Familial Mediterranean fever (FMF) is classically an autosomal recessive periodic inflammatory di... more Familial Mediterranean fever (FMF) is classically an autosomal recessive periodic inflammatory disease occurring in Mediterranean and Middle Eastern populations. It is caused by mutations affecting both alleles of MEFV, a gene that encodes pyrin (marenostrin), an uncharacterized neutrophil protein. Occasional reports of autosomal dominant FMF have often been discounted, on the basis that asymptomatic FMF carriers are common in certain populations, and give rise to pseudo-dominant inheritance. We performed comprehensive MEFV genotyping in five families in whom FMF appeared to be inherited dominantly. Transmission proved to be pseudo-dominant in two cases, but true dominant inheritance of FMF with variable penetrance was supported by the genotyping results in the other three families. The disease in these cases was associated with heterozygosity for either pyrin DeltaM694 alone or the compound pyrin variant E148Q/M694I, the latter occurring in two unrelated families. Complete MEFV sequencing failed to identify any coding region abnormality in the other allele in any of these cases, and, in the largest kindred, single-allele disease transmission was further supported by analysis of silent single nucleotide polymorphisms, which proved that affected individuals had at least three different complementary alleles. Studies of two further unrelated British patients with FMF associated with simple heterozygosity for pyrin DeltaM694 were also consistent with autosomal dominant inheritance. The clinical features of dominantly inherited FMF were absolutely typical, including AA amyloidosis in a patient with pyrin DeltaM694. These findings extend the spectrum of FMF, and suggest that the methionine residue at position 694 makes a crucial contribution to pyrin's function, and that a 50% complement of normal pyrin activity does not prevent susceptibility to FMF.
AA amyloidosis is a life-threatening complication of the hereditary periodic fever syndromes (HPF... more AA amyloidosis is a life-threatening complication of the hereditary periodic fever syndromes (HPFS), which are otherwise often compatible with normal life expectancy. This study was undertaken to determine the characteristics, presentation, natural history, and response to treatment in 46 patients who had been referred for evaluation at the UK National Amyloidosis Centre. Disease activity was monitored by serial measurement of serum amyloid A. Renal function was assessed by measurement of serum creatinine and albumin levels, the estimated glomerular filtration rate, and proteinuria from 24-hour urine collections. The amyloid load was measured by serum amyloid P scintigraphy. Twenty-four patients had familial Mediterranean fever, 12 patients had tumor necrosis factor receptor-associated periodic syndrome, 6 patients had cryopyrin-associated periodic syndromes, and 4 patients had mevalonate kinase deficiency. The median age at onset of HPFS was 5 years; median age at presentation with AA amyloidosis was 38 years. Diagnosis of an HPFS had not been considered prior to presentation with AA amyloidosis in 23 patients (50%). Eleven patients (24%) had end-stage renal failure (ESRF) at presentation; of these, 3 had received transplants prior to referral. A further 13 patients developed ESRF over the followup period, with 10 undergoing renal transplantation. The median time to progression to ESRF from onset of AA amyloidosis was 3.3 years (interquartile range [IQR] 2-8), with a median time to transplant of 4 years (IQR 3-6). Eleven patients (24%) died. The median survival in the entire cohort was 19 years from diagnosis of AA amyloidosis. Of the 37 patients who were treated successfully, or in whom at least partial suppression of the underlying HPFS was achieved, 17 (46%) showed amyloid regression, 14 (38%) showed a stable amyloid load, and 2 (5%) showed increased amyloid deposition over the followup period. AA amyloidosis remains a challenging and serious late complication of HPFS; however, outcomes are excellent when HPFS is diagnosed early enough to allow effective treatment, thus preventing or retarding further amyloid deposition and organ damage.
To characterize the multisystem chronic inflammatory phenotype, dermatopathologic features, and r... more To characterize the multisystem chronic inflammatory phenotype, dermatopathologic features, and response to therapy with interleukin 1 receptor antagonist (anakinra) in patients with mutations in the CIAS-1/NALP3 gene. Retrospective review of medical records and evaluation of histologic findings. The National Amyloidosis Centre, London, and a tertiary referral clinic for urticaria. Twenty-two individuals from 13 families with autoinflammatory disease associated with CIAS-1/NALP3 mutations. Phenotype, genotype, skin histologic findings, and response to treatment with anakinra. Five heterozygous missense mutations were identified in CIAS-1/NALP3. Skin histologic findings revealed marked vascular dilatation and neutrophilic infiltration involving small vessels and eccrine glands. Serologic evidence of intense inflammation was present in untreated patients, with median serum amyloid A protein and C-reactive protein levels of 141 and 38 mg/L, respectively. Fifteen patients received anakinra for up to 39 months, all of whom achieved serologic remission and complete resolution of fever, rash, conjunctivitis, and rheumatic symptoms, without any adverse effects. Six patients had AA (reactive systemic) amyloidosis, 2 of whom died of renal failure complications before interleukin 1-inhibiting therapy was available; 1 patient underwent renal transplantation and remains clinically well taking anakinra, and in the remaining 3 patients, anakinra therapy resulted in remission of their nephrotic syndrome. Anakinra therapy was well tolerated and has sustained efficacy on dermatologic and rheumatic manifestations in these patients with CIAS-1/NALP3 mutations. This treatment also resulted in resolution of AA amyloidosis-associated nephrotic syndrome in all affected patients.
Familial Mediterranean fever (FMF) is classically an autosomal recessive periodic inflammatory di... more Familial Mediterranean fever (FMF) is classically an autosomal recessive periodic inflammatory disease occurring in Mediterranean and Middle Eastern populations. It is caused by mutations affecting both alleles of MEFV, a gene that encodes pyrin (marenostrin), an uncharacterized neutrophil protein. Occasional reports of autosomal dominant FMF have often been discounted, on the basis that asymptomatic FMF carriers are common in certain populations, and give rise to pseudo-dominant inheritance. We performed comprehensive MEFV genotyping in five families in whom FMF appeared to be inherited dominantly. Transmission proved to be pseudo-dominant in two cases, but true dominant inheritance of FMF with variable penetrance was supported by the genotyping results in the other three families. The disease in these cases was associated with heterozygosity for either pyrin DeltaM694 alone or the compound pyrin variant E148Q/M694I, the latter occurring in two unrelated families. Complete MEFV sequencing failed to identify any coding region abnormality in the other allele in any of these cases, and, in the largest kindred, single-allele disease transmission was further supported by analysis of silent single nucleotide polymorphisms, which proved that affected individuals had at least three different complementary alleles. Studies of two further unrelated British patients with FMF associated with simple heterozygosity for pyrin DeltaM694 were also consistent with autosomal dominant inheritance. The clinical features of dominantly inherited FMF were absolutely typical, including AA amyloidosis in a patient with pyrin DeltaM694. These findings extend the spectrum of FMF, and suggest that the methionine residue at position 694 makes a crucial contribution to pyrin's function, and that a 50% complement of normal pyrin activity does not prevent susceptibility to FMF.
AA amyloidosis is a life-threatening complication of the hereditary periodic fever syndromes (HPF... more AA amyloidosis is a life-threatening complication of the hereditary periodic fever syndromes (HPFS), which are otherwise often compatible with normal life expectancy. This study was undertaken to determine the characteristics, presentation, natural history, and response to treatment in 46 patients who had been referred for evaluation at the UK National Amyloidosis Centre. Disease activity was monitored by serial measurement of serum amyloid A. Renal function was assessed by measurement of serum creatinine and albumin levels, the estimated glomerular filtration rate, and proteinuria from 24-hour urine collections. The amyloid load was measured by serum amyloid P scintigraphy. Twenty-four patients had familial Mediterranean fever, 12 patients had tumor necrosis factor receptor-associated periodic syndrome, 6 patients had cryopyrin-associated periodic syndromes, and 4 patients had mevalonate kinase deficiency. The median age at onset of HPFS was 5 years; median age at presentation with AA amyloidosis was 38 years. Diagnosis of an HPFS had not been considered prior to presentation with AA amyloidosis in 23 patients (50%). Eleven patients (24%) had end-stage renal failure (ESRF) at presentation; of these, 3 had received transplants prior to referral. A further 13 patients developed ESRF over the followup period, with 10 undergoing renal transplantation. The median time to progression to ESRF from onset of AA amyloidosis was 3.3 years (interquartile range [IQR] 2-8), with a median time to transplant of 4 years (IQR 3-6). Eleven patients (24%) died. The median survival in the entire cohort was 19 years from diagnosis of AA amyloidosis. Of the 37 patients who were treated successfully, or in whom at least partial suppression of the underlying HPFS was achieved, 17 (46%) showed amyloid regression, 14 (38%) showed a stable amyloid load, and 2 (5%) showed increased amyloid deposition over the followup period. AA amyloidosis remains a challenging and serious late complication of HPFS; however, outcomes are excellent when HPFS is diagnosed early enough to allow effective treatment, thus preventing or retarding further amyloid deposition and organ damage.
To characterize the multisystem chronic inflammatory phenotype, dermatopathologic features, and r... more To characterize the multisystem chronic inflammatory phenotype, dermatopathologic features, and response to therapy with interleukin 1 receptor antagonist (anakinra) in patients with mutations in the CIAS-1/NALP3 gene. Retrospective review of medical records and evaluation of histologic findings. The National Amyloidosis Centre, London, and a tertiary referral clinic for urticaria. Twenty-two individuals from 13 families with autoinflammatory disease associated with CIAS-1/NALP3 mutations. Phenotype, genotype, skin histologic findings, and response to treatment with anakinra. Five heterozygous missense mutations were identified in CIAS-1/NALP3. Skin histologic findings revealed marked vascular dilatation and neutrophilic infiltration involving small vessels and eccrine glands. Serologic evidence of intense inflammation was present in untreated patients, with median serum amyloid A protein and C-reactive protein levels of 141 and 38 mg/L, respectively. Fifteen patients received anakinra for up to 39 months, all of whom achieved serologic remission and complete resolution of fever, rash, conjunctivitis, and rheumatic symptoms, without any adverse effects. Six patients had AA (reactive systemic) amyloidosis, 2 of whom died of renal failure complications before interleukin 1-inhibiting therapy was available; 1 patient underwent renal transplantation and remains clinically well taking anakinra, and in the remaining 3 patients, anakinra therapy resulted in remission of their nephrotic syndrome. Anakinra therapy was well tolerated and has sustained efficacy on dermatologic and rheumatic manifestations in these patients with CIAS-1/NALP3 mutations. This treatment also resulted in resolution of AA amyloidosis-associated nephrotic syndrome in all affected patients.
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