NLRP3 E311K mutation in a large family with Muckle-Wells syndrome--description of a heterogeneous phenotype and response to treatment

Arthritis Res Ther. 2011;13(6):R196. doi: 10.1186/ar3526. Epub 2011 Dec 6.


Introduction: Muckle-Wells syndrome (MWS) is an inherited autoinflammatory disease characterized by fever, rash, arthralgia, conjunctivitis, sensorineural deafness and potentially life-threatening amyloidosis. The NLRP3/CIAS1 E311K mutation caused a heterogeneous phenotype of MWS in a large family. This study analyzes the clinical spectrum, patterns of inflammatory parameters and reports on response to treatment.

Methods: A total of 42 patients and family members were screened for the presence of the NLRP3 mutation. Clinical symptoms were reviewed in all family members. Classical (erythrocyte sedimentation rate (ESR, C-reactive protein (CRP)) and novel MWS inflammatory markers (serum amyloid A (SAA), cytokines, cytokine receptor levels) were determined. Patients were treated with the IL-1 inhibitors Anakinra or Canakinumab.

Results: All 13 clinically affected patients were heterozygous carriers of the amino acid substitution p.Glu311Lys/E311K encoded by exon 3 of the NLRP3 gene, but none of the healthy family members. Disease manifestations varied widely. Except for one child, all carriers suffered from hearing loss and severe fatigue. TNF-α, IL-6, TNF-RI, and TNF-RII levels as well as SAA were elevated in three, two, one, six and ten patients, respectively. Both clinical and laboratory parameters responded quickly and sustainedly to treatment with Anakinra or Canakinumab.

Conclusion: The NLRP3 E311K mutation is associated with a heterogeneous clinical spectrum, which may expand the view on MWS presentation. The leading symptom was hearing loss. Pericarditis, a rare but severe clinical feature of MWS, was diagnosed in three patients. One patient had a severe course, which led to renal failure secondary to amyloidosis. IL-1 inhibition leads to rapid and sustained improvement of symptoms.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Amino Acid Substitution
  • Antibodies, Monoclonal / therapeutic use
  • Antibodies, Monoclonal, Humanized
  • Antirheumatic Agents / therapeutic use
  • Carrier Proteins / genetics*
  • Child
  • Child, Preschool
  • Cryopyrin-Associated Periodic Syndromes / drug therapy*
  • Cryopyrin-Associated Periodic Syndromes / genetics*
  • Cryopyrin-Associated Periodic Syndromes / pathology
  • Family Health
  • Female
  • Genetic Heterogeneity
  • Humans
  • Interleukin 1 Receptor Antagonist Protein / therapeutic use
  • Interleukin-1beta / antagonists & inhibitors
  • Male
  • Middle Aged
  • Mutation*
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Pedigree
  • Phenotype
  • Treatment Outcome
  • Young Adult


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antirheumatic Agents
  • Carrier Proteins
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • canakinumab