title: Identification of unsuspected Wolfram syndrome cases through clinical assessment and WFS1 gene screening in type 1 diabetes mellitus patients.
abstract: OBJECTIVE
  Wolfram syndrome (WS) is a severe autosomal recessive pleiotropic disease primarily characterized by the association of juvenile-onset diabetes mellitus and optic atrophy. Earlier reports have shown that a proportion of WS cases may remain unrecognized due to misdiagnosis as type 1 diabetes mellitus (T1DM). The objectives of this work were to estimate the prevalence of patients fulfilling clinical criteria for WS in a cohort of subjects diagnosed as T1DM and to identify causal WFS1 gene mutations in those individuals meeting clinical criteria for the disease.
  
  
  METHODS
  A cohort of 131 unrelated Mexican T1DM patients was collected, including 77 females and 54 males. Additional clinical anomalies suggesting WS were identified through review of medical files, detailed physical examination and/or specialized tests. WFS1 gene analysis was performed using exon-by-exon PCR amplification and direct Sanger sequencing on genomic DNA from patients reaching WS clinical criteria.
  
  
  RESULTS
  Clinical criteria for a WS diagnosis were reached in 6 probands, corresponding to a 4.58% frequency of the disease. WFS1 mutations were identified in 4 out of 5 (80%) individuals fulfilling WS clinical criteria, including two homozygous, one compound heterozygous, and one patient with a single allele mutation. No WFS1 mutations were identified in the remaining subject.
  
  
  CONCLUSIONS
  In our cohort, approximately 6% of cases diagnosed as T1DM were in fact patients with Wolfram syndrome. WFS1 mutations were identified in 4 out of 5 individuals (80%) fulfilling clinical criteria for WS. Clinical and genetic analyses of large cohorts of T1DM patients from different ethnic origins would help to better estimate the occurrence of WS and will lead to a better management of such patients.
authors.affiliation: Department of Genetics, Hospital Materno Perinatal "Monica Pretelini Sainz", Instituto de Salud del Estado de México, Toluca, Mexico.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Blanco-Aguirre
authors.affiliation: Centro de Atención Integral del Paciente con Diabetes, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Mexico City, Mexico.
authors.forename: David Rivera-De
authors.initials: DR
authors.lastname: la Parra
authors.affiliation: Toluca, Mexico.
authors.forename: Hugo
authors.initials: H
authors.lastname: Tapia-Garcia
authors.affiliation: Glaucoma Department, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico.
authors.forename: Johanna
authors.initials: J
authors.lastname: Gonzalez-Rodriguez
authors.forename: Daniela
authors.initials: D
authors.lastname: Welschen
authors.affiliation: Ophthalmology Service, Hospital General de México, O.D, Mexico City, Mexico.
authors.forename: Daniela
authors.initials: D
authors.lastname: Welskin
authors.affiliation: Ophthalmology Service, Hospital General de México, O.D, Mexico City, Mexico.
authors.forename: Maria Estela
authors.initials: ME
authors.lastname: Arroyo-Yllanes
authors.affiliation: Servicio de Endocrinología, Centro Médico Nacional "20 de Noviembre" ISSSTE. Mexico City, Mexico.
authors.forename: Irineo
authors.initials: I
authors.lastname: Escudero
authors.affiliation: Hospital para el Niño, Instituto Materno Infantil del Estado de México, Toluca, Mexico.
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Nuñez-Hernandez
authors.affiliation: Department of Endocrinology, Hospital Infantil de Mexico "Federico Gomez", Mexico City, Mexico.
authors.forename: Patricia
authors.initials: P
authors.lastname: Medina-Bravo
authors.affiliation: Department of Genetics-Research Unit, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico; Department of Biochemistry, Faculty of Medicine, UNAM, Mexico City, Mexico. Electronic address: jczenteno@institutodeoftalmologia.org.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Zenteno
mesh_terms: D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D014929:Wolfram Syndrome / Q000175:diagnosis* / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; C114987:wolframin protein
keywords: Optic atrophy; Syndromic type 1 diabetes mellitus; WFS1 mutation; Wolfram syndrome