Phenotypic variability and the gender paradox in the R363C variant of Fabry disease
Abstract Fabry disease is an X‐linked lysosomal disease caused by variants in the GLA gene. Although Fabry disease is X‐linked, GLA gene variants in females can exhibit a wide range of symptoms, challenging the traditional view of Fabry as an X‐linked recessive disease. A family is presented here wi...
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| Format: | Article |
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Wiley
2025-01-01
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| Series: | JIMD Reports |
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| Online Access: | https://doi.org/10.1002/jmd2.12466 |
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| author | Alison C. Leslie Jeanine Jarnes Alia Ahmed Sofia Shrestha Jeffrey Wang Chester B. Whitley Nishitha R. Pillai |
| author_facet | Alison C. Leslie Jeanine Jarnes Alia Ahmed Sofia Shrestha Jeffrey Wang Chester B. Whitley Nishitha R. Pillai |
| author_sort | Alison C. Leslie |
| collection | DOAJ |
| description | Abstract Fabry disease is an X‐linked lysosomal disease caused by variants in the GLA gene. Although Fabry disease is X‐linked, GLA gene variants in females can exhibit a wide range of symptoms, challenging the traditional view of Fabry as an X‐linked recessive disease. A family is presented here with a 36‐year‐old female who is symptomatic with chronic kidney disease and her oligosymptomatic 70‐year‐old father, both of whom have a heterozygous and hemizygous GLA pathogenic variant, respectively, c.1087C>T (p.R363C). Interestingly, the proband's Lyso‐GL‐3 levels were lower than her father's despite her more severe clinical presentation. The discordance between clinical severity and Lyso‐GL‐3 levels, particularly in the context of migalastat therapy, raises questions about the appropriate interpretation and use of this biomarker. The earlier and more severe symptom onset in the female proband suggests the potential role of genetic modifiers or other factors influencing disease expression. This report underscores the complexity of Fabry disease phenotypes and the limitations of current biomarkers in predicting disease severity, particularly in females. The observed paradox between clinical symptoms and biomarker levels suggests the need for a deeper understanding of the underlying mechanisms driving phenotypic variability in Fabry disease. |
| format | Article |
| id | doaj-art-15014477b8a442f481ad2d19bb4eba69 |
| institution | Kabale University |
| issn | 2192-8312 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
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| series | JIMD Reports |
| spelling | doaj-art-15014477b8a442f481ad2d19bb4eba692025-01-28T07:38:32ZengWileyJIMD Reports2192-83122025-01-01661n/an/a10.1002/jmd2.12466Phenotypic variability and the gender paradox in the R363C variant of Fabry diseaseAlison C. Leslie0Jeanine Jarnes1Alia Ahmed2Sofia Shrestha3Jeffrey Wang4Chester B. Whitley5Nishitha R. Pillai6University of Minnesota Medical School Minneapolis Minnesota USADivision of Genetics and Metabolism, Department of Pediatrics University of Minnesota Minneapolis Minnesota USADivision of Genetics and Metabolism, Department of Pediatrics University of Minnesota Minneapolis Minnesota USADivision of Genetics and Metabolism, Department of Pediatrics University of Minnesota Minneapolis Minnesota USADivision of Nephrology Hennepin County Medical Center Minneapolis Minnesota USADivision of Genetics and Metabolism, Department of Pediatrics University of Minnesota Minneapolis Minnesota USADivision of Genetics and Metabolism, Department of Pediatrics University of Minnesota Minneapolis Minnesota USAAbstract Fabry disease is an X‐linked lysosomal disease caused by variants in the GLA gene. Although Fabry disease is X‐linked, GLA gene variants in females can exhibit a wide range of symptoms, challenging the traditional view of Fabry as an X‐linked recessive disease. A family is presented here with a 36‐year‐old female who is symptomatic with chronic kidney disease and her oligosymptomatic 70‐year‐old father, both of whom have a heterozygous and hemizygous GLA pathogenic variant, respectively, c.1087C>T (p.R363C). Interestingly, the proband's Lyso‐GL‐3 levels were lower than her father's despite her more severe clinical presentation. The discordance between clinical severity and Lyso‐GL‐3 levels, particularly in the context of migalastat therapy, raises questions about the appropriate interpretation and use of this biomarker. The earlier and more severe symptom onset in the female proband suggests the potential role of genetic modifiers or other factors influencing disease expression. This report underscores the complexity of Fabry disease phenotypes and the limitations of current biomarkers in predicting disease severity, particularly in females. The observed paradox between clinical symptoms and biomarker levels suggests the need for a deeper understanding of the underlying mechanisms driving phenotypic variability in Fabry disease.https://doi.org/10.1002/jmd2.12466Fabry diseasegenetic modifierskidney diseaseLyso‐GL‐3phenotypic variability |
| spellingShingle | Alison C. Leslie Jeanine Jarnes Alia Ahmed Sofia Shrestha Jeffrey Wang Chester B. Whitley Nishitha R. Pillai Phenotypic variability and the gender paradox in the R363C variant of Fabry disease JIMD Reports Fabry disease genetic modifiers kidney disease Lyso‐GL‐3 phenotypic variability |
| title | Phenotypic variability and the gender paradox in the R363C variant of Fabry disease |
| title_full | Phenotypic variability and the gender paradox in the R363C variant of Fabry disease |
| title_fullStr | Phenotypic variability and the gender paradox in the R363C variant of Fabry disease |
| title_full_unstemmed | Phenotypic variability and the gender paradox in the R363C variant of Fabry disease |
| title_short | Phenotypic variability and the gender paradox in the R363C variant of Fabry disease |
| title_sort | phenotypic variability and the gender paradox in the r363c variant of fabry disease |
| topic | Fabry disease genetic modifiers kidney disease Lyso‐GL‐3 phenotypic variability |
| url | https://doi.org/10.1002/jmd2.12466 |
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