Pablo Sanjurjo

Identification of SLC7A7, encoding y+LAT-1, as the lysinuric protein intolerance gene.

Lysinuric protein intolerance (LPI; OMIM 222700) is a rare, recessive disorder with a worldwide distribution, but with a high prevalence in the Finnish population; symptoms include failure to thrive, growth retardation, muscle hypotonia and hepatosplenomegaly. A defect in the plasma membrane transport of dibasic amino acids has been demonstrated at the basolateral membrane of epithelial cells in small intestine and in renal tubules and in plasma membrane of cultured skin fibroblasts from LPI patients. The gene causing LPI has been assigned by linkage analysis to 14q11-13. Here we report mutations in SLC7A7 cDNA (encoding y+L amino acid transporter-1, y+LAT-1), which expresses dibasic amino-acid transport activity and is located in the LPI region, in 31 Finnish LPI patients and 1 Spanish patient. The Finnish patients are homozygous for a founder missense mutation leading to a premature stop codon. The Spanish patient is a compound heterozygote with a missense mutation in one allele and a frameshift mutation in the other. The frameshift mutation generates a premature stop codon, eliminating the last one-third of the protein. The missense mutation abolishes y+LAT-1 amino-acid transport activity when co-expressed with the heavy chain of the cell-surface antigen 4F2 (4F2hc, also known as CD98) in Xenopus laevis oocytes. Our data establish that mutations in SLC7A7 cause LPI.

Brain Docosahexaenoic Acid Status and Learning in Young Rats Submitted to Dietary Long-Chain Polyunsaturated Fatty Acid Deficiency and Supplementation Limited to Lactation

N-3 fatty acid deficiency has been related to decreased docosahexaenoic acid (DHA) and increased docosapentaenoic acid (DPA) levels in brain and to learning disadvantages. The influence of n-3 deficiency and supplementation on brain fatty acids and learning were investigated in young rats. Newborn Wistar rats were assigned to three groups of cross-foster mothers. The control group (C) was nursed by mothers that received essential fatty acids during pregnancy and lactation, and the deficient group (D) was nursed by mothers that did not receive those fatty acids. The supplemental group (S) had the same conditions as D, receiving an additional DHA and arachidonic acid supplement during lactation. Cerebral cortex and hippocampus fatty acid composition was examined using thin-layer and capillary column gas chromatography, and learning was measured by passive-avoidance procedure. D brains showed low DHA and high DPA levels, but S brain composition was similar to C. Learning in the S group was unaffected, but in the D group, it was poorer than C. Learning was directly correlated with DHA levels and inversely with DPA levels in brain. Low DHA and high DPA brain levels both were correlated with poor learning. DPA seems not to be a suitable brain functional analogue of DHA, and DHA supplementation reversed both biochemical and learning adverse effects observed in n-3 deficiency.

Polyunsaturated fatty acid status in patients with phenylketonuria

SummaryTo determine whether then−6 andn−3 polyunsaturated fatty acid levels can be affected by the PKU diet, fatty acid composition was studied in PKU subjects and controls together with their lipid intake. The study population consisted of 40 PKU patients treated with a phenylalanine-restricted diet. Controls were 50 children on whom preoperative tests had been carried out for minor surgery. Methyl esters were obtained from plasma and red blood-cells and separated by gas chromatography. PKU patients showed lower docosahexaenoic acid levels (22:6n−3) (p<0.001) and highern−6 series levels in plasma (18:2n−6) (p<0.001) and in red blood-cells (20:4n−6) (p<0.001) than the control population. Since docosahexaenoic and arachidonic acids are fundamental structural components for normal brain development, it seems necessary to consider a dietary adjustment in these patients.

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.

Supplementation with docosahexaenoic acid in the last trimester of pregnancy: maternal-fetal biochemical findings.

The nutritional significance of long-chain polyunsaturated fatty acids (LCPS) during the perinatal period is becoming increasingly important. There are currently very few studies on dietary intervention during gestation. The aim of the study was to analyze the effect of docosahexaenoic acid (DHA) supplementation during pregnancy on levels in both the newborn and the mother. A randomized placebo controlled study was carried out on 20 pregnant women in study group receiving 200 mg/day of docosahexaenoic acid-(DHA) during the last trimester of pregnancy. Results in both groups (A supplemented, B non-supplemented) highlighted a decrease in plasma arachidonic acid (5.99 +/- 0.91 vs. 4.51 +/- 0.71 p<0.001 for group A and 5.84 +/- 0.71 vs. 4.80 +/- 0.51 p<0.01 for group B) in the baseline-final intra-group comparison. The intergroup comparison revealed a significant difference in plasma DHA at delivery: it was found to be higher in the population of supplemented pregnant women (3.17 +/- 0.26 vs. 2.77 +/- 0.31). The neonate population displayed no significant differences between the two groups. The results show that LCPS are consumed during the final stages of pregnancy and that oral supplementation with 200 mg/day of DHA is reflected in an increase in the plasma level of this fatty acid in the mother. One could speculate that there would be a corresponding increase in DHA bioavailability for the fetus.

Intake of long chain w3 polyunsaturated fatty acids during pregnancy and the influence of levels in the mother on newborn levels

OBJECTIVE To assess the relationship between the free intake of long chain w3 polyunsaturated fatty acid (w3 LCP) during pregnancy and the levels in the mother with the levels in the neonate. DESIGN Cross-sectional study. SETTING University hospital. SUBJECTS One hundred and sixty-two mother-neonate pairs from normal at-term pregnancies. MAIN OUTCOME MEASURE Dietetic interview in order to assess the w3 LCP intake. w3 LCPs were analyzed by capillary gas chromatography in plasma (expressed as percentage and as total amount) and in erythrocyte phospholipids (expressed as percentage) from mothers and neonates. RESULTS The w3 LCP intake assessed by the dietetic interview was significantly correlated with w3 LCP levels in the plasma of both mothers and neonates. The levels of w3 LCPs in mothers and neonates were significantly correlated both in plasma fatty acids (expressed both as a percentage and absolute values) and in erythrocyte phospholipids (in percentage) (r=0.49-0.22). CONCLUSION In an apparently well-nourished population the w3 LCP levels of the newborn infants are clearly influenced by those of their mothers. The higher the levels in mothers, the higher those in the neonates. The w3 LCP intake assessed by an interview also showed a significant influence, but to a lesser extent.

Longitudinal study of fatty acids in plasma and erythrocyte phospholipids during pregnancy.

Abstract Aim: To assess the modifications of the main fatty acids (FA) in plasma and red blood cells during pregnancy. Methods: A longitudinal study of 36 normal pregnant women was carried out with 3 cut-off points: first trimester, second trimester and third trimester. 14 FA in plasma and erythrocyte phospholipids were measured using capillary gas chromatography. Measurements were expressed in percentages and in absolute values. Results: In plasma there was a significant increase in the proportion of saturated FA and a decrease in the proportion of long chain polyunsaturated fatty acids (PUFA) both in the omega 6 (ω6) and omega 3 (ω3) series. On the other hand, in erythrocyte phospholipids there was a decrease in the proportion of eicosapentaenoic acid and an increase in that of docosahexaenoic acid. In the ω6 series, dihomo-gamma-linolenic acid increased, whereas the ω6 docosapentaenoic acid decreased. Conclusion: There was a significant decrease in the proportion of ω3 PUFA in plasma from the first to the third trimester. Thus, it is suggested that the ω3 PUFA intake during pregnancy should be increased in the last trimester.

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.

Inborn errors of metabolism with a protein-restricted diet : Effect on polyunsaturated fatty acids

Previous studies have shown that phenylketonuric patients display a deficiency in long-chain polyunsaturated fatty acids. A study has now been performed on 13 cases (5 with methylmalonic acidaemia and 8 with urea cycle disorders) whose dietary treatment also implies a limitation in protein-rich food. Plasma and red-cell phospholipid fatty acid profiles were studied. The most relevant results were a lower percentage of docosahexaenoic acid in plasma and red-cell phospholipids (0.91% ± 0.53% vs 2.88% ± 1.17% and 2.07% ± 0.92% vs 3.62% ± 1.01% (p < 0.001)) and a lower percentage of arachidonic acid in plasma (5.22% ± 2.02% vs 8.3% ± 2.11% (p < 0.001)).A long-chain polyunsaturated acid deficiency has also been confirmed in this group of metabolic patients and a dietary supplement is recommended since this population is subject to a special risk factor with regard to adequate psychomotor development. By extrapolating these data to the general population, the possibility can be inferred that long-chain polyunsaturated fatty acids are semi-essential in infant nutrition far beyond the breast-feeding period.

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.