RARE DISEASE
Imerslund-Gräsbeck syndrome
Imerslund-Gräsbeck syndrome
Imerslund-Gräsbeck syndrome
Synonyms: Familial megaloblastic anemia, Selective cobalamin malabsorption with proteinuria
Synonyms: Familial megaloblastic anemia, Selective cobalamin malabsorption with proteinuria
Synonyms: Familial megaloblastic anemia, Selective cobalamin malabsorption with proteinuria
Drug discovery
0
drugs
With orphan designations
Overview
Imerslund-Gräsbeck syndrome (IGS) is a rare autosomal recessive disorder caused by AMN or CUBN gene mutations, impairing intestinal vitamin B12 absorption. It presents in infancy/childhood with megaloblastic anemia, failure to thrive, recurrent infections, and neurological symptoms. Approximately 50% of cases exhibit non-pathologic proteinuria. Diagnosis requires confirming B12 deficiency, excluding other malabsorption etiologies, and genetic testing. Lifelong parenteral vitamin B12 therapy reverses hematologic and neurological manifestations [1][8][12][13].
Burden
Categories: rare gastroenterological diseases, rare genetic diseases, rare hematological diseases, rare inborn errors of metabolism, rare renal diseases
Research Papers
24 drug discovery papers about Imerslund-Gräsbeck syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
24 drug discovery papers about Imerslund-Gräsbeck syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-01-01 | Treatment strategies for Imerslund-Gräsbeck syndrome: a systematic review of vitamin B12 dosage and routes of administration
Abstract Purpose Imerslund-Gräsbeck syndrome (IGS) is a rare autosomal recessive disorder causing vitamin B12 malabsorption due to variants in CUBN or AMN. Current treatment relies on lifelong B12 supplementation, but standardized protocols are lacking. This systematic review synthesizes reported B12 regimens to evaluate dosing strategies and clinical outcomes. Methods A PRISMA-compliant systematic review of PubMed/Medline (inception–January 2026) for case reports/series detailing IGS treatment was conducted. Included studies provided explicit B12 dosage, route, and outcomes. Data from 27 studies (34 patients) were analyzed descriptively, with a heatmap comparing symptom resolution by administration route. The protocol registration number is CRD420251076543. Results Patients (mean age at onset: 6 years; 55.9% female) were treated with intramuscular (79.4%), oral (11.8%), or combined (8.8%) B12. A two-phase regimen (initial loading, then lifelong maintenance) was frequently employed. Hematologic and neurologic normalization were reported with both intramuscular (IM) and oral vitamin B12, with IM representing the standard, most reliably documented approach. Neurological recovery was linked to early treatment initiation. Molecular diagnosis was confirmed in 35% of patients. Conclusion IGS management predominantly uses intramuscular B12, but oral therapy may suffice in select cases. A two-phase dosing strategy (loading + maintenance) is widely employed, though optimal dosing requires further study. Early diagnosis and treatment are critical to prevent irreversible complications.
2025-03-25 | “Cytopenias and proteinuria as key diagnostic features of Imerslund-Gräsbeck Syndrome: a case series of four Argentine patients”
Imerslund-Gräsbeck syndrome (IGS) is a rare autosomal recessive disorder caused by pathogenic variants in CUBN or AMN genes, leading to selective vitamin B12 malabsorption. Symptoms include failure to thrive, cytopenia, and proteinuria. This study aims to analyze clinical, biochemical, and molecular genetic profiles of 4 patients diagnosed with IGS at a single center in Argentina. Macrocytic anemia and neutropenia were present in three cases, two with thrombocytopenia. All had proteinuria. A novel CUBN : c.2450G>A; p.(Cys817Tyr) variant was found in three patients, while the fourth carried AMN : c.1006+34_1007-31del in homozygous state. Early and lifelong parenteral vitamin B12 ensures an excellent prognosis.
2023-11-14 | Imerslund-Gräsbeck Syndrome in a child with a novel compound heterozygous mutations in the AMN gene: a case report
Abstract Background Imerslund-Gräsbeck syndrome (IGS) is an autosomal recessive disorder characterized by selective vitamin B12 malabsorption, resulting in vitamin B12 deficiency and impaired reabsorption of proximal tubular proteins.This case highlights a previously unidentified compound heterozygous variant in the Amnionless（AMN） gene that causes IGS syndrome and underscores the importance of long-term oral vitamin B12 replacement therapy in managing the condition. Case presentation In this retrospective analysis, we present the clinical data of a 3-year and 6-month-old female child diagnosed with IGS at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology in November 2018. The child was admitted to the hospital due to a history of anemia persisting for over a month. There was no significant medical history. The admission examination revealed megaloblastic anemia with proteinuria. Serum vitamin B12 levels were decreased, while folic acid and renal function were normal.The patient was diagnosed with megaloblastic anemia and started long-term oral vitamin B12 replacement therapy. Throughout the follow-up period, blood tests consistently showed normal results, while proteinuria persisted. In November 2019, the child and her parents underwent a whole-exon gene test, which revealed a novel compound heterozygous variant in the AMN gene: c.162 + 1G> A and c.922C> T (p.Q308X) in the child, c.162 + 1G> A in the father, and c.922C> T (p.Q308X) in the mother.Therefore, this child was further diagnosed with IGS. Conclusions In this case, oral vitamin B12 treatment also demonstrated positive clinical effects for the child, offering a new option for patients who are unable to undergo intramuscular vitamin B12 replacement therapy.
2021-11-12 | [Clinical analysis of two brothers with Imerslund-Gräsbeck syndrome].
The clinical data of two children with Imerslund-Gräsbeck syndrome (IGS) who were admitted to the First Affiliated Hospital of Zhengzhou University in August 2019 was analyzed retrospectively. The two cases were siblings, aged 8 years and 8 months and 6 years and 2 months, respectively. These two boys had megaloblastic anemia, low level of vitamin B12, hyperhomocysteinemia, accompanied by proteinuria and renal tubular injury, while they showed normal folate level and renal function. Blood tandem mass spectrometry and urine organic acid analysis suggested methylmalonic acidemia (MMA). The initial diagnosis was MMA with homocysteinemia. No known pathogenic gene mutation related to MMA was found by gene sequencing. Compound heterozygous variants of amnionless (AMN) gene were detected: c.43+5G>A and c.C717G. The corrected diagnosis was IGS. Both brothers were treated with long-term intramuscular injection of vitamin B12. After follow-up for one year, these two cases had no clinical symptoms, and their blood indicators remained normal, but proteinuria and renal tubular injury persisted. Blood tandem mass spectrometry and urine organic acid analysis alone may easily lead to misdiagnosis, but combined with genetic testing can improve the accuracy of diagnosis of IGS. Lifelong parenteral vitamin B12 replacement therapy can effectively reverse the clinical and biochemical results, but is uncertain in alleviating albuminuria and renal tubule injury. It's necessary to monitor the renal function regularly. 回顾分析郑州大学第一附属医院2019年8月收治的两例Imerslund-Gräsbeck综合征（IGS）患儿的临床资料。两例患儿为同胞兄弟，年龄分别为8岁8个月和6岁2个月，检查均示巨幼红细胞性贫血，血清维生素B12减低，血同型半胱氨酸明显升高，叶酸测定及肾功能均正常，均伴有蛋白尿、肾小管损伤。血串联质谱及尿有机酸分析示甲基丙二酸血症（MMA）。初诊为MMA伴同型半胱氨酸血症。基因测序未发现与MMA相关的已知致病基因突变，检测到AMN基因的复合杂合变异：c.43+5G>A和c.C717G。修正诊断为IGS，给予长期肌内注射维生素B12治疗，随访1年，无临床症状，血指标正常，但蛋白尿及肾小管损伤持续。单靠血串联质谱及尿有机酸分析易造成误诊，联合基因检测可提高IGS的诊断。终生肠外维生素B12替代治疗可有效逆转临床和生化结果，但对蛋白尿及肾小管损伤疗效待定，定期监测肾功能是必要的。.
2021-08-16 | Imerslund-Grasbeck syndrome in a cross-breed dog.
Imerslund-Gräsbeck syndrome is an autosomal recessive disease reported only in certain pure-breed dogs. An 18-month-old, male neutered beagle cross-breed was presented for evaluation of severe lethargy, progressive weakness and anorexia. Main clinicopathological findings included low body condition score (2.5/9), severe muscle atrophy, several neurological abnormalities, mild normochromic, normocytic, non-regenerative anaemia, severe hypocobalaminemia and mild proteinuria. Extensive diagnostic tests ruled out most of differential diagnoses for the aforementioned clinicopathological abnormalities and genetic evaluation showed that the dog was heterozygous for two previously described mutations affecting the CUBN gene, the beagle and the border collie variants. The dog showed an excellent clinical response to oral cobalamin supplementation with no relapse after 4 months. In conclusion, this case creates awareness that Imerslund-Gräsbeck syndrome should be considered even in mixed-breed dogs with compatible clinical signs and that two different pathogenic CUBN mutations in compound heterozygosity can lead to a typical Imerslund-Gräsbeck syndrome phenotype.
proteins
2025-01-27 | WCN25-901 CLINICAL AND GENETIC CHARACTERISTICS CHILDREN WITH PROTEINURIA ASSOCIATED WITH CUBN VARIANTS
Persistent glomerular proteinuria is independent predictor for progression to chronic kidney disease. Mutations in the CUBN gene commonly cause Imerslund-Gräsbeck syndrome, while isolated proteinuria as a result of CUBN variants is rarely reported. The aim of the study was to investigate clinical and genetic characteristics in children with persistent proteinuria, associated with CUBN variants.
gene therapies
2026-03-25 | WCN26-3555 Altered Localization of the CUBN–AMN Complex in Renal Tissue of a Patient with PROCHOB
Cubilin (CUBN) is expressed at the proximal tubule brush border, where it forms a complex with Amnionless (AMN) at its N-terminus to mediate albumin reabsorption. AMN and CUBN are known to be interdependent for their plasma membrane expression. Because CUBN forms a complex with AMN at its N-terminus, pathogenic variants in the CUBN N-terminus or AMN result in the failure of CUBN to be expressed at the cell membrane. Since CUBN is also involved in vitamin B12 absorption in the small intestine, pathogenic variants in the CUBN N-terminus or AMN have long been known to cause Imerslund-Gräsbeck Syndrome (IGS), characterized by tubular proteinuria and megaloblastic anemia due to vitamin B12 malabsorption.
small molecules
2026-01-01 | Treatment strategies for Imerslund-Gräsbeck syndrome: a systematic review of vitamin B12 dosage and routes of administration
Abstract Purpose Imerslund-Gräsbeck syndrome (IGS) is a rare autosomal recessive disorder causing vitamin B12 malabsorption due to variants in CUBN or AMN. Current treatment relies on lifelong B12 supplementation, but standardized protocols are lacking. This systematic review synthesizes reported B12 regimens to evaluate dosing strategies and clinical outcomes. Methods A PRISMA-compliant systematic review of PubMed/Medline (inception–January 2026) for case reports/series detailing IGS treatment was conducted. Included studies provided explicit B12 dosage, route, and outcomes. Data from 27 studies (34 patients) were analyzed descriptively, with a heatmap comparing symptom resolution by administration route. The protocol registration number is CRD420251076543. Results Patients (mean age at onset: 6 years; 55.9% female) were treated with intramuscular (79.4%), oral (11.8%), or combined (8.8%) B12. A two-phase regimen (initial loading, then lifelong maintenance) was frequently employed. Hematologic and neurologic normalization were reported with both intramuscular (IM) and oral vitamin B12, with IM representing the standard, most reliably documented approach. Neurological recovery was linked to early treatment initiation. Molecular diagnosis was confirmed in 35% of patients. Conclusion IGS management predominantly uses intramuscular B12, but oral therapy may suffice in select cases. A two-phase dosing strategy (loading + maintenance) is widely employed, though optimal dosing requires further study. Early diagnosis and treatment are critical to prevent irreversible complications.
2025-03-25 | “Cytopenias and proteinuria as key diagnostic features of Imerslund-Gräsbeck Syndrome: a case series of four Argentine patients”
Imerslund-Gräsbeck syndrome (IGS) is a rare autosomal recessive disorder caused by pathogenic variants in CUBN or AMN genes, leading to selective vitamin B12 malabsorption. Symptoms include failure to thrive, cytopenia, and proteinuria. This study aims to analyze clinical, biochemical, and molecular genetic profiles of 4 patients diagnosed with IGS at a single center in Argentina. Macrocytic anemia and neutropenia were present in three cases, two with thrombocytopenia. All had proteinuria. A novel CUBN : c.2450G>A; p.(Cys817Tyr) variant was found in three patients, while the fourth carried AMN : c.1006+34_1007-31del in homozygous state. Early and lifelong parenteral vitamin B12 ensures an excellent prognosis.
2023-11-14 | Imerslund-Gräsbeck Syndrome in a child with a novel compound heterozygous mutations in the AMN gene: a case report
Abstract Background Imerslund-Gräsbeck syndrome (IGS) is an autosomal recessive disorder characterized by selective vitamin B12 malabsorption, resulting in vitamin B12 deficiency and impaired reabsorption of proximal tubular proteins.This case highlights a previously unidentified compound heterozygous variant in the Amnionless（AMN） gene that causes IGS syndrome and underscores the importance of long-term oral vitamin B12 replacement therapy in managing the condition. Case presentation In this retrospective analysis, we present the clinical data of a 3-year and 6-month-old female child diagnosed with IGS at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology in November 2018. The child was admitted to the hospital due to a history of anemia persisting for over a month. There was no significant medical history. The admission examination revealed megaloblastic anemia with proteinuria. Serum vitamin B12 levels were decreased, while folic acid and renal function were normal.The patient was diagnosed with megaloblastic anemia and started long-term oral vitamin B12 replacement therapy. Throughout the follow-up period, blood tests consistently showed normal results, while proteinuria persisted. In November 2019, the child and her parents underwent a whole-exon gene test, which revealed a novel compound heterozygous variant in the AMN gene: c.162 + 1G> A and c.922C> T (p.Q308X) in the child, c.162 + 1G> A in the father, and c.922C> T (p.Q308X) in the mother.Therefore, this child was further diagnosed with IGS. Conclusions In this case, oral vitamin B12 treatment also demonstrated positive clinical effects for the child, offering a new option for patients who are unable to undergo intramuscular vitamin B12 replacement therapy.
2021-11-12 | [Clinical analysis of two brothers with Imerslund-Gräsbeck syndrome].
The clinical data of two children with Imerslund-Gräsbeck syndrome (IGS) who were admitted to the First Affiliated Hospital of Zhengzhou University in August 2019 was analyzed retrospectively. The two cases were siblings, aged 8 years and 8 months and 6 years and 2 months, respectively. These two boys had megaloblastic anemia, low level of vitamin B12, hyperhomocysteinemia, accompanied by proteinuria and renal tubular injury, while they showed normal folate level and renal function. Blood tandem mass spectrometry and urine organic acid analysis suggested methylmalonic acidemia (MMA). The initial diagnosis was MMA with homocysteinemia. No known pathogenic gene mutation related to MMA was found by gene sequencing. Compound heterozygous variants of amnionless (AMN) gene were detected: c.43+5G>A and c.C717G. The corrected diagnosis was IGS. Both brothers were treated with long-term intramuscular injection of vitamin B12. After follow-up for one year, these two cases had no clinical symptoms, and their blood indicators remained normal, but proteinuria and renal tubular injury persisted. Blood tandem mass spectrometry and urine organic acid analysis alone may easily lead to misdiagnosis, but combined with genetic testing can improve the accuracy of diagnosis of IGS. Lifelong parenteral vitamin B12 replacement therapy can effectively reverse the clinical and biochemical results, but is uncertain in alleviating albuminuria and renal tubule injury. It's necessary to monitor the renal function regularly. 回顾分析郑州大学第一附属医院2019年8月收治的两例Imerslund-Gräsbeck综合征（IGS）患儿的临床资料。两例患儿为同胞兄弟，年龄分别为8岁8个月和6岁2个月，检查均示巨幼红细胞性贫血，血清维生素B12减低，血同型半胱氨酸明显升高，叶酸测定及肾功能均正常，均伴有蛋白尿、肾小管损伤。血串联质谱及尿有机酸分析示甲基丙二酸血症（MMA）。初诊为MMA伴同型半胱氨酸血症。基因测序未发现与MMA相关的已知致病基因突变，检测到AMN基因的复合杂合变异：c.43+5G>A和c.C717G。修正诊断为IGS，给予长期肌内注射维生素B12治疗，随访1年，无临床症状，血指标正常，但蛋白尿及肾小管损伤持续。单靠血串联质谱及尿有机酸分析易造成误诊，联合基因检测可提高IGS的诊断。终生肠外维生素B12替代治疗可有效逆转临床和生化结果，但对蛋白尿及肾小管损伤疗效待定，定期监测肾功能是必要的。.
2021-08-16 | Imerslund-Grasbeck syndrome in a cross-breed dog.
Imerslund-Gräsbeck syndrome is an autosomal recessive disease reported only in certain pure-breed dogs. An 18-month-old, male neutered beagle cross-breed was presented for evaluation of severe lethargy, progressive weakness and anorexia. Main clinicopathological findings included low body condition score (2.5/9), severe muscle atrophy, several neurological abnormalities, mild normochromic, normocytic, non-regenerative anaemia, severe hypocobalaminemia and mild proteinuria. Extensive diagnostic tests ruled out most of differential diagnoses for the aforementioned clinicopathological abnormalities and genetic evaluation showed that the dog was heterozygous for two previously described mutations affecting the CUBN gene, the beagle and the border collie variants. The dog showed an excellent clinical response to oral cobalamin supplementation with no relapse after 4 months. In conclusion, this case creates awareness that Imerslund-Gräsbeck syndrome should be considered even in mixed-breed dogs with compatible clinical signs and that two different pathogenic CUBN mutations in compound heterozygosity can lead to a typical Imerslund-Gräsbeck syndrome phenotype.
proteins
2025-01-27 | WCN25-901 CLINICAL AND GENETIC CHARACTERISTICS CHILDREN WITH PROTEINURIA ASSOCIATED WITH CUBN VARIANTS
Persistent glomerular proteinuria is independent predictor for progression to chronic kidney disease. Mutations in the CUBN gene commonly cause Imerslund-Gräsbeck syndrome, while isolated proteinuria as a result of CUBN variants is rarely reported. The aim of the study was to investigate clinical and genetic characteristics in children with persistent proteinuria, associated with CUBN variants.
gene therapies
2026-03-25 | WCN26-3555 Altered Localization of the CUBN–AMN Complex in Renal Tissue of a Patient with PROCHOB
Cubilin (CUBN) is expressed at the proximal tubule brush border, where it forms a complex with Amnionless (AMN) at its N-terminus to mediate albumin reabsorption. AMN and CUBN are known to be interdependent for their plasma membrane expression. Because CUBN forms a complex with AMN at its N-terminus, pathogenic variants in the CUBN N-terminus or AMN result in the failure of CUBN to be expressed at the cell membrane. Since CUBN is also involved in vitamin B12 absorption in the small intestine, pathogenic variants in the CUBN N-terminus or AMN have long been known to cause Imerslund-Gräsbeck Syndrome (IGS), characterized by tubular proteinuria and megaloblastic anemia due to vitamin B12 malabsorption.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
0 orphan drug designations.
0 orphan drug designations.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.