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. 2024 Sep 10:2:101891.
doi: 10.1016/j.gimo.2024.101891. eCollection 2024.

Prospective characterization of early symptom onset and progression in young pediatric patients with variants in the G LA gene across 5 years: Longitudinal data from the Fabry MOPPet Study

D A Laney  1 , M F Houde  1 , A L Foley  1 , D S Peck  2 , A M Atherton  3 , L P Manwaring  4 , D K Grange  4 , B A Heese  5 , M D Holida  6 , A L Quillin  1 , R Vinson  1 , C Auray-Blais  7 , R J Hopkin  8
Affiliations

Prospective characterization of early symptom onset and progression in young pediatric patients with variants in the G LA gene across 5 years: Longitudinal data from the Fabry MOPPet Study

D A Laney et al. Genet Med Open. .

Abstract

Purpose: This prospective, longitudinal study was designed to determine the natural history of Fabry disease (FD) in early pediatric patients across the disease spectrum.

Methods: In this observational study of children under 5 years of age with variants in the GLA gene, prospective phenotypic and urinary biomarker data were collected annually over 5 years.

Results: The study population included 40 participants (35 male, 5 female) with GLA variants including 15 with classic pathogenic variants (CFD), 6 with nonclassic pathogenic variants (NFD), and 19 with a variant of uncertain significance. The most common first symptoms reported were in participants with CFD and included gastrointestinal symptoms (13/15), heat intolerance (13/15), reduced sweating after previously sweating normally (6/15), and neuropathic pain/uncomfortable feet/hands (3/15). Mapping symptom onset and progression reveals a consistent pattern of frequency and severity occurring in the first years of life and beginning at an average age of 23.4 months (range 11-32 months) in males with CFD. Participants with nonclassic pathogenic variants and variant of uncertain significance did not exhibit consistency in symptom onset or progression during the study period.

Conclusion: This study highlights the onset and pattern of progression of the earliest Fabry-related symptoms in children with CFD.

Keywords: Fabry disease; Lysosomal storage disorders; Natural history; Newborn screening; Pediatric.

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Conflict of interest statement

D.A. Laney is a member of the North American Fabry Registry Board, consults and/or has been an investigator and coordinator in clinical trials sponsored by 4DMT, Amicus Therapeutics, Chiesi Farmaceutici, Protalix BioTherapeutics, Sangamo, Sanofi-Genzyme, Spark Therapeutics, and Takeda-Shire. These activities have been monitored and found to be in compliance with the conflict of interest policies at the Emory University School of Medicine. R.J. Hopkin is a member of the Fabry Registry Advisory Board and the FollowMe registry, consults with Sanofi and Amicus Therapeutics, Chiesi Farmaceutici and Freeline, and has been an investigator in clinical trials sponsored by Amicus Therapeutics, Idorsia, Protalix BioTherapeutics, Sangamo Therapeutics, Sanofi, and Takeda. These activities have been monitored and found to be in compliance with the conflict of interest policies at Cincinnati Children’s Hospital Medical Center. C. Auray-Blais has received research grants from Shire/Takeda, Sanofi-Genzyme, BioMarin Pharmaceuticals Inc. and Amicus Therapeutics. She has been a consultant for Amicus Therapeutics Inc. and Biomarin Pharmaceuticals Inc. She has received financial support for service contracts from Protalix Biotherapeutics, Avrobio, Moderna Therapeutics, Sigilon Therapeutics, 4D- Molecular Therapeutics, and Chiesi Farmaceutici. She has received honoraria and traveling funds for lectures from Amicus Therapeutics, Shire/Takeda, Sanofi-Genzyme, BioMarin Pharmaceuticals Inc. and traveling funds from Waters Corp for lectures given. These activities have been disclosed at the Faculty of Medicine and Health Sciences at the Université de Sherbrooke. M.D. Holida has been an investigator and coordinator in clinical trials sponsored by Amicus Therapeutics, Chiesi Farmaceutici, Protalix BioTherapeutics, and Sanofi-Genzyme. These activities have been monitored and found to be in compliance with the conflict of interest policies at the University of Iowa. A.M. Atherton is an employee at Amgen, Inc and has stock in the company. M.F. Houde is an employee at Takeda. All other authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Progression of symptoms in children with classic Fabry disease by organ system. A. Progression of gastrointestinal symptoms in children with classic Fabry disease not on enzyme replacement therapy. B. Progression of heat intolerance/hypohidrosis in children with classic Fabry disease not on enzyme replacement therapy. C. Progression of neuropathy in children with classic Fabry disease not on enzyme replacement therapy.
Figure 1
Figure 1
Progression of symptoms in children with classic Fabry disease by organ system. A. Progression of gastrointestinal symptoms in children with classic Fabry disease not on enzyme replacement therapy. B. Progression of heat intolerance/hypohidrosis in children with classic Fabry disease not on enzyme replacement therapy. C. Progression of neuropathy in children with classic Fabry disease not on enzyme replacement therapy.
Figure 2
Figure 2
Urinary biomarkers in males with classic Fabry disease not on enzyme replacement therapy. A. Total urinary lysoGb3 levels by age in males with classic Fabry disease collected during the study. B. Longitudinal total urinary lysoGb3 levels by age in males with classic Fabry disease. C. Total urinary Gb3 levels by age in males with classic Fabry disease. D. Longitudinal total urinary Gb3 levels by age in males with classic Fabry disease.
Supplementary Figure 1
Supplementary Figure 1
Supplementary Figure 2a
Supplementary Figure 2a
Supplementary Figure 2c
Supplementary Figure 2c
See this image and copyright information in PMC

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