title: Natural disease history and characterisation of SUMF1 molecular defects in ten unrelated patients with multiple sulfatase deficiency.
abstract: BACKGROUND
  Multiple sulfatase deficiency is a rare inherited metabolic disorder caused by mutations in the SUMF1 gene. The disease remains poorly known, often leading to a late diagnosis. This study aimed to provide improved knowledge of the disease, through complete clinical, biochemical, and molecular descriptions of a cohort of unrelated patients. The main objective was to identify prognostic markers, both phenotypic and genotypic, to accelerate the diagnosis and improve patient care.
  
  
  METHODS
  The phenotypes of ten unrelated patients were fully documented at the clinical and biochemical levels. The long-term follow-up of each patient allowed correlations of the phenotypes to the disease outcomes. Each patient's molecular defects were also identified. Site-directed mutagenesis was used to individually express the mutants and assess their stability. Characterisation of the protein mutants was completed by in silico analyses based on sequence comparisons and structural models.
  
  
  RESULTS
  The most severe cases were characterised by the presence of non-neurological symptoms as well as the occurrence of psychomotor regression before 2 years of age. Nine novel SUMF1 mutations were identified. Clinically severe forms were often associated with SUMF1 mutations that strongly affected the protein stability and/or catalytic function as predicted from in silico and western blot analyses.
  
  
  CONCLUSIONS
  This detailed clinical description and follow-up of a cohort of patients, together with the molecular characterisation of their underlying defects, contribute to improved knowledge of multiple sulfatase deficiency. Predictors of a bad prognosis were the presence of several non-neurological symptoms and the onset of psychomotor regression before 2 years of age. No strict correlation existed between in vitro residual sulfatase activity and disease severity. Genotype-phenotype correlations related to previously reported mutants were strengthened. These and previous observations allow not only improved prediction of the disease outcome but also provision of appropriate care for patients, in the expectation of specific treatment development.
authors.affiliation: Laboratoire de Biochimie Métabolique, IFB, CHU Purpan, Toulouse, France. frederique.sabourdy@inserm.fr.|INSERM UMR 1037, CRCT, Université Paul Sabatier Toulouse-III, Toulouse, France. frederique.sabourdy@inserm.fr.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Sabourdy
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale (IPBS), Centre National de la Recherche Scientifique (CNRS), Toulouse, France. Lionel.Mourey@ipbs.fr.|Université de Toulouse, Université Paul Sabatier, IPBS, Toulouse, France. Lionel.Mourey@ipbs.fr.
authors.forename: Lionel
authors.initials: L
authors.lastname: Mourey
authors.affiliation: Laboratoire de Biochimie Métabolique, IFB, CHU Purpan, Toulouse, France. letrionnaire.e@chu-toulouse.fr.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Le Trionnaire
authors.affiliation: Service de Néonatologie, Alix de Champagne, CHU de Reims, Reims, France. nbednarek@chu-reims.fr.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bednarek
authors.affiliation: Laboratoire de Biochimie, Métabolomique et Protéomique, Hôpital Necker Enfants Malades, Paris, France. catherine.caillaud@inserm.fr.
authors.forename: Catherine
authors.initials: C
authors.lastname: Caillaud
authors.affiliation: Hôpital des Enfants, CHU Purpan, and INSERM UMR 825 Imagerie Cérébrale et Handicaps Neurologiques, Université Paul Sabatier Toulouse-III, CHU Purpan, Toulouse, France. chaix.y@chu-toulouse.fr.
authors.forename: Yves
authors.initials: Y
authors.lastname: Chaix
authors.affiliation: Service de Génétique Médicale, CHU Pellegrin, et laboratoire Maladies Rares, Génétique et Métabolisme, Université Bordeaux 2, Bordeaux, France. marie-ange.delrue@chu-bordeaux.fr.
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Delrue
authors.affiliation: Service de Neuropédiatrie, CHU de Bicêtre, Kremlin-Bicêtre, France. dusser.anne@gmail.com.
authors.forename: Anne
authors.initials: A
authors.lastname: Dusser
authors.affiliation: Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Bron, France. roseline.froissart@chu-lyon.fr.
authors.forename: Roseline
authors.initials: R
authors.lastname: Froissart
authors.affiliation: Laboratoire de biologie et de recherche pédiatriques, American Memorial Hospital, CHU Reims, Reims, France. rgarnotel@chu-reims.fr.
authors.forename: Roselyne
authors.initials: R
authors.lastname: Garnotel
authors.affiliation: Centre de Référence des Maladies Héréditaires du Métabolisme, Lyon, France. nathalie.guffon-fouilhoux@chu-lyon.fr.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Guffon
authors.affiliation: Unité de Génétique Médicale et Laboratoire Associé INSERM UMR_S910, Université Saint-Joseph, Beirut, Lebanon. megarbane@usj.edu.lb.|Institut Jérôme Lejeune, Paris, France. megarbane@usj.edu.lb.
authors.forename: André
authors.initials: A
authors.lastname: Megarbane
authors.affiliation: Centre Référence des Maladies Héréditaires du Métabolisme, CHU Robert Debré, APHP, Paris, France. helene.ogier@rdb.aphp.fr.
authors.forename: Hélène
authors.initials: H
authors.lastname: Ogier de Baulny
authors.affiliation: Service de neurologie pédiatrique, Université Bordeaux 2, Bordeaux, France. jean-michel.pedespan@chu-bordeaux.fr.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Pédespan
authors.affiliation: Centre Référence des Maladies Héréditaires du Métabolisme, CHU Robert Debré, APHP, Paris, France. samia.pichard@rdb.aphp.fr.
authors.forename: Samia
authors.initials: S
authors.lastname: Pichard
authors.affiliation: Centre de référence-maladies métaboliques, Hôpital Necker Enfants malades, Paris, France. vassili.valaya@nck.aphp.fr.
authors.forename: Vassili
authors.initials: V
authors.lastname: Valayannopoulos
authors.affiliation: Service de Génétique Clinique, CHU Robert Debré, Paris, France. alain.verloes@rdb.aphp.fr.
authors.forename: Alain
authors.initials: A
authors.lastname: Verloes
authors.affiliation: Laboratoire de Biochimie Métabolique, IFB, CHU Purpan, Toulouse, France. thierry.levade@inserm.fr.|INSERM UMR 1037, CRCT, Université Paul Sabatier Toulouse-III, Toulouse, France. thierry.levade@inserm.fr.
authors.forename: Thierry
authors.initials: T
authors.lastname: Levade
mesh_terms: D002648:Child; D002675:Child, Preschool; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D052517:Multiple Sulfatase Deficiency Disease / Q000235:genetics* / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D050862:Oxidoreductases Acting on Sulfur Group Donors; D010641:Phenotype; D011487:Protein Conformation; D013429:Sulfatases / Q000235:genetics / Q000378:metabolism*
chemical_list: D050862:Oxidoreductases Acting on Sulfur Group Donors; C480483:SUMF1 protein, human; D013429:Sulfatases