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Int. J. Mol. Sci. 2016, 17(12), 2010; doi:10.3390/ijms17122010

The Large Phenotypic Spectrum of Fabry Disease Requires Graduated Diagnosis and Personalized Therapy: A Meta-Analysis Can Help to Differentiate Missense Mutations

1
Dipartimento di Biologia, Università Federico II, 80126 Napoli, Italy
2
Istituto di Genetica e Biofisica ‘A. Buzzati-Traverso’, CNR, 80131 Napoli, Italy
3
Istituto di Chimica Biomolecolare, CNR, 80078 Pozzuoli, Italy
4
Albrecht-Kossel-Institute for Neuroregeneration, University Rostock Medical Center, 18147 Rostock, Germany
*
Authors to whom correspondence should be addressed.
Academic Editor: Ritva Tikkanen
Received: 9 October 2016 / Revised: 23 November 2016 / Accepted: 24 November 2016 / Published: 1 December 2016
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Abstract

Fabry disease is caused by mutations in the GLA gene 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 of GLA mutants 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. View Full-Text
Keywords: Fabry disease/drug therapy; α-galactosidase; pharmacological chaperones; 1-deoxynojirimycin Fabry disease/drug therapy; α-galactosidase; pharmacological chaperones; 1-deoxynojirimycin
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MDPI and ACS Style

Citro, V.; Cammisa, M.; Liguori, L.; Cimmaruta, C.; Lukas, J.; Cubellis, M.V.; Andreotti, G. The Large Phenotypic Spectrum of Fabry Disease Requires Graduated Diagnosis and Personalized Therapy: A Meta-Analysis Can Help to Differentiate Missense Mutations. Int. J. Mol. Sci. 2016, 17, 2010.

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