Coexistence of Alport Syndrome and Fabry Disease in a Female with R112H Variant - Early Progression of Fabry Nephropathy

Sep 30, 2026

Fabry disease is an X-linked lysosomal disorder caused by GLA mutations, usually leading to glycosphingolipid accumulation and a broad range of clinical phenotypes. The p.R112H variant is typically associated with a predominantly renal, non-classic form with mild biochemical abnormalities and slow progression. A case of a young woman with the R112H mutation showed early kidney involvement and unexpectedly rapid progression to end-stage renal disease. Initial biopsy supported Fabry nephropathy, but later review revealed Alport-like glomerular basement membrane remodeling. Genetic testing confirmed heterozygous pathogenic COL4A4 (G912R), establishing coexistence of Fabry disease and autosomal dominant Alport syndrome, likely driving accelerated renal decline.

LanguageEnglish

CategoryHealthcare

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Reading Time23 min

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Abstract

1. Introduction

Case Report Coexistence of Alport Syndrome and Fabry Disease in a Female with R112H Variant: Early Progression of Fabry Nephropathy Amedeo Grimaldi 1,2, *, Alessandra Auletta 1,2, Francesca Ciurli 2, Valeria Aiello 2, Gisella Vischini 2, Benedetta Fabbrizio 3, Francesca Becherucci 4,5, Gianandrea Pasquinelli 3, Gaetano La Manna 1,2, Irene Capelli 1,2 and Renzo Mignani 1,2 1 Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum—University of Bologna, 40126 Bologna, Italy; [alessandra.auletta@studio.unibo.it](alessandra.auletta@studio.unibo.it) (A.A.) 2 Nephrology, Dialysis and Kidney Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40126 Bologna, Italy 3 Pathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40126 Bologna, Italy; [gianandr.pasquinelli@unibo.it](gianandr.pasquinelli@unibo.it) (G.P.) 4 Nephrology and Dialysis, Meyer Children’s Hospital IRCCS, 50139 Florence, Italy 5 Department of Biomedical, Experimental and Clinical Sciences, University of Florence, 50121 Florence, Italy * Correspondence: [amedeo.grimaldi@studio.unibo.it](amedeo.grimaldi@studio.unibo.it) Abstract Fabry disease (FD) is an X-linked lysosomal disorder caused by GLA mutations, typically associated with glycosphingolipid accumulation and a wide phenotypic spectrum. The p.R112H variant is generally linked to a non-classic predominantly renal phenotype with mild biochemical abnormalities and slow progression. We report the case of a young woman carrying the R112H mutation who exhibited early-onset kidney involvement and unusually rapid progression to end-stage renal disease. Clinical history, serial evaluations, and kidney biopsy findings initially supported a diagnosis of Fabry nephropathy; however, re-evaluation of the native kidney biopsy revealed marked remodeling and multilamellation of the glomerular basement membrane, suggesting Alport-like lesions. Subsequent genetic testing confirmed a heterozygous pathogenic COL4A4 variant (G912R), indicating coexistence of Fabry disease and autosomal dominant Alport syndrome. This dual genetic condition likely accounted for the accelerated decline in kidney function, in contrast with the typically mild phenotype associated with R112H. Our literature review indicates that coexistence of these two inherited nephropathies has not previously been confirmed either histologically or genetically. This case underscores the importance of integrating genetic and ultrastructural assessment in patients with atypical or rapidly progressive renal disease Academic Editor: Dmitry B. Zorov Received: 5 December 2025 Revised: 23 December 2025 Accepted: 25 December 2025 Published: 26 December 2025 Copyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. Keywords: Fabry disease; Alport syndrome; p.R112H variant; COL4A4 variant; chronic kidney disease 1. Introduction Fabry disease (FD, OMIM 301500) is a rare inherited storage disorder caused by mutations in the GLA gene (located at Xq22) that result in deficient or absent lysosomal α-galactosidase A (GLA) activity [1] . The ubiquitous presence of lysosomes, essential for breaking down and recycling cellular materials, suggests that FD has a broad impact, influencing various organs and exhibiting a range of phenotypes shaped by the degree of their involvement [2] . Enzymatic defects lead to an accumulation of glycosphingolipids, such as globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3), in multiple cell types, tissues, and organs [3] . It has been demonstrated that exposure to plasma lyso-Gb3 correlates with the severity of disease manifestations [4] . The clinical presentation of FD is highly variable, with phenotypes ranging from the early onset “classic form”(no residual enzymatic activity, markedly elevated lysoGb3 leve

FAQs

What genetic conditions are confirmed in the reported patient?

The patient carries the Fabry disease p.R112H mutation and a heterozygous pathogenic COL4A4 variant (G912R), indicating coexistence of Fabry disease and autosomal dominant Alport syndrome.

Why did the kidney disease progress more rapidly than expected for the R112H variant?

The accelerated decline is attributed to the dual genetic conditions, combining Fabry-related nephropathy features with Alport-like glomerular basement membrane remodeling.

How did the diagnosis evolve from the initial biopsy to the final conclusion?

Clinical history and the initial biopsy findings supported Fabry nephropathy; re-evaluation of the native kidney biopsy later showed marked remodeling and multilamellation of the glomerular basement membrane suggestive of Alport-like lesions, followed by confirmatory genetic testing.

Sep 30, 2026

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