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Expanding the p.(Arg85Trp) Variant-Specific Phenotype of HNF4A: Features of Glycogen Storage Disease, Liver Cirrhosis, Impaired Mitochondrial Function, and Glomerular Changes

Authors :
Mara Grassi
Bernard Laubscher
Amit V. Pandey
Sibylle Tschumi
Franziska Graber
André Schaller
Marco Janner
Daniel Aeberli
Ekkehard Hewer
Jean-Marc Nuoffer
Matthias Gautschi
Source :
Molecular Syndromology. :1-15
Publication Year :
2023
Publisher :
S. Karger AG, 2023.

Abstract

Introduction: The p.(Arg85Trp) variant-specific phenotype of hepatocyte nuclear factor 4 alpha shows a complex clinical picture affecting three different organ systems and their corresponding metabolisms. Little is known about the molecular mechanisms involved and their relationship with the diverse symptoms seen in the context of this specific variant. Here, we present data of a new patient that expand the clinical phenotype, suggesting possible disease mechanisms. Case Presentation: Clinical data were extracted from the patient’s charts. The liver, kidney, and muscle were analyzed with routine histology and electron microscopy. Mitochondrial function was assessed by respirometric analyses and enzymatic activity assays. Structure and sequence analyses of this specific variant were investigated by in silico analyses. Our patient showed the known features of the variant-specific phenotype, including macrosomia, congenital hyperinsulinism, transient hepatomegaly, and renal Fanconi syndrome. In addition to that, she showed liver cirrhosis, chronic kidney failure, and altered mitochondrial morphology and function. The clinical and biochemical phenotype had features of a new type of glycogen storage disease. Discussion: This case expands the p.(Arg85Trp) variant-specific phenotype. Possible pathomechanistic explanations for the documented multiorgan involvement and changes of symptoms and signs during development of this ultra-rare but instructive disorder are discussed.

Subjects

Subjects :
Genetics
Genetics (clinical)

Details

ISSN :
16618777 and 16618769
Database :
OpenAIRE
Journal :
Molecular Syndromology
Accession number :
edsair.doi...........f838b57296a534f8c4347ae0107e8212
Full Text :
https://doi.org/10.1159/000529306