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1.
Curr Allergy Asthma Rep ; 19(9): 41, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31321571

RESUMO

PURPOSE OF THE REVIEW: This review aims at presenting the most significant data obtained in the field of the genetics of autoinflammatory disorders (AID) over the last past 5 years. RECENT FINDINGS: More than 15 genes have been implicated in AID since 2014, unveiling new pathogenic pathways. Recent data have revealed atypical modes of transmission in several inherited AID, such as somatic mosaicism and digenism. First pieces of evidence showing an involvement of epigenetic modifications in the pathogenesis of AID have also been brought to light. Novel genetic data have been obtained on the molecular bases of genetically complex AID. The development of next-generation sequencing in routine clinical practice has led to an explosion in the identification of new AID genes. Advances in the knowledge of AID further blur the limits between monogenic and multifactorial forms of these syndromes, and between autoinflammatory and autoimmune conditions.

2.
Orphanet J Rare Dis ; 14(1): 177, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300002

RESUMO

BACKGROUND: Although metreleptin replacement therapy was shown to improve metabolic alterations in lipodystrophic syndromes, patients' adherence and satisfaction with treatment have never been evaluated. The 20 patients with lipodystrophic syndromes participating in the French compassionate program of metreleptin therapy filled in a self-questionnaire including an Adherence Evaluation Test, the Treatment Satisfaction Questionnaire for Medication (TSQM®-vII), and items about physical appearance. RESULTS: 15 patients were women, median age was 32.5 years (IQT 25-75 (16.2;49.5), 18 had diabetes. Adherence with metreleptin (one daily subcutaneous injection) was poor in 25%, excellent in 25% and acceptable in 50% of patients. On a 0-to-100 scale, patients' satisfaction scores reached 66.7 (52.1;81.2) for effectiveness, 55.6 (44.4;66.7) for ease/comfort of use, and 83.3 (52.1;83.3) for global satisfaction with metreleptin therapy. Self-reported side effects were frequent injection site reactions 100 (79.2;100). Satisfaction scores did not differ in patients with partial (n = 10) or generalized (n = 10) lipodystrophic syndromes, did not correlate with metabolic improvement, but were significantly higher in compliant patients with fewer side effects. Morphological appearance was reported improved under metreleptin therapy in 13 among 17 patients. CONCLUSIONS: Metreleptin increases health self-perception and decreases morphotype-associated stigmatization in most patients with lipodystrophic syndromes, but poor comfort of use and local side effects weaken adherence.

3.
Curr Med Res Opin ; : 1-10, 2018 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-30296183

RESUMO

BACKGROUND: Lipodystrophic syndromes are rare diseases of genetic or acquired origin characterized by partial or generalized lack of body fat. Early detection and diagnosis are crucial to prevent and manage associated metabolic dysfunctions, i.e. insulin resistance, dyslipidemia, fatty liver, and diabetes, and to provide appropriate genetic counseling. By means of several representative case studies, this article illustrates the diagnostic and management challenges of lipodystrophic syndromes. REVIEW: Berardinelli-Seip congenital lipodystrophy (BSCL) is typically diagnosed at birth, or soon thereafter, with generalized lipoatrophy and hepatomegaly secondary to hepatic steatosis. Physicians must also consider this diagnosis in adults with atypical non-autoimmune diabetes, hypertriglyceridemia, and a lean and muscular phenotype. The BSCL1 subtype due to mutations in the AGPAT2 gene can have an unusual presentation, especially in neonates and infants. Particular attention should be paid to infants presenting failure to thrive who also have hepatomegaly and metabolic derangements. The BSCL2 sub-type due to mutations in the BSCL gene tends to be more severe than BSCL1, and is characterized by greater fat loss, mild intellectual disability, earlier onset of diabetes, and higher incidence of premature death. Effective management from an earlier age may moderate the natural disease course. Partial lipodystrophies may easily be confused with common central obesity and/or metabolic syndrome. In patients with unexplained pancreatitis and hypertriglyceridemia, lipodystrophies such as familial partial lipodystrophy type 2 (FPLD2; Dunnigan type, due to LMNA mutations) should be considered. Oral combined contraceptives, which can reveal the disease by inducing severe hypertriglyceridemia, are contraindicated. Endogenous estrogens may also lead to "unmasking" of the FPLD2 phenotype, which often appears at puberty, and is more severe in females than males. CONCLUSIONS: Diet and exercise, adapted to age and potential comorbidities, are essential prerequisites for therapeutic management of lipodystrophic syndromes. Metreleptin therapy can be useful to manage lipodystrophy-related metabolic complications.

4.
J Clin Lipidol ; 2018 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-30158064

RESUMO

BACKGROUND: Multiple symmetric lipomatosis (MSL) is characterized by upper-body lipomatous masses frequently associated with metabolic and neurological signs. MFN2 pathogenic variants were recently implicated in a very rare autosomal recessive form of MSL. MFN2 encodes mitofusin-2, a mitochondrial fusion protein previously involved in Charcot-Marie-Tooth neuropathy. OBJECTIVE: To investigate the clinical, metabolic, tissular, and molecular characteristics of MFN2-associated MSL. METHODS: We sequenced MFN2 in 66 patients referred for altered fat distribution with one or several lipomas or lipoma-like regions and performed clinical and metabolic investigations in patients with positive genetic testing. Lipomatous tissues were studied in 3 patients. RESULTS: Six patients from 5 families carried a homozygous p.Arg707Trp pathogenic variant, representing the largest reported series of MFN2-associated MSL. Patients presented both lipomatous masses and a lipodystrophic syndrome (lipoatrophy, low leptinemia and adiponectinemia, hypertriglyceridemia, insulin resistance and/or diabetes). Charcot-Marie-Tooth neuropathy was of highly variable clinical severity. Lipomatous tissue mainly contained hyperplastic unilocular adipocytes, with few multilocular cells. It displayed numerous mitochondrial alterations (increased number and size, structural defects). As compared to control subcutaneous fat, mRNA and protein expression of leptin and adiponectin was strikingly decreased, whereas the CITED1 and fibroblast growth factor 21 (FGF21) thermogenic markers were strongly overexpressed. Consistently, serum FGF21 was markedly increased, and 18F-FDG-PET-scan revealed increased fat metabolic activity. CONCLUSION: MFN2-related MSL is a novel mitochondrial lipodystrophic syndrome involving both lipomatous masses and lipoatrophy. Its complex neurological and metabolic phenotype justifies careful clinical evaluation and multidisciplinary care. Low leptinemia and adiponectinemia, high serum FGF21, and increased 18F-FDG body fat uptake may be disease markers.

5.
Nucleus ; 9(1): 235-248, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29578370

RESUMO

Mutations in LMNA, encoding A-type lamins, are responsible for laminopathies including muscular dystrophies, lipodystrophies, and premature ageing syndromes. LMNA mutations have been shown to alter nuclear structure and stiffness, binding to partners at the nuclear envelope or within the nucleoplasm, gene expression and/or prelamin A maturation. LMNA-associated lipodystrophic features, combining generalized or partial fat atrophy and metabolic alterations associated with insulin resistance, could result from altered adipocyte differentiation or from altered fat structure. Recent studies shed some light on how pathogenic A-type lamin variants could trigger lipodystrophy, metabolic complications, and precocious cardiovascular events. Alterations in adipose tissue extracellular matrix and TGF-beta signaling could initiate metabolic inflexibility. Premature senescence of vascular cells could contribute to cardiovascular complications. In affected families, metabolic alterations occur at an earlier age across generations, which could result from epigenetic deregulation induced by LMNA mutations. Novel cellular models recapitulating adipogenic developmental pathways provide scalable tools for disease modeling and therapeutic screening.

6.
J Med Genet ; 54(6): 413-416, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28408391

RESUMO

BACKGROUND: Type-2 familial partial lipodystrophy (FPLD2) is a rare autosomal dominant lipodystrophic disorder due to mutations in LMNA encoding lamin A/C, a key epigenetic regulator. FPLD2 severity is determined by the occurrence of metabolic complications, especially diabetes and hypertriglyceridaemia. We evaluated the disease history and severity over generations. METHODS: This retrospective study of the largest cohort of patients with FPLD2 reported to date investigates 85 patients from 24 families comprising three generations (G1: n=39; G2: n=41; G3: n=5). RESULTS: Lipodystrophy appears with the same characteristics and at the same age in first generation (G1;18.6±1.5 years) and second generation (G2;15.9±0.8 years). Despite similar body mass index (23.7±0.6 vs 23.8±0.6 kg/m2), the mean delay between the onset of lipodystrophy and diabetes was far shorter in G2 (10.5±2.4 years) than in G1 (29.0±3.5 years) (p=0.0002). The same is true for the delay preceding hypertriglyceridaemia (G2: 4.5±1.4; G1: 19.3±3.2 years) (p=0.002), revealing an anticipation phenomenon. Observations in G3, and analysis within each family of disease history and diagnostic procedures, confirmed this result. CONCLUSIONS: This study is a rare example of anticipation unrelated to a trinucleotide expansion. Discovery of this early occurrence of metabolic complications in young generations underlines the utility of presymptomatic genetic diagnosis, with careful metabolic screening and preventive lifestyle in all at-risk individuals.


Assuntos
Lamina Tipo A/genética , Lipodistrofia Parcial Familiar/genética , Lipodistrofia/genética , Adolescente , Índice de Massa Corporal , Diabetes Mellitus/genética , Feminino , Humanos , Hipertrigliceridemia/genética , Masculino , Mutação/genética , Fenótipo , Estudos Retrospectivos
8.
Cytokine Growth Factor Rev ; 33: 19-34, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27916611

RESUMO

Hereditary fever syndromes (HFS) include a group of disorders characterized by recurrent self-limited episodes of fever accompanied by inflammatory manifestations occurring in the absence of infection or autoimmune reaction. Advances in the genetics of HFS have led to the identification of new gene families and pathways involved in the regulation of inflammation and innate immunity. The key role of several cytokine networks in the pathogenesis of HFS has been underlined by several groups, and supported by the rapid response of patients to targeted cytokine blocking therapies. This can be due to the direct effect of cytokine overproduction or to an absence of receptor antagonist resulting in dysbalance of downstream pro- and anti-inflammatory cytokine networks. The aim of this study was to present an overview and to discuss the major concepts regarding the cellular and molecular immunology of HFS, with a particular focus on their specific cytokine signatures and physiopathological implications. Based on their molecular and cellular mechanisms, HFS have been classified into intrinsic and extrinsic IL-1ß activation disorders or inflammasomopathies, and protein misfolding disorders. This review integrates all recent data in an updated classification of HFS.


Assuntos
Citocinas/sangue , Doenças Hereditárias Autoinflamatórias/imunologia , Animais , Células Cultivadas , Síndromes Periódicas Associadas à Criopirina/imunologia , Síndromes Periódicas Associadas à Criopirina/metabolismo , Citocinas/genética , Citocinas/imunologia , Febre Familiar do Mediterrâneo/imunologia , Febre Familiar do Mediterrâneo/metabolismo , Doenças Hereditárias Autoinflamatórias/metabolismo , Humanos , Imunidade Inata , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Leucócitos Mononucleares/imunologia , Lipopolissacarídeos/imunologia , Deficiência de Mevalonato Quinase , Camundongos
10.
Sci Transl Med ; 8(332): 332ra45, 2016 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-27030597

RESUMO

Pyrin responds to pathogen signals and loss of cellular homeostasis by forming an inflammasome complex that drives the cleavage and secretion of interleukin-1ß (IL-1ß). Mutations in the B30.2/SPRY domain cause pathogen-independent activation of pyrin and are responsible for the autoinflammatory disease familial Mediterranean fever (FMF). We studied a family with a dominantly inherited autoinflammatory disease, distinct from FMF, characterized by childhood-onset recurrent episodes of neutrophilic dermatosis, fever, elevated acute-phase reactants, arthralgia, and myalgia/myositis. The disease was caused by a mutation in MEFV, the gene encoding pyrin (S242R). The mutation results in the loss of a 14-3-3 binding motif at phosphorylated S242, which was not perturbed by FMF mutations in the B30.2/SPRY domain. However, loss of both S242 phosphorylation and 14-3-3 binding was observed for bacterial effectors that activate the pyrin inflammasome, such as Clostridium difficile toxin B (TcdB). The S242R mutation thus recapitulated the effect of pathogen sensing, triggering inflammasome activation and IL-1ß production. Successful therapy targeting IL-1ß has been initiated in one patient, resolving pyrin-associated autoinflammation with neutrophilic dermatosis. This disease provides evidence that a guard-like mechanism of pyrin regulation, originally identified for Nod-like receptors in plant innate immunity, also exists in humans.


Assuntos
Doenças Hereditárias Autoinflamatórias/complicações , Doenças Hereditárias Autoinflamatórias/patologia , Neutrófilos/patologia , Pirina/metabolismo , Dermatopatias/complicações , Dermatopatias/patologia , Feminino , Células HEK293 , Doenças Hereditárias Autoinflamatórias/imunologia , Humanos , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Masculino , Mutação/genética , Linhagem , Dermatopatias/imunologia
12.
Arthritis Rheumatol ; 66(9): 2621-7, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24891336

RESUMO

OBJECTIVE: Autoinflammatory disorders are caused by a primary dysfunction of the innate immune system. Among these disorders are hereditary recurrent fevers, which are characterized by recurrent episodes of fever and inflammatory manifestations affecting multiple tissues. Hereditary recurrent fevers often lack objective diagnostic criteria, thereby hampering the identification of disease-causing genes. This study was undertaken to identify a gene responsible for hereditary recurrent fevers. METHODS: Copy number variations and point mutations were sought by array-comparative genomic hybridization and polymerase chain reaction sequencing, respectively. Serum cytokine levels were measured using Luminex technology. The effect of TNFRSF11A molecular defects on NF-κB signaling in cells expressing wild-type and mutated forms of the receptor was evaluated by luciferase assay. RESULTS: A patient with multiple congenital anomalies and hereditary recurrent fever was found to carry a de novo heterozygous complex chromosomal rearrangement encompassing a duplication of TNFRSF11A, a gene known to regulate fever in rodents. We also identified a heterozygous frameshift mutation (p.Met416Cysfs*110) in TNFRSF11A in a mother and daughter with isolated hereditary recurrent fever. This mutation was associated with increased secretion of several inflammatory cytokines (tumor necrosis factor α [TNFα], interleukin-18 [IL-18], IL-1 receptor antagonist, interferon-γ) and altered the biologic effects of the receptor on NF-κB signaling. The disease in the patients described herein exhibits striking clinical similarities to TNF receptor-associated periodic syndrome, another hereditary recurrent fever involving a gene of the same family (TNFRSF1A). CONCLUSION: The involvement of TNFRSF11A in hereditary recurrent fever highlights the key role of this receptor in innate immunity. The present results also suggest that TNFRSF11A screening could serve as a new diagnostic test for autoinflammatory disorders.


Assuntos
Variações do Número de Cópias de DNA , Doenças Hereditárias Autoinflamatórias/genética , Imunidade Inata/genética , Mutação , Receptor Ativador de Fator Nuclear kappa-B/genética , Adulto , Pré-Escolar , Feminino , Genótipo , Doenças Hereditárias Autoinflamatórias/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Receptor Ativador de Fator Nuclear kappa-B/metabolismo
13.
PLoS One ; 8(7): e69757, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23894535

RESUMO

OBJECTIVES: TNFRSF1A is involved in an autosomal dominant autoinflammatory disorder called TNFR-associated periodic syndrome (TRAPS). Most TNFRSF1A mutations are missense changes and, apart from those affecting conserved cysteines, their deleterious effect remains often questionable. This is especially true for the frequent R92Q mutation, which might not be responsible for TRAPS per se but represents a susceptibility factor to multifactorial inflammatory disorders. This study investigates TRAPS pathophysiology in a family exceptional by its size (13 members) and compares the consequences of several mutations affecting arginine 92. METHODS: TNFRSF1A screening was performed by PCR-sequencing. Comparison of the 3-dimensional structure and electrostatic properties of wild-type and mutated TNFR1 proteins was performed by in silico homology modeling. TNFR1 expression was assessed by FACS analysis, western blotting and ELISA in lysates and supernatants of HEK293T cells transiently expressing wild-type and mutated TNFR1. RESULTS: A TNFRSF1A heterozygous missense mutation, R92W (c.361C>T), was shown to perfectly segregate with typical TRAPS manifestations within the family investigated (p<5.10(-4)). It was associated with very high disease penetrance (0.9). Prediction of its impact on the protein structure revealed local conformational changes and alterations of the receptor electrostatic properties. R92W also impairs the TNFR1 expression at the cell surface and the levels of soluble receptor. Similar results were obtained with R92P, another mutation previously identified in a very small familial form with incomplete penetrance and variable expressivity. In contrast, TNFR1-R92Q behaves like the wild-type receptor. CONCLUSIONS: These data demonstrate the pathogenicity of a mutation affecting arginine 92, a residue whose involvement in inflammatory disorders is deeply debated. Combined with previous reports on arginine 92 mutations, this study discloses an unusual situation in which different amino acid substitutions at the same position in the protein are associated with a clinical spectrum bridging Mendelian to multifactorial conditions.


Assuntos
Doenças Hereditárias Autoinflamatórias/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Adolescente , Adulto , Arginina/química , Arginina/genética , Western Blotting , Criança , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Genótipo , Doenças Hereditárias Autoinflamatórias/genética , Humanos , Masculino , Mutação de Sentido Incorreto/genética , Linhagem , Reação em Cadeia da Polimerase , Transporte Proteico , Receptores Tipo I de Fatores de Necrose Tumoral/química , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Eletricidade Estática , Adulto Jovem
14.
PLoS One ; 8(7): e68431, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23844200

RESUMO

BACKGROUND: Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder due to MEFV mutations and one of the most frequent Mediterranean genetic diseases. The observation of many heterozygous patients in whom a second mutated allele was excluded led to the proposal that heterozygosity could be causal. However, heterozygosity might be coincidental in many patients due to the very high rate of mutations in Mediterranean populations. OBJECTIVE: To better delineate the pathogenicity of heterozygosity in order to improve genetic counselling and disease management. METHODS: Complementary statistical approaches were used: estimation of FMF prevalence at population levels, genotype comparison in siblings from 63 familial forms, and genotype study in 557 patients from four Mediterranean populations. RESULTS: At the population level, we did not observe any contribution of heterozygosity to disease prevalence. In affected siblings of patients carrying two MEFV mutations, 92% carry two mutated alleles, whereas 4% are heterozygous with typical FMF diagnosis. We demonstrated statistically that patients are more likely to be heterozygous than healthy individuals, as shown by the higher ratio heterozygous carriers/non carriers in patients (p<10(-7)-p<0.003). The risk for heterozygotes to develop FMF was estimated between 2.1 × 10(-3) and 5.8 × 10(-3) and the relative risk, as compared to non carriers, between 6.3 and 8.1. CONCLUSIONS: This is the first statistical demonstration that heterozygosity is not responsible for classical Mendelian FMF per se, but constitutes a susceptibility factor for clinically-similar multifactorial forms of the disease. We also provide a first estimate of the risk for heterozygotes to develop FMF.


Assuntos
Proteínas do Citoesqueleto/genética , Febre Familiar do Mediterrâneo/genética , Predisposição Genética para Doença , Heterozigoto , Mutação , Alelos , Grupos Étnicos/genética , Febre Familiar do Mediterrâneo/epidemiologia , Frequência do Gene , Humanos , Linhagem , Prevalência , Pirina , Estudos Retrospectivos , Risco , Irmãos
15.
Nat Rev Rheumatol ; 9(10): 624-9, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23838615

RESUMO

The notion of 'autoinflammatory' disease was introduced at the end of the 1990s, and, since then, this concept has rapidly evolved. As a result, multiple definitions of autoinflammatory disease, and classifications of conditions encompassed by these definitions, have been proposed; this succession highlights advances that have been made in understanding of the innate immune system, and especially the roles of IL-1ß and the inflammasome in autoinflammtory conditions. However, the definitions and classifications that have been suggested to date face a number of structure and content issues. We therefore propose another, more clinically-oriented, definition: autoinflammatory diseases are diseases with clinical signs of inflammation, associated with elevated levels of acute-phase reactants, which are attributable to dysfunction of the innate immune system, genetically-determined or triggered by an endogenous factor. From this foundation, we propose a clinically-based classification of autoinflammatory diseases, and go on to discuss how immunological diseases as a whole, including autoimmune diseases, can be appropriately located within a continuum only if the classification process is multidimensional. For this purpose, we appeal to the philosophical concepts of family resemblance and signature.


Assuntos
Doenças Autoimunes/classificação , Doenças Hereditárias Autoinflamatórias/classificação , Doenças Reumáticas/classificação , Doenças Autoimunes/fisiopatologia , Doenças Hereditárias Autoinflamatórias/fisiopatologia , Humanos , Imunidade Inata/fisiologia , Inflamassomos/fisiologia , Interleucina-1beta/fisiologia , Doenças Reumáticas/fisiopatologia , Transdução de Sinais/fisiologia
16.
Arthritis Rheum ; 65(6): 1654-62, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23508419

RESUMO

OBJECTIVE: Familial Mediterranean fever (FMF) is an autosomal-recessive autoinflammatory disease due to mutations in MEFV. Descriptions of disease manifestations among patients carrying a single mutated MEFV allele are becoming more frequent, although no data are available on the long-term outcome. We undertook this study to assess the accuracy of clinical diagnosis in children carrying a single mutated MEFV allele with symptoms of recurrent autoinflammatory disorder. METHODS: We performed a retrospective single-center study of 33 patients with autoinflammatory disorders age <6 years at disease onset with 1 mutated MEFV allele. The phenotype of the patients was investigated in detail, and the clinical picture and outcome of 18 patients with an initial FMF diagnosis according to current clinical criteria were compared to those of 25 homozygous or compound heterozygous FMF patients. RESULTS: No major differences in presenting signs or initial response to colchicine were observed between patient groups. During followup, heterozygotes had a milder disease course compared to homozygotes and were less prone than homozygotes to experience new clinical signs of FMF. At puberty, clinical signs of FMF completely disappeared in 5 of 18 heterozygotes, allowing them to discontinue colchicine without recurrence of symptoms or increases in inflammatory marker levels. CONCLUSION: Our data suggest that the clinical diagnosis of FMF in very young heterozygous children should be made with caution. At this young age they can present with an FMF-like disease-similar to that seen in patients carrying 2 mutated alleles-that is not necessarily predictive of life-long illness.


Assuntos
Febre Familiar do Mediterrâneo/diagnóstico , Triagem de Portadores Genéticos , Adolescente , Criança , Pré-Escolar , Febre Familiar do Mediterrâneo/genética , Heterozigoto , Homozigoto , Humanos , Mutação , Estudos Retrospectivos , Adulto Jovem
17.
Nephrol Dial Transplant ; 27(5): 1898-901, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-21931121

RESUMO

BACKGROUND: Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder, for which systemic AA amyloidosis is the major complication revealed most of the time by renal abnormalities. Current treatment is daily colchicine that prevents both recurrent inflammatory attacks and amyloidosis deposition in most patients. However, some patients still develop amyloidosis and renal failure. Functional studies suggest that interleukin (IL)-1 is implicated in the inflammatory reaction in FMF and therefore, IL-1 inhibitors could be a new approach to treat FMF. The aim of this series study was to evaluate anakinra in patients with FMF complicated with amyloidosis and renal failure. METHODS: We studied a series of adult patients with FMF complicated with amyloidosis and treated with anakinra in one reference centre were reviewed. A search for published patients with FMF associated amyloidosis treated with anakinra was performed by screening PubMed. RESULTS: We report four cases of patients with FMF-associated amyloidosis treated with anakinra and discuss the clinical pertinence of its use in these particular clinical settings. CONCLUSIONS: Anakinra has a strong effect on both inflammatory attacks and general status in patients with FMF-associated amyloidosis. It may contribute to changing the prognosis of these patients. Long-term studies are needed to appreciate the effect of anakinra or other IL-1 inhibitors on the natural history of amyloidosis in these patients.


Assuntos
Amiloidose/etiologia , Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1/antagonistas & inibidores , Falência Renal Crônica/etiologia , Adulto , Febre Familiar do Mediterrâneo/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Resultado do Tratamento
18.
Arthritis Rheum ; 63(5): 1459-64, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21538323

RESUMO

OBJECTIVE: To gain insight into the molecular bases of genetically unexplained periodic fever syndromes (PFS) by screening NLRP12, a gene in which only a nonsense and a splice site mutation have so far been identified, and to assess the functional consequences of the identified missense variation. METHODS: NLRP12 was screened for mutations by direct sequencing. Functional assays were performed in HEK 293T cells stably expressing the proapoptotic protein ASC and procaspase 1, in order to determine the effects of normal and mutated NLRP12 proteins on speck formation, caspase 1 signaling, and NF-κB activation. RESULTS: A heterozygous NLRP12 missense mutation involving a CpG site (c.1054C>T; p.Arg352Cys) was identified in exon 3, which encodes the nucleotide-binding site (NBS) of the protein, in 2 patients from different countries and carrying different NLRP12 haplotypes. The mutation, which does not alter the inhibitory effect of NLRP12 on NF-κB activation, increases speck formation and activates caspase 1 signaling. To define this new class of PFS, we propose the term NLRP12-associated disorders (NLRP12AD). CONCLUSION: Given the rarity of known NLRP12-associated disorders, the identification of this NLRP12 molecular defect contributes to the delineation of the clinical spectrum associated with mutations in this gene and highlights the importance of screening NLRP12 in patients presenting with unexplained PFS. This study also demonstrates, by means of functional assays, the deleterious effect of this recurrent missense mutation; the gain of function for speck formation and caspase 1 signaling associated with this NBS mutation is consistent with the inflammatory phenotype of PFS.


Assuntos
Doenças Hereditárias Autoinflamatórias/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação de Sentido Incorreto/genética , Humanos , Fenótipo
19.
Arthritis Rheum ; 63(7): 2142-8, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21480187

RESUMO

OBJECTIVE: A new class of autoinflammatory syndromes called NLRP12-associated disorders (NLRP12AD) has been associated with mutations in NLRP12. Conflicting data on the putative role of NLRP12 in interleukin-1ß (IL-1ß) signaling have been found in in vitro analyses. This prospective study was undertaken to assess the secretion of IL-1ß and 3 IL-1ß-induced cytokines (IL-1 receptor antagonist [IL-1Ra], IL-6, and tumor necrosis factor α [TNFα]) in patients' peripheral blood mononuclear cells (PBMCs) cultured ex vivo and to evaluate the patients' response to IL-1Ra (anakinra), a major drug used in the treatment of autoinflammatory disorders. METHODS: Patients' disease manifestations and cytokine measurements were recorded before anakinra treatment was started, during 14 months of therapy, and after discontinuation of anakinra treatment. RESULTS: Spontaneous secretion of IL-1ß by patients' PBMCs was found to be dramatically increased (80-175 fold) compared to healthy controls. Consistent with these findings, anakinra initially led to a marked clinical improvement and to a rapid near-normalization of IL-1ß secretion. However, a progressive clinical relapse occurred secondarily, associated with an increase in TNFα secretion, persistent elevated levels of IL-1Ra and IL-6, and a reactivation of IL-1ß secretion. Anakinra was discontinued after 14 months of therapy. CONCLUSION: Our findings provide in vivo evidence of the crucial role of IL-1ß in the pathophysiology of NLRP12AD. This is the first time anakinra has been used to treat this disorder. This study provides new insights into the mechanisms underlying resistance to anti-IL-1 therapy observed in a few patients with autoinflammatory syndromes. Our data also point to the potential of ex vivo cytokine measurements as predictors of response to treatment.


Assuntos
Doenças Hereditárias Autoinflamatórias/imunologia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1beta/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Ensaio de Imunoadsorção Enzimática , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Doenças Hereditárias Autoinflamatórias/genética , Humanos , Masculino , Estudos Prospectivos , Transdução de Sinais
20.
Arthritis Rheum ; 62(4): 1176-85, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20131254

RESUMO

OBJECTIVE: To gain insight into the pathophysiology of an atypical familial form of an autoinflammatory disorder, characterized by autosomal-dominant sensorineural hearing loss, systemic inflammation, increased secretion of interleukin-1beta (IL-1beta), and the absence of any cutaneous manifestations, and to assess the functional consequences of a missense mutation identified in the leucine-rich repeat (LRR) domain of NLRP3. METHODS: Microsatellite markers were used to test the familial segregation of the NLRP3 locus with the disease phenotype. All NLRP3 exons were screened for mutations by sequencing. Functional assays were performed in HEK 293T cells to determine the effects of mutated (versus normal) NLRP3 proteins on NF-kappaB activation, caspase 1 signaling, and speck formation. RESULTS: A heterozygous NLRP3 missense mutation (p.Tyr859Cys) was identified in exon 6, which encodes the LRR domain of the protein. This mutation was found to segregate with the disease phenotype within the family, and had a moderate activating effect on speck formation and procaspase 1 processing and did not alter the inhibitory properties of NLRP3 on NF-kappaB signaling. CONCLUSION: This report is the first to describe a familial form of a cryopyrinopathy associated with a mutation outside of exon 3 of NLRP3. This finding, together with the known efficacy of anti-IL-1 treatments in these disorders, underlines the importance of screening all exons of NLRP3 in patients who present with atypical manifestations. In addition, the gain of function associated with this mutation in terms of activation of caspase 1 signaling was consistent with the observed inflammatory phenotype. Therefore, this study of the functional consequences of an LRR mutation sheds new light on the clinical relevance of in vitro assays.


Assuntos
Proteínas de Transporte/genética , Mutação em Linhagem Germinativa , Doenças Hereditárias Autoinflamatórias/genética , Sequência de Aminoácidos , Linhagem Celular , Citocinas/sangue , DNA/genética , Primers do DNA , Feminino , Variação Genética , Doenças Hereditárias Autoinflamatórias/fisiopatologia , Humanos , Interleucina-1beta/sangue , Rim/embriologia , Masculino , Monócitos/patologia , Mães , Mutação de Sentido Incorreto , Proteína 3 que Contém Domínio de Pirina da Família NLR , Plasmídeos , Irmãos
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