title: Diagnostic dilemmas in Fabry disease: a case series study on GLA mutations of unknown clinical significance.
abstract: Fabry disease' (FD) phenotype is heterogeneous: alpha-galactosidase A gene mutations (GLA) can lead to classical or non-classical FD, or no FD. The aim of this study is to describe pitfalls in diagnosing non-classical FD and assess the diagnostic value of plasma globotriaosylsphingosine. This is a case series study. Family 1 (p.A143T) presented with hypertrophic cardiomyopathy (HCM), absent classical FD signs, high residual alpha-galactosidase A activity (AGAL-A) and normal plasma globotriaosylsphingosine. Co-segregating sarcomeric mutations were found. Cardiac biopsy excluded FD. In family 2 (p.P60L), FD was suspected after kidney biopsy in a female with chloroquine use. Males had residual AGAL-A, no classical FD signs and minimally increased plasma globotriaosylsphingosine, indicating that p.P60L is most likely non-pathogenic. Non-specific complications and histology can be explained by chloroquine and alternative causes. Males of two unrelated families (p.R112H) show AGAL-A <5%, but slightly elevated plasma globotriaosylsphingosine (1.2-2.0 classical males >50 nmol/l). Histological evidence suggests a variable penetrance of this mutation. Patients with GLA mutations and non-specific findings such as HCM may have non-classical FD or no FD. Other (genetic) causes of FD-like findings should be excluded, including medication inducing FD-like storage. Plasma globotriaosylsphingosine may serve as a diagnostic tool, but histology of an affected organ is often mandatory.
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Centre of Amsterdam, Amsterdam, The Netherlands.
authors.forename: B E
authors.initials: BE
authors.lastname: Smid
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Centre of Amsterdam, Amsterdam, The Netherlands.
authors.forename: C E M
authors.initials: CE
authors.lastname: Hollak
authors.affiliation: Department of Genetic Metabolic Diseases, Academic Medical Centre of Amsterdam, Amsterdam, The Netherlands.
authors.forename: B J H M
authors.initials: BJ
authors.lastname: Poorthuis
authors.affiliation: Department of Pathology, Academic Medical Centre of Amsterdam, Amsterdam, The Netherlands.
authors.forename: M A
authors.initials: MA
authors.lastname: van den Bergh Weerman
authors.affiliation: Department of Pathology, Academic Medical Centre of Amsterdam, Amsterdam, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Florquin
authors.affiliation: Department of Cardiology, Academic Medical Centre of Amsterdam, Amsterdam, The Netherlands.
authors.forename: W E M
authors.initials: WE
authors.lastname: Kok
authors.affiliation: Department of Clinical Genetics, Academic Medical Centre of Amsterdam, Amsterdam, The Netherlands.
authors.forename: R H
authors.initials: RH
authors.lastname: Lekanne Deprez
authors.affiliation: Department of Cardiology, RadboudUMC, Nijmegen, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Timmermans
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Centre of Amsterdam, Amsterdam, The Netherlands.
authors.forename: G E
authors.initials: GE
authors.lastname: Linthorst
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001706:Biopsy; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics*; D000795:Fabry Disease / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D005915:Globosides / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D012189:Retrospective Studies; D055815:Young Adult; D000519:alpha-Galactosidase / Q000235:genetics*
chemical_list: D005915:Globosides; C576330:GLA protein, human; D000519:alpha-Galactosidase
keywords: Fabry disease; cardiac variant; diagnosis; phenotype; renal variant; screening; variant of unknown significance (VUS)