Dunnigan lipodystrophy syndrome: French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins).

Dunnigan syndrome, or Familial Partial Lipodystrophy type 2 (FPLD2; ORPHA 2348), is a rare autosomal dominant disorder due to pathogenic variants of the LMNA gene. The objective of the French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins), is to provide health professionals with a guide to optimal management and care of patients with FPLD2, based on a critical literature review and multidisciplinary expert consensus. The PNDS, written by members of the French National Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), is available on the French Health Authority website (in French). Dunnigan syndrome is characterized by a partial atrophy of the subcutaneous adipose tissue and by an insulin resistance syndrome, associated with a risk of metabolic, cardiovascular and muscular complications. Its prevalence, assessed at 1/100.000 in Europe, is probably considerably underestimated. Thorough clinical examination is key to diagnosis. Biochemical testing frequently shows hyperinsulinemia, abnormal glucose tolerance and hypertriglyceridemia. Elevated hepatic transaminases (hepatic steatosis) and creatine phosphokinase, and hyperandrogenism in women, are common. Molecular analysis of the LMNA gene confirms diagnosis and allows for family investigations. Regular screening and multidisciplinary monitoring of the associated complications are necessary. Diabetes frequently develops from puberty onwards. Hypertriglyceridemia may lead to acute pancreatitis. Early atherosclerosis and cardiomyopathy should be monitored. In women, polycystic ovary syndrome is common. Overall, the management of patients with Dunnigan syndrome requires the collaboration of several health care providers. The attending physician, in conjunction with the national care network, will ensure that the patient receives optimal care through regular follow-up and screening. The various elements of this PNDS are described to provide such a support.

The regulation of MEFV expression and its role in health and familial Mediterranean fever.

Familial Mediterranean fever (FMF) is a hereditary recurrent fever associated with mutations in the gene MEFV encoding pyrin. It is expressed mainly in neutrophils and macrophages, and modulates the production of the potent pro-inflammatory cytokine interleukin-1ß through regulation of nuclear factor-κB and caspase-1. The MEFV gene expression depends on multiple levels of regulation. Sequence variants located in the promoter and at the 3'-untranslated region of the gene modulate this expression. Two studies demonstrated decreased mRNA levels in FMF patients compared with healthy subjects, whereas two others found no significant differences. The diverse experimental settings may have resulted in variable quantification of the 15 splice variants that have been identified recently. Some of these isoforms are regulated by nonsense-mediated decay in both cell- and transcript-specific manner, and may be differentially translated in THP1 cells. In addition, pyrin may be cleaved by caspase 1. The full-length pyrin was less abundant than the cleaved fragment in mononuclear cells from FMF patients than in controls, whereas the opposite was observed in granulocytes. Altogether, the regulation of MEFV expression is more complex than anticipated in both physiological and pathological conditions. Its deregulation is likely to alter the inflammasome function and subsequently result in uncontrolled inflammation as seen in FMF.

[Inflammasome and interleukin 1]. / Inflammasome et interleukine 1.

The innate immune system, which corresponds to the first line of defense against microorganisms, brings into play cell surface and intracellular sensors that detect pathogen ligands and danger signals. Among them, NOD-like receptors (NLRs) are intracellular proteins involved in inflammatory signaling pathways. NLRs are part of multiprotein complexes, called inflammasomes, which usually bring into play a NLR, an adaptor protein called ASC, and the pro-inflammatory caspase 1 protein. The activation of inflammasome by different stimuli triggers the proteolytic cleavage of pro-caspase 1 into active caspase 1, which, in turn, converts pro-interleukin 1ß (pro-IL1ß) into the mature IL1ß. IL1ß plays a crucial role in systemic inflammation due to its ability to induce the expression of a large panel of pro-inflammatory genes and to act on various target organs. Mutations in NLR genes are responsible for several autoinflammatory and/or autoimmune disorders. For example, mutations in NLRP3, which are responsible for three Mendelian autoinflammatory disorders called cryopyrinopathies, lead to inflammasome autoactivation. Peripheral blood mononuclear cells from patients carrying NLRP3 mutations secrete high levels of IL1ß; in many patients presenting with autoinflammatory disorders, blocking IL1 activity by anti-IL1 therapy significantly improves their manifestations. The mechanisms leading to IL1ß hypersecretion in other autoinflammatory disorders remain to be identified, as is the case for the role of each inflammasome in vivo. Better knowledge in this field should also contribute to the development of new anti-inflammatory treatments.

Mutations in the autoinflammatory cryopyrin-associated periodic syndrome gene: epidemiological study and lessons from eight years of genetic analysis in France.

BACKGROUND: Cryopyrin-associated periodic syndromes (CAPS) consist of a continuum of autoinflammatory diseases caused by a defect in interleukin 1ß regulation. Although symptoms may vary widely, the discovery, in 2001, of the gene involved (NLRP3) has dramatically helped diagnosis. OBJECTIVES: To define the spectrum and prevalence of NLRP3 mutations in France and to delineate initial criteria before molecular analysis. METHODS: Retrospective review (2001-9) of genetic analysis data and request forms of patients living in France with an NLRP3 mutation since the set up of CAPS molecular diagnosis by the three French laboratories providing this test (GenMAI network). RESULTS: Over 800 analyses of this gene have been conducted, identifying 135 cases with an NLRP3 mutation (55 probands; 33 multiplex families); the estimated prevalence in France was equal to 1/360 000. A total of 21 different sequence variants were detected, among which four are common and nine are new mutations. CONCLUSIONS: Although the number of NLRP3 test requests has doubled over the past 5 years, genetic screening has not contributed to enhanced detection of new index cases each year. There are two possible reasons for this: (i) no clinical prerequisite for genetic diagnosis and (ii) few new large families are now identified (unlike the initial study based on a selection by linkage). A set of initial clinical criteria have been drawn up which it is recommended should be fulfilled before a patient is tested: at least three recurrent bouts, age at disease onset < 20 years and elevated levels of C-reactive protein, especially in individuals with urticaria and moderate fever.

Mutations in NALP12 cause hereditary periodic fever syndromes.

NALP proteins, also known as NLRPs, belong to the CATERPILLER protein family involved, like Toll-like receptors, in the recognition of microbial molecules and the subsequent activation of inflammatory and immune responses. Current advances in the function of NALPs support the recently proposed model of a disease continuum bridging autoimmune and autoinflammatory disorders. Among these diseases, hereditary periodic fevers (HPFs) are Mendelian disorders associated with sequence variations in very few genes; these variations are mostly missense mutations whose deleterious effect, which is particularly difficult to assess, is often questionable. The growing number of identified sporadic cases of periodic fever syndrome, together with the lack of discriminatory clinical criteria, has greatly hampered the identification of new disease-causing genes, a step that is, however, essential for appropriate management of these disorders. Using a candidate gene approach, we identified nonambiguous mutations in NALP12 (i.e., nonsense and splice site) in two families with periodic fever syndromes. As shown by means of functional studies, these two NALP12 mutations have a deleterious effect on NF-kappaB signaling. Overall, these data identify a group of HPFs defined by molecular defects in NALP12, opening up new ways to manage these disorders. The identification of these first NALP12 mutations in patients with autoinflammatory disorder also clearly demonstrates the crucial role of NALP12 in inflammatory signaling pathways, thereby assigning a precise function to this particular member of an emerging family of proteins whose putative biological properties are currently inferred essentially through in vitro means.

PYPAF1 nonsense mutation in a patient with an unusual autoinflammatory syndrome: role of PYPAF1 in inflammation.

OBJECTIVE: To gain insight into the pathophysiology of an unusual autoinflammatory syndrome, in a patient of Armenian origin, that mimicked familial Mediterranean fever (FMF) but with episodes triggered by generalized exposure to cold, and to further elucidate the controversial function of the protein encoded by PYPAF1, whose mutations (exclusively missense to date) have been identified in 3 hereditary recurrent fever syndromes. METHODS: The patient's DNA was screened for mutations in both MEFV, the gene responsible for FMF, and PYPAF1. The ability of different recombinant PYPAF1 isoforms, expressed in HEK 293 cells, to regulate NF-kappaB signaling was subsequently assessed. RESULTS: No disease-causing mutation was found in MEFV. However, a nonsense mutation (p.Arg554X) was identified in PYPAF1; this defect resulted in a truncated protein lacking all leucine-rich repeats. Study of the wild-type and mutant PYPAF1 recombinant proteins revealed that PYPAF1 inhibited NF-kappaB proinflammatory pathways, and that the identified nonsense mutation impaired this property. CONCLUSION: These molecular and clinical findings, together with the clinical manifestations in the patient, which call into question the current nosology of the hereditary recurrent fever syndromes, are consistent with the hypothesis that PYPAF1 acts as an inhibitor of NF-kappaB signaling. They also provide a clear elucidation of the functional consequences of this nonsense PYPAF1 mutation not previously described in the literature, which result in a partial loss of function and may thereby explain the pathophysiology of the autoinflammatory syndrome observed in this patient.

[Biochemical aspects in the pathogenesis of senile cataract]. / Aspecte biochimice ale patogeniei cataractei senile.

The content of sialic acids has been investigated in the lacrimal liquid in patients with senile cataract as well as in the intracapsular extracted crystalline lenses. The highest level of sialic acids was detected in the lacrimal liquid and in the extracted crystalline lenses of patients with mature senile cataract. In this patients a higher frequency of the incipient senile cataract at the other eyeball has been noted.

[The treatment of penetrating eye injuries]. / Tratamentul plagilor oculare penetrante.

Data about eye traumatism at the Republican Ophthalmologic Center are presented. 791 patients have been investigated: 52.3% with penetrated wounds; in 19.3% cases we detected foreign intraocular bodies. Fibrinolysin and dexamethazone have been introduced during operation in the case of fibrinoplastic inflammatory process with crystalline lens masses in the anterior camera. As a result we noted a positive evolution in the postoperative period.

[The role of zinc in the appearance of cataract]. / Rolul zincului în aparitia cataractei.

The level of zinc in 259 crystalline lenses removed after extraction of cataract (senile and traumatic) has been determined. The lowest concentration of zinc in crystalline lenses has been detected in patients with mature senile cataract while the highest concentration-in patients with traumatic cataract. Since many enzymes contain zinc we can suppose that their activity decrease as senile cataract develops. Higher level of zinc in traumatic cataract indicates moderate disturbances of crystalline lens metabolism as compared with senile cataract.

[The characteristics of the pathogenesis and immunomodulator treatment in the postoperative period in pseudophakia patients]. / Particularitati ale patogeniei si tratamentul imunomodulator în perioada postoperatorie la bolnavii cu pseudofac.

The investigation has revealed an immunological character of the exudative reaction in postoperative period of patients with artificial crystalline lens. We noted a cellular immunodeficiency and an increase of immunoglobulins G and A in the lacrimal liquid. The administration of 5-FU (5-fluoroucile) and levamizol decreased the inflammation in the postoperative period.