title: Autoimmune polyendocrine syndrome type 1 in Norway: phenotypic variation, autoantibodies, and novel mutations in the autoimmune regulator gene.
abstract: BACKGROUND
  The autoimmune polyendocrine syndrome type I (APS I) is a rare disease that previously was difficult to diagnose. Autoantibody screening as well as mutational analysis of the disease gene autoimmune regulator (AIRE) are important diagnostic tools for this life-threatening syndrome.
  
  
  OBJECTIVE
  The objective of the study was to identify all patients with APS I in Norway and correlate their clinical features with their autoantibody profiles and mutations in the AIRE gene.
  
  
  METHODS
  We identified 36 Norwegian patients from 24 families with APS I (20 males, 16 females) during a nationwide survey for patients with Addison's disease and polyendocrine syndromes, seven of them only after their death.
  
  
  METHODS
  Clinical data were collected from questionnaires and patient records. AIRE mutations were determined by DNA sequencing. Most autoantibodies were measured in RIAs against recombinant autoantigens, but anti-type I interferon (IFN) antibodies were titrated in ELISA or antiviral interferon neutralization assays.
  
  
  RESULTS
  The prevalence of APS I in Norway was estimated to be about 1:90,000. Several patients exhibited a milder phenotype with few APS I disease components and onset only in late adolescent or adulthood. The others showed about the same distribution of disease components as reported in Finnish patients. Eleven different mutations were identified in the AIRE gene, six of these were novel, i.e. c.22C>T (p.Arg8Cys), c.290T>C (p.Leu97Pro), c.402delC (p.Ser135GlnfsX12), c.879 + 1G>A (p.IVS7 + 1G>A), c.1249dupC (p.Leu417ProfsX7), and c.1336T>G (p.Cys446Gly). The 13-bp deletion in exon 8 (c.967-979del13) was the most prevalent mutation, present in 23 of 48 (48%) of the alleles. The presence of neutralizing autoantibodies against IFN-omega was the most specific marker of APS I, being found in all but one Norwegian patient. Some other common APS I-associated autoantibodies appeared de novo during long-term follow-up of younger patients.
  
  
  CONCLUSIONS
  Norwegian patients with APS I clinically resemble those from Finland and other European countries, but some have milder phenotypes. In total, six new mutations were identified in the Norwegian APS I patients. Anti-type I IFN autoantibodies are easily detectable; their APS I specificity and persistently high titers render them reliable markers of APS I, even in prodromal or atypical cases. Both the clinical features and the AIRE mutations are more diverse in the Norwegian population than previously thought.
authors.affiliation: Institute of Medicine, University of Bergen, Bergen, Norway.
authors.forename: Anette S B
authors.initials: AS
authors.lastname: Wolff
authors.forename: Martina M
authors.initials: MM
authors.lastname: Erichsen
authors.forename: Anthony
authors.initials: A
authors.lastname: Meager
authors.forename: Ng'weina Francis
authors.initials: NF
authors.lastname: Magitta
authors.forename: Anne Grethe
authors.initials: AG
authors.lastname: Myhre
authors.forename: Jens
authors.initials: J
authors.lastname: Bollerslev
authors.forename: Kristian J
authors.initials: KJ
authors.lastname: Fougner
authors.forename: Kari
authors.initials: K
authors.lastname: Lima
authors.forename: Per M
authors.initials: PM
authors.lastname: Knappskog
authors.forename: Eystein S
authors.initials: ES
authors.lastname: Husebye
mesh_terms: D000224:Addison Disease / Q000453:epidemiology / Q000235:genetics / Q000276:immunology; D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000097:blood*; D002648:Child; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D014644:Genetic Variation; D006801:Humans; D007370:Interferon Type I / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009664:Norway / Q000453:epidemiology; D010641:Phenotype; D017354:Point Mutation; D016884:Polyendocrinopathies, Autoimmune / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology*; D016036:Seroepidemiologic Studies; D014157:Transcription Factors / Q000235:genetics*; D000096927:AIRE Protein
chemical_list: D001323:Autoantibodies; D007370:Interferon Type I; D014157:Transcription Factors; D000096927:AIRE Protein