Fernando Andrade

Persistence of essential fatty acid deficiency in cystic fibrosis despite nutritional therapy.

To study the evolution of plasma fatty acid composition of patients with cystic fibrosis (CF) in relation to nutritional status, pancreatic function, and development of CF-related liver disease (CFRLD) and diabetes mellitus, 24 CF pediatric patients with stable pulmonary disease were studied before and after an approximate period of 8 y. Nutritional status, pulmonary function, pancreatic function, and presence of CFRLD or diabetes mellitus were recorded. Results were compared with data obtained in 83 healthy children. Patients with CF have significantly lower linoleic acid (LA), docosahexaenoic acid (DHA), lignoceric acid, and LA × DHA product and higher oleic acid, mead acid, dihomo-γ-linoleic acid, and docosapentaenoic acid (DPA). Comparison of samples taken at first and second studies revealed a significant decrease in LA levels and lignoceric acid associated with a significant increase in dihomo-γ-linoleic acid levels. Patients with CFRLD showed significantly higher mead acid/arachidonic acid ratio and lower total ω6 polyunsaturated fatty acids content. There was no relation of plasma fatty acids composition with pancreatic function, pulmonary function, or diabetes mellitus. Follow-up of patients with CF shows that essential fatty acids deficiency, particularly in LA and DHA content, persisted unmodified along time despite an adequate nutritional therapy. Future studies after supplementation with ω3 polyunsaturated fatty acids should be undertaken.

Fatty acid deficiency profile in children with food allergy managed with elimination diets

Aim: To evaluate plasma fatty acid (FA) composition of children with food allergy undergoing elimination diets that avoided the offending antigens.

Asymmetric Dimethylarginine, Endothelial Dysfunction and Renal Disease

l-Arginine (Arg) is oxidized to l-citrulline and nitric oxide (NO) by the action of endothelial nitric oxide synthase (NOS). In contrast, protein-incorporated Arg residues can be methylated with subsequent proteolysis giving rise to methylarginine compounds, such as asymmetric dimethylarginine (ADMA) that competes with Arg for binding to NOS. Most ADMA is degraded by dimethylarginine dimethyaminohydrolase (DDAH), distributed widely throughout the body and regulates ADMA levels and, therefore, NO synthesis. In recent years, several studies have suggested that increased ADMA levels are a marker of atherosclerotic change, and can be used to assess cardiovascular risk, consistent with ADMA being predominantly absorbed by endothelial cells. NO is an important messenger molecule involved in numerous biological processes, and its activity is essential to understand both pathogenic and therapeutic mechanisms in kidney disease and renal transplantation. NO production is reduced in renal patients because of their elevated ADMA levels with associated reduced DDAH activity. These factors contribute to endothelial dysfunction, oxidative stress and the progression of renal damage, but there are treatments that may effectively reduce ADMA levels in patients with kidney disease. Available data on ADMA levels in controls and renal patients, both in adults and children, also are summarized in this review.

Fatty acid profile in patients with phenylketonuria and its relationship with bone mineral density

BackgroundPatients with phenylketonuria (PKU) undergo a restrictive vegan-like diet, with almost total absence of n-3 fatty acids, which have been proposed as potential contributors to bone formation in the healthy population. The PKU diet might lead these patients to bone mass loss and, consequently, to the development of osteopenia/osteoporosis. Therefore, we proposed to analyze their plasma fatty acid profile status and its relationship with bone health.MethodsWe recruited 47 PKU patients for this cross-sectional study and divided the cohort into three age groups (6–10 years, 11–18 years, 19–42 years). We measured their plasma fatty acid profile and bone mineral density (BMD) (both at the femoral neck and the lumbar spine). Seventy-seven healthy controls also participated as reference values of plasma fatty acids.ResultsDocosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) and total n-3 fatty acids were significantly diminished in PKU patients compared with healthy controls. DHA, EPA, and total n-3 fatty acids were also positively associated with bone mineral density (r = 0.83, p = 0.010; r = 0.57, p = 0.006; r = 0.73, p = 0.040, respectively). There was no association between phenylalanine (Phe), Index of Dietary Control (IDC), calcium, 25-hydroxivitamin D concentrations, daily calcium intake, and BMD.ConclusionOur results suggest a possible influence of essential fatty acids over BMD in PKU patients. The lack of essential n-3 fatty acids intake in the PKU diet might affect bone mineralization. Further clinical trials are needed to confirm the effect of the n-3 essential fatty acids on bone accrual in a cohort of PKU patients.

Arachidonic acid content in adipose tissue is associated with insulin resistance in healthy children.

Background: The fatty acid composition of membrane structural lipids, which is partly dependent on dietary intake, is associated with insulin action. Aim: To examine the association between fatty acid composition of adipose tissue and skeletal muscle phospholipids with insulin resistance markers in a healthy pediatric population. Methods: Using a cross-sectional design, we studied 83 healthy children divided into 3 groups, ages 2 to 5, 6 to 10 and more than 10 years. Measurements: Fatty acid composition of adipose tissue triacylglycerols and skeletal muscle phospholipids, plasma lipid profile and fasting plasma levels of glucose and insulin were measured. Results: There was a linear increase of insulinemia, glycemia and homeostasis adipose tissue model assessment (HOMA) index throughout the pediatric age range. Linoleic acid proportion in skeletal muscle and arachidonic acid proportion in adipose tissue also increased significantly with age. An age-independent positive correlation between insulinemia or HOMA index and arachidonic acid content in adipose tissue triacylglycerols (r = 0.47, P < 0.001) was found. An age-dependent negative correlation was present between insulinemia or HOMA index and oleic acid content in skeletal muscle phospholipids (r = −0.30, P = 0.03 and r = −0.28, P < 0.04, respectively). Trans fatty acids content did not correlate with any marker of insulin resistance. Conclusion: Healthy children present a prepubertal increase of insulin resistance, which is significantly correlated with arachidonic acid content in adipose tissue.

Methionine and S-Adenosylmethionine levels are critical regulators of PP2A activity modulating lipophagy during steatosis

BACKGROUND & AIMS Glycine N-methyltransferase (GNMT) expression is decreased in some patients with severe non-alcoholic fatty liver disease. Gnmt deficiency in mice (Gnmt-KO) results in abnormally elevated serum levels of methionine and its metabolite S-adenosylmethionine (SAMe), and this leads to rapid liver steatosis development. Autophagy plays a critical role in lipid catabolism (lipophagy), and defects in autophagy have been related to liver steatosis development. Since methionine and its metabolite SAMe are well known inactivators of autophagy, we aimed to examine whether high levels of both metabolites could block autophagy-mediated lipid catabolism. METHODS We examined methionine levels in a cohort of 358 serum samples from steatotic patients. We used hepatocytes cultured with methionine and SAMe, and hepatocytes and livers from Gnmt-KO mice. RESULTS We detected a significant increase in serum methionine levels in steatotic patients. We observed that autophagy and lipophagy were impaired in hepatocytes cultured with high methionine and SAMe, and that Gnmt-KO livers were characterized by an impairment in autophagy functionality, likely caused by defects at the lysosomal level. Elevated levels of methionine and SAMe activated PP2A by methylation, while blocking PP2A activity restored autophagy flux in Gnmt-KO hepatocytes, and in hepatocytes treated with SAMe and methionine. Finally, normalization of methionine and SAMe levels in Gnmt-KO mice using a methionine deficient diet normalized the methylation capacity, PP2A methylation, autophagy, and ameliorated liver steatosis. CONCLUSIONS These data suggest that elevated levels of methionine and SAMe can inhibit autophagic catabolism of lipids contributing to liver steatosis.

Sanfilippo syndrome: Overall review.

Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) is a lysosomal storage disorder, caused by a deficiency in one of the four enzymes involved in the catabolism of glycosaminoglycan heparan sulfate. It is characterized by progressive cognitive decline and severe hyperactivity, with relatively mild somatic features. This review focuses on clinical features, diagnosis, treatment, and follow‐up of MPS III, and provides information about supplementary tests and differential diagnosis. Given that few reviews of MPS III have been published, several studies were compiled to establish diagnostic recommendations. Quantitative urinary glycosaminoglycan analysis is strongly recommended, and measurement of disaccharides, heparin cofactor II–thrombin complex and gangliosides is also used. Enzyme activity of the different enzymes in blood serum, leukocytes or fibroblasts, and mutational analysis for SGSH, NAGLU, HGSNAT or GNS genes are required to confirm diagnosis and differentiate four subtypes of MPS III. Although there is no global consensus for treatment, enzyme replacement therapy and gene therapy can provide appropriate results. In this regard, recent publications on treatment and follow‐up are discussed.

Anthropometric characteristics and nutrition in a cohort of PAH-deficient patients.

BACKGROUND & AIMS Treating phenylketonuria based upon strict vegetarian diets has occasionally been found to hamper physical development, some patients presenting with growth retardation and malnutrition. In addition, some researchers have reported an association between higher protein intakes and attaining better developmental outcomes, although it remains unclear which protein fraction (natural or synthetic) has the greatest influence on growth. The present study aimed to evaluate anthropometric characteristics and nutrition in a cohort of patients with phenylketonuria and mild-hyperphenylalaninaemia from birth to adulthood. METHODS We conducted a retrospective longitudinal study comparing anthropometric characteristics (weight, height, body mass index, and growth rate) in our patients and healthy subjects, with the measurements expressed as z-scores. Nutritional issues were also considered. Data were collected every 6 months from birth to 18 years of age. RESULTS Growth impairment was observed in phenylketonuric patients. Specifically, there were two well-differentiated periods throughout which height fell well below z-score = 0: from birth to two years of age, and on reaching adulthood. We also found height and weight to be positively correlated with phenylalanine intake. No growth retardation was seen in the patients with mild-hyperphenylalaninaemia. CONCLUSIONS Phenylketonuric patients showed growth impairment in the early stages, with higher phenylalanine intakes being associated with attaining better developmental outcomes in this period. Therefore, prescribing very stringent diets in the early years might predispose phenylketonuric patients to retarded growth later in life, with growth outcomes in adulthood being well below the 50th percentile for healthy subjects.

Vitamin and mineral status in patients with hyperphenylalaninemia.

Natural sources of protein and some vitamins and minerals are limited in phenylketonuria (PKU) treated patients, who should receive optimal supplementation although this is not yet fully established. We conducted a cross-sectional observational multicenter study including 156 patients with hyperphenylalaninemia. Patients were stratified by age, phenotype, disease detection and type of treatment. Annual median blood phenylalanine (Phe) levels, Phe tolerance, anthropometric measurements, and biochemical parameters (total protein, prealbumin, electrolytes, selenium, zinc, B12, folic acid, ferritin, 25-OH vitamin D) were collected in all patients. 81.4% of patients had biochemical markers out of recommended range but no clinical symptoms. Total protein, calcium, phosphorus, B12, ferritin, and zinc levels were normal in most patients. Prealbumin was reduced in 34.6% of patients (74% with PKU phenotype and 94% below 18 years old), showing almost all (96.3%) an adequate adherence to diet. Selenium was diminished in 25% of patients (95% with PKU phenotype) and also 25-OHD in 14%. Surprisingly, folic acid levels were increased in 39% of patients, 66% with classic PKU. Phosphorus and B12 levels were found diminished in patients with low adherence to diet. Patients under BH4 therapy only showed significant lower levels of B12. This study shows a high percentage of prealbumin and selenium deficiencies as well as an increased level of folic acid in PKU treated patients, which should lead us to assess an adjustment for standards supplements formulated milks.

Tetrahydrobiopterin therapy vs phenylalanine-restricted diet: Impact on growth in PKU

BACKGROUND Treatment of phenylketonuria based upon strict vegetarian diets, with very low phenylalanine intake and supplemented by phenylalanine-free formula, has proven to be effective in preventing the development of long-term neurological sequelae due to phenylalanine accumulation. On the other hand, such diets have occasionally been reported to hinder normal development, some individuals presenting with growth retardation. Tetrahydrobiopterin therapy has opened up new treatment options for a significant proportion of phenylketonuric patients, enabling them to eat normal diets and be freed from the need to take synthetic supplements. However, little is known about how this therapy affects their physical development. METHODS We conducted a retrospective longitudinal study examining anthropometric characteristics (height, weight, body mass index and growth speed Z-scores) in a cohort of phenylketonuric patients on tetrahydrobiopterin therapy (38 subjects) comparing their characteristics with those of a group of phenylketonuric patients on phenylalanine-restricted diets (76 subjects). Nutritional issues were also considered, to further explore the possibility of higher natural protein intake being associated with better physical development. Data were collected every six months over two different periods of time (two or five years). RESULTS No improvement was observed in the aforementioned anthropometric variables in the cohort on tetrahydrobiopterin therapy, from prior to starting treatment to when they had been taking the drug for two or five years. Rather, in almost all cases there was a fall in the mean Z-score for the variables during these periods, although the changes were not significant in any case. Further, we found no statistically differences between the two groups at any considered time point. Growth impairment was also noted in the phenylketonuric patients on low-phenylalanine diets. Individuals on tetrahydrobiopterin therapy increased their natural protein intake and, in some instances, this treatment enabled individuals to eat normal diets, with protein intake meeting RDAs. No association was found, however, between higher protein intake and growth. CONCLUSION Our study identified growth impairment in patients with phenylketonuria on tetrahydrobiopterin, despite higher intakes of natural proteins. In fact, individuals undergoing long-term tetrahydrobiopterin treatment seemed to achieve similar developmental outcomes to those attained by individuals on more restricted diets.