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Orphanet J Rare Dis. 2015 Mar 15;10:31. doi: 10.1186/s13023-015-0244-7.

Natural disease history and characterisation of SUMF1 molecular defects in ten unrelated patients with multiple sulfatase deficiency.

Author information

1
Laboratoire de Biochimie Métabolique, IFB, CHU Purpan, Toulouse, France. frederique.sabourdy@inserm.fr.
2
INSERM UMR 1037, CRCT, Université Paul Sabatier Toulouse-III, Toulouse, France. frederique.sabourdy@inserm.fr.
3
Institut de Pharmacologie et de Biologie Structurale (IPBS), Centre National de la Recherche Scientifique (CNRS), Toulouse, France. Lionel.Mourey@ipbs.fr.
4
Université de Toulouse, Université Paul Sabatier, IPBS, Toulouse, France. Lionel.Mourey@ipbs.fr.
5
Laboratoire de Biochimie Métabolique, IFB, CHU Purpan, Toulouse, France. letrionnaire.e@chu-toulouse.fr.
6
Service de Néonatologie, Alix de Champagne, CHU de Reims, Reims, France. nbednarek@chu-reims.fr.
7
Laboratoire de Biochimie, Métabolomique et Protéomique, Hôpital Necker Enfants Malades, Paris, France. catherine.caillaud@inserm.fr.
8
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.
9
Service de Génétique Médicale, CHU Pellegrin, et laboratoire Maladies Rares, Génétique et Métabolisme, Université Bordeaux 2, Bordeaux, France. marie-ange.delrue@chu-bordeaux.fr.
10
Service de Neuropédiatrie, CHU de Bicêtre, Kremlin-Bicêtre, France. dusser.anne@gmail.com.
11
Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Bron, France. roseline.froissart@chu-lyon.fr.
12
Laboratoire de biologie et de recherche pédiatriques, American Memorial Hospital, CHU Reims, Reims, France. rgarnotel@chu-reims.fr.
13
Centre de Référence des Maladies Héréditaires du Métabolisme, Lyon, France. nathalie.guffon-fouilhoux@chu-lyon.fr.
14
Unité de Génétique Médicale et Laboratoire Associé INSERM UMR_S910, Université Saint-Joseph, Beirut, Lebanon. megarbane@usj.edu.lb.
15
Institut Jérôme Lejeune, Paris, France. megarbane@usj.edu.lb.
16
Centre Référence des Maladies Héréditaires du Métabolisme, CHU Robert Debré, APHP, Paris, France. helene.ogier@rdb.aphp.fr.
17
Service de neurologie pédiatrique, Université Bordeaux 2, Bordeaux, France. jean-michel.pedespan@chu-bordeaux.fr.
18
Centre Référence des Maladies Héréditaires du Métabolisme, CHU Robert Debré, APHP, Paris, France. samia.pichard@rdb.aphp.fr.
19
Centre de référence-maladies métaboliques, Hôpital Necker Enfants malades, Paris, France. vassili.valaya@nck.aphp.fr.
20
Service de Génétique Clinique, CHU Robert Debré, Paris, France. alain.verloes@rdb.aphp.fr.
21
Laboratoire de Biochimie Métabolique, IFB, CHU Purpan, Toulouse, France. thierry.levade@inserm.fr.
22
INSERM UMR 1037, CRCT, Université Paul Sabatier Toulouse-III, Toulouse, France. thierry.levade@inserm.fr.

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.

PMID:
25885655
PMCID:
PMC4375846
DOI:
10.1186/s13023-015-0244-7
[Indexed for MEDLINE]
Free PMC Article

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