Imerslund-Gräsbeck Syndrome in an Infant with a Novel Intronic Variant in the AMN Gene: A Case Report.

Alessandra Pacitto,Stefania Ceppi,Carla Cerri,Grazia Gurdo,Paolo Prontera,Maurizio Stefanelli,Susanna Esposito,Annalisa Mencarelli,Gabriela Stangoni

doi:10.3390/ijms20030527

Alessandra Pacitto, Stefania Ceppi + Show 7 more

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https://doi.org/10.3390/ijms20030527

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Abstract

Imerslund-Gräsbeck syndrome (IGS) is a rare autosomal recessive disorder clinically characterized by megaloblastic anemia, benign mild proteinuria, and other nonspecific symptoms. Several pathogenetic variants in the amnionless (AMN) or cubilin (CUBN) genes have been described in IGS. We describe a case of IGS with urinary tract infection and mild but persistent proteinuria at onset in an 11-month-old female child. With the appearance of macrocytic anemia, aphthous stomatitis, and neurological signs, IGS was clinically suspected, and vitamin B12 parenteral therapy was started. Sequence analysis showed the presence of a novel intronic variant c.513+5G>A of AMN, never before described in the literature, that was in compound heterozygosity with the known pathogenetic variant c.1006+34_1007-31del. Analysis extension to the parents revealed the presence of variant c.1006+34_1007-31 in the father and c.513+5G>A in the mother. In the present case with IGS, the novel intronic variant of AMN was identified in “trans” with a known pathogenic variant (c.1006-31 del) and the new variant was interpreted to be pathogenetic since it was not found in the public database of polymorphisms and because it was predicted to alter a donor splicing site. Our case underlines the relevance in detecting certain subtle symptoms, such as mild but persistent proteinuria associated with megaloblastic anemia, to reach a correct diagnosis of a rare but treatable disorder.

Highlights

IntroductionImerslund-Gräsbeck syndrome (IGS), known as “Juvenile Megaloblastic anemia type 1” or “Selective vitamin B12 malabsorption with proteinuria”, is a rare genetic disorder inherited through an autosomal recessive pathway [1]
Imerslund-Gräsbeck syndrome (IGS), known as “Juvenile Megaloblastic anemia type 1” or “Selective vitamin B12 malabsorption with proteinuria”, is a rare genetic disorder inherited through an autosomal recessive pathway [1].IGS impairs the absorption of vitamin B12 and in some cases the reabsorption of proteins in the kidney [2,3]
Imerslund-Gräsbeck syndrome (IGS) is a rare autosomal recessive disorder clinically characterized by megaloblastic anemia, benign mild proteinuria, and other nonspecific symptoms

Summary

Introduction

Imerslund-Gräsbeck syndrome (IGS), known as “Juvenile Megaloblastic anemia type 1” or “Selective vitamin B12 malabsorption with proteinuria”, is a rare genetic disorder inherited through an autosomal recessive pathway [1]. The molecular basis of selective malabsorption of vitamin B12 and proteinuria are linked to mutations of cubilin (CUBN) or amnionless genes (AMN). Treatment consists of lifelong vitamin B12 parental therapy and, when started early, guarantees an excellent prognosis, preventing psychomotor delay in children. This case report describes a new intronic variant (c.513+5G>A) located in “trans” with an already-known pathogenetic variant (c.1006-31del) in the AMN gene in an infant with IGS

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Discussion

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