title: Genotypic classification of patients with Wolfram syndrome: insights into the natural history of the disease and correlation with phenotype.
abstract: OBJECTIVE
  Wolfram syndrome is a degenerative, recessive rare disease with an onset in childhood. It is caused by mutations in WFS1 or CISD2 genes. More than 200 different variations in WFS1 have been described in patients with Wolfram syndrome, which complicates the establishment of clear genotype-phenotype correlation. The purpose of this study was to elucidate the role of WFS1 mutations and update the natural history of the disease.
  
  
  METHODS
  This study analyzed clinical and genetic data of 412 patients with Wolfram syndrome published in the last 15 years.
  
  
  RESULTS
  (i) 15% of published patients do not fulfill the current -inclusion criterion; (ii) genotypic prevalence differences may exist among countries; (iii) diabetes mellitus and optic atrophy might not be the first two clinical features in some patients; (iv) mutations are nonuniformly distributed in WFS1; (v) age at onset of diabetes mellitus, hearing defects, and diabetes insipidus may depend on the patient's genotypic class; and (vi) disease progression rate might depend on genotypic class.
  
  
  CONCLUSIONS
  New genotype-phenotype correlations were established, disease progression rate for the general population and for the genotypic classes has been calculated, and new diagnostic criteria have been proposed. The conclusions raised could be important for patient management and counseling as well as for the development of treatments for Wolfram syndrome.
authors: Laboratorio de Genética Molecular, IDIBELL, l'Hospitalet de Llobregat, Barcelona, Spain. mlopezheredia@idibell.cat
authors: Miguel López
authors: ML
authors: de Heredia
authors: Ramón
authors: R
authors: Clèries
authors: Virginia
authors: V
authors: Nunes
mesh_terms: D017668:Age of Onset; D003919:Diabetes Insipidus / Q000235:genetics; D003920:Diabetes Mellitus / Q000453:epidemiology / Q000235:genetics; D056726:Genetic Association Studies; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009896:Optic Atrophy / Q000235:genetics; D014929:Wolfram Syndrome / Q000145:classification / Q000175:diagnosis* / Q000209:etiology / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; C114987:wolframin protein