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.

Effect of weight reduction on leptin, total ghrelin and obestatin concentrations in prepubertal children.

The aim of the study was to evaluate fasting levels of glucose, insulin, leptin, total ghrelin, and obestatin in a group of prepubescent obese children before and after weight loss. We enrolled 64 prepubescent obese children, but only 35 completed the study (mean age 7.6 +- 0.9 years, 19 females) and 20 normal-weight prepubescent children as controls. Fasting plasma concentration of glucose, insulin, Homeostasis Model assessment for insulin resistance (HOMA-IR), and leptin, total ghrelin, and obestatin levels were measured at baseline and after a 6-month lifestyle intervention (i.e. improved nutrition and increased physical activity). At baseline, obese children showed significantly (p less than 0.001) higher leptin and obestatin levels, and lower total ghrelin concentrations than control subjects. Weight loss significantly (p less than 0.001) diminished plasma leptin and insulin levels and increased ghrelin and obestatin concentrations. Weight loss in prepubescent children is associated with a significant change in leptin, ghrelin and obestatin concentrations. These results confirm the hypothesis that levels of these hormones are closely associated with obesity in childhood and might take part, as consequence but not as a cause, in glucose, fat, and energy metabolism.

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.