To investigate the clinical manifestations, renal pathological characteristics, and potential mechanisms of Imerslund-Gräsbeck syndrome (IGS) caused by AMN gene mutations, and to analyze the characteristics of renal involvement through a literature review.

A male child (patient 1), aged 11 years and 7 months, diagnosed with AMN mutation-related IGS at the Department of Pediatric Nephrology, West China Second University Hospital (Tianfu), Sichuan University on August 19, 2025, was selected as the research subject. A retrospective analysis was conducted on clinical manifestations, laboratory examinations, renal biopsy findings, and genetic testing results. Additionally, a literature search was performed regarding AMN gene mutation-related IGS and the renal pathological findings associated with IGS. The procedures followed in this study were in line with the requirements of the newly revised World Medical Association Declaration of Helsinki in 2013.

①The primary clinical features of patient 1 included recurrent megaloblastic anemia, vitamin B₁₂ deficiency, and persistent proteinuria. Urinary protein component analysis indicated predominantly tubular proteinuria accompanied by elevated albuminuria. Light microscopy of the renal biopsy revealed mild mesangial proliferation. Electron microscopy showed diffuse thinning of the glomerular basement membrane (GBM) in approximately 70% of the capillary loops, along with segmental fusion of podocyte foot processes. Whole exome sequencing (WES) identified a novel homozygous frameshift mutation in the AMN gene: c. 624del (p.Ser209ArgfsTer51). Sanger sequencing confirmed that both parents were heterozygous carriers of this variant. This variant was not recorded in the gnomAD, ClinVar, or HGMD databases, and no relevant published reports were identified in the literature search. According to the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) guidelines, the variant was classified as pathogenic. ② The literature review identified 22 publications on pediatric patients with AMN mutation-related IGS. Including patient 1 from the present study, a total of 33 patients were included in the analysis, among whom anemia was reported in 32 cases (97.0%), decreased serum vitamin B₁₂ levels in 31 cases (93.9%), and proteinuria in 29 cases (87.9%). AMN mutation-related IGS is mainly characterized by megaloblastic anemia, vitamin B₁₂ deficiency, and proteinuria, with onset occurring predominantly from infancy to the preschool years. Following vitamin B₁₂ replacement therapy, anemia and vitamin B₁₂ deficiency were generally improved, whereas proteinuria often persisted. In addition, 12 publications reporting renal biopsy findings in patients with IGS were included; together with patient 1 from the present study, a total of 22 patients underwent renal biopsy. Renal pathological changes in patients with IGS were generally mild; among cases with a defined genotype, patients with AMN mutations usually exhibited only mild pathological alterations, whereas those with CUBN variants could also present with proximal tubular abnormalities.

Patients with IGS associated with the novel homozygous frameshift mutation of the AMN gene may exhibit ultrastructural glomerular abnormalities: specifically GBM thinning and podocyte alterations, in addition to impaired proximal renal tubular reabsorption. The clinical significance of these findings warrants further investigation.