title: The Large Phenotypic Spectrum of Fabry Disease Requires Graduated Diagnosis and Personalized Therapy: A Meta-Analysis Can Help to Differentiate Missense Mutations.
abstract: Fabry disease is caused by mutations in theGLAgene and is characterized by a large genotypic and phenotypic spectrum. Missense mutations pose a special problem for graduating diagnosis and choosing a cost-effective therapy. Some mutants retain enzymatic activity, but are less stable than the wild type protein. These mutants can be stabilized by small molecules which are defined as pharmacological chaperones. The first chaperone to reach clinical trial is 1-deoxygalactonojirimycin, but others have been tested in vitro. Residual activity ofGLAmutants has been measured in the presence or absence of pharmacological chaperones by several authors. Data obtained from transfected cells correlate with those obtained in cells derived from patients, regardless of whether 1-deoxygalactonojirimycin was present or not. The extent to which missense mutations respond to 1-deoxygalactonojirimycin is variable and a reference table of the results obtained by independent groups that is provided with this paper can facilitate the choice of eligible patients. A review of other pharmacological chaperones is provided as well. Frequent mutations can have residual activity as low as one-fourth of normal enzyme in vitro. The reference table with residual activity of the mutants facilitates the identification of non-pathological variants.
authors.affiliation: Dipartimento di Biologia, Università Federico II, 80126 Napoli, Italy. vale.ctr@gmail.com.
authors.forename: Valentina
authors.initials: V
authors.lastname: Citro
authors.affiliation: Istituto di Genetica e Biofisica 'A. Buzzati-Traverso', CNR, 80131 Napoli, Italy. cammisamarco.py@gmail.com.
authors.forename: Marco
authors.initials: M
authors.lastname: Cammisa
authors.affiliation: Istituto di Chimica Biomolecolare, CNR, 80078 Pozzuoli, Italy. lud.liguori@gmail.com.
authors.forename: Ludovica
authors.initials: L
authors.lastname: Liguori
authors.affiliation: Dipartimento di Biologia, Università Federico II, 80126 Napoli, Italy. chiaracimmaruta@yahoo.it.|Istituto di Chimica Biomolecolare, CNR, 80078 Pozzuoli, Italy. chiaracimmaruta@yahoo.it.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cimmaruta
authors.affiliation: Albrecht-Kossel-Institute for Neuroregeneration, University Rostock Medical Center, 18147 Rostock, Germany. jan.lukas@med.uni-rostock.de.
authors.forename: Jan
authors.initials: J
authors.lastname: Lukas
authors.affiliation: Dipartimento di Biologia, Università Federico II, 80126 Napoli, Italy. cubellis@unina.it.
authors.forename: Maria Vittoria
authors.initials: MV
authors.lastname: Cubellis
authors.affiliation: Istituto di Chimica Biomolecolare, CNR, 80078 Pozzuoli, Italy. gandreotti@icb.cnr.it.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Andreotti
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000795:Fabry Disease / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics; D057285:Precision Medicine; D054852:Small Molecule Libraries / Q000627:therapeutic use; D000519:alpha-Galactosidase / Q000235:genetics*
chemical_list: D018832:Molecular Chaperones; D054852:Small Molecule Libraries; D017485:1-Deoxynojirimycin; C090092:migalastat; C576330:GLA protein, human; D000519:alpha-Galactosidase
keywords: 1-deoxynojirimycin; Fabry disease/drug therapy; pharmacological chaperones; α-galactosidase