Imerslund-Gräsbeck syndrome: a comprehensive review of reported cases

Kingma, Sandra D.K.; Neven, Julie; Bael, An; Meuwissen, Marije E.C.; van den Akker, Machiel

doi:10.1186/s13023-023-02889-x

Cited by 4 publications

(1 citation statement)

References 98 publications

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“…On the other hand, Cubilin posttranslational modification and apical membrane expression, are highly dependent on normal amnionless function and localization. It is, therefore, reasonable to assume that mutations in CUBN or AMN gene with proteinuric phenotypes may affect the general expression or that the mutations themselves can lead to cubilin truncation or ultimately affect the clinical phenotype by affecting the cell surface expression of cubilin in patients with AMN mutations [ 17 , 18 ] Human C-terminal CUBN variants are proven to associate with chronic proteinuria and normal renal function through podocyte apoptosis via the PI-3 K/PKB pathway which leads to the reduction ability of cubilin-binding with albumin and more free albumin binding with megalin [ 19 ]. Bedin et al report 39 patients of chronic isolated proteinuria and normal function with CUBN variants, while most of them present minimal change disease or no lesions and only two are in the early stage of FSGS [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

Controversy between biopsy and risk in children with proteinuria: is there a paradigm war?

Yang,

Liu

2024

BMC Nephrol

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Background Proteinuria is a prevalent symptom of pediatric nephrology, while kidney biopsy remains the gold standard for kidney tissue analysis, and it is currently controversial. We report the rare case that the mutation in the AMN gene was considered to cause chronically isolated proteinuria and also suggest that renal biopsy should be chosen with caution in children with chronic isolated non-nephrotic levels of proteinuria and that genetic testing may be feasible for the early precise diagnosis. Case presentation A 35-month-old boy presented with excessive urine foaming for more than half a month; his proteinuria was considered non-nephrotic range and urine protein electrophoresis was suggestive of mixed proteinuria; other than that, the investigations are non-specific. Given the child’s chronic isolated proteinuria and good renal function, we chose to refine the genetic test rather than a renal biopsy; a compound heterozygous variant was found in the AMN gene of this child which was caused by a point mutation in the father, and a partial chromosomal deletion in the mother. Conclusions Cubilin(encoded by CUBN), amnionless(encoded by AMN), and megalin form a multiligand receptor complex; CUBN or AMN gene variants have been implicated as a hereditary cause of megaloblastic anemia, proteinuria, and neurological impairment. In the past few decades, chronic isolated proteinuria caused by CUBN gene variants is benign, non-progressive, and has normal renal function. However, the child is the first reported case of isolated proteinuria of AMN gene mutation, indicating that the earlier diagnostic genetic sequencing in an otherwise well, not nephrotic proteinuria child may be a convenient, cost-effective, and harmless option, challenging the traditional paradigm.

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Section: Discussionmentioning

confidence: 99%

Controversy between biopsy and risk in children with proteinuria: is there a paradigm war?

Yang,

Liu

2024

BMC Nephrol

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Imerslund-Gräsbeck syndrome in a child with a novel compound heterozygous mutations in the AMN gene: a case report

Zhang,

Liu,

et al. 2024

Ital J Pediatr

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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, China, in November 2018. The child was admitted to the hospital due to a history of anemia persisting for over a month. There was no previous 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 whole exome sequencing analysis, which revealed a novel compound heterozygous variant in the AMN gene: c.162 + 1G > A and c.922 C > T (p.Q308X) in the child, c.162 + 1G > A in the father, and c.922 C > T (p.Q308X) in the mother. Therefore, this child was further diagnosed with IGS. Conclusions In this case, whole exome sequencing proves to be highly practical in daily healthcare for diagnosing and refining rare or ultra-rare diseases with ambiguous phenotypes or genetic diversity. It is also valuable for prognostic evaluation and personalized management. Additionally, the oral vitamin B12 treatment demonstrated positive clinical effects for the child, offering a new option for patients unable to undergo intramuscular vitamin B12 replacement therapy.

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Severe pancytopenia at the presentation of Imerslund-Gräsbeck syndrome in a 23-month-old Italian boy

Di Sario,

Piloni,

Gasparini

et al. 2024

Ital J Pediatr

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Background Imerslund-Gräsbeck syndrome (IGS) is a rare autosomal recessive disorder characterized by megaloblastic anemia due to selective cobalamin malabsorption and benign proteinuria. IGS is caused by a disfunction of the cubam receptor, which mediates the reabsorption of cobalamin in the ileum and the reuptake of albumin in renal proximal tubules. Case presentation We describe the case of a 23-month-old-italian infant presenting with severe pancytopenia and failure to thrive in whom the diagnosis of IGS was made and vitamin B12 replacement therapy was resolutive. Genetic analysis (NGS with CNV analysis including 214 genes involved in bone marrow failure and anemia), showed the presence of two pathogenetic variants in the AMN gene (c-208–2 A > G and c.1006 + 34_1007-31del). These variants have been previously described in the literature, but their combination has never been reported. Conclusions Imerslund-Gräsbeck syndrome should be considered in the differential diagnosis of children with severe pancytopenia even in those without neurological involvement. This case emphasizes the importance of an early diagnosis and prompt treatment, to prevent irreversible neurological injury.

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Imerslund-Gräsbeck syndrome: a comprehensive review of reported cases

Cited by 4 publications

References 98 publications

Controversy between biopsy and risk in children with proteinuria: is there a paradigm war?

Controversy between biopsy and risk in children with proteinuria: is there a paradigm war?

Imerslund-Gräsbeck syndrome in a child with a novel compound heterozygous mutations in the AMN gene: a case report

Severe pancytopenia at the presentation of Imerslund-Gräsbeck syndrome in a 23-month-old Italian boy

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