Variable clinical features of patients with Fabry disease and outcome of enzyme replacement therapy

Marina Dutra-Clarke; Daisy Tapia; Emily Curtin; Dennis Rünger; Grace K. Lee; Anita Lakatos; Zyza Alandy-Dy; Linda Freedkin; Kathy Hall; Nesrin Ercelen; Jousef Alandy-Dy; Margaret Knight; Madeleine Pahl; Dawn Lombardo; Virginia Kimonis

Molecular Genetics and Metabolism Reports (Mar 2021)

Variable clinical features of patients with Fabry disease and outcome of enzyme replacement therapy

Marina Dutra-Clarke,
Daisy Tapia,
Emily Curtin,
Dennis Rünger,
Grace K. Lee,
Anita Lakatos,
Zyza Alandy-Dy,
Linda Freedkin,
Kathy Hall,
Nesrin Ercelen,
Jousef Alandy-Dy,
Margaret Knight,
Madeleine Pahl,
Dawn Lombardo,
Virginia Kimonis

Affiliations

Marina Dutra-Clarke: Division of Genetics and Genomic Medicine, Department of Pediatrics, University of California, Irvine, Irvine, CA, USA; Division of Genetics, Department of Pediatrics, University of California, Los Angeles, CA, USA
Daisy Tapia: Division of Genetics and Genomic Medicine, Department of Pediatrics, University of California, Irvine, Irvine, CA, USA
Emily Curtin: Division of Genetics and Genomic Medicine, Department of Pediatrics, University of California, Irvine, Irvine, CA, USA
Dennis Rünger: Department of Medicine Statistics Core, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
Grace K. Lee: Division of Genetics and Genomic Medicine, Department of Pediatrics, University of California, Irvine, Irvine, CA, USA
Anita Lakatos: Division of Genetics and Genomic Medicine, Department of Pediatrics, University of California, Irvine, Irvine, CA, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, CA, USA
Zyza Alandy-Dy: Division of Genetics and Genomic Medicine, Department of Pediatrics, University of California, Irvine, Irvine, CA, USA
Linda Freedkin: Division of Genetics and Genomic Medicine, Department of Pediatrics, University of California, Irvine, Irvine, CA, USA
Kathy Hall: Division of Genetics and Genomic Medicine, Department of Pediatrics, University of California, Irvine, Irvine, CA, USA
Nesrin Ercelen: Division of Genetics and Genomic Medicine, Department of Pediatrics, University of California, Irvine, Irvine, CA, USA; Department of Genetics, Amerikan Hospital, Istanbul, Turkey
Jousef Alandy-Dy: Division of Genetics and Genomic Medicine, Department of Pediatrics, University of California, Irvine, Irvine, CA, USA
Margaret Knight: Division of Genetics and Genomic Medicine, Department of Pediatrics, University of California, Irvine, Irvine, CA, USA
Madeleine Pahl: Division of Nephrology, Department of Medicine, University of California, Irvine, CA, USA
Dawn Lombardo: Division of Cardiology, Department of Medicine, University of California, Irvine, CA, USA
Virginia Kimonis: Division of Genetics and Genomic Medicine, Department of Pediatrics, University of California, Irvine, Irvine, CA, USA; Department of Pathology, University of California, Irvine, CA, USA; Department of Neurology, University of California, Irvine, Irvine, CA, USA; Environmental and Occupational Health, University of California, Irvine, CA, USA; Corresponding author at: Division of Genetics & Genomic Medicine, University of California, Irvine, USA.

Journal volume & issue: Vol. 26
p. 100700

Abstract

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Fabry disease (FD) is an X-linked lysosomal storage disorder caused by a deficiency in the enzyme α-galactosidase A due to mutations in the GLA gene. This leads to an accumulation of globotriaosylceramide (GL-3) in many tissues, which results in progressive damage to the kidneys, heart, and nervous system. We present the molecular and clinical characteristics and long-term outcomes of FD patients from a multidisciplinary clinic at the University of California, Irvine treated with agalsidase beta enzyme replacement therapy (ERT) for 2–20 years. This cohort comprised 24 adults (11 males, 13 females) and two male children (median age 45; range 10–68 years). Of the 26 patients in this cohort, 20 were on ERT (12 males, 8 females). We describe one novel variant not previously reported in the literature in a patient with features of ‘classic’ FD. The vast majority of patients in this cohort presented with symptoms of ‘classic’ FD including peripheral neuropathic pain, some form of cardiac involvement, angiokeratomas, corneal verticillata, hypohidrosis, tinnitus, and gastrointestinal symptoms, primarily abdominal pain. The majority of males had clinically evident renal involvement. An annual eGFR reduction of −1.88 mL/min/1.73 m2/yr during the course of ERT was seen in this cohort. The most common renal presentation was proteinuria, and one individual required a renal transplant. Other common findings were pulmonary involvement, lymphedema, hearing loss, and significantly, three patients had strokes. Notably, there was a high prevalence of endocrine dysfunction and low bone mineral density, including several with osteoporosis.While enzyme replacement therapy (ERT) cleared plasma GL-3 in this cohort, there was limited improvement in renal function or health-related quality of life based on the patient-reported SF-36 Health Survey. Physical functioning significantly declined over the course of ERT treatment, which may be, in part, due to the late initiation of ERT in several patients. Further delineation of the phenotypic and genotypic spectrum in patients with FD and the long-term outcome of ERT will help improve management and treatment options for this disease.

Published in Molecular Genetics and Metabolism Reports

ISSN: 2214-4269 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Medicine (General); Science: Biology (General)
Website: http://www.journals.elsevier.com/molecular-genetics-and-metabolism-reports/

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