LMNA gene mutation as a model of cardiometabolic dysfunction: from genetic analysis to treatment response.

AIM: This report highlights the metabolic, endocrine and cardiovascular comorbidities in a case of familial partial lipodystrophy (FPLD), and also evaluates the efficacy and safety of metformin therapy. METHODS: Mutational analysis was carried out of the LMNA gene in a teenage girl with an FPLD phenotype. Insulin resistance, sex hormones and metabolic parameters were also evaluated, and echocardiography, electrocardiography and 24-h blood pressure monitoring were also done. RESULTS: The patient showed atypical fat distribution, insulin resistance and hypertrophic cardiomyopathy. Physical examination revealed muscle hypertrophy with a paucity of fat in the extremities, trunk and gluteal regions, yet excess fat deposits in the face, neck and dorsal cervical region. LMNA sequencing revealed a heterozygous missense mutation (c.1543A>G) in exon 9, leading to substitution of lysine by glutamic acid at position 515 (K515E). Moderate hypertension and secondary polycystic ovary syndrome were also assessed. Treatment with metformin resulted in progressive improvement of metabolic status, while blood pressure values normalized with atenolol therapy. CONCLUSIONS: Very rapid and good results with no side-effects were achieved with metformin therapy for FPLD. The association of an unusual mutation in the LMNA gene was also described.

TLR2 and TLR4 gene polymorphisms and atopic dermatitis in Italian children: a multicenter study.

BACKGROUND Genetic factors have an important role in atopic dermatitis (AD) predisposition. Toll like receptor (TLR) are important mediators between environment and immune system. There are incosnsitent studies about TLSR polymorphisms in AD. OBJECTIVE This study examined whether single nucleotide polimorphisms (SNPs) in the genes for TLR2 and TLR4 could be associated with the AD phenotypes and with its clinical severity in a large group of Italian children. METHODS 187 children with Ad and 150 healthy children were recruited. AD severity was assessed by SCORAD. TLR2 (A-16934T and R753Q polymorphisms) and TLR4 (D299G and T399I SNPs) were genotyped by PCR-RFLP. RESULTS The frequency of the R753Q was significantly higher in AD children (16.0 percent) compared with controls (6.0 percent, P =0.004; OR2.99, 95 percent CI 1.39-6.41; RR 1.46, 95 percent CI 1.14-1.69). AD patients a significantly different frequency of the D299G SNP (14.9 percent) in comparison with the controls (6.6 percent, P = 0.01; OR 2.46, 95 percent CI 1.17–5.17; RR 2.24; 95 percent CI 1.15-4.45). CONCLUSION Children with AD may have a distinct genotype and the TLR-2 R753Q SNP was prevalent in a subset of patients with AD characterized by a more severe clinical picture.

Gene-environment interaction in childhood asthma.

The importance of early life environmental influences on the etiology of asthma is implied by the observed geographic and temporal variation in the prevalence of the disease among children. There is evidence pointing to the role of exposure to allergen, various aspects of diet and hygiene-related factors in the etiology of asthma. There is also evidence that heritable factors influence the impact of hygiene-related exposures on the risk of having asthma. A number of important gene-environment interactions have been identified. These interactions point to the biology of environmental exposures as the involved genetic variation is suggestive of certain underlying mechanisms. Polymorphisms within genes coding for the toll-like receptor-lipopolysaccharide (TLR-LPS) signalling pathway may underlie variations in effects of hygiene-related exposures, including specifically endotoxin, on the risk of developing allergic sensitization and allergic disease. This review presents recent findings illustrating the role of gene-environment interactions in childhood asthma susceptibility.

The almond milk: a new approach to the management of cow-milk allergy/intolerance in infants.

AIM: Elimination of the offending food is imperative in the management of children with cow-milk allergy/intolerance (CMA/CMI). Herein we report the result of randomized clinical trial carried out to test the efficacy and safety of a new almond-based food (hereinafter named almond milk) in a group of infant with CMI/CMA. METHODS: A group of 52 infants aged 5 to 9 months and with documented CMI/CMA was enrolled and randomized to: almond milk (Group A, n=26); soy-based formula (Group B, n=13); protein hydrolysate-based formula (n=13). The main efficacy outcomes were the improvement in clinical symptoms and the decrease in serum levels of soluble CD30 (a potential marker for atopic disorders; sCD30). RESULTS: Elimination of the offending food and supplementation with a milk protein-free formula produced a considerable improvement of clinical manifestations within 5-12 days in all cases examined (at the onset of the study: 26.4+/-5.4 U/mL and 7.9+/-5.2 U/mL in IgE+ and IgE- infants respectively, after 6 months of supplementation: 16.6+/-4.8 U/mL and 7.1+/-4.5 U/mL in IgE+ and IgE- infants respectively). No difference in growth rate (increment of weight, length and head circumference) was found, during the entire study, between infants given the almond milk and babies given the soy-based formula or the protein hydrolysate-based formula. Supplementation with the soy-based and protein hydrolysate-based formulas caused the development, in some subjects, of a secondary sensitization (23% to soy-based and 15% protein hydrolysate-based formula), whereas supplementation with the almond milk did not. CONCLUSIONS: Though preliminary, the present findings seem to demonstrate that the almond milk may an efficacious substitute of cow milk in infants with CMA/CMI. One could speculate that some active principles contained in the almond milk could contribute to its beneficial effect observed in CMI/CMA-affected infants.

Molecular analysis of sequence variants in the Fcepsilon receptor I beta gene and IL-4 gene promoter in Italian atopic families.

BACKGROUND: The genetic variants in the Fcepsilon receptor I beta gene (Glu237Gly) and the T allele of the (C590T) polymorphism of interleukin (IL)-4 gene promoter were reported to be associated with atopy. But the data of the studies in different populations are contrasting with one another. METHODS: A group of 25 Italian nuclear families were studied. In each family at least two allergic subjects were present. The allergic children were 65 and the allergic relatives were 35. One hundred and three nonallergic unrelated controls included outpatiens with no history of atopy. The (C590T) promoter polymorphism of the IL-4 and the genetic variant Glu237Gly of Fcepsilon RI beta genes were analysed by the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: A significant difference was observed in the genotype frequency at codon 237 of the Fcepsilon RI beta gene between allergic children and nonatopic control (P < 0.01) and in the allergic relatives (P < 0.001). In the children, the Glu237Gly polymorphism was also associated with elevated circulating levels of immunoglobulin E. The -590C/T allele of IL-4 promoter gene showed no association with atopy. CONCLUSIONS: In our study, the Glu237Gly polymorphism of the Fcepsilon RI beta gene was associated with atopy. Our results have not pointed out an association between the (C590T) promoter polymorphism of the IL-4 gene and atopy. These data suggest the potential role of the Fc RI beta gene in the development of the allergy.

Serum levels of malondialdehyde and 4-hydroxy-2,3-nonenal in patients affected by familial chronic nail candidiasis.

Familial chronic nail candidiasis (FCNC.MIM 607644) is a rare disorder characterized by early onset infections caused by different species of Candida and restricted to the nails; this disorder is genetically associated with low serum concentration of intercellular adhesion molecule 1 (ICAM-1). Herein we report the evidence of high circulating levels of malondialdehyde (MDA) and 4-hydroxy-2,3-nonenal (HNE) in seven patients of a five-generation Italian family affected by FCNC.MIM 607644. The present data evidence, in these patients, an increase in circulating MDA and HNE levels. Only some merely speculative hypotheses may be suggested to explain the mechanisms subserving the oxidative stress condition observed in these genetically ICAM-1 deficient patients; however, one has to point out that a chronic oxidative stress condition could contribute to the development of concurrent pathological alterations in which an overproduction of free radicals may play a central role.

Protein carbonyl group content in patients affected by familiar chronic nail candidiasis.

Familiar chronic nail candidiasis (FCNC) is a rare disorder characterized by early-onset infections caused by different species of Candida, restricted to the nail of the hands and feet, and associated with a low serum concentration of intercellular adhesion molecule 1. Host defense mechanisms against candidiasis require the cooperation of many immune cells through several candidacidal mechanisms, including oxygen-dependent killing mechanisms, mediated by a superoxide anion radical myeloperoxidase--H2O2--halide system, and reactive nitrogen intermediates. We analyzed protein carbonyl groups (considered a useful marker of oxidative stress) in the serum of patients belonging to a five-generation Italian family with an isolated form of FCNC. Serum protein carbonyl groups in FCNC patients were significantly lower than those measured in healthy donors. Also, if this hypothesis is merely speculative, we could suggest that the decreased circulating level of protein carbonyl groups in these patients is not a marker of a lower oxidative stress condition, but might be linked to a lower protease activity.

A gene for familial isolated chronic nail candidiasis maps to chromosome 11p12-q12.1.

Chronic mucocutaneous candidiases (CMC) are a group of rare disorders where an altered immune response against Candida leads to persistent and/or recurrent infections of the skin, nails, and mucous membranes. We analysed a five-generation Italian family with an isolated form of CMC, affecting nails only, in the presence of low serum concentration of intercellular adhesion molecule I (ICAM-1). We excluded linkage to candidate regions on chromosomes 2p (CMC with thyroid disease), 21q22.3 (APECED), and 19q13 (ICAM-1). We then carried out a genome-wide scan and assigned the CMC locus to a 19 cM pericentromeric region on chromosome 11.