title: Broad spectrum of Fabry disease manifestation in an extended Spanish family with a new deletion in the GLA gene.
abstract: BACKGROUND
  Fabry disease (FD) is an X-linked inherited disease based on the absence or reduction of lysosomal-galactosidase (Gla) activity. The enzymatic defect results in progressive impairment of cerebrovascular, renal and cardiac function. Normally, female heterozygote mutation carriers are less strongly affected than male hemizygotes aggravating disease diagnosis.
  
  
  METHODS
  Close examination of the patients by renal biopsy, echo- and electrocardiography and MRI. Blood work and subsequent DNA analysis were carried out utilizing approved protocols for PCR and Sequencing. MLPA analysis was done to unveil deletions within the GLA gene locus. Quantitative detection of Glycolipids in patient plasma and urine were carried out using HPLC/MS-MS and ESI-MS.
  
  
  RESULTS
  In the presented case, a female index patient led to the examination of three generations of a Spanish family. She presented with severe oto-cochlear symptoms and covert renal and cardiac involvement. While conventional sequencing failed to detect a causative mutation, MLPA analysis revealed a deletion within the GLA gene locus, which we were able to map to a region spanning exon 2 and adjacent intronic parts. The analysis of different biomarkers revealed elevated lyso-Gb3 levels in all affected family members.
  
  
  CONCLUSIONS
  Our findings highlight the broad intrafamilial spectrum of symptoms of FD and emphasise the need to use MLPA screening in symptomatic females without conclusive sequencing result. Finally, plasma lyso-Gb3 proved to be a reliable biomarker for the diagnosis of FD.
authors.affiliation: Albrecht-Kossel Institute for Neuroregeneration, Medical Faculty , University of Rostock , Rostock , Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Lukas
authors.affiliation: Hospital Universitari de Bellvitge, IDIBELL, L'Hospitalet , Barcelona , Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Torras
authors.affiliation: Hospital Universitari de Bellvitge, IDIBELL, L'Hospitalet , Barcelona , Spain.
authors.forename: Itziar
authors.initials: I
authors.lastname: Navarro
authors.affiliation: Albrecht-Kossel Institute for Neuroregeneration, Medical Faculty , University of Rostock , Rostock , Germany.
authors.forename: Anne-Katrin
authors.initials: AK
authors.lastname: Giese
authors.affiliation: Albrecht-Kossel Institute for Neuroregeneration, Medical Faculty , University of Rostock , Rostock , Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Böttcher
authors.affiliation: Pharm-analyt Labor GmbH , Ferdinand-Pichler-Gasse 2, Baden 2500 , Austria.
authors.forename: Hermann
authors.initials: H
authors.lastname: Mascher
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine , Medical Center of the Johannes Gutenberg University , Mainz , Germany.
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Lackner
authors.affiliation: Laboratory of Metabolic Diseases, Department of Pediatrics and Clinical Institute of Medical and Chemical Laboratory Diagnosis , Medical University of Graz , Auenbruggerplatz 30, Graz 8036 , Austria.
authors.forename: Guenter
authors.initials: G
authors.lastname: Fauler
authors.affiliation: Laboratory of Metabolic Diseases, Department of Pediatrics and Clinical Institute of Medical and Chemical Laboratory Diagnosis , Medical University of Graz , Auenbruggerplatz 30, Graz 8036 , Austria.
authors.forename: Eduard
authors.initials: E
authors.lastname: Paschke
authors.affiliation: Hospital Universitari de Bellvitge, IDIBELL, L'Hospitalet , Barcelona , Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Cruzado
authors.affiliation: Department of Neurology, Medical Faculty , University of Rostock , Rostock , Germany.
authors.forename: Ales
authors.initials: A
authors.lastname: Dudesek
authors.affiliation: Department of Neurology, Medical Faculty , University of Rostock , Rostock , Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Wittstock
authors.affiliation: Barts and the London School of Medicine and Dentistry , Queen Mary University of London , London , UK.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Meyer
authors.affiliation: Albrecht-Kossel Institute for Neuroregeneration, Medical Faculty , University of Rostock , Rostock , Germany ; Centogene GmbH, Institute for Molecular Diagnostics , Schillingallee 68, Rostock , Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Rolfs
keywords: Fabry disease; lyso-Gb3; multiple sclerosis; renal involvement