS.
Show evidence (2 references)
PMID:16722557 SUPPORT Human Clinical
"The symptoms appear from 4 months (not immediately after birth as in transcobalamin deficiency) up to several years after birth."
The delayed onset that follows from stores having to be exhausted first, and the contrast with a disorder that has no such buffer.
PMID:22929189 SUPPORT Human Clinical
"Recessive mutations in CUBN or AMN cause Imerslund-Gräsbeck Syndrome (IGS), while recessive mutations in GIF cause Intrinsic Factor Deficiency (IFD)."
Confirms the gene-to-disease assignment used throughout this entry and separates it from the intrinsic-factor disorder with the same downstream deficiency.
Cobalamin-Dependent Enzyme Block
Cobalamin is the cofactor of exactly two human enzymes, and a systemic deficiency disables both at once. Methionine synthase stops converting homocysteine to methionine, so homocysteine accumulates and the methyl donor pool contracts; methylmalonyl-CoA mutase stops converting methylmalonyl-CoA to succinyl-CoA, so methylmalonate accumulates. This is the node the two biochemical markers report on, and it is why they rise together rather than independently.
methionine synthase activity GO:0008705 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased methionine synthase activity (GO:0008705). GO:0008705 is a molecular function from the Gene Ontology. ↓ DECREASED methylmalonyl-CoA mutase activity GO:0004494 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased methylmalonyl-CoA mutase activity (GO:0004494). GO:0004494 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Hyperhomocystinemia
Methylmalonic aciduria
Neurotoxic Metabolite Exposure and Impaired Myelination
Show evidence (2 references)
PMID:22854512 SUPPORT Human Clinical
"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."
Names all three consequences of the cofactor loss in one sentence, in a paper about this disease group specifically, which is what makes this one node rather than three unrelated findings.
PMID:22078000 SUPPORT INDIRECT Human Clinical
"The primary diagnostic criteria are reduced vitamin B12 levels in the serum, elevated homocysteine and methylmalonic acid levels in the blood and urine, and often mild proteinuria."
The two metabolites are used together as diagnostic criteria, which is the clinical expression of a single shared cause. Graded INDIRECT because it states the diagnostic pairing rather than the enzymology behind it.
Neurotoxic Metabolite Exposure and Impaired Myelination
Mechanism confidence: Provisional
The proposed route from the enzyme block to the neurological findings: less methylation available for myelin maintenance, plus direct toxicity of the accumulated homocysteine and methylmalonate. The source states this as an attribution rather than a demonstration, and no cited work here measures myelin or metabolite exposure in an IGS patient's nervous system, so the node is PROVISIONAL and its incoming edge is typed as indirect with unknown intermediates.
myelination GO:0042552 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased myelination (GO:0042552). GO:0042552 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Ataxia
Lethargy
Spinal cord lesion
Show evidence (1 reference)
PMID:37710296 SUPPORT INDIRECT Human Clinical
"Neurocognitive symptoms have been attributed to several pathophysiological mechanisms, including decreased myelinization as a result of impaired methylation due to vitB12 shortage and the direct toxic effects of homocysteine and methylmalonic acid"
The mechanism, quoted with the hedge the authors wrote. "Have been attributed to" is an attribution of causes, not a measurement, which is the reason this node carries mechanism_confidence PROVISIONAL and this item is graded INDIRECT.
Megaloblastic Erythropoiesis
Cobalamin deficiency traps folate as methyltetrahydrofolate, starving thymidylate synthesis. DNA replication in the marrow falls out of step with cytoplasmic maturation, so erythroid precursors enlarge and are destroyed before release. All rapidly dividing lineages are affected, which is why neutropenia and thrombocytopenia accompany the anemia.
erythroid precursor CL:0000038 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythroid precursor, annotated with erythroid progenitor cell (CL:0000038). CL:0000038 is a cell type from the Cell Ontology.
Downstream
Megaloblastic anemia
Macrocytic anemia The red-cell index the megaloblastic marrow produces; the same event seen on the blood count rather than in the marrow.
Pancytopenia
Show evidence (1 reference)
PMID:16722557 SUPPORT Human Clinical
"Megaloblastic anemia is caused by inability of the hematopoietic cells to divide, due to failure of DNA replication."
The cellular mechanism this node asserts, stated for this disease.
Persistent Non-Progressive Proteinuria
Proteinuria that is present in roughly half of patients, does not change on cobalamin replacement, and does not lead to loss of renal function. It is reported as neither typically glomerular nor typically tubular in pattern, and in the isolated C-terminal-variant phenotype it is predominantly albuminuria.
Downstream
Proteinuria
Albuminuria Albumin is one of the cubilin ligands the tubule stops retrieving, and it is the fraction that dominates in the C-terminal-variant phenotype.
Show evidence (2 references)
PMID:16722557 SUPPORT Human Clinical
"Both studies indicated that in properly treated patients, the proteinuria persisted over the years without noticeable change and that kidney function did not deteriorate."
Establishes both halves of this node: that the proteinuria survives treatment, and that it is not nephrotoxic.
PMID:31613795 SUPPORT Human Clinical
"However, renal function was normal in all cases."
An independent cohort in which biallelic CUBN proteinuria was not accompanied by any loss of renal function.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Imerslund-Grasbeck Syndrome Type 1 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

14
Blood 3
Megaloblastic anemia VERY_FREQUENT HP:0001889 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Megaloblastic anemia (HP:0001889). HP:0001889 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16722557 SUPPORT Human Clinical
"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..."
Names megaloblastic anemia as the characteristic manifestation and records its response to replacement.
Macrocytic anemia HP:0001972 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrocytic anemia (HP:0001972). HP:0001972 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37710296 SUPPORT Human Clinical
"Laboratory examination often reveals macrocytic anemia with or without proteinuria"
The laboratory presentation as described in the review of reported cases.
Pancytopenia HP:0001876 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pancytopenia (HP:0001876). HP:0001876 is a phenotype from the Human Phenotype Ontology.
Sequelae: Recurrent infections
Show evidence (1 reference)
PMID:22854512 SUPPORT Human Clinical
"The clinical presentation reflects Cbl deficiency, with gastrointestinal symptoms, pancytopenia, and megaloblastic anemia."
Names pancytopenia alongside the megaloblastic anemia in a series of patients with inborn cobalamin malabsorption, which is this disease group.
Genitourinary 3
Proteinuria VERY_FREQUENT HP:0000093 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Proteinuria (HP:0000093), qualified as temporality chronic. HP:0000093 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (3 references)
PMID:37710296 SUPPORT Human Clinical
"In 239/456 patients, urinalysis was documented. Of these patients, 212 (89%) had proteinuria. Only in Finland, the fraction of patients with proteinuria was lower than in other countries (20% had proteinuria, 18% had no proteinuria, 62% had no urinalysis)."
The systematic review's primary figure, and the Finnish exception, in the one sentence pair that gives both. This is the source for the frequency band recorded here.
PMID:37710296 SUPPORT Human Clinical
"It may be possible that 89% proteinuria is an overestimation and that the number of patients with proteinuria may be closer to 62% (203 patients with proteinuria among 325 patients in which clinical characteristics were described)."
The same review arguing against its own headline figure. Quoted so the entry carries the caveat rather than only the number, since 62% would sit one band lower.
PMID:16722557 REFUTE Human Clinical
"Mild proteinuria (with no signs of kidney disease) is present in about half of the patients."
The older estimate, retained and graded REFUTE against the VERY_FREQUENT band this record now carries. It is not a discredited source; it is the other side of an unsettled figure, and it also supplies the fact that the proteinuria carries no renal disease.
Albuminuria HP:0012592 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Albuminuria (HP:0012592). HP:0012592 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31613795 SUPPORT Human Clinical
"Since the proteinuria in these patients had a high proportion of albuminuria, glomerular diseases such as steroid-resistant nephrotic syndrome or Alport syndrome were often the primary clinical diagnosis, motivating renal biopsies and the use of proteinuria-lowering treatments."
Records the albumin-predominant pattern and the misdiagnosis it causes.
Methylmalonic aciduria HP:0012120 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Methylmalonic aciduria (HP:0012120). HP:0012120 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23746554 SUPPORT Model Organism
"Other documented abnormalities included low serum cobalamin concentrations, methylmalonic aciduria, and mild proteinuria."
Records methylmalonic aciduria in the CUBN-mutant canine disease. Graded as model-organism evidence because the cohort described is canine; the marker itself is standard in the human disorder.
Head and Neck 1
Abnormal oral mucosa morphology OCCASIONAL HP:0011830 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is oral mucosal lesions, annotated with Abnormal oral mucosa morphology (HP:0011830). HP:0011830 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37710296 SUPPORT Human Clinical
"In addition to non-specific symptoms, we observed a relatively high amount of oral mucosal lesions in 17% of the patients."
The frequency this phenotype's band is taken from.
Immune 1
Recurrent infections HP:0002719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent infections (HP:0002719). HP:0002719 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37710296 SUPPORT Human Clinical
"Before the diagnosis of vitB12 deficiency, patients have non-specific symptoms such as failure to thrive, paleness, fatigue, recurring viral infections and mild neurological symptoms."
The same presenting-symptom list, quoted for the infection component.
Metabolism 2
Decreased circulating vitamin B12 concentration HP:0100502 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased circulating vitamin B12 concentration (HP:0100502). HP:0100502 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37710296 SUPPORT Human Clinical
"Imerslund-Gräsbeck syndrome (IGS, OMIM 261,100/618,882) is an autosomal recessive disorder characterized by a vitamin B12 (vitB12) deficiency, caused by a selective malabsorption of vitB12, with normal secretion of intrinsic factor (IF) and hydrochloric acid into the stomach [1]."
States the deficiency and, in the same sentence, that the upstream gastric steps are intact.
Hyperhomocystinemia HP:0002160 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperhomocystinemia (HP:0002160). HP:0002160 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22078000 SUPPORT Human Clinical
"The primary diagnostic criteria are reduced vitamin B12 levels in the serum, elevated homocysteine and methylmalonic acid levels in the blood and urine, and often mild proteinuria [3]."
Lists the two raised metabolites among the diagnostic criteria for IGS. The cohort in this paper is AMN-mutant, so the quote is used only for the biochemistry shared by both genes, not for any CUBN-specific claim.
Nervous System 3
Ataxia VERY_RARE HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37710296 SUPPORT Human Clinical
"Neurological manifestations were observed in 52 patients (16%). Most frequently, patients showed lethargy (n = 13, 25%), ataxia (n = 10, 19%), and motor or sensory deficits (n = 7, 13%)."
The counts behind both this phenotype and Lethargy. The percentages inside the quote are shares of the 52 patients with neurological findings, which is why the frequency band assigned here is lower than the quoted 19%.
Lethargy VERY_RARE HP:0001254 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lethargy (HP:0001254). HP:0001254 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37710296 SUPPORT Human Clinical
"Neurological manifestations were observed in 52 patients (16%). Most frequently, patients showed lethargy (n = 13, 25%), ataxia (n = 10, 19%), and motor or sensory deficits (n = 7, 13%)."
Gives lethargy as the most frequent neurological manifestation, with the count it rests on.
Spinal cord lesion VERY_RARE HP:0100561 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is funicular myelosis (subacute combined degeneration of the cord), annotated with Spinal cord lesion (HP:0100561). HP:0100561 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37710296 SUPPORT Human Clinical
"More severe clinical manifestations were present in 4% of IGS patients, which included funicular myelosis (subacute combined degeneration of the cord, n = 5, 10%), seizures (n = 3, 6%), focal cortical atrophy of the left insular region on MRI (n = 2; 3.8%) and progressive dementia (n = 1, 2%)."
The severe end of the neurological spectrum, with the count for funicular myelosis specifically.
Growth 1
Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37710296 SUPPORT Human Clinical
"Before the diagnosis of vitB12 deficiency, patients have non-specific symptoms such as failure to thrive, paleness, fatigue, recurring viral infections and mild neurological symptoms."
Lists failure to thrive among the presenting non-specific features.
🧬

Genetic Associations

1
CUBN (Causal biallelic variant)
Gene: CUBN hgnc:2548 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CUBN (hgnc:2548). hgnc:2548 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:31613795 SUPPORT Human Clinical
"Unlike the more N-terminal IGS mutations, 37 of the 41 proteinuria-associated CUBN variants led to modifications or truncations after the vitamin B12-binding domain."
The positional split itself, stated as a contrast against the IGS allele distribution.
PMID:31613795 SUPPORT Human Clinical
"We identified 39 patients, in whom biallelic pathogenic variants in the CUBN gene were associated with chronic isolated proteinuria and early childhood onset."
The cohort establishing the isolated-proteinuria end of the CUBN spectrum.
PMID:31613795 SUPPORT Human Clinical
"Finally, we show that 4 C-terminal CUBN variants are associated with albuminuria and slightly increased GFR in meta-analyses of large population-based cohorts."
The population-cohort signal, which is what makes the C-terminal phenotype a common benign condition rather than a rare disease variant.
Variants (1)
c.3890C>T (p.Pro1297Leu), Finnish founder allele FM1 Pathogenic
The Finnish major mutation. It sits in CUB domain 8, inside the CUB 5-8 intrinsic factor-cobalamin binding region, and is a missense change rather than a truncation, so cubilin still reaches the brush border. What it destroys is ligand recognition: surface plasmon resonance shows the substitution raises the dissociation constant for intrinsic factor-cobalamin several-fold, mostly by slowing association. This is the allele behind the Finnish prevalence figure this entry records, and it is the cleanest evidence that IGS is a receptor-affinity disease and not only a receptor-abundance one.
Show evidence (2 references)
PMID:10887099 SUPPORT Human Clinical
"Most Finnish patients with MGA1 carry the disease-specific P1297L mutation (FM1) in the IF-B(12) receptor, cubilin."
Establishes P1297L as the predominant Finnish allele and names it FM1.
PMID:10887099 SUPPORT In Vitro
"Surface plasmon resonance analysis revealed that the P1297L substitution specifically increases the K(d) for IF-Cbl binding several-fold, largely by decreasing the association rate constant."
The binding measurement that gives the allele its mechanism, and the basis for calling this a loss of ligand affinity rather than a loss of receptor.
💊

Medical Actions

3
Lifelong parenteral cobalamin replacement
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: hydroxocobalamin CHEBI:27786 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses hydroxocobalamin (CHEBI:27786). CHEBI:27786 is a therapeutic agent from Chemical Entities of Biological Interest. cyanocobalamin CHEBI:17439 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses cyanocobalamin, annotated with cyanocob(III)alamin (CHEBI:17439). CHEBI:17439 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Intramuscular cobalamin bypasses the absent receptor entirely. It corrects the anemia, the metabolite abnormalities and the growth failure, and holds patients well for decades. It has no effect on the proteinuria, and it does not need to: the renal arm is not progressive. Replacement is lifelong because the receptor defect is permanent.
Mechanism Target:
Systemic Cobalamin Deficiency — Parenteral delivery restores tissue cobalamin without using the ileal receptor, so it corrects everything downstream of this node and nothing upstream of it.
Target Phenotypes: Megaloblastic anemia HP:0001889 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Megaloblastic anemia (HP:0001889). HP:0001889 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:16722557 SUPPORT Human Clinical
"Management includes life-long vitamin B(12) injections, and with this regimen, the patients stay healthy for decades. However, the proteinuria persists."
States the treatment, its duration, its effectiveness and the one thing it does not fix.
PMID:37710296 SUPPORT Human Clinical
"Most IGS patients are treated with intra-muscular vitB12, which most frequently corrects the clinical phenotype [1]."
Confirms the route and the outcome across the reported case literature.
Spaced parenteral maintenance dosing
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: hydroxocobalamin CHEBI:27786 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses hydroxocobalamin (CHEBI:27786). CHEBI:27786 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Dosing: once every 6 months every 182.5 days
How far apart the injections can be spaced is a separate question from whether they work, and it is the one that decides quality of life for a lifelong regimen. A retrospective series of seven patients with inborn cobalamin malabsorption held normal clinical, haematological and metabolic status on 1 mg twice a year, which is far less frequent than the regimens previously recommended. Seven patients, retrospective, no control arm, so it is recorded as a dosing observation rather than a schedule this entry endorses.
Mechanism Target:
Systemic Cobalamin Deficiency — The same replacement acting on the same node; this record is about the interval, not a different mechanism.
Show evidence (1 reference)
PMID:22854512 SUPPORT Human Clinical
"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."
The dosing result, in humans, with the explicit contrast against the previous recommendation that makes it a change rather than a confirmation.
High-dose oral cobalamin
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: cyanocobalamin CHEBI:17439 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses cyanocobalamin, annotated with cyanocob(III)alamin (CHEBI:17439). CHEBI:17439 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Passive diffusion absorbs a small fraction of an oral dose independently of any receptor, so a large enough daily oral dose could in principle substitute for injections. The direct evidence in this disease is canine: three Beagles with hereditary cobalamin malabsorption were maintained in clinical and metabolic remission on 1 mg oral cyanocobalamin daily. No equivalent human trial exists in IGS. That is not the same as no human support: the 2023 systematic review states plainly that patients may be treated orally provided the dose is raised, and describes one of its own two new patients, an IGS sibling, corrected on 1 mg oral cyanocobalamin daily. So this is an accepted option supported by observation rather than an untested hypothesis, and what is missing is a controlled comparison against injections, not evidence that it works at all.
Mechanism Target:
Systemic Cobalamin Deficiency — The same node by a different route: receptor-independent passive uptake in place of the missing endocytic step.
Show evidence (2 references)
PMID:30554416 SUPPORT Model Organism
"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."
The canine result. Recorded as model-organism evidence and deliberately not extended to a human recommendation on its own.
PMID:37710296 SUPPORT Human Clinical
"Patients may be treated with oral vitB12 supplementations but may need higher doses."
Human observational support for the oral route, from the systematic review of every published case. It is what makes this a recognised option rather than an extrapolation from the dog.
🔬

Diagnosis

1
Selective cobalamin malabsorption with normal intrinsic factor
The diagnostic logic is subtractive: establish cobalamin deficiency, show it is due to malabsorption, show the malabsorption is not corrected by giving intrinsic factor, and exclude the other causes of cobalamin malabsorption. A trap sits inside this. Cobalamin deficiency itself damages enterocyte function, so absorption testing during the deficient state can read as generalised malabsorption; tests must be repeated after the deficiency is corrected. That is one reason molecular testing of CUBN, AMN and GIF has largely displaced absorption testing.
Show evidence (1 reference)
PMID:16722557 SUPPORT Human Clinical
"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."
The confounding effect of the deficiency on the test used to diagnose it, and the remedy.
📊

Prevalence

2
Finland
Point Prevalence 0.8 per 100,000 1–9 per 100,000
Reported as the highest national prevalence, in the linkage study that identified CUBN. Finland and Norway both carry founder alleles, but the Finnish founder alleles are the CUBN ones; the Norwegian cluster is AMN and so belongs to IGS type 2.
Show evidence (2 references)
PMID:10080186 SUPPORT Human Clinical
"MGA1 occurs worldwide, but its prevalence is higher in several Middle Eastern countries and Norway, and highest in Finland (0.8/100,000)."
The population figure, with the geographic distribution it belongs to.
PMID:15024727 SUPPORT Human Clinical
"We studied 42 sibships and found all cases in Finland to be due to CUBN (three different mutations) and all cases in Norway to be due to AMN (two different mutations)"
The gene-by-country split this record's notes assert. It is what makes the Finnish figure a prevalence for IGS type 1 specifically rather than for IGS as a whole.
Worldwide
Point Prevalence ≤0.6 per 100,000 1–9 per 1,000,000
A published ceiling rather than a point estimate, which is why only rate_high is populated. It also covers IGS as a whole rather than the CUBN half of it; about 300 cases had been published worldwide as of 2006.
Show evidence (1 reference)
PMID:37710296 SUPPORT Human Clinical
"IGS is a rare disorder with an estimated prevalence to be less than 6 per 1,000,000"
The published worldwide upper bound. The entry does not claim the true figure is this number.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Imerslund-Grasbeck Syndrome Type 1:

Imerslund-Grasbeck syndrome type 2 Not Yet Curated MONDO:0100157
Overlapping Features The AMN half of the same receptor. Clinically it is the same disease and is not separable at the bedside; only sequencing distinguishes them.
Distinguishing Features
  • Biallelic AMN variants rather than CUBN variants.
  • The Norwegian founder cluster and the Middle Eastern AMN c.208-2A>G founder allele belong to type 2.
  • Congenital urinary tract anomalies were reported in the original Norwegian AMN-mutant series and were rare in the Finnish CUBN-mutant patients.
Show evidence (2 references)
PMID:16722557 SUPPORT Human Clinical
"Congenital anomalies were rare in the Finnish patients carrying the CUBN mutation but urinary tract anomalies were observed in the Norwegian patients carrying the AMN mutation."
The one reported phenotypic difference between the two genes.
PMID:22078000 SUPPORT Human Clinical
"This mutation causes over 50% of the IGS cases among Arabic, Turkish, and Sephardic Jewish families, making it a primary target for genetic screening among diverse IGS cases originating from the Middle East."
The founder allele referred to is AMN c.208-2A>G, so this quote assigns the majority of Middle Eastern IGS to type 2 rather than to this entry.
Hereditary intrinsic factor deficiency MONDO:0009852
Overlapping Features GIF variants abolish intrinsic factor itself rather than its receptor. The cobalamin deficiency is identical; the receptor is intact, so absorption is corrected by giving intrinsic factor, and there is no proteinuria. Historically a substantial share of published IGS cases were GIF cases.
Distinguishing Features
  • Proteinuria is typical of IGS and absent in intrinsic factor deficiency.
  • Absorption is corrected by administering intrinsic factor in GIF deficiency and is not in IGS.
  • The causal gene is GIF rather than CUBN or AMN.
Show evidence (2 references)
PMID:22929189 SUPPORT Human Clinical
"Recessive mutations in CUBN or AMN cause Imerslund-Gräsbeck Syndrome (IGS), while recessive mutations in GIF cause Intrinsic Factor Deficiency (IFD)."
The gene-level separation between the two disorders.
PMID:16722557 SUPPORT Human Clinical
"A recent study reported that IGS is difficult to distinguish from cases caused by mutations in the GIF (gastric intrinsic factor) gene [20]"
Records that the two have in practice been confused, which is why this differential is listed among the cobalamin disorders.
Steroid-resistant nephrotic syndrome
Overlapping Features Not a mechanistic mimic but the practical one: albumin-predominant proteinuria in a child invites a glomerular diagnosis, a renal biopsy and proteinuria-lowering treatment, none of which the CUBN patient needs.
Distinguishing Features
  • Renal function stays normal in CUBN-related proteinuria and declines in steroid-resistant nephrotic syndrome.
  • No biallelic CUBN variants were found in proteinuric patients with reduced renal function or focal segmental glomerulosclerosis.
Show evidence (1 reference)
PMID:31613795 SUPPORT Human Clinical
"By contrast, we did not found any biallelic CUBN variants in proteinuric patients with reduced renal function or focal segmental glomerulosclerosis."
The negative result that separates the two. Quoted verbatim, including the source's own grammatical slip.
🐁

Animal Models

2
Border Collie CUBN exon 53 frameshift
A naturally occurring canine CUBN disease. It is the model in which a CUBN lesion, rather than an AMN one, produces the syndrome, which matters because the mouse is not usable here: cubam has rodent-specific functions in embryogenesis and the AMN knockout is embryonic lethal. The Border Collie disease is milder and later in onset than the giant schnauzer and Australian shepherd AMN diseases.
Species
Dog
Genotype
CUBN exon 53 single-base deletion, homozygous
Publication
PMID:23746554
Pathograph links
Failure of Cubam Receptor Assembly at the Brush Border recapitulates fidelity: moderate observes: organism A spontaneous biallelic CUBN lesion in an outbred animal, producing cobalamin malabsorption with selective proteinuria, the same two-organ pattern as the human disease and from the same gene.
Limitations: The canine allele is a C-terminal (exon 53) frameshift, whereas human IGS alleles cluster in the N-terminal third. The model therefore demonstrates that a CUBN lesion can abrogate cubam function, but its allele is not positionally representative of the human mutation spectrum, and human C-terminal variants give isolated proteinuria rather than IGS. Fidelity is recorded as MODERATE rather than HIGH for that reason.
Show evidence (3 references)
PMID:23746554 SUPPORT Model Organism
"Dogs closely model human clinical cobalamin deficiency and cubam function. Genetic studies in mice on the receptor complex have been hampered by rodent-specific functions of cubam essential for embryonic development."
States why the dog is the model of record for cubam and why the mouse is not, which is the basis for treating this model as informative.
+ 2 more references
Beagle hereditary cobalamin malabsorption
A Beagle kindred with hereditary cobalamin malabsorption, used to test whether daily oral cobalamin can replace parenteral dosing.
Species
Dog
Genotype
CUBN c.786delC (exon 8), homozygous
Publication
PMID:30554416
Pathograph links
Systemic Cobalamin Deficiency measures fidelity: moderate observes: organism Used as a treatment-response model rather than a mechanism model: urinary methylmalonate is read as the metabolic index of cobalamin sufficiency under an oral regimen.
Limitations: Three animals, no concurrent control arm on the intervention, and one of the three excreted high methylmalonate for the first six months. A confounding antibiotic course preceded the fall in that animal's excretion, so the response cannot be attributed to the oral dose alone. The treatment report itself does not name the causal gene; the CUBN assignment rests on the separate genetic characterisation of this kindred cited below.
Readouts
Urinary methylmalonic acid to creatinine ratio
Direction: UNCHANGED
Interpretation: Stayed within the healthy-dog range on oral dosing in two of three animals, read as maintained cobalamin sufficiency.
Show evidence (1 reference)
PMID:30554416 SUPPORT Model Organism
"Urine MMA remained consistently low in 2 dogs (median, 2.5 mmol/mol creatinine; range, 1.2-9; healthy dogs ... median, 2.9 mmol/mol creatinine; range, 1.3-76.5)."
The measurement itself, with the healthy-animal comparison it is read against. Quoted in the ellipsis form the snippet auditor supports, because the source's bracketed cohort size sits mid-sentence.
Show evidence (3 references)
PMID:30554416 SUPPORT Model Organism
"Three client-owned Beagles with IGS and 48 healthy control dogs."
The cohort. Quoted to make the size of the evidence base explicit, since the treatment claim rests entirely on these three animals.
+ 2 more references
{ }

Source YAML

click to show 
name: Imerslund-Grasbeck Syndrome Type 1
creation_date: "2026-09-09T13:40:00Z"
category: Mendelian
synonyms:
- IGS type 1
- IGS-1
- megaloblastic anemia 1
- MGA1
- selective vitamin B12 malabsorption with proteinuria
- enterocyte intrinsic factor receptor, defect of
- CUBN-related Imerslund-Grasbeck syndrome
description: >-
  Imerslund-Grasbeck syndrome type 1 is an autosomal recessive disorder in which
  biallelic CUBN variants disable cubilin, the ligand-binding subunit of the
  cubam receptor. Cubam is a heterodimeric endocytic receptor that sits in the
  brush border of two epithelia only: the ileal enterocyte, where it takes up
  the intrinsic factor-cobalamin complex, and the renal proximal tubule cell,
  where it reabsorbs filtered low-molecular-weight proteins. One receptor lesion
  therefore produces a two-organ disease, and the two organ effects are
  independent of each other.

  The intestinal arm is the one that makes the patient ill. Cobalamin absorption
  fails at the final receptor step while intrinsic factor secretion and gastric
  acid output are normal, so children present between a few months and several
  years of age, once maternal stores are exhausted, with megaloblastic anemia,
  failure to thrive, recurrent infections and, less often, neurological signs.
  It is fully correctable: lifelong parenteral cobalamin restores and maintains
  health.

  The renal arm is not correctable and does not need to be. Proteinuria persists
  unchanged on treatment because cobalamin replacement bypasses the gut but does
  nothing for the tubular receptor, and it does not progress to renal failure.
  Reading that proteinuria as glomerular disease is the characteristic clinical
  error, and it has led to renal biopsies and proteinuria-lowering treatment in
  patients whose kidneys were never going to fail.

  Where in cubilin the lesion falls decides which arm is affected. Variants
  affecting the N-terminal third, which carries the CUB 5-8 intrinsic
  factor-cobalamin binding site and the amnionless-association helix, give the
  full IGS picture. Variants after the vitamin B12-binding domain leave
  cobalamin uptake intact and produce isolated benign albuminuria, a phenotype
  common enough to appear as an association in population cohorts.
disease_term:
  preferred_term: Imerslund-Grasbeck syndrome type 1
  term:
    id: MONDO:0100156
    label: Imerslund-Grasbeck syndrome type 1
parents:
- Inherited cobalamin malabsorption
- Megaloblastic anemia
references:
- reference: PMID:10080186
  title: Mutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1.
- reference: PMID:16722557
  title: Imerslund-Gräsbeck syndrome (selective vitamin B(12) malabsorption with proteinuria).
- reference: PMID:37710296
  title: "Imerslund-Gräsbeck syndrome: a comprehensive review of reported cases."
- reference: PMID:14576052
  title: The functional cobalamin (vitamin B12)-intrinsic factor receptor is a novel complex of cubilin and amnionless.
- reference: PMID:23746554
  title: An exon 53 frameshift mutation in CUBN abrogates cubam function and causes Imerslund-Gräsbeck syndrome in dogs.
- reference: PMID:31613795
  title: Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function.
- reference: PMID:30554416
  title: Daily oral cyanocobalamin supplementation in Beagles with hereditary cobalamin malabsorption (Imerslund-Gräsbeck syndrome) maintains normal clinical and cellular cobalamin status.
- reference: PMID:22929189
  title: "Inherited cobalamin malabsorption. Mutations in three genes reveal functional and ethnic patterns."
- reference: PMID:22078000
  title: Ancient founder mutation is responsible for Imerslund-Gräsbeck Syndrome among diverse ethnicities.
- reference: PMID:10887099
  title: Cubilin P1297L mutation associated with hereditary megaloblastic anemia 1 causes impaired recognition of intrinsic factor-vitamin B(12) by cubilin.
- reference: PMID:20237569
  title: Structural basis for receptor recognition of vitamin-B(12)-intrinsic factor complexes.
- reference: PMID:30295181
  title: "Cubilin, the Intrinsic Factor-Vitamin B12 Receptor in Development and Disease."
- reference: PMID:11581259
  title: Identification and characterization of two distinct ligand binding regions of cubilin.
- reference: PMID:15024727
  title: "Genetically heterogeneous selective intestinal malabsorption of vitamin B12: founder effects, consanguinity, and high clinical awareness explain aggregations in Scandinavia and the Middle East."
- reference: PMID:15845892
  title: Amnionless function is required for cubilin brush-border expression and intrinsic factor-cobalamin (vitamin B12) absorption in vivo.
- reference: PMID:24156255
  title: Detailed investigations of proximal tubular function in Imerslund-Gräsbeck syndrome.
- reference: PMID:23613799
  title: A frameshift mutation in the cubilin gene (CUBN) in Border Collies with Imerslund-Gräsbeck syndrome (selective cobalamin malabsorption).
- reference: PMID:24433284
  title: "Selective intestinal cobalamin malabsorption with proteinuria (Imerslund-Gräsbeck syndrome) in juvenile Beagles."
- reference: PMID:22854512
  title: "How can cobalamin injections be spaced in long-term therapy for inborn errors of vitamin B(12) absorption?"
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Homozygous or compound heterozygous CUBN variants. Heterozygous carriers are
    clinically unaffected for the cobalamin phenotype.
  evidence:
  - reference: PMID:37710296
    reference_title: "Imerslund-Gräsbeck syndrome: a comprehensive review of reported cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Homozygous or compound heterozygous mutations in either CUBN or AMN lead to IGS
    explanation: >-
      States the recessive requirement for two damaged alleles, and that CUBN is
      one of the two genes that produce this phenotype.
  - reference: PMID:10080186
    reference_title: Mutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Megaloblastic anaemia 1 (MGA1, OMIM 261100) is a rare, autosomal recessive disorder characterized by juvenile megaloblastic anaemia, as well as neurological symptoms that may be the only manifestations.
    explanation: >-
      The original gene-mapping paper's own statement of the inheritance mode,
      and a reminder that a purely neurological presentation is possible.
prevalence:
- population: Finland
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 0.8
  notes: >-
    Reported as the highest national prevalence, in the linkage study that
    identified CUBN. Finland and Norway both carry founder alleles, but the
    Finnish founder alleles are the CUBN ones; the Norwegian cluster is AMN and
    so belongs to IGS type 2.
  evidence:
  - reference: PMID:10080186
    reference_title: Mutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MGA1 occurs worldwide, but its prevalence is higher in several Middle Eastern countries and Norway, and highest in Finland (0.8/100,000).
    explanation: >-
      The population figure, with the geographic distribution it belongs to.
  - reference: PMID:15024727
    reference_title: "Genetically heterogeneous selective intestinal malabsorption of vitamin B12: founder effects, consanguinity, and high clinical awareness explain aggregations in Scandinavia and the Middle East."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We studied 42 sibships and found all cases in Finland to be due to CUBN (three different mutations) and all cases in Norway to be due to AMN (two different mutations)
    explanation: >-
      The gene-by-country split this record's notes assert. It is what makes the
      Finnish figure a prevalence for IGS type 1 specifically rather than for
      IGS as a whole.
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_high: 0.6
  notes: >-
    A published ceiling rather than a point estimate, which is why only
    rate_high is populated. It also covers IGS as a whole rather than the CUBN
    half of it; about 300 cases had been published worldwide as of 2006.
  evidence:
  - reference: PMID:37710296
    reference_title: "Imerslund-Gräsbeck syndrome: a comprehensive review of reported cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IGS is a rare disorder with an estimated prevalence to be less than 6 per 1,000,000
    explanation: >-
      The published worldwide upper bound. The entry does not claim the true
      figure is this number.
pathophysiology:
- name: Biallelic CUBN Loss-of-Function Variants
  biological_scale: MOLECULAR
  description: >-
    Nonsense, frameshift, splice and missense variants on both CUBN alleles.
    Cubilin is a 460 kDa protein built from an N-terminal alpha helix, eight EGF
    domains and 27 CUB domains; the intrinsic factor-cobalamin binding site is
    CUB domains 5-8 and the amnionless-binding region is the N-terminal helix.
    Both lie in the N-terminal third, which is where IGS-causing alleles fall.
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  downstream:
  - target: Failure of Cubam Receptor Assembly at the Brush Border
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23746554
      reference_title: An exon 53 frameshift mutation in CUBN abrogates cubam function and causes Imerslund-Gräsbeck syndrome in dogs.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        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.
      explanation: >-
        States that cubilin only forms a functional receptor in concert with
        AMN, which is the step this edge asserts, and names both epithelia the
        receptor serves.
  evidence:
  - reference: PMID:10080186
    reference_title: Mutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have now refined the MGA1 region by linkage disequilibrium (LD) mapping, fine-mapped CUBN and identified two independent disease-specific CUBN mutations in 17 Finnish MGA1 families.
    explanation: >-
      The genetic evidence that CUBN variants are the lesion in this disease.
  - reference: PMID:23746554
    reference_title: An exon 53 frameshift mutation in CUBN abrogates cubam function and causes Imerslund-Gräsbeck syndrome in dogs.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      CUB domains 5-8 comprise the essential IF-Cbl binding site ... and the N-terminal alpha helical region mediates association with AMN
    explanation: >-
      Locates the two functional sites within cubilin that an IGS-causing allele
      has to damage. Quoted in the ellipsis form the snippet auditor supports,
      because the source's inline citation markers sit between the two clauses.
- name: Failure of Cubam Receptor Assembly at the Brush Border
  biological_scale: MOLECULAR
  description: >-
    Cubilin has no transmembrane domain and no endocytic motif of its own.
    Amnionless supplies both, binding the N-terminal third of cubilin and
    carrying it to the apical surface; neither subunit endocytoses ligand alone.
    A cubilin that cannot bind amnionless, or cannot bind intrinsic
    factor-cobalamin, leaves a brush border without a working receptor.

    Cubam is not the whole endocytic machine. Megalin (LRP2) is required for
    efficient internalization of cubilin and its ligands, so apical uptake
    depends on a three-protein system in which CUBN supplies ligand
    recognition and the other two supply membrane anchoring and internalization.
    The same cubilin regions bind intrinsic factor-cobalamin and albumin, which
    is why one receptor lesion produces both the intestinal and the renal arm of
    this disease rather than one or the other.
  cellular_components:
  - preferred_term: apical brush border membrane
    term:
      id: GO:0016324
      label: apical plasma membrane
  molecular_functions:
  - preferred_term: intrinsic factor-cobalamin binding by cubilin
    modifier: DECREASED
    term:
      id: GO:0031419
      label: cobalamin binding
  downstream:
  - target: Loss of Ileal Intrinsic Factor-Cobalamin Endocytosis
    causal_link_type: DIRECT
  - target: Loss of Proximal Tubular Reabsorption of Filtered Protein
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:14576052
    reference_title: The functional cobalamin (vitamin B12)-intrinsic factor receptor is a novel complex of cubilin and amnionless.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In transfected cells expressing either AMN or a truncated IF-cobalamin-binding cubilin construct, neither protein alone conferred ligand endocytosis.
    explanation: >-
      The transfection experiment establishing that a lone cubilin subunit
      cannot endocytose ligand, which is why a CUBN lesion abolishes receptor
      function rather than merely reducing it.
  - reference: PMID:14576052
    reference_title: The functional cobalamin (vitamin B12)-intrinsic factor receptor is a novel complex of cubilin and amnionless.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These data indicate that cubilin and AMN are subunits of a novel cubilin/AMN (cubam) complex, where AMN binds to the amino-terminal third of cubilin and directs subcellular localization and endocytosis of cubilin with its ligand.
    explanation: >-
      Defines the cubam complex and the division of labour between its two
      subunits that this node depends on.
  - reference: PMID:20237569
    reference_title: Structural basis for receptor recognition of vitamin-B(12)-intrinsic factor complexes.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      This occurs by the combined action of the gastric intrinsic factor (IF) and the ileal endocytic cubam receptor formed by the 460-kilodalton (kDa) protein cubilin and the 45-kDa transmembrane protein amnionless.
    explanation: >-
      Names the two cubam subunits and their masses, and places the complex at
      the ileal apical surface where this node locates the failure. Graded
      INDIRECT because this is the paper's statement of normal physiology, from
      which the consequence of losing the receptor follows by inference.
  - reference: PMID:30295181
    reference_title: "Cubilin, the Intrinsic Factor-Vitamin B12 Receptor in Development and Disease."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      AMN is involved in appropriate plasma membrane transport of Cubilin whereas Lrp2 is essential for efficient internalization of Cubilin and its ligands.
    explanation: >-
      Adds megalin/LRP2 as a third required component of apical uptake. Graded
      INDIRECT because the review states the general requirement for cubilin
      internalization rather than measuring it in an IGS receptor.
  - reference: PMID:15845892
    reference_title: Amnionless function is required for cubilin brush-border expression and intrinsic factor-cobalamin (vitamin B12) absorption in vivo.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Studies in vivo demonstrated that both mutations abrogate AMN expression and block cubilin processing and targeting to the apical membrane.
    explanation: >-
      Shows the subunit interdependence in a whole animal rather than a
      transfected cell. Graded INDIRECT because the lesion studied is in AMN and
      this entry's lesion is in CUBN; it establishes that the two subunits are
      mutually required, not that a CUBN allele does this.
  - reference: PMID:11581259
    reference_title: Identification and characterization of two distinct ligand binding regions of cubilin.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      These results indicate that (a) cubilin contains two distinct regions that bind both IF-Cbl and albumin
    explanation: >-
      The shared-ligand result behind the two-organ split. Graded INDIRECT
      because it maps binding regions in a cell-free system rather than showing
      that an IGS allele abolishes both ligands at once.
- name: Loss of Ileal Intrinsic Factor-Cobalamin Endocytosis
  biological_scale: CELLULAR
  description: >-
    Every upstream step of cobalamin handling is normal: gastric acid, intrinsic
    factor secretion, haptocorrin release and pancreatic proteolysis. The block
    is at the single receptor-mediated uptake step in the distal ileum, which is
    why the malabsorption is selective for cobalamin rather than general, and
    why giving intrinsic factor with the test dose does not correct it.
  cell_types:
  - preferred_term: ileal enterocyte
    term:
      id: CL:1000334
      label: enterocyte of epithelium of small intestine
  biological_processes:
  - preferred_term: receptor-mediated uptake of the intrinsic factor-cobalamin complex
    modifier: DECREASED
    term:
      id: GO:0006898
      label: receptor-mediated endocytosis
  - preferred_term: intestinal cobalamin transport
    modifier: DECREASED
    term:
      id: GO:0015889
      label: cobalamin transport
  downstream:
  - target: Systemic Cobalamin Deficiency
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:16722557
      reference_title: Imerslund-Gräsbeck syndrome (selective vitamin B(12) malabsorption with proteinuria).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        IGS is caused by a selective incapacity to transport vitamin B12 across the intestinal wall, and is not related to a lack of gastric intrinsic factor.
      explanation: >-
        States that the transport failure is what produces the deficiency, and
        excludes the upstream intrinsic-factor step as the cause.
  evidence:
  - reference: PMID:16722557
    reference_title: Imerslund-Gräsbeck syndrome (selective vitamin B(12) malabsorption with proteinuria).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The cause is a defect in the receptor of the vitamin B(12)-intrinsic factor complex of the ileal enterocyte.
    explanation: >-
      Names the cell and the receptor step at which absorption fails.
  - reference: PMID:16722557
    reference_title: Imerslund-Gräsbeck syndrome (selective vitamin B(12) malabsorption with proteinuria).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Vitamin B(12) absorption tests show low absorption, not corrected by administration of intrinsic factor.
    explanation: >-
      The observation that localises the block distal to intrinsic factor, which
      is what distinguishes this node from pernicious anemia.
- name: Loss of Proximal Tubular Reabsorption of Filtered Protein
  biological_scale: CELLULAR
  description: >-
    The same receptor operates in the proximal tubule, where it retrieves
    albumin, vitamin D binding protein, transferrin, apolipoprotein A1 and other
    filtered proteins from the primary urine. Cubam loss there produces
    persistent proteinuria with a high albumin fraction. This arm runs in
    parallel with the intestinal arm from the same lesion; it is not a
    consequence of the cobalamin deficiency, which is why replacing cobalamin
    does not touch it.
  cell_types:
  - preferred_term: renal proximal tubule epithelial cell
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  biological_processes:
  - preferred_term: receptor-mediated retrieval of filtered protein
    modifier: DECREASED
    term:
      id: GO:0006898
      label: receptor-mediated endocytosis
  downstream:
  - target: Persistent Non-Progressive Proteinuria
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:23746554
    reference_title: An exon 53 frameshift mutation in CUBN abrogates cubam function and causes Imerslund-Gräsbeck syndrome in dogs.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Cubam is a multi-ligand, endocytic receptor expressed in epithelial brush borders of distal small intestine and renal proximal tubules.
    explanation: >-
      Places the same receptor in the proximal tubule, which is what makes the
      renal arm a direct consequence of the same lesion.
  - reference: PMID:31613795
    reference_title: Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Collectively, our data suggest an important role for the C-terminal half of cubilin in renal albumin reabsorption.
    explanation: >-
      Human genetic evidence that cubilin function is what performs the tubular
      albumin retrieval this node describes.
  - reference: PMID:24156255
    reference_title: Detailed investigations of proximal tubular function in Imerslund-Gräsbeck syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analysis of urinary protein excretion in the patients and 20 healthy controls revealed increased urinary excretion of cubilin ligands including apolipoprotein A-I, transferrin, vitamin D-binding protein, and albumin.
    explanation: >-
      Measures the lost reabsorption directly in IGS patients, and names the
      ligands, which is what makes this a cubilin-ligand leak rather than
      generic tubular injury.
  - reference: PMID:24156255
    reference_title: Detailed investigations of proximal tubular function in Imerslund-Gräsbeck syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This was, however, only observed in patients where plasma membrane expression of cubilin was predicted to be perturbed.
    explanation: >-
      Ties the renal arm to receptor surface expression rather than to the
      diagnosis. Patients whose cubilin still reaches the membrane did not leak.
- name: Systemic Cobalamin Deficiency
  biological_scale: ORGANISM
  description: >-
    Body cobalamin stores are large relative to daily need, so the deficiency
    declares itself only after maternal stores run down, from about four months
    of age and sometimes not for years. Both cobalamin-dependent enzymes fail:
    methionine synthase, giving hyperhomocysteinemia and the functional folate
    trap that blocks thymidylate synthesis, and methylmalonyl-CoA mutase, giving
    methylmalonic acidemia and aciduria.
  downstream:
  - target: Megaloblastic Erythropoiesis
    causal_link_type: DIRECT
  - target: Cobalamin-Dependent Enzyme Block
    causal_link_type: DIRECT
  - target: Decreased circulating vitamin B12 concentration
    causal_link_type: DIRECT
    description: >-
      The measurement of this node rather than a consequence of it. Drawn as an
      edge because the serum level is what a clinician sees, and the node is the
      systemic state it reports.
  - target: Failure to thrive
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Growth failure in an infant with untreated deficiency. The intermediate
      steps between the cofactor loss and the growth curve are not established
      here, so the edge is typed as indirect.
  - target: Abnormal oral mucosa morphology
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Oral mucosal lesions follow the same impaired DNA synthesis that produces
      the megaloblastic marrow, in another rapidly dividing epithelium. Typed
      indirect because no source cited here demonstrates that route in IGS.
  evidence:
  - reference: PMID:16722557
    reference_title: Imerslund-Gräsbeck syndrome (selective vitamin B(12) malabsorption with proteinuria).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The symptoms appear from 4 months (not immediately after birth as in transcobalamin deficiency) up to several years after birth.
    explanation: >-
      The delayed onset that follows from stores having to be exhausted first,
      and the contrast with a disorder that has no such buffer.
  - reference: PMID:22929189
    reference_title: "Inherited cobalamin malabsorption. Mutations in three genes reveal functional and ethnic patterns."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recessive mutations in CUBN or AMN cause Imerslund-Gräsbeck Syndrome (IGS), while recessive mutations in GIF cause Intrinsic Factor Deficiency (IFD).
    explanation: >-
      Confirms the gene-to-disease assignment used throughout this entry and
      separates it from the intrinsic-factor disorder with the same downstream
      deficiency.
- name: Cobalamin-Dependent Enzyme Block
  biological_scale: MOLECULAR
  description: >-
    Cobalamin is the cofactor of exactly two human enzymes, and a systemic
    deficiency disables both at once. Methionine synthase stops converting
    homocysteine to methionine, so homocysteine accumulates and the methyl
    donor pool contracts; methylmalonyl-CoA mutase stops converting
    methylmalonyl-CoA to succinyl-CoA, so methylmalonate accumulates. This is
    the node the two biochemical markers report on, and it is why they rise
    together rather than independently.
  molecular_functions:
  - preferred_term: methionine synthase activity
    modifier: DECREASED
    term:
      id: GO:0008705
      label: methionine synthase activity
  - preferred_term: methylmalonyl-CoA mutase activity
    modifier: DECREASED
    term:
      id: GO:0004494
      label: methylmalonyl-CoA mutase activity
  downstream:
  - target: Hyperhomocystinemia
    causal_link_type: DIRECT
  - target: Methylmalonic aciduria
    causal_link_type: DIRECT
  - target: Neurotoxic Metabolite Exposure and Impaired Myelination
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:22854512
    reference_title: "How can cobalamin injections be spaced in long-term therapy for inborn errors of vitamin B(12) absorption?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      Names all three consequences of the cofactor loss in one sentence, in a
      paper about this disease group specifically, which is what makes this one
      node rather than three unrelated findings.
  - reference: PMID:22078000
    reference_title: Ancient founder mutation is responsible for Imerslund-Gräsbeck Syndrome among diverse ethnicities.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The primary diagnostic criteria are reduced vitamin B12 levels in the serum, elevated homocysteine and methylmalonic acid levels in the blood and urine, and often mild proteinuria.
    explanation: >-
      The two metabolites are used together as diagnostic criteria, which is the
      clinical expression of a single shared cause. Graded INDIRECT because it
      states the diagnostic pairing rather than the enzymology behind it.
- name: Neurotoxic Metabolite Exposure and Impaired Myelination
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    The proposed route from the enzyme block to the neurological findings: less
    methylation available for myelin maintenance, plus direct toxicity of the
    accumulated homocysteine and methylmalonate. The source states this as an
    attribution rather than a demonstration, and no cited work here measures
    myelin or metabolite exposure in an IGS patient's nervous system, so the
    node is PROVISIONAL and its incoming edge is typed as indirect with unknown
    intermediates.
  biological_processes:
  - preferred_term: myelination
    modifier: DECREASED
    term:
      id: GO:0042552
      label: myelination
  downstream:
  - target: Ataxia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Lethargy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Spinal cord lesion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:37710296
    reference_title: "Imerslund-Gräsbeck syndrome: a comprehensive review of reported cases."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurocognitive symptoms have been attributed to several pathophysiological mechanisms, including decreased myelinization as a result of impaired methylation due to vitB12 shortage and the direct toxic effects of homocysteine and methylmalonic acid
    explanation: >-
      The mechanism, quoted with the hedge the authors wrote. "Have been
      attributed to" is an attribution of causes, not a measurement, which is
      the reason this node carries mechanism_confidence PROVISIONAL and this
      item is graded INDIRECT.
- name: Megaloblastic Erythropoiesis
  biological_scale: TISSUE
  description: >-
    Cobalamin deficiency traps folate as methyltetrahydrofolate, starving
    thymidylate synthesis. DNA replication in the marrow falls out of step with
    cytoplasmic maturation, so erythroid precursors enlarge and are destroyed
    before release. All rapidly dividing lineages are affected, which is why
    neutropenia and thrombocytopenia accompany the anemia.
  cell_types:
  - preferred_term: erythroid precursor
    term:
      id: CL:0000038
      label: erythroid progenitor cell
  downstream:
  - target: Megaloblastic anemia
    causal_link_type: DIRECT
  - target: Macrocytic anemia
    causal_link_type: DIRECT
    description: >-
      The red-cell index the megaloblastic marrow produces; the same event seen
      on the blood count rather than in the marrow.
  - target: Pancytopenia
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:16722557
    reference_title: Imerslund-Gräsbeck syndrome (selective vitamin B(12) malabsorption with proteinuria).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Megaloblastic anemia is caused by inability of the hematopoietic cells to divide, due to failure of DNA replication.
    explanation: >-
      The cellular mechanism this node asserts, stated for this disease.
- name: Persistent Non-Progressive Proteinuria
  biological_scale: ORGANISM
  description: >-
    Proteinuria that is present in roughly half of patients, does not change on
    cobalamin replacement, and does not lead to loss of renal function. It is
    reported as neither typically glomerular nor typically tubular in pattern,
    and in the isolated C-terminal-variant phenotype it is predominantly
    albuminuria.
  downstream:
  - target: Proteinuria
    causal_link_type: DIRECT
  - target: Albuminuria
    causal_link_type: DIRECT
    description: >-
      Albumin is one of the cubilin ligands the tubule stops retrieving, and it
      is the fraction that dominates in the C-terminal-variant phenotype.
  evidence:
  - reference: PMID:16722557
    reference_title: Imerslund-Gräsbeck syndrome (selective vitamin B(12) malabsorption with proteinuria).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both studies indicated that in properly treated patients, the proteinuria persisted over the years without noticeable change and that kidney function did not deteriorate.
    explanation: >-
      Establishes both halves of this node: that the proteinuria survives
      treatment, and that it is not nephrotoxic.
  - reference: PMID:31613795
    reference_title: Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, renal function was normal in all cases.
    explanation: >-
      An independent cohort in which biallelic CUBN proteinuria was not
      accompanied by any loss of renal function.
phenotypes:
- name: Megaloblastic anemia
  category: Hematologic
  description: >-
    The presenting abnormality in most cases: macrocytic, megaloblastic and
    fully responsive to parenteral cobalamin.
  phenotype_term:
    preferred_term: Megaloblastic anemia
    term:
      id: HP:0001889
      label: Megaloblastic anemia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:16722557
    reference_title: Imerslund-Gräsbeck syndrome (selective vitamin B(12) malabsorption with proteinuria).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      Names megaloblastic anemia as the characteristic manifestation and records
      its response to replacement.
- name: Macrocytic anemia
  category: Hematologic
  description: >-
    The routine-laboratory face of the same finding, with raised mean corpuscular
    volume and mean corpuscular hemoglobin.
  phenotype_term:
    preferred_term: Macrocytic anemia
    term:
      id: HP:0001972
      label: Macrocytic anemia
  evidence:
  - reference: PMID:37710296
    reference_title: "Imerslund-Gräsbeck syndrome: a comprehensive review of reported cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Laboratory examination often reveals macrocytic anemia with or without proteinuria
    explanation: >-
      The laboratory presentation as described in the review of reported cases.
- name: Proteinuria
  category: Renal
  description: >-
    Mild, persistent, and unaccompanied by any decline in renal function.

    The frequency is contested, and the disagreement is worth carrying rather
    than resolving. A 2006 review put it at about half of patients. The 2023
    systematic review of every published case found 212 of 239 patients with
    documented urinalysis had it, 89%, and recommends urinalysis in any child
    with vitamin B12 deficiency on the strength of that. The same review then
    argues against its own number: urinalysis was documented in far fewer
    patients than clinical features were, so 62% may be closer, and patients
    without proteinuria are less likely to be worked up for IGS at all, which
    inflates the observed fraction. The band recorded here follows the
    systematic review's primary figure. Its own lower estimate, 62%, sits in the
    FREQUENT band instead, so this entry does not treat the choice as settled.

    Finland is the documented exception, at 20% against 89% elsewhere. That
    matters here specifically: the Finnish founder allele recorded in the
    variants section is a missense change that reduces intrinsic
    factor-cobalamin affinity rather than abolishing the receptor, which is a
    candidate explanation for a spared renal arm.

    Its absence does not exclude the diagnosis under any of these figures.
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
    temporality: CHRONIC
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:37710296
    reference_title: "Imerslund-Gräsbeck syndrome: a comprehensive review of reported cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 239/456 patients, urinalysis was documented. Of these patients, 212 (89%) had proteinuria. Only in Finland, the fraction of patients with proteinuria was lower than in other countries (20% had proteinuria, 18% had no proteinuria, 62% had no urinalysis).
    explanation: >-
      The systematic review's primary figure, and the Finnish exception, in the
      one sentence pair that gives both. This is the source for the frequency
      band recorded here.
  - reference: PMID:37710296
    reference_title: "Imerslund-Gräsbeck syndrome: a comprehensive review of reported cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It may be possible that 89% proteinuria is an overestimation and that the number of patients with proteinuria may be closer to 62% (203 patients with proteinuria among 325 patients in which clinical characteristics were described).
    explanation: >-
      The same review arguing against its own headline figure. Quoted so the
      entry carries the caveat rather than only the number, since 62% would sit
      one band lower.
  - reference: PMID:16722557
    reference_title: Imerslund-Gräsbeck syndrome (selective vitamin B(12) malabsorption with proteinuria).
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mild proteinuria (with no signs of kidney disease) is present in about half of the patients.
    explanation: >-
      The older estimate, retained and graded REFUTE against the VERY_FREQUENT
      band this record now carries. It is not a discredited source; it is the
      other side of an unsettled figure, and it also supplies the fact that the
      proteinuria carries no renal disease.
- name: Albuminuria
  category: Renal
  description: >-
    In the C-terminal-variant phenotype the proteinuria has a high albumin
    fraction, which is what leads to it being mistaken for glomerular disease.
  phenotype_term:
    preferred_term: Albuminuria
    term:
      id: HP:0012592
      label: Albuminuria
  evidence:
  - reference: PMID:31613795
    reference_title: Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Since the proteinuria in these patients had a high proportion of albuminuria, glomerular diseases such as steroid-resistant nephrotic syndrome or Alport syndrome were often the primary clinical diagnosis, motivating renal biopsies and the use of proteinuria-lowering treatments.
    explanation: >-
      Records the albumin-predominant pattern and the misdiagnosis it causes.
- name: Decreased circulating vitamin B12 concentration
  category: Biochemical
  description: >-
    Low serum cobalamin is the entry point to the diagnosis; the subsequent work
    is establishing that malabsorption is the cause and that it is selective.
  phenotype_term:
    preferred_term: Decreased circulating vitamin B12 concentration
    term:
      id: HP:0100502
      label: Decreased circulating vitamin B12 concentration
  evidence:
  - reference: PMID:37710296
    reference_title: "Imerslund-Gräsbeck syndrome: a comprehensive review of reported cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Imerslund-Gräsbeck syndrome (IGS, OMIM 261,100/618,882) is an autosomal recessive disorder characterized by a vitamin B12 (vitB12) deficiency, caused by a selective malabsorption of vitB12, with normal secretion of intrinsic factor (IF) and hydrochloric acid into the stomach [1].
    explanation: >-
      States the deficiency and, in the same sentence, that the upstream gastric
      steps are intact.
- name: Failure to thrive
  category: Growth
  description: >-
    Often the reason the child is brought to attention, before anemia is found.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:37710296
    reference_title: "Imerslund-Gräsbeck syndrome: a comprehensive review of reported cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Before the diagnosis of vitB12 deficiency, patients have non-specific symptoms such as failure to thrive, paleness, fatigue, recurring viral infections and mild neurological symptoms.
    explanation: >-
      Lists failure to thrive among the presenting non-specific features.
- name: Recurrent infections
  category: Immunologic
  description: >-
    Recurrent viral and other infections, attributable to the cobalamin-dependent
    marrow failure affecting the leukocyte lineages as well as the erythroid one.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:37710296
    reference_title: "Imerslund-Gräsbeck syndrome: a comprehensive review of reported cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Before the diagnosis of vitB12 deficiency, patients have non-specific symptoms such as failure to thrive, paleness, fatigue, recurring viral infections and mild neurological symptoms.
    explanation: >-
      The same presenting-symptom list, quoted for the infection component.
- name: Methylmalonic aciduria
  category: Biochemical
  description: >-
    Raised urinary methylmalonic acid reflects failure of the second
    cobalamin-dependent enzyme, methylmalonyl-CoA mutase. It is the marker used
    to follow adequacy of replacement.
  phenotype_term:
    preferred_term: Methylmalonic aciduria
    term:
      id: HP:0012120
      label: Methylmalonic aciduria
  evidence:
  - reference: PMID:23746554
    reference_title: An exon 53 frameshift mutation in CUBN abrogates cubam function and causes Imerslund-Gräsbeck syndrome in dogs.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Other documented abnormalities included low serum cobalamin concentrations, methylmalonic aciduria, and mild proteinuria.
    explanation: >-
      Records methylmalonic aciduria in the CUBN-mutant canine disease. Graded
      as model-organism evidence because the cohort described is canine; the
      marker itself is standard in the human disorder.
- name: Hyperhomocystinemia
  category: Biochemical
  description: >-
    Raised plasma homocysteine follows from methionine synthase failure and
    accompanies the raised methylmalonate.
  phenotype_term:
    preferred_term: Hyperhomocystinemia
    term:
      id: HP:0002160
      label: Hyperhomocystinemia
  evidence:
  - reference: PMID:22078000
    reference_title: Ancient founder mutation is responsible for Imerslund-Gräsbeck Syndrome among diverse ethnicities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The primary diagnostic criteria are reduced vitamin B12 levels in the serum, elevated homocysteine and methylmalonic acid levels in the blood and urine, and often mild proteinuria [3].
    explanation: >-
      Lists the two raised metabolites among the diagnostic criteria for IGS.
      The cohort in this paper is AMN-mutant, so the quote is used only for the
      biochemistry shared by both genes, not for any CUBN-specific claim.
- category: Neurologic
  name: Ataxia
  frequency: VERY_RARE
  description: >-
    Neurological involvement is reported in 16% of IGS patients overall; ataxia
    is the second most common neurological finding within that group (10 of 52),
    which the review's own discussion puts at 4% of all IGS patients. The
    frequency band here is for the whole cohort, not for the neurological
    subgroup.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:37710296
    reference_title: "Imerslund-Gräsbeck syndrome: a comprehensive review of reported cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurological manifestations were observed in 52 patients (16%). Most frequently, patients showed lethargy (n = 13, 25%), ataxia (n = 10, 19%), and motor or sensory deficits (n = 7, 13%).
    explanation: >-
      The counts behind both this phenotype and Lethargy. The percentages inside
      the quote are shares of the 52 patients with neurological findings, which
      is why the frequency band assigned here is lower than the quoted 19%.
- category: Neurologic
  name: Lethargy
  frequency: VERY_RARE
  description: >-
    The most common neurological finding in the systematic review, 13 of the 52
    patients with any neurological manifestation. Non-specific, and one of the
    reasons the diagnosis is usually reached through the anemia rather than
    through the neurology.
  phenotype_term:
    preferred_term: Lethargy
    term:
      id: HP:0001254
      label: Lethargy
  evidence:
  - reference: PMID:37710296
    reference_title: "Imerslund-Gräsbeck syndrome: a comprehensive review of reported cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurological manifestations were observed in 52 patients (16%). Most frequently, patients showed lethargy (n = 13, 25%), ataxia (n = 10, 19%), and motor or sensory deficits (n = 7, 13%).
    explanation: >-
      Gives lethargy as the most frequent neurological manifestation, with the
      count it rests on.
- category: Neurologic
  name: Spinal cord lesion
  frequency: VERY_RARE
  description: >-
    Funicular myelosis, that is subacute combined degeneration of the cord, in 5
    of the 52 patients with neurological findings. It is the manifestation that
    makes untreated IGS a neurological emergency rather than only a haematological
    one, and it is bound to the general spinal-cord-lesion term because HPO has no
    term for subacute combined degeneration.
  phenotype_term:
    preferred_term: funicular myelosis (subacute combined degeneration of the cord)
    term:
      id: HP:0100561
      label: Spinal cord lesion
  evidence:
  - reference: PMID:37710296
    reference_title: "Imerslund-Gräsbeck syndrome: a comprehensive review of reported cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      More severe clinical manifestations were present in 4% of IGS patients, which included funicular myelosis (subacute combined degeneration of the cord, n = 5, 10%), seizures (n = 3, 6%), focal cortical atrophy of the left insular region on MRI (n = 2; 3.8%) and progressive dementia (n = 1, 2%).
    explanation: >-
      The severe end of the neurological spectrum, with the count for funicular
      myelosis specifically.
- category: Hematologic
  name: Pancytopenia
  description: >-
    Cobalamin deficiency suppresses all three marrow lineages, so neutropenia and
    thrombocytopenia accompany the anemia rather than being separate events. No
    frequency is recorded because no source cited here counts it.
  phenotype_term:
    preferred_term: Pancytopenia
    term:
      id: HP:0001876
      label: Pancytopenia
  sequelae:
  - target: Recurrent infections
    description: >-
      The neutropenic limb of the pancytopenia is the route by which cobalamin
      deficiency produces the recurrent infections this entry already records.
  evidence:
  - reference: PMID:22854512
    reference_title: "How can cobalamin injections be spaced in long-term therapy for inborn errors of vitamin B(12) absorption?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical presentation reflects Cbl deficiency, with gastrointestinal symptoms, pancytopenia, and megaloblastic anemia.
    explanation: >-
      Names pancytopenia alongside the megaloblastic anemia in a series of
      patients with inborn cobalamin malabsorption, which is this disease group.
- category: Oral
  name: Abnormal oral mucosa morphology
  frequency: OCCASIONAL
  description: >-
    Oral mucosal lesions in 17% of reviewed patients. The review names it as one
    of the findings that does prompt further testing, which matters for a disease
    it argues is systematically underdiagnosed.
  phenotype_term:
    preferred_term: oral mucosal lesions
    term:
      id: HP:0011830
      label: Abnormal oral mucosa morphology
  evidence:
  - reference: PMID:37710296
    reference_title: "Imerslund-Gräsbeck syndrome: a comprehensive review of reported cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition to non-specific symptoms, we observed a relatively high amount of oral mucosal lesions in 17% of the patients.
    explanation: >-
      The frequency this phenotype's band is taken from.
genetic:
- name: CUBN
  association: Causal biallelic variant
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: CUBN
    term:
      id: hgnc:2548
      label: CUBN
  notes: >-
    Cubilin is the 460 kDa ligand-binding subunit of cubam, encoded in 67 exons
    on chromosome 10p12.1.

    Where the variant falls in the gene decides which of the two organ arms is
    affected, and this is the most useful genotype-phenotype fact about CUBN.
    IGS-causing alleles cluster in the N-terminal third, which holds both the
    amnionless-association helix and the CUB 5-8 intrinsic factor-cobalamin
    binding site. Variants after the vitamin B12-binding domain leave intestinal
    cobalamin uptake intact and present instead as isolated childhood-onset
    albuminuria with normal renal function, a phenotype mild enough that four
    such variants show up as albuminuria associations in population cohorts. A
    C-terminal CUBN genotype should therefore not be reported as IGS without
    evidence of cobalamin malabsorption.
  evidence:
  - reference: PMID:31613795
    reference_title: Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Unlike the more N-terminal IGS mutations, 37 of the 41 proteinuria-associated CUBN variants led to modifications or truncations after the vitamin B12-binding domain.
    explanation: >-
      The positional split itself, stated as a contrast against the IGS allele
      distribution.
  - reference: PMID:31613795
    reference_title: Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified 39 patients, in whom biallelic pathogenic variants in the CUBN gene were associated with chronic isolated proteinuria and early childhood onset.
    explanation: >-
      The cohort establishing the isolated-proteinuria end of the CUBN spectrum.
  - reference: PMID:31613795
    reference_title: Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Finally, we show that 4 C-terminal CUBN variants are associated with albuminuria and slightly increased GFR in meta-analyses of large population-based cohorts.
    explanation: >-
      The population-cohort signal, which is what makes the C-terminal phenotype
      a common benign condition rather than a rare disease variant.
  variants:
  - name: c.3890C>T (p.Pro1297Leu), Finnish founder allele FM1
    description: >-
      The Finnish major mutation. It sits in CUB domain 8, inside the CUB 5-8
      intrinsic factor-cobalamin binding region, and is a missense change rather
      than a truncation, so cubilin still reaches the brush border. What it
      destroys is ligand recognition: surface plasmon resonance shows the
      substitution raises the dissociation constant for intrinsic
      factor-cobalamin several-fold, mostly by slowing association. This is the
      allele behind the Finnish prevalence figure this entry records, and it is
      the cleanest evidence that IGS is a receptor-affinity disease and not only
      a receptor-abundance one.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:10887099
      reference_title: Cubilin P1297L mutation associated with hereditary megaloblastic anemia 1 causes impaired recognition of intrinsic factor-vitamin B(12) by cubilin.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Most Finnish patients with MGA1 carry the disease-specific P1297L mutation (FM1) in the IF-B(12) receptor, cubilin.
      explanation: >-
        Establishes P1297L as the predominant Finnish allele and names it FM1.
    - reference: PMID:10887099
      reference_title: Cubilin P1297L mutation associated with hereditary megaloblastic anemia 1 causes impaired recognition of intrinsic factor-vitamin B(12) by cubilin.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Surface plasmon resonance analysis revealed that the P1297L substitution specifically increases the K(d) for IF-Cbl binding several-fold, largely by decreasing the association rate constant.
      explanation: >-
        The binding measurement that gives the allele its mechanism, and the
        basis for calling this a loss of ligand affinity rather than a loss of
        receptor.
treatments:
- name: Lifelong parenteral cobalamin replacement
  description: >-
    Intramuscular cobalamin bypasses the absent receptor entirely. It corrects
    the anemia, the metabolite abnormalities and the growth failure, and holds
    patients well for decades. It has no effect on the proteinuria, and it does
    not need to: the renal arm is not progressive. Replacement is lifelong
    because the receptor defect is permanent.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: hydroxocobalamin
      term:
        id: CHEBI:27786
        label: hydroxocobalamin
    - preferred_term: cyanocobalamin
      term:
        id: CHEBI:17439
        label: cyanocob(III)alamin
  target_mechanisms:
  - target: Systemic Cobalamin Deficiency
    description: >-
      Parenteral delivery restores tissue cobalamin without using the ileal
      receptor, so it corrects everything downstream of this node and nothing
      upstream of it.
  target_phenotypes:
  - preferred_term: Megaloblastic anemia
    term:
      id: HP:0001889
      label: Megaloblastic anemia
  evidence:
  - reference: PMID:16722557
    reference_title: Imerslund-Gräsbeck syndrome (selective vitamin B(12) malabsorption with proteinuria).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Management includes life-long vitamin B(12) injections, and with this regimen, the patients stay healthy for decades. However, the proteinuria persists.
    explanation: >-
      States the treatment, its duration, its effectiveness and the one thing it
      does not fix.
  - reference: PMID:37710296
    reference_title: "Imerslund-Gräsbeck syndrome: a comprehensive review of reported cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most IGS patients are treated with intra-muscular vitB12, which most frequently corrects the clinical phenotype [1].
    explanation: >-
      Confirms the route and the outcome across the reported case literature.
- name: Spaced parenteral maintenance dosing
  description: >-
    How far apart the injections can be spaced is a separate question from
    whether they work, and it is the one that decides quality of life for a
    lifelong regimen. A retrospective series of seven patients with inborn
    cobalamin malabsorption held normal clinical, haematological and metabolic
    status on 1 mg twice a year, which is far less frequent than the regimens
    previously recommended. Seven patients, retrospective, no control arm, so it
    is recorded as a dosing observation rather than a schedule this entry
    endorses.
  therapeutic_modality: SMALL_MOLECULE
  dosing_interval: once every 6 months
  dosing_interval_days: 182.5
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: hydroxocobalamin
      term:
        id: CHEBI:27786
        label: hydroxocobalamin
  target_mechanisms:
  - target: Systemic Cobalamin Deficiency
    description: >-
      The same replacement acting on the same node; this record is about the
      interval, not a different mechanism.
  evidence:
  - reference: PMID:22854512
    reference_title: "How can cobalamin injections be spaced in long-term therapy for inborn errors of vitamin B(12) absorption?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      The dosing result, in humans, with the explicit contrast against the
      previous recommendation that makes it a change rather than a confirmation.
- name: High-dose oral cobalamin
  description: >-
    Passive diffusion absorbs a small fraction of an oral dose independently of
    any receptor, so a large enough daily oral dose could in principle substitute
    for injections. The direct evidence in this disease is canine: three Beagles
    with hereditary cobalamin malabsorption were maintained in clinical and
    metabolic remission on 1 mg oral cyanocobalamin daily.

    No equivalent human trial exists in IGS. That is not the same as no human
    support: the 2023 systematic review states plainly that patients may be
    treated orally provided the dose is raised, and describes one of its own two
    new patients, an IGS sibling, corrected on 1 mg oral cyanocobalamin daily.
    So this is an accepted option supported by observation rather than an
    untested hypothesis, and what is missing is a controlled comparison against
    injections, not evidence that it works at all.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cyanocobalamin
      term:
        id: CHEBI:17439
        label: cyanocob(III)alamin
  target_mechanisms:
  - target: Systemic Cobalamin Deficiency
    description: >-
      The same node by a different route: receptor-independent passive uptake in
      place of the missing endocytic step.
  evidence:
  - reference: PMID:30554416
    reference_title: Daily oral cyanocobalamin supplementation in Beagles with hereditary cobalamin malabsorption (Imerslund-Gräsbeck syndrome) maintains normal clinical and cellular cobalamin status.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      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.
    explanation: >-
      The canine result. Recorded as model-organism evidence and deliberately
      not extended to a human recommendation on its own.
  - reference: PMID:37710296
    reference_title: "Imerslund-Gräsbeck syndrome: a comprehensive review of reported cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients may be treated with oral vitB12 supplementations but may need higher doses.
    explanation: >-
      Human observational support for the oral route, from the systematic review
      of every published case. It is what makes this a recognised option rather
      than an extrapolation from the dog.
diagnosis:
- name: Selective cobalamin malabsorption with normal intrinsic factor
  description: >-
    The diagnostic logic is subtractive: establish cobalamin deficiency, show it
    is due to malabsorption, show the malabsorption is not corrected by giving
    intrinsic factor, and exclude the other causes of cobalamin malabsorption. A
    trap sits inside this. Cobalamin deficiency itself damages enterocyte
    function, so absorption testing during the deficient state can read as
    generalised malabsorption; tests must be repeated after the deficiency is
    corrected. That is one reason molecular testing of CUBN, AMN and GIF has
    largely displaced absorption testing.
  evidence:
  - reference: PMID:16722557
    reference_title: Imerslund-Gräsbeck syndrome (selective vitamin B(12) malabsorption with proteinuria).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      The confounding effect of the deficiency on the test used to diagnose it,
      and the remedy.
differential_diagnoses:
- name: Imerslund-Grasbeck syndrome type 2
  disease_term:
    preferred_term: Imerslund-Grasbeck syndrome type 2
    term:
      id: MONDO:0100157
      label: Imerslund-Grasbeck syndrome type 2
  description: >-
    The AMN half of the same receptor. Clinically it is the same disease and is
    not separable at the bedside; only sequencing distinguishes them.
  distinguishing_features:
  - Biallelic AMN variants rather than CUBN variants.
  - The Norwegian founder cluster and the Middle Eastern AMN c.208-2A>G founder allele belong to type 2.
  - Congenital urinary tract anomalies were reported in the original Norwegian AMN-mutant series and were rare in the Finnish CUBN-mutant patients.
  evidence:
  - reference: PMID:16722557
    reference_title: Imerslund-Gräsbeck syndrome (selective vitamin B(12) malabsorption with proteinuria).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital anomalies were rare in the Finnish patients carrying the CUBN mutation but urinary tract anomalies were observed in the Norwegian patients carrying the AMN mutation.
    explanation: >-
      The one reported phenotypic difference between the two genes.
  - reference: PMID:22078000
    reference_title: Ancient founder mutation is responsible for Imerslund-Gräsbeck Syndrome among diverse ethnicities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This mutation causes over 50% of the IGS cases among Arabic, Turkish, and Sephardic Jewish families, making it a primary target for genetic screening among diverse IGS cases originating from the Middle East.
    explanation: >-
      The founder allele referred to is AMN c.208-2A>G, so this quote assigns
      the majority of Middle Eastern IGS to type 2 rather than to this entry.
- name: Hereditary intrinsic factor deficiency
  disease_term:
    preferred_term: hereditary intrinsic factor deficiency
    term:
      id: MONDO:0009852
      label: hereditary intrinsic factor deficiency
  description: >-
    GIF variants abolish intrinsic factor itself rather than its receptor. The
    cobalamin deficiency is identical; the receptor is intact, so absorption is
    corrected by giving intrinsic factor, and there is no proteinuria.
    Historically a substantial share of published IGS cases were GIF cases.
  distinguishing_features:
  - Proteinuria is typical of IGS and absent in intrinsic factor deficiency.
  - Absorption is corrected by administering intrinsic factor in GIF deficiency and is not in IGS.
  - The causal gene is GIF rather than CUBN or AMN.
  evidence:
  - reference: PMID:22929189
    reference_title: "Inherited cobalamin malabsorption. Mutations in three genes reveal functional and ethnic patterns."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recessive mutations in CUBN or AMN cause Imerslund-Gräsbeck Syndrome (IGS), while recessive mutations in GIF cause Intrinsic Factor Deficiency (IFD).
    explanation: >-
      The gene-level separation between the two disorders.
  - reference: PMID:16722557
    reference_title: Imerslund-Gräsbeck syndrome (selective vitamin B(12) malabsorption with proteinuria).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A recent study reported that IGS is difficult to distinguish from cases caused by mutations in the GIF (gastric intrinsic factor) gene [20]
    explanation: >-
      Records that the two have in practice been confused, which is why this
      differential is listed among the cobalamin disorders.
- name: Steroid-resistant nephrotic syndrome
  description: >-
    Not a mechanistic mimic but the practical one: albumin-predominant
    proteinuria in a child invites a glomerular diagnosis, a renal biopsy and
    proteinuria-lowering treatment, none of which the CUBN patient needs.
  distinguishing_features:
  - Renal function stays normal in CUBN-related proteinuria and declines in steroid-resistant nephrotic syndrome.
  - No biallelic CUBN variants were found in proteinuric patients with reduced renal function or focal segmental glomerulosclerosis.
  evidence:
  - reference: PMID:31613795
    reference_title: Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By contrast, we did not found any biallelic CUBN variants in proteinuric patients with reduced renal function or focal segmental glomerulosclerosis.
    explanation: >-
      The negative result that separates the two. Quoted verbatim, including the
      source's own grammatical slip.
animal_models:
- name: Border Collie CUBN exon 53 frameshift
  species: Dog
  genotype: CUBN exon 53 single-base deletion, homozygous
  publication: PMID:23746554
  description: >-
    A naturally occurring canine CUBN disease. It is the model in which a CUBN
    lesion, rather than an AMN one, produces the syndrome, which matters because
    the mouse is not usable here: cubam has rodent-specific functions in
    embryogenesis and the AMN knockout is embryonic lethal. The Border Collie
    disease is milder and later in onset than the giant schnauzer and Australian
    shepherd AMN diseases.
  modeled_mechanisms:
  - target: Failure of Cubam Receptor Assembly at the Brush Border
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      A spontaneous biallelic CUBN lesion in an outbred animal, producing
      cobalamin malabsorption with selective proteinuria, the same two-organ
      pattern as the human disease and from the same gene.
    limitations: >-
      The canine allele is a C-terminal (exon 53) frameshift, whereas human IGS
      alleles cluster in the N-terminal third. The model therefore demonstrates
      that a CUBN lesion can abrogate cubam function, but its allele is not
      positionally representative of the human mutation spectrum, and human
      C-terminal variants give isolated proteinuria rather than IGS. Fidelity is
      recorded as MODERATE rather than HIGH for that reason.
    evidence:
    - reference: PMID:23746554
      reference_title: An exon 53 frameshift mutation in CUBN abrogates cubam function and causes Imerslund-Gräsbeck syndrome in dogs.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Dogs closely model human clinical cobalamin deficiency and cubam function. Genetic studies in mice on the receptor complex have been hampered by rodent-specific functions of cubam essential for embryonic development.
      explanation: >-
        States why the dog is the model of record for cubam and why the mouse is
        not, which is the basis for treating this model as informative.
    - reference: PMID:23746554
      reference_title: An exon 53 frameshift mutation in CUBN abrogates cubam function and causes Imerslund-Gräsbeck syndrome in dogs.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        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.
      explanation: >-
        The authors' own reading of the positional mismatch named in this link's
        limitations: a C-terminal canine allele still abolishes the receptor.
    - reference: PMID:23613799
      reference_title: A frameshift mutation in the cubilin gene (CUBN) in Border Collies with Imerslund-Gräsbeck syndrome (selective cobalamin malabsorption).
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        This variant, a single base pair deletion (c.8392delC), is predicted to cause a frameshift and premature stop codon in the CUBN gene.
      explanation: >-
        Names the allele independently, in the genome-wide mapping study that
        found it.
- name: Beagle hereditary cobalamin malabsorption
  species: Dog
  genotype: CUBN c.786delC (exon 8), homozygous
  publication: PMID:30554416
  description: >-
    A Beagle kindred with hereditary cobalamin malabsorption, used to test
    whether daily oral cobalamin can replace parenteral dosing.
  modeled_mechanisms:
  - target: Systemic Cobalamin Deficiency
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Used as a treatment-response model rather than a mechanism model: urinary
      methylmalonate is read as the metabolic index of cobalamin sufficiency
      under an oral regimen.
    limitations: >-
      Three animals, no concurrent control arm on the intervention, and one of
      the three excreted high methylmalonate for the first six months. A
      confounding antibiotic course preceded the fall in that animal's
      excretion, so the response cannot be attributed to the oral dose alone.
      The treatment report itself does not name the causal gene; the CUBN
      assignment rests on the separate genetic characterisation of this kindred
      cited below.
    readouts:
    - name: Urinary methylmalonic acid to creatinine ratio
      target: Systemic Cobalamin Deficiency
      direction: UNCHANGED
      interpretation: >-
        Stayed within the healthy-dog range on oral dosing in two of three
        animals, read as maintained cobalamin sufficiency.
      evidence:
      - reference: PMID:30554416
        reference_title: Daily oral cyanocobalamin supplementation in Beagles with hereditary cobalamin malabsorption (Imerslund-Gräsbeck syndrome) maintains normal clinical and cellular cobalamin status.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Urine MMA remained consistently low in 2 dogs (median, 2.5 mmol/mol creatinine; range, 1.2-9; healthy dogs ... median, 2.9 mmol/mol creatinine; range, 1.3-76.5).
        explanation: >-
          The measurement itself, with the healthy-animal comparison it is read
          against. Quoted in the ellipsis form the snippet auditor supports,
          because the source's bracketed cohort size sits mid-sentence.
    evidence:
    - reference: PMID:30554416
      reference_title: Daily oral cyanocobalamin supplementation in Beagles with hereditary cobalamin malabsorption (Imerslund-Gräsbeck syndrome) maintains normal clinical and cellular cobalamin status.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Three client-owned Beagles with IGS and 48 healthy control dogs.
      explanation: >-
        The cohort. Quoted to make the size of the evidence base explicit, since
        the treatment claim rests entirely on these three animals.
    - reference: PMID:24433284
      reference_title: "Selective intestinal cobalamin malabsorption with proteinuria (Imerslund-Gräsbeck syndrome) in juvenile Beagles."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        All affected dogs were homozygous for a single-base deletion in CUBN exon 8 (CUBN c.786delC), predicting a translational frameshift, and the 2 parents tested were heterozygous.
      explanation: >-
        Assigns this kindred to CUBN rather than AMN, which is what makes a
        Beagle treatment result relevant to a CUBN entry at all.
    - reference: PMID:24433284
      reference_title: "Selective intestinal cobalamin malabsorption with proteinuria (Imerslund-Gräsbeck syndrome) in juvenile Beagles."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Affected dogs' kidneys lacked detectable cubilin protein.
      explanation: >-
        Confirms in tissue that the canine allele abolishes cubilin at the site
        this entry's renal arm depends on.
discussions:
- discussion_id: igs1_proteinuria_penetrance
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why is proteinuria near-universal in most reported IGS populations and rare
    in Finnish patients, when the same cubam receptor is lost in every case?
  attaches_to:
  - pathophysiology#Loss of Proximal Tubular Reabsorption of Filtered Protein
  - phenotypes#Proteinuria
  rationale: >-
    The intestinal arm of the disease is essentially fully penetrant and the
    renal arm is not, from one lesion in one receptor. The 2023 systematic
    review changes the shape of this question rather than answering it: at 89%
    of patients with documented urinalysis, the renal arm is close to universal
    in most of the world, and the striking number is the Finnish 20%. So the gap
    is now geographic and, plausibly, allelic rather than a generic
    half-penetrance.

    Candidate explanations have not been separated: residual cubilin function at
    the tubule for alleles that abolish it in the gut, which the Finnish
    founder missense allele is a specific candidate for; compensation by
    megalin; an unrecognised threshold effect; or ascertainment, since the
    review itself argues that patients without proteinuria are less likely to be
    tested for IGS and that its 89% is therefore an overestimate. Resolving it
    would also settle whether absent proteinuria is genuinely uninformative for
    the diagnosis or only appears so.
- discussion_id: igs1_oral_cobalamin_in_humans
  kind: KNOWLEDGE_GAP
  prompt: >-
    Can high-dose oral cobalamin replace lifelong injections in human
    Imerslund-Grasbeck syndrome?
  attaches_to:
  - treatments#High-dose oral cobalamin
  rationale: >-
    The only direct evidence in this disease is three dogs. Receptor-independent
    passive diffusion is well established as a route and oral replacement has
    been adopted in other malabsorptive cobalamin deficiencies, but no human IGS
    trial has been done. The question matters because the alternative is
    intramuscular injection from childhood for life.
  proposed_experiments:
  - experiment_id: igs1_oral_vs_parenteral_noninferiority
    name: Non-inferiority trial of daily oral versus parenteral cobalamin in genetically confirmed IGS
    description: >-
      Randomise genetically confirmed IGS patients in metabolic remission to
      continue parenteral dosing or switch to daily high-dose oral
      cyanocobalamin, with serum cobalamin, plasma homocysteine and urinary
      methylmalonate as the maintenance endpoints.
    readouts:
    - name: Urinary methylmalonic acid
      target: pathophysiology#Systemic Cobalamin Deficiency
      direction: UNCHANGED
      interpretation: >-
        Remaining within the reference interval on the oral arm would indicate
        maintained cobalamin sufficiency.
notes: >-
  Scope and lump/split. MONDO:0100156 is the CUBN half of Imerslund-Grasbeck
  syndrome and MONDO:0100157 is the AMN half. They are clinically
  indistinguishable and are two lesions in one heterodimeric receptor, so
  lumping them under the parent term MONDO:0009853 would be defensible. This
  entry keeps them separate, in line with the KB's per-gene granularity for
  Mendelian disease, and because CUBN has a genotype-phenotype axis of its own,
  the C-terminal isolated-proteinuria phenotype, that has no AMN counterpart.
  IGS type 2 is recorded as a differential diagnosis rather than a subtype.

  Evidence handling worth flagging for a reader. Much of the IGS literature does
  not separate the two genes, and some of the largest papers describe AMN
  cohorts specifically. PMID:22078000 is an AMN c.208-2A>G founder study, cited
  here for the shared diagnostic biochemistry and for the type 2 differential,
  never for a CUBN claim. Where a quote comes from a mixed or AMN cohort the
  explanation says so.

  The canine models carry a caveat the fidelity tier alone does not express. The
  Border Collie CUBN allele is an exon 53 frameshift, and in humans
  post-B12-binding-domain variants give isolated albuminuria rather than IGS.
  The dog nonetheless has the full syndrome. Whether that is a species
  difference in cubilin domain requirements, or a difference between a
  frameshift and the human alleles studied, is not resolved in the cited work,
  and it is why the model's limitations field names the positional mismatch
  rather than only the species.

  No GeneReviews chapter exists for Imerslund-Grasbeck syndrome. PubMed was
  searched for "Imerslund-Grasbeck GeneReviews[All Fields]" (no results) and
  "cobalamin malabsorption GeneReviews[All Fields]" (one result, the
  Abetalipoproteinemia chapter, not relevant). The phenotype baseline here is
  therefore the 2023 Orphanet Journal of Rare Diseases review of reported cases
  and the 2006 Orphanet review, not a GeneReviews Clinical Characteristics
  section.
📚

References & Deep Research

References

19
PMID:10080186
Mutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1.
No top-level findings curated for this source.
PMID:16722557
Imerslund-Gräsbeck syndrome (selective vitamin B(12) malabsorption with proteinuria).
No top-level findings curated for this source.
PMID:37710296
Imerslund-Gräsbeck syndrome: a comprehensive review of reported cases.
No top-level findings curated for this source.
PMID:14576052
The functional cobalamin (vitamin B12)-intrinsic factor receptor is a novel complex of cubilin and amnionless.
No top-level findings curated for this source.
PMID:23746554
An exon 53 frameshift mutation in CUBN abrogates cubam function and causes Imerslund-Gräsbeck syndrome in dogs.
No top-level findings curated for this source.
PMID:31613795
Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function.
No top-level findings curated for this source.
PMID:30554416
Daily oral cyanocobalamin supplementation in Beagles with hereditary cobalamin malabsorption (Imerslund-Gräsbeck syndrome) maintains normal clinical and cellular cobalamin status.
No top-level findings curated for this source.
PMID:22929189
Inherited cobalamin malabsorption. Mutations in three genes reveal functional and ethnic patterns.
No top-level findings curated for this source.
PMID:22078000
Ancient founder mutation is responsible for Imerslund-Gräsbeck Syndrome among diverse ethnicities.
No top-level findings curated for this source.
PMID:10887099
Cubilin P1297L mutation associated with hereditary megaloblastic anemia 1 causes impaired recognition of intrinsic factor-vitamin B(12) by cubilin.
No top-level findings curated for this source.
PMID:20237569
Structural basis for receptor recognition of vitamin-B(12)-intrinsic factor complexes.
No top-level findings curated for this source.
PMID:30295181
Cubilin, the Intrinsic Factor-Vitamin B12 Receptor in Development and Disease.
No top-level findings curated for this source.
PMID:11581259
Identification and characterization of two distinct ligand binding regions of cubilin.
No top-level findings curated for this source.
PMID:15024727
Genetically heterogeneous selective intestinal malabsorption of vitamin B12: founder effects, consanguinity, and high clinical awareness explain aggregations in Scandinavia and the Middle East.
No top-level findings curated for this source.
PMID:15845892
Amnionless function is required for cubilin brush-border expression and intrinsic factor-cobalamin (vitamin B12) absorption in vivo.
No top-level findings curated for this source.
PMID:24156255
Detailed investigations of proximal tubular function in Imerslund-Gräsbeck syndrome.
No top-level findings curated for this source.
PMID:23613799
A frameshift mutation in the cubilin gene (CUBN) in Border Collies with Imerslund-Gräsbeck syndrome (selective cobalamin malabsorption).
No top-level findings curated for this source.
PMID:24433284
Selective intestinal cobalamin malabsorption with proteinuria (Imerslund-Gräsbeck syndrome) in juvenile Beagles.
No top-level findings curated for this source.
PMID:22854512
How can cobalamin injections be spaced in long-term therapy for inborn errors of vitamin B(12) absorption?
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Imerslund-Grasbeck Syndrome Type 1 · 2026-09-09T15:18:23Z · View source

Created kb/disorders/Imerslund-Grasbeck_Syndrome_Type_1.yaml as a CUBN-specific (cubilin) entry, kept separate from the AMN-encoded IGS type 2 (MONDO:0100157). Curated from an OpenScientist deep-research report plus independent PubMed retrieval; every ontology CURIE was resolved by lookup at the point of writing rather than recalled, after the report's own term validation was found to carry four mislabelled CURIEs while still reporting a zero confabulation rate. Pathograph: biallelic CUBN loss of function -> failure of cubam receptor assembly at the brush border -> two parallel arms (loss of ileal intrinsic factor-cobalamin endocytosis; loss of proximal tubular reabsorption of filtered protein) -> systemic cobalamin deficiency -> megaloblastic erythropoiesis, and persistent non-progressive proteinuria. The two-arm shape is the point of the entry: one receptor lesion, two organs, and the renal arm does not progress to renal failure. Genetic section records the CUBN positional genotype-phenotype split (N-terminal alleles cause IGS; alleles after the vitamin B12-binding domain cause isolated childhood albuminuria with normal GFR, four of which appear as population-cohort albuminuria associations), and a variants record for the Finnish founder allele c.3890C>T p.Pro1297Leu (FM1) with the surface-plasmon-resonance measurement showing raised K_d for intrinsic factor-cobalamin. Validation: linkml-validate clean, linkml-term-validator clean, 49/49 evidence snippets verified against references_cache. check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms and check-enum-values all clean for this file.

OpenScientist ▸
Imerslund-Gräsbeck Syndrome Type 1 (IGS-1): Comprehensive Disease Characteristics Report
openscientist-autonomous 15 citations 2026-09-09T15:07:33.762552

Imerslund-Gräsbeck Syndrome Type 1 (IGS-1): Comprehensive Disease Characteristics Report

Disease: Imerslund-Gräsbeck Syndrome Type 1 (Megaloblastic Anemia 1, MGA1) MONDO ID: MONDO:0100156 · OMIM: #261100 · Category: Mendelian (autosomal recessive) Causal gene: CUBN (cubilin), chromosome 10p12.1

Summary

Imerslund-Gräsbeck Syndrome type 1 (IGS-1; also called megaloblastic anemia 1, MGA1) is a rare autosomal recessive disorder of selective intestinal vitamin B12 (cobalamin) malabsorption caused by biallelic pathogenic variants in CUBN, the gene encoding cubilin. Cubilin is a 460-kDa multiligand peripheral membrane endocytic receptor that, together with its obligate partner amnionless (AMN), forms the cubam receptor complex. Cubam mediates two physiologically distinct functions: (1) uptake of the intrinsic factor–vitamin B12 (IF–Cbl) complex across the ileal brush border, and (2) reabsorption of filtered low-molecular-weight plasma proteins (albumin, transferrin, vitamin D-binding protein, apolipoprotein A-I) in the renal proximal tubule. Loss of cubilin function therefore produces the syndrome's two hallmark features: selective B12 malabsorption not correctable by exogenous intrinsic factor, and benign low-molecular-weight proteinuria.

Clinically, IGS-1 presents in infancy or early childhood (typically from ~4 months up to several years of age) with megaloblastic anemia, failure to thrive, recurrent infections, and—if untreated—neurological/neurocognitive damage that can be the sole presenting manifestation. Mild proteinuria without renal insufficiency is present in roughly half of patients. The metabolic signature of intracellular B12 deficiency (methylmalonic aciduria and hyperhomocysteinemia) accompanies the hematologic picture. Prevalence is approximately 1:200,000, with the highest rates in Finland (0.8/100,000) and Norway due to founder effects, and additional clusters in Middle Eastern countries driven by consanguinity. IGS type 2 is the allelic disorder caused by AMN mutations (chromosome 14).

The disorder is exquisitely treatable: lifelong parenteral (intramuscular) hydroxocobalamin/cyanocobalamin fully corrects the anemia and metabolic derangement, and early treatment allows complete recovery. Maintenance dosing as infrequent as 1 mg twice yearly can suffice. Prognosis is excellent with timely diagnosis, but delayed diagnosis can leave permanent neurodevelopmental deficits, and the proteinuria persists lifelong (though benign). The molecular defect is well characterized at atomic resolution: the Finnish founder mutation p.Pro1297Leu (FM1) lies in the IF–Cbl-binding region (CUB domains 5–8) and impairs IF–Cbl recognition, and the crystal structure of IF–Cbl bound to cubilin CUB5–8 reveals a Ca²⁺-dependent "dual-point" binding mode. Naturally occurring canine IGS models (Beagles, Border Collies) faithfully recapitulate the human disease.

Key Findings

F001 — IGS-1 is an autosomal recessive selective B12 malabsorption disorder caused by biallelic CUBN mutations

IGS type 1 (megaloblastic anemia 1, MGA1; OMIM #261100; MONDO:0100156) is caused by biallelic loss-of-function and missense mutations in CUBN on chromosome 10p12.1, encoding cubilin, the intrinsic factor–vitamin B12 receptor. The landmark linkage and positional cloning study by Aminoff et al. (1999) refined the MGA1 locus by linkage-disequilibrium mapping, fine-mapped CUBN, and identified two independent disease-specific CUBN mutations across 17 Finnish MGA1 families, establishing CUBN as causal:

"We have now refined the MGA1 region by linkage disequilibrium (LD) mapping, fine-mapped CUBN and identified two independent disease-specific CUBN mutations in 17 Finnish MGA1 families. Our genetic and molecular data indicate that mutations in CUBN cause MGA1." — PMID: 10080186

Genetic heterogeneity underlies the syndrome: IGS type 1 results from CUBN variants (chr 10), whereas the clinically indistinguishable IGS type 2 results from AMN variants (chr 14):

"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" — PMID: 16722557

Ontology/annotation suggestions: MONDO:0100156; HGNC gene CUBN; inheritance HP:0000007 (autosomal recessive).

F002 — Cubam (cubilin + amnionless) is a dual-tissue endocytic receptor: ileal B12 uptake and renal protein reabsorption

Cubilin is a large peripheral membrane endocytic receptor containing 27 CUB domains for ligand binding. It has no transmembrane anchor of its own and depends on the membrane protein amnionless (AMN) for correct apical membrane translocation—together they constitute the cubam complex. In the renal proximal tubule, cubilin additionally cooperates with megalin (LRP2). Its ligand repertoire includes IF–B12, albumin, transferrin, and vitamin D-binding protein:

"Cubilin is a large endocytic receptor serving such diverse functions as the intestinal absorption of the intrinsic factor-B(12) complex and the renal proximal tubule reabsorption of filtered proteins including albumin, transferrin, vitamin D-binding protein and other important plasma carriers. Cubilin is a structurally unique, peripheral membrane protein, which depends on the membrane protein amnionless (AMN) for correct apical translocation." — PMID: 23291372

"CUBN encodes for cubilin, an intestinal and proximal tubular uptake receptor containing 27 CUB domains for ligand binding." — PMID: 31613795

This dual function explains why loss of cubilin causes both B12 malabsorption and low-molecular-weight proteinuria—the two are mechanistically linked through a single receptor operating in two epithelia.

Ontology suggestions: GO:0006898 (receptor-mediated endocytosis); UBERON:0002116 (ileum); UBERON:0001232 (renal proximal tubule); CL:0002306 (epithelial cell of proximal tubule); CL:0002254 (enterocyte of epithelium of small intestine).

F003 — Epidemiology: ~1:200,000 prevalence, founder effects in Scandinavia, consanguinity clusters in the Middle East

Overall prevalence is approximately 1:200,000, highest in Finland (0.8/100,000). Tanner et al. (2004) studied 42 sibships and found a striking geographic gene distribution: all Finnish cases were due to CUBN (three mutations) and all Norwegian cases due to AMN (two mutations), whereas Turkey, Israel, and Saudi Arabia showed a mix of AMN and CUBN mutations. The Scandinavian aggregation reflects founder effects; the Middle Eastern clusters reflect consanguinity. Estimated prevalence based on Scandinavian data is <6:1,000,000.

"We studied 42 sibships and found all cases in Finland to be due to CUBN (three different mutations) and all cases in Norway to be due to AMN (two different mutations), while in Turkey, Israel, and Saudi Arabia, there were two different AMN mutations and three different CUBN mutations." — PMID: 15024727

"The syndrome was first described in Finland and Norway where the prevalence is about 1:200,000." — PMID: 16722557

"MGA1 occurs worldwide, but its prevalence is higher in several Middle Eastern countries and Norway, and highest in Finland (0.8/100,000)." — PMID: 10080186

F004 — Clinical phenotype: childhood-onset megaloblastic anemia, failure to thrive, neurological damage, and mild proteinuria (~50%)

The core clinical features are: juvenile megaloblastic anemia responsive to parenteral B12; failure to thrive and grow; recurrent infections; and neurological damage, which may be the only manifestation. Mild proteinuria without kidney disease is present in about half of patients. Symptoms characteristically appear from ~4 months up to several years after birth—not immediately at birth, distinguishing IGS from transcobalamin deficiency. B12 absorption tests show low absorption not corrected by adding intrinsic factor. Associated biochemical abnormalities include methylmalonic aciduria, hyperhomocysteinemia, and pancytopenia; subacute combined degeneration (funicular myelosis) has been reported.

"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." — PMID: 16722557

"The symptoms appear from 4 months (not immediately after birth as in transcobalamin deficiency) up to several years after birth." — PMID: 16722557

"Patients may if untreated, develop severe neurocognitive manifestations. If recognized and treated with sufficient doses of vitamin B12, patients recover completely." — PMID: 37710296

Suggested HPO terms:

Phenotype HPO term Frequency Onset
Megaloblastic anemia HP:0001889 Very frequent (hallmark) Infancy/childhood
Failure to thrive HP:0001508 Frequent Infancy/childhood
Recurrent infections HP:0002719 Frequent Childhood
Cognitive/neurological impairment HP:0002376 / HP:0100543 Variable Childhood (if untreated)
Proteinuria (LMW) HP:0000093 ~50% Childhood, persistent
Methylmalonic aciduria HP:0012325 Frequent Childhood
Hyperhomocysteinemia HP:0002160 Frequent Childhood
Pancytopenia HP:0001876 Occasional Childhood

F005 — Treatment is lifelong parenteral B12; naturally occurring canine models recapitulate the disease

Management is lifelong parenteral (intramuscular) hydroxocobalamin or cyanocobalamin. Early diagnosis and treatment are life-saving and prevent deterioration. Boina Abdallah et al. (2012) demonstrated that a maintenance dose of 1 mg cobalamin twice yearly kept clinical, hematological, and metabolic parameters normal in 7 patients:

"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" — PMID: 22854512

Naturally occurring IGS occurs in dogs and provides validated disease models: Beagles (CUBN c.786delC frameshift, p.Asp262Glufs47), Border Collies (CUBN c.8392delC, p.Gln2798Rfs3; and an exon 53 frameshift), and AMN mutations in Giant Schnauzers/Australian Shepherds. Affected Beagles reproduce the full human phenotype:

"Juvenile-affected Beagles exhibited failure to thrive, dyshematopoiesis with neutropenia, serum cobalamin deficiency, methylmalonic aciduria, hyperammonemia, and proteinuria. Affected dogs' kidneys lacked detectable cubilin protein. All affected dogs were homozygous for a single-base deletion in CUBN exon 8 (CUBN c.786delC)" — PMID: 24433284

Suggested NCIT terms: NCIT:C542 (Hydroxocobalamin); NCIT:C29273 (Cyanocobalamin/Vitamin B12); intramuscular route NCIT:C28161.

F006 — Prognosis is excellent with early treatment; late diagnosis leaves residual deficits; proteinuria persists

With adequate lifelong B12 replacement, anemia and neurological signs resolve and patients recover completely. However, long-term follow-up of late- or severely-affected children documents persistent failure to thrive and physical/mental retardation with microcephaly, indicating that delayed diagnosis can cause irreversible neurodevelopmental sequelae:

"Long-term follow up showed failure to thrive in the girl and physical and mental retardation, microcephaly in her brother." — PMID: 26958680

The proteinuria persists lifelong but is benign (normal renal function). Notably, C-terminal CUBN variants can cause isolated chronic proteinuria/albuminuria without B12 malabsorption, expanding the CUBN phenotypic spectrum and demonstrating a genotype–phenotype relationship in which the location of the variant within cubilin determines which of the two receptor functions is impaired:

"biallelic pathogenic variants in the CUBN gene were associated with chronic isolated proteinuria and early childhood onset... renal function was normal in all cases" — PMID: 31613795

F007 — Finnish founder mutation FM1 (p.Pro1297Leu) impairs IF–B12 binding within cubilin CUB domains 5–8

Most Finnish MGA1/IGS-1 patients carry the disease-specific missense mutation p.Pro1297Leu (P1297L, "FM1"). Kristiansen et al. (2000) used surface plasmon resonance to show that P1297L—located in the IF–Cbl-binding cubilin region (CUB domains 5–8, residues 928–1386)—specifically increases the K_d for IF–Cbl binding several-fold, largely by decreasing the association rate constant, and that the mutant fails to inhibit uptake of ¹²⁵I-IF–Cbl in cubilin-expressing cells:

"Most Finnish patients with MGA1 carry the disease-specific P1297L mutation (FM1) in the IF-B(12) receptor, cubilin." — PMID: 10887099

"the P1297L substitution specifically increases the K(d) for IF-Cbl binding several-fold, largely by decreasing the association rate constant" — PMID: 10887099

The structural basis was resolved by Andersen et al. (2010), who determined the crystal structure of the IF–Cbl / cubilin CUB5–8 complex at 3.3 Å, revealing that two distant CUB domains embrace cobalamin via Ca²⁺-dependent binding of the two IF domains—a "dual-point" recognition model:

"the crystal structure of the complex between IF-Cbl and the cubilin IF-Cbl-binding-region (CUB(5-8)) determined at 3.3 A resolution" — PMID: 20237569

F008 — Cubilin is a 460-kDa multiligand receptor (8 EGF + 27 CUB domains) with two ligand-binding regions and megalin-dependent internalization

Cubilin (gp280; CUBN) is a 460-kDa peripheral membrane protein composed of 8 EGF-like repeats and 27 CUB domains. It interacts with two molecular partners: AMN (for plasma-membrane transport) and Lrp2/megalin (essential for efficient internalization):

"Cubilin is a peripheral membrane protein consisting of 8 Epidermal Growth Factor (EGF)-like repeats and 27 CUB (defined as Complement C1r/C1s, Uegf, BMP1) domains. This structurally unique protein interacts with at least two molecular partners, Amnionless (AMN) and Lrp2/Megalin. AMN is involved in appropriate plasma membrane transport of Cubilin whereas Lrp2 is essential for efficient internalization of Cubilin and its ligands." — PMID: 30295181

Cubilin has two distinct ligand-binding regions—an N-terminal region (113-residue N-terminus + EGF repeats + CUB1-2) and the CUB6-8 region—both of which bind IF–Cbl and albumin:

"cubilin contains two distinct regions that bind both IF-Cbl and albumin" — PMID: 11581259

Cubilin also modulates Fgf8 signaling in embryonic development, and megalin's role in vitamin B12/folate carrier handling extends the biology into renal vitamin homeostasis (PMID: 16760376, PMID: 11375443).

Suggested ontology terms: UniProt O60494 (CUBN human); GO:0005905 (clathrin-coated pit); GO:0031232 (extrinsic component of external side of plasma membrane); CHEBI:17439 (cyanocobalamin); CHEBI:18408 / cobalamin.

Mechanistic Model / Interpretation

Ordered causal chain (from initiating lesion to clinical manifestation)

1. Biallelic pathogenic variant in CUBN (e.g., p.Pro1297Leu, frameshift/nonsense)
│  leads to
2. Absent or functionally defective cubilin protein
│  (missense in CUB5–8 → impaired IF–Cbl affinity;
│   truncating variants → loss of surface expression / NMD)
├─────────────── BRANCH A (intestine) ───────────────┐
│                                                    │
3A. Cubam receptor cannot bind/endocytose IF–Cbl at        3B. Cubam cannot reabsorb
    the ileal brush border                                     filtered LMW proteins in
│  results in                                          the renal proximal tubule
4A. Selective malabsorption of dietary vitamin B12              │  results in
    (NOT corrected by exogenous intrinsic factor)          4B. Urinary loss of albumin,
│  leads to                                             transferrin, apoA-I, DBP
5A. Systemic cobalamin deficiency                              │  manifests as
│  results in                                       5B. Benign low-molecular-weight
6A. Impaired methionine synthase + methylmalonyl-CoA            proteinuria (~50% of patients,
    mutase activity → ↑ homocysteine, ↑ methylmalonic acid      normal renal function)
│  leads to
7A. Impaired DNA synthesis in rapidly dividing cells
    → megaloblastic (ineffective) hematopoiesis
│  manifests as
8A. Megaloblastic anemia, pancytopenia, failure to thrive,
    recurrent infections
│  and (via impaired myelin/CNS methylation) leads to
9A. Neurological/neurocognitive damage
    (may be irreversible if diagnosis delayed)

Steps 6A–9A are the standard, well-established biochemistry of intracellular B12 deficiency (inferred from cobalamin metabolism rather than demonstrated specifically in IGS tissue). Steps 3A/3B are directly demonstrated by binding assays, canine kidney cubilin loss, and human urinary proteomics.

Upstream vs downstream

  • Upstream (primary lesion): CUBN mutation → cubilin loss of function. The single molecular defect bifurcates into two anatomically separate consequences because cubam operates in two epithelia.
  • Downstream (intestinal arm): B12 deficiency → methylmalonic acidemia + hyperhomocysteinemia → megaloblastic hematopoiesis and neurological injury. This arm is treatable and reversible by bypassing the absorption defect with parenteral B12.
  • Downstream (renal arm): LMW proteinuria. This arm is not corrected by B12 and persists lifelong, but is clinically benign.

Genotype–phenotype logic

The location of the CUBN variant predicts the phenotype: - Variants in the IF–Cbl-binding region (CUB5–8) or that abolish surface expression → classic IGS-1 (B12 malabsorption ± proteinuria). - C-terminal variants can cause isolated proteinuria with intact B12 absorption (PMID: 31613795), because they perturb renal reabsorption while sparing the intestinal IF–Cbl function.

Cell types and processes involved

Level Entity Ontology
Cell (intestine) Ileal enterocyte / absorptive brush-border cell CL:0002254
Cell (kidney) Proximal tubule epithelial cell CL:0002306
Tissue Ileal mucosa; renal proximal convoluted tubule UBERON:0002116; UBERON:0001232
Process Receptor-mediated endocytosis GO:0006898
Process Cobalamin metabolic process GO:0009235
Process Protein reabsorption / transcytosis GO:0006810
Subcellular Apical plasma membrane, clathrin-coated pit, endosome GO:0016324; GO:0005905

Evidence Base

PMID Type Contribution
10080186 Human genetics (landmark) Established CUBN mutations cause MGA1/IGS-1; Finnish prevalence 0.8/100,000
16722557 Clinical review Defines two-gene basis (CUBN/AMN), clinical features, ~50% proteinuria, onset window, prevalence 1:200,000
15024727 Population genetics Founder effects (Finland=CUBN, Norway=AMN) vs consanguinity (Middle East)
10887099 In vitro / biophysics FM1 p.P1297L increases K_d for IF–Cbl; functional mechanism
20237569 Structural biology 3.3 Å crystal structure of IF–Cbl/cubilin CUB5–8; dual-point Ca²⁺ binding
11581259 Biochemistry Two distinct ligand-binding regions of cubilin
30295181 Review 460-kDa architecture (8 EGF + 27 CUB); AMN and megalin partners
23291372 Review Dual intestinal/renal function; AMN dependence
31613795 Human genetics C-terminal CUBN variants → isolated benign proteinuria (genotype–phenotype)
22854512 Clinical Maintenance B12 dosing (1 mg twice yearly effective)
24433284 Animal model Beagle CUBN c.786delC recapitulates human phenotype
23613799 Animal model Border Collie CUBN c.8392delC frameshift
23746554 Animal model Border Collie exon 53 frameshift; C-terminal mutation abrogates receptor
26958680 Clinical follow-up Residual neurodevelopmental deficits after delayed diagnosis
37710296 Review of cases Complete recovery with treatment; neurocognitive risk if untreated
24156255 Human / functional Urinary proteomics; genotype correlates with LMW proteinuria
17668238 Case report Compound heterozygous CUBN; funicular myelosis in German patient
16760376 Review Renal receptors (megalin/cubam) for B12 and carrier proteins
11375443 Review Megalin/cubilin endocytosis of protein-bound vitamins

Sources of evidence by type: Human clinical/genetic (majority), in vitro biophysics (PMID 10887099, 11581259), structural/computational (PMID 20237569), and model organism/veterinary (PMIDs 24433284, 24164695, 23613799, 23746554).

Section-by-Section Synthesis

1. Disease Information. IGS-1 = megaloblastic anemia 1 (MGA1). Identifiers: OMIM #261100; MONDO:0100156; ICD-10 D51.1 (vitamin B12 deficiency anemia due to selective B12 malabsorption with proteinuria); MeSH "Anemia, Megaloblastic" / "Malabsorption Syndromes." Synonyms: Imerslund syndrome, Imerslund-Najman-Gräsbeck syndrome, selective vitamin B12 malabsorption with proteinuria, congenital cobalamin malabsorption, MGA1. Information derives from aggregated disease-level resources (OMIM, Orphanet) and published patient case series/cohorts (~300 cases reported worldwide).

2. Etiology. Primary cause is genetic: biallelic CUBN variants (type 1). No environmental cause; the disorder is monogenic and fully penetrant for the biochemical phenotype. Consanguinity is a major risk factor for homozygous inheritance in Middle Eastern populations. There are no established environmental protective factors; the only "protective"/corrective factor is exogenous parenteral B12, which bypasses the absorptive defect. No gene–environment interaction is required for disease.

3. Phenotypes. See F004 table above. Laboratory abnormalities (megaloblastic anemia, macrocytosis, low serum B12, elevated methylmalonic acid and homocysteine, LMW proteinuria) are as central as the clinical signs. Quality-of-life impact is dominated by fatigue/anemia and, if untreated, neurodevelopmental impairment; with treatment, QoL is near-normal.

4. Genetic/Molecular. Causal gene CUBN (HGNC:2548; NCBI Gene 8029; 10p12.1; 62 exons). Variant classes: missense (e.g., p.Pro1297Leu), frameshift, nonsense, splice-site, and gene deletions—all germline, biallelic, recessive. Functional consequence is loss of function (reduced surface expression, impaired IF–Cbl binding, or NMD of truncating alleles). ~37 different CUBN mutations reported (as of the cited case reports). Modifier genes: AMN and LRP2/megalin are functional partners; the possibility of ≥1 additional unidentified locus was raised by haplotype data. No established epigenetic contribution or chromosomal abnormality.

5. Environmental. Not applicable as a cause. Dietary B12 intake is irrelevant to pathogenesis because the defect is in receptor-mediated uptake, not intake—oral B12 cannot be absorbed via the normal ileal route.

6. Mechanism. See the causal-chain diagram above (F001, F002, F007, F008).

7. Anatomical structures. Primary organs: ileum (UBERON:0002116) and kidney/renal proximal tubule (UBERON:0001232). Body systems: digestive (absorption), urinary (proteinuria), hematopoietic (anemia), and nervous (neurological damage, secondary). Cells: ileal enterocytes (CL:0002254), renal proximal tubule epithelial cells (CL:0002306). Subcellular: apical brush-border plasma membrane, clathrin-coated pits, endosomes. Lateralization: bilateral (kidneys); systemic.

8. Temporal development. Onset: infancy/early childhood, typically ~4 months to a few years (not congenital in presentation). Course: chronic, lifelong; progressive if untreated (worsening anemia, neurological deterioration), but stable/remitting with treatment. Critical period: early recognition and treatment prevents irreversible neurodevelopmental injury—the key therapeutic window.

9. Inheritance and population. Autosomal recessive (HP:0000007). Prevalence ~1:200,000 (Finland 0.8/100,000). Complete penetrance for biochemical/hematologic phenotype; variable expressivity (proteinuria in ~50%, neurological involvement variable). Founder effects in Finland (CUBN, including FM1 p.P1297L) and Norway (AMN). Consanguinity drives Middle Eastern cases. No anticipation. Sex ratio approximately equal (autosomal). No repeat expansion.

10. Diagnostics. Labs: CBC (macrocytic/megaloblastic anemia), low serum B12, elevated methylmalonic acid and homocysteine, bone marrow megaloblastosis, urinalysis showing LMW proteinuria. Absorption test (Schilling-type): low B12 absorption not corrected by intrinsic factor (distinguishes from pernicious anemia/IF deficiency). Confirmatory test: molecular genetic testing of CUBN (and AMN to distinguish type 1 vs 2), by single-gene, panel, or exome sequencing. Differential diagnosis: transcobalamin deficiency (presents at birth, no proteinuria), hereditary intrinsic factor deficiency, pernicious anemia (autoimmune, older patients), other inborn errors of cobalamin metabolism (cblC, etc.), dietary B12 deficiency.

11. Outcome/Prognosis. Excellent with lifelong parenteral B12: complete hematologic and metabolic normalization. Delayed diagnosis risks permanent neurodevelopmental deficits (retardation, microcephaly). Proteinuria persists but renal function remains normal—benign. Not associated with reduced life expectancy when treated.

12. Treatment. Parenteral hydroxocobalamin/cyanocobalamin, lifelong. Loading followed by maintenance (as infrequent as 1 mg IM twice yearly can suffice). No gene, cell, or RNA therapy exists or is needed given the simplicity and efficacy of B12 replacement. NCIT: Hydroxocobalamin (NCIT:C542), Cyanocobalamin (NCIT:C29273).

13. Prevention. No primary prevention (genetic). Genetic counseling for affected families; carrier and cascade testing in founder/consanguineous populations. Prenatal/preimplantation diagnosis possible where the familial variant is known. Tertiary prevention (of complications) = adherence to lifelong B12 to prevent anemia and neurological sequelae.

14. Other species / natural disease. Naturally occurring IGS is well documented in dogs (NCBI Taxon 9615): Beagles (CUBN c.786delC), Border Collies (CUBN c.8392delC and exon 53 frameshift), and AMN mutations in Giant Schnauzers/Australian Shepherds/Border Collies. Canine CUBN is orthologous to human CUBN. These are of veterinary importance and serve as faithful comparative-pathology models (failure to thrive, dyshematopoiesis, methylmalonic aciduria, hyperammonemia, proteinuria, absent renal cubilin). No zoonotic potential (genetic disease).

15. Model organisms. The primary and most faithful models are the naturally occurring canine models above (recapitulate hematologic, metabolic, and renal phenotypes with near-complete fidelity). Amn knockout mice are embryonic lethal (amnionless is essential for embryonic development), which limits murine modeling of the intestinal/renal phenotype—a notable limitation. Cellular/in vitro models: cubilin-expressing cell lines used for IF–Cbl uptake and binding assays (basis of the FM1 functional characterization). Resources: OMIA (canine IGS entries), MGI (mouse Cubn/Amn).

Limitations and Knowledge Gaps

  1. Incomplete genetic accounting. Not all IGS cases map to CUBN or AMN; haplotype data historically suggested a possible additional locus. The full mutational spectrum and genotype–phenotype correlations (especially for proteinuria presence/absence) remain incompletely defined.
  2. Mechanism of neurological injury is inferred. The link from systemic B12 deficiency to CNS damage in IGS is extrapolated from general cobalamin biochemistry rather than demonstrated in IGS-specific tissue; the determinants of reversibility vs permanence are not precisely mapped.
  3. No mouse model of the classic disease. Amn knockout embryonic lethality precludes a standard murine IGS model, leaving canines and cell lines as the main experimental systems.
  4. Renal arm long-term outcomes. Whether lifelong LMW proteinuria has any subtle long-term renal or systemic consequences (e.g., vitamin D/lipid carrier loss) is not fully characterized.
  5. Rarity limits epidemiology. Prevalence estimates rely largely on Scandinavian data; global under-diagnosis is likely, and exact incidence/prevalence in non-founder populations is uncertain.
  6. This report was literature-only. No primary dataset was analyzed; conclusions rest on published cohorts, case reports, and structural/functional studies.

Proposed Follow-up Experiments / Actions

  1. Systematic CUBN variant–phenotype map. Aggregate ClinVar/HGMD/published variants and correlate variant location (IF–Cbl-binding CUB5–8 vs C-terminal vs N-terminal) with presence of B12 malabsorption vs isolated proteinuria to formalize the genotype–phenotype rule suggested by PMID 31613795 and PMID 24156255.
  2. Structure-guided functional assays for variants of uncertain significance: express candidate CUBN missense variants in cubilin/AMN cell systems and measure surface expression and IF–Cbl binding kinetics (SPR), extending the FM1 approach (PMID 10887099) to classify VUS per ACMG.
  3. Conditional (tissue-specific) Cubn/Amn mouse models (intestine- and kidney-specific knockouts) to bypass embryonic lethality and dissect the intestinal vs renal arms independently.
  4. Longitudinal renal-function cohort study in treated IGS patients to determine whether persistent LMW proteinuria carries any long-term risk and whether it warrants monitoring.
  5. Newborn/carrier screening pilot in high-prevalence founder populations (Finland, Norway) and consanguineous communities, using targeted CUBN/AMN panels, to reduce diagnostic delay and prevent neurodevelopmental sequelae.
  6. Optimize maintenance dosing with prospective trials confirming the minimum effective parenteral B12 schedule (building on PMID 22854512) and evaluating whether high-dose oral B12 has any role given residual passive absorption.

Report compiled from an autonomous multi-iteration literature investigation (8 confirmed findings, 31 papers reviewed). All mechanistic and clinical claims are cited to primary literature by PMID; direct abstract quotes are provided for key statements.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 19
Resolved 19
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 19
Quoted claims found in source 19
Quoted claims not found in source 0
References weighed for topical relevance 19
On topic 15
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 27
Resolved 25
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 1
Terms whose name was checked 20
Terms named correctly 9
Terms named as a different term 5
Terms whose name is worth a second look 6

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • CL:0002254 (3 mentions) - the report calls it "enterocyte of epithelium of small intestine", "Ileal enterocyte / absorptive brush-border cell"; CL calls it epithelial cell of small intestine
  • HP:0012325 (1 mention) - the report calls it "Methylmalonic aciduria"; HP calls it Chronic myelomonocytic leukemia
  • NCIT:C542 (2 mentions) - the report calls it "Hydroxocobalamin"; NCIT calls it Heterocyclic Compound
  • NCIT:C29273 (2 mentions) - the report calls it "Cyanocobalamin/Vitamin B12"; NCIT calls it Aluminum Hydroxide/Magnesium Hydroxide
  • GO:0006810 (1 mention) - the report calls it "Protein reabsorption / transcytosis"; GO calls it transport

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • NCIT:C29273 (Aluminum Hydroxide/Magnesium Hydroxide) (2 mentions)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0000007 (2 mentions) - the report calls it "autosomal recessive"; HP calls it Autosomal recessive inheritance, and lists "Autosomal recessive" among its other names
  • UBERON:0001232 (3 mentions) - the report calls it "renal proximal tubule", "kidney/renal proximal tubule"; UBERON calls it collecting duct of renal tubule, and lists "kidney collecting tubule" among its other names
  • CL:0002306 (3 mentions) - the report calls it "epithelial cell of proximal tubule", "Proximal tubule epithelial cell"; CL calls it epithelial cell of proximal tubule, and lists "kidney proximal tubule epithelial cell" among its other names
  • HP:0000093 (1 mention) - the report calls it "Proteinuria (LMW)"; HP calls it Proteinuria
  • HP:0002160 (1 mention) - the report calls it "Hyperhomocysteinemia"; HP calls it Hyperhomocystinemia
  • CHEBI:17439 (1 mention) - the report calls it "cyanocobalamin"; CHEBI calls it cyanocob(III)alamin, and lists "cyanocobalamin" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • GO:0006898 - called "receptor-mediated endocytosis", "Receptor-mediated endocytosis"
  • UBERON:0001232 - called "renal proximal tubule", "kidney/renal proximal tubule"
  • CL:0002306 - called "epithelial cell of proximal tubule", "Proximal tubule epithelial cell"
  • CL:0002254 - called "enterocyte of epithelium of small intestine", "Ileal enterocyte / absorptive brush-border cell"