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

Abstract

IntroductionMuckle-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.MethodsA 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.ResultsAll 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.ConclusionThe 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.

Treatment of autoinflammatory diseases: results from the Eurofever Registry and a literature review

“…Furthermore, 127 (90%) of the total 141 patients did not relapse and had normal C reactive protein (CRP)/serum amyloid A levels 21. This effect is also seen in smaller pilot studies 22 23. Another IL-1 targeted drug, rilonacept, also induced a significant improvement in 47 patients enrolled in a RCT and in five patients in a pilot study 24 25…”

“…Combined data of 107 patients from cohort studies show that 84 (79%) achieved complete remission with anakinra and, in some young patients, hearing improved as well 22 26–33. However, since anakinra does not always normalise the acute phase reactants, it may be necessary to increase the dose in order to induce and maintain complete remission 32.…”

NLRP3 Is Expressed in the Spiral Ganglion Neurons and Associated with Both Syndromic and Nonsyndromic Sensorineural Deafness

“…After targeted NGS failed to identify any causative mutation in 144 known deafness genes, an E313K mutation in NLRP3 was revealed by whole exome sequencing which has been previously linked to syndromic deafness Muckle-Wells Syndrome (MWS, OMIM # 191900) [9]. Reports on such cases may improve the precise genetic diagnosis of deafness.…”

Nephrotic Syndrome and AA Amyloidosis Revealing Adult-Onset Cryopyrin-Associated Periodic Syndrome

“…Serositis is not typically associated with CAPS, although pericarditis has been described in MWS with E311K mutation. 12 The possibility of this being merely incidental or due to a false positive exudate cannot be ruled out.…”