Correspondence
Molecular Mechanisms of Amyloidosis
N Engl J Med 2003; 349:1872-1873November 6, 2003
- Article
To the Editor:
In the review article by Merlini and Bellotti (Aug. 7 issue),1 familial Mediterranean fever was listed as one of the common periodic-fever syndromes that may lead to reactive (amyloid protein A, or AA) amyloidosis. However, there is no correlation between the frequency and severity of periodic febrile attacks and AA amyloidosis.2 The serum level of amyloid protein A is not constantly elevated. Some patients with frequent periodic febrile attacks are spared from the development of amyloidosis, whereas in other patients there is very early amyloid deposition. The major effect of colchicine seems to be the prevention of the formation and deposition of amyloid A.
2 ReferencesCem I. Sungur, M.D.
Bayindir Hospital, Ankara 06520, Turkey
csungur@ttnet.net. tr 1
Merlini G ,Bellotti V . Molecular mechanisms of amyloidosis. N Engl J Med 2003;349:583-596
Full Text | Web of Science | Medline2
Cakar N ,Yalcinkaya F ,Ozkaya N , et al. Familial Mediterranean fever (FMF)-associated amyloidosis in childhood: clinical features, course and outcome. Clin Exp Rheumatol 2001;19:Suppl 24:S63-S67
Web of Science | Medline
To the Editor:
Merlini and Bellotti highlight AA amyloidosis as a complication of the hereditary periodic fever syndromes (in Table 1 of their article), and they specifically list the hyper-IgD periodic-fever syndrome (HIDS). Although AA amyloidosis is indeed a frequent complication of familial Mediterranean fever (affecting 10 to 37 percent of patients),1 the tumor necrosis factor receptor–associated periodic syndrome (affecting 14 percent of patients),2 and the Muckle–Wells syndrome (affecting 35 percent of patients), it has never been reported in patients with HIDS, nor has it been seen in any of the patients listed in the international Nijmegen HIDS registry. This registry contains clinical data on 195 published and unpublished cases worldwide (information is available at http://hids.net).
HIDS is a periodic-fever syndrome caused by a genetic defect in mevalonate kinase.3 Despite a frequent, often persistent,4 and vigorous acute-phase response similar to that seen in patients with other periodic-fever syndromes, amyloidosis does not develop in patients with HIDS. This intriguing finding suggests that mevalonate kinase deficiency may provide protection against amyloidosis.
4 ReferencesJeroen C.H. van der Hilst, M.D.
Anna Simon, M.D.
Joost P.H. Drenth, M.D., Ph.D.
University Medical Center St. Radboud, 6500 HB Nijmegen, the Netherlands
a.simon@aig. umcn. nl 1
Grateau G . The relation between familial Mediterranean fever and amyloidosis. Curr Opin Rheumatol 2000;12:61-64
CrossRef | Web of Science | Medline2
Hull KM ,Drewe E ,Aksentijevich I , et al. The TNF receptor-associated periodic syndrome (TRAPS): emerging concepts of an autoinflammatory disorder. Medicine (Baltimore) 2002;81:349-368
CrossRef | Web of Science | Medline3
Drenth JPH ,van der Meer JWM . Hereditary periodic fever. N Engl J Med 2001;345:1748-1757
Full Text | Web of Science | Medline4
Havenaar EC ,Drenth JP ,van Ommen EC ,van der Meer JW ,van Dijk W . Elevated serum level and altered glycosylation of alpha 1-acid glycoprotein in hyperimmunoglobulinemia D and periodic fever syndrome: evidence for persistent inflammation. Clin Immunol Immunopathol 1995;76:279-284
CrossRef | Medline
Author/Editor Response
Dr. Sungur and Dr. van der Hilst and colleagues highlight the wide variability in the risk of reactive (AA) amyloidosis among patients with hereditary periodic-fever syndromes and note that the severity of familial Mediterranean fever does not fully account for the occurrence of AA amyloidosis. In familial Mediterranean fever, very high concentrations of serum amyloid A (SAA) have been reported at the onset of acute attacks (mean value, approximately 150 times that in a control group),1 and in most patients, SAA levels are significantly elevated during attack-free periods,2 indicating the continuous presence of subclinical inflammation. Increased levels of SAA during asymptomatic periods may contribute to the risk of AA amyloidosis in patients with familial Mediterranean fever. Moreover, variations in the incidence of AA amyloidosis within and among different ethnic groups suggest that there are genetic factors, environmental factors, or both that modify the risk. The development of renal amyloidosis in patients with familial Mediterranean fever is affected by homozygosity for the M694V allele (although this association may not be significant in Turkish persons), the SAA1 α/α genotype, male sex, and attacks of arthritis.3 How these factors affect SAA levels or the amyloidogenicity of SAA is unknown.
We are grateful to the Nijmegen group for pointing out that amyloidosis has not yet been reported in their registry as a complication of HIDS. HIDS is a heterogeneous disease,4 and 24 percent of patients with clinically diagnosed HIDS have normal mevalonate kinase activity (variant-type HIDS),5 indicating that other factors, in addition to or rather than mevalonate kinase deficiency, lower the risk of amyloidosis. More data about variations in the HIDS phenotype in ethnic groups other than the Dutch and French will improve our understanding of the molecular mechanisms underlying the reduced susceptibility to amyloidosis in patients with HIDS.
5 ReferencesGiampaolo Merlini, M.D.
Vittorio Bellotti, M.D., Ph.D.
University of Pavia, 27100 Pavia, Italy
gmerlini@smatteo.pv. it 1
Knecht A ,de Beer FC ,Pras M . Serum amyloid A protein in familial Mediterranean fever. Ann Intern Med 1985;102:71-72
Web of Science | Medline2
Duzova A ,Bakkaloglu A ,Besbas N , et al. Role of A-SAA in monitoring subclinical inflammation and in colchicine dosage in familial Mediterranean fever. Clin Exp Rheumatol 2003;21:509-514
Web of Science | Medline3
Gershoni-Baruch R ,Brik R ,Zacks N ,Shinawi M ,Lidar M ,Livneh A . The contribution of genotypes at the MEFV and SAA1 loci to amyloidosis and disease severity in patients with familial Mediterranean fever. Arthritis Rheum 2003;48:1149-1155
CrossRef | Web of Science | Medline4
Frenkel J ,Houten SM ,Waterham HR , et al. Clinical and molecular variability in childhood periodic fever with hyperimmunoglobulinaemia D. Rheumatology (Oxford) 2001;40:579-584
CrossRef | Web of Science | Medline5
Simon A ,Cuisset L ,Vincent MF , et al. Molecular analysis of the mevalonate kinase gene in a cohort of patients with the hyper-IgD and periodic fever syndrome: its application as a diagnostic tool. Ann Intern Med 2001;135:338-343
Web of Science | Medline
- Citing Articles (3)
Citing Articles
1
Alexandra I Mot, Anthony G Wedd, Layla Sinclair, David R Brown, Steven J Collins, Marcus W Brazier. (2011) Metal attenuating therapies in neurodegenerative disease. Expert Review of Neurotherapeutics 11:12, 1717-1745
CrossRef2
Jeroen C. H. Hilst, Joost Frenkel. (2010) Hyperimmunoglobulin D Syndrome in Childhood. Current Rheumatology Reports 12:2, 101-107
CrossRef3
JCH van der Hilst, JPH Drenth, EJ Bodar, J Bijzet, JWM van der Meer, A Simon. (2005) Serum amyloid A serum concentrations and genotype do not explain low incidence of amyloidosis in Hyper-IgD syndrome. Amyloid 12:2, 115-119
CrossRef
