title: Severe congenital cutis laxa with cardiovascular manifestations due to homozygous deletions in ALDH18A1.
abstract: Autosomal recessive cutis laxa (ARCL) type 2 constitutes a heterogeneous group of diseases mainly characterized by lax and wrinkled skin, skeletal anomalies, and a variable degree of intellectual disability. ALDH18A1-related ARCL is the most severe form within this disease spectrum. Here we report on the clinical and molecular findings of two affected individuals from two unrelated families. The patients presented with typical features of de Barsy syndrome and an overall progeroid appearance. However, the phenotype was highly variable including cardiovascular involvement in the more severe case. Investigation of a skin biopsy of one patient revealed not only the typical alterations of elastic fibers, but also an altered structure of mitochondria in cutaneous fibroblasts. Using conventional sequencing and copy number analysis we identified a frameshift deletion of one nucleotide and a microdeletion affecting the ALDH18A1 gene, respectively, in a homozygous state in both patients. Expression analysis in dermal fibroblasts from the patient carrying the microdeletion showed an almost complete absence of the ALDH18A1 mRNA resulting in an absence of the ALDH18A1 protein. So far, only 13 affected individuals from seven unrelated families suffering from ALDH18A1-related cutis laxa have been described in literature. Our findings provide new insights into the clinical spectrum and show that beside point mutations microdeletions are a possible cause of ALDH18A1-ARCL.
authors.affiliation: Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Max-Planck-Institut fuer Molekulare Genetik, FG Development & Disease, Ihnestr. 63-73, 14195 Berlin, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Fischer
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Bert
authors.initials: B
authors.lastname: Callewaert
authors.affiliation: Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Phillipe
authors.initials: P
authors.lastname: Schröter
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coucke
authors.affiliation: Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Claire
authors.initials: C
authors.lastname: Schlack
authors.affiliation: Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Max-Planck-Institut fuer Molekulare Genetik, FG Development & Disease, Ihnestr. 63-73, 14195 Berlin, Germany.
authors.forename: Claus-Eric
authors.initials: CE
authors.lastname: Ott
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Neuroscience and Cell Biology, School of Medicine, Università Politecnica delle Marche and Electron Microscopy Unit, United Hospitals, Ancona, Italy.
authors.forename: Manrico
authors.initials: M
authors.lastname: Morroni
authors.affiliation: Neonatologie, Christliches Kinderhospital Osnabrück, Osnabrück, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Homann
authors.affiliation: Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Max-Planck-Institut fuer Molekulare Genetik, FG Development & Disease, Ihnestr. 63-73, 14195 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitaetsmedizin Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.affiliation: Tulane University Medical Center, Hayward Genetics Center, New Orleans, LA, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Morava
authors.affiliation: Rare diseases Regional Centre, Pediatric Institute of Maternal-Infantile Sciences Department, Polytechnic University of Marche, Salesi Hospital of United Hospitals of Ancona, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Ficcadenti
authors.affiliation: Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Max-Planck-Institut fuer Molekulare Genetik, FG Development & Disease, Ihnestr. 63-73, 14195 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitaetsmedizin Berlin, Germany. Electronic address: uwe.kornak@charite.de.
authors.forename: Uwe
authors.initials: U
authors.lastname: Kornak
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D000596:Amino Acids / Q000097:blood; D001483:Base Sequence; D002318:Cardiovascular Diseases / Q000097:blood / Q000150:complications* / Q000235:genetics*; D002675:Child, Preschool; D003483:Cutis Laxa / Q000097:blood / Q000150:complications / Q000151:congenital* / Q000235:genetics*; D017809:Fatal Outcome; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000473:pathology / Q000648:ultrastructure
chemical_list: D000596:Amino Acids; D012333:RNA, Messenger; C000596432:ALDH18A1 protein, human; D000444:Aldehyde Dehydrogenase
keywords: ALDH18A1; Autosomal recessive cutis laxa; Homozygous deletion 10q24.3; Mitochondria; PYCR1; Progeroid features