Hansjosef Böhles

The roles of long-chain polyunsaturated fatty acids in pregnancy, lactation and infancy: review of current knowledge and consensus recommendations

Abstract This paper reviews current knowledge on the role of the long-chain polyunsaturated fatty acids (LC-PUFA), docosahexaenoic acid (DHA, C22:6n-3) and arachidonic acid (AA, 20:4n-6), in maternal and term infant nutrition as well as infant development. Consensus recommendations and practice guidelines for health-care providers supported by the World Association of Perinatal Medicine, the Early Nutrition Academy, and the Child Health Foundation are provided. The fetus and neonate should receive LC-PUFA in amounts sufficient to support optimal visual and cognitive development. Moreover, the consumption of oils rich in n-3 LC-PUFA during pregnancy reduces the risk for early premature birth. Pregnant and lactating women should aim to achieve an average daily intake of at least 200 mg DHA. For healthy term infants, we recommend and fully endorse breastfeeding, which supplies preformed LC-PUFA, as the preferred method of feeding. When breastfeeding is not possible, we recommend use of an infant formula providing DHA at levels between 0.2 and 0.5 weight percent of total fat, and with the minimum amount of AA equivalent to the contents of DHA. Dietary LC-PUFA supply should continue after the first six months of life, but currently there is not sufficient information for quantitative recommendations.

Parenteral Fat Emulsions Based on Olive and Soybean Oils: A Randomized Clinical Trial in Preterm Infants

Objective To evaluate in premature infants a new parenteral lipid emulsion based on olive and soybean oils (ratio 4:1), with less polyunsaturated fatty acids (PUFA) and more &agr;-tocopherol than standard soybean oil emulsion. Study design Premature infants (gestational age, 28–<37 weeks) were randomized to receive one of the two emulsions within the first 72 hours of life. The triglyceride dose was increased to 2 g/kg/day within 3 days. Plasma phospholipid fatty acids, &agr;-tocopherol/lipid ratio, and urinary malondialdehyde (MDA) excretion were determined at baseline and after 7 days. Results Of 45 recruited infants, 33 completed the study per protocol (15 soybean oil, 18 olive oil emulsion). At study end, groups did not differ in plasma phospholipid arachidonic acid, total n-6 and n-3 metabolites, but the olive oil group showed higher values of the PUFA intermediates C18:3n-6 (0.19% ± 0.01% vs. 0.13% ± 0.02%, P < 0.05) and C20:3n-6 (2.92% ± 0.12% vs. 2.21% ± 0.17%, P = 0.005). The plasma &agr;-tocopherol/total lipd ratio was higher in the olive oil group (2.45 ± 0.27 &mgr;mol/mmol vs. 1.90 ± 0.08 &mgr;mol/mmol, P = 0.001), whereas urinary MDA excretion did not differ. Conclusion The lower PUFA supply with the olive/soybean oil emulsion appears to enhance linoleic acid conversion. The reduced PUFA content, combined with a higher antioxidant intake in the olive oil group, results in an improved vitamin E status. The olive oil-based emulsion is a valuable alternative for parenteral feeding of preterm infants who are often exposed to oxidative stress, while their antioxidative defense is weak.

Mitochondrial Phosphate–Carrier Deficiency: A Novel Disorder of Oxidative Phosphorylation

The mitochondrial phosphate carrier SLC25A3 transports inorganic phosphate into the mitochondrial matrix, which is essential for the aerobic synthesis of adenosine triphosphate (ATP). We identified a homozygous mutation--c.215G-->A (p.Gly72Glu)--in the alternatively spliced exon 3A of this enzyme in two siblings with lactic acidosis, hypertrophic cardiomyopathy, and muscular hypotonia who died within the 1st year of life. Functional investigation of intact mitochondria showed a deficiency of ATP synthesis in muscle but not in fibroblasts, which correlated with the tissue-specific expression of exon 3A in muscle versus exon 3B in fibroblasts. The enzyme defect was confirmed by complementation analysis in yeast. This is the first report of patients with mitochondrial phosphate-carrier deficiency.

Cerebrovascular complications of L-asparaginase in the therapy of acute lymphoblastic leukemia.

l-asparaginase is frequently used in combination therapy for the treatment of lymphoid malignancies. We report 5 children aged between 8 and 14 years with neurologic complications presenting with headache and seizures during the first three weeks of l-asparaginase treatment. Three patients had venous thrombosis, one presented a parenchymal hemorrhage, and one showed a peculiar encephalopathy with extended cortical and subcortical lesions suggesting a neurotoxic reaction. Decreased fibrinogen and antithrombin III levels were found. Early MRI is critical even in cases with mild neurologic symptoms. Diagnosis should be followed by early cessation of l-asparaginase application.

Carnitine esters in metabolic disease

Carnitine (~-OH-trimethylaminobutyric acid) is a quaternary amine with a key role in facilitating the transport of fatty acids across the inner mitochondrial membrane prior to [3-oxidation. A second and possibly equally important role in the control of key metabolic processes, and hence of mitochondrial homeostasis has been identified more recently [14]. This better understanding reveals the important diagnostic implications of this compound.

N-carbamylglutamate protects patients with decompensated propionic aciduria from hyperammonaemia.

SummaryIn patients with propionic aciduria, the accumulating metabolite propionyl-CoA causes a disturbance of the urea cycle via the inhibition of N-acetylglutamate synthesis. Lack of this allosteric activator results in an inhibition of carbamoylphosphate synthase (CPS). This finally leads to hyperammonaemia. In two patients with decompensated propionic aciduria the CPS activator carbamylglutamate was tested for its ability to antagonize the propionyl-CoA associated hyperammonaemia. Oral carbamyl glutamate administration resulted in a significant increase in ammonia detoxification and could avoid further dialysis therapy. Safe, fast and easy to administer, carbamyl glutamate improves the acute therapy of decompensated propionic aciduria by increasing ammonia detoxification and avoiding hyperammonaemia.

Docosahexaenoic and arachidonic acid content of serum and red blood cell membrane phospholipids of preterm infants fed breast milk, standard formula or formula supplemented with n-3 and n-6 long-chain polyunsaturated fatty acids.

The contents of docosahexaenoic (DHA) and arachidonic acid (AA) of plasma and red blood cell membrane phospholipids were studied in 41 very low birth weight infants fed either breast milk (n=18), a standard formula without long-chain polyunsaturated fatty acids with 20 or 22 carbon atoms (LCP) but with α-linolenic acid and linoleic acid (n=11) or a formula additionally supplemented with n-3 and n-6 LCP in relations typical for human milk (n=12) after 2, 6, and 10 weeks of feeding. The content of DHA and AA in plasma phospholipids declined in the infants fed the LCP-free formula but remained more or less constant during the whole feeding period in those infants fed breast milk as well as in those fed the LCP-supplemented formula. The differences between the group fed the LCP-free standard formula and the two groups fed LCP-containing diets became significant during the first 2 weeks of feeding. In contrast, there were no differences between the group fed breast milk and the group fed the supplemented formula during the study period. Similar effects could be observed regarding the composition of red blood cell membrane phospholipids, but the differences between the infants fed the LCP-free standard formula and the two other groups with LCP-containing diets were significant only for AA. The data indicate that very low birth weight infants are unable to synthesize LCP from α-linolenic acid and linoleic acid in sufficient amounts to prevent a decline of LCP in plasma and red blood cell phospholipids. Additionally, the data show, that supplementation of formulas with n-3 and n-6 LCP in amounts typical for human milk fat results in similar fatty acid profiles of plasma and red blood cell membrane phospholipids as found during breast milk feeding.ConclusionSupplementation of formula with long-chain polyunsaturated fatty acids improves the LCP status of very low birth weight infants.

N-carbamylglutamate enhances ammonia detoxification in a patient with decompensated methylmalonic aciduria

In patients with methylmalonic aciduria (MMA), the accumulating metabolite propiony-CoA results in an inhibition of the urea circle via the decreased synthesis of N-acetylglutamate, an essential activator of carbamylphosphat synthetase (CPS). This results in one of the major clinical problems which is hyperammonaemia. In a patient with decompensated MMA, the CPS activator carbamylglutamate was tested for its ability to antagonize the propionyl-CoA-induced hyperammonaemia. Oral carbamylgutamate administration resulted in an impressive increase in ammonia detoxification compared to peritoneal dialysis. Safe, fast and easy to administer, carbamylglutamate improves the acute therapy of decompensated MMA by increasing ammonia detoxification and avoiding hyperammonaemia.

4,5-dimethyl-3-hydroxy-2[5H]-furanone (sotolone)--the odour of maple syrup urine disease.

Maple syrup urine disease is an autosomal recessive inherited disorder of branched-chain amino acid metabolism due to deficiency of the branched-chain α-keto acid dehydrogenase complex. The disease was originally named after the characteristic sweet aroma, reminiscent of maple syrup, present in the body fluids of affected patients. Until now, the substance responsible for the odour has not been positively identified. Using enantioselective multidimensional gas chromatography-mass spectrometry (enantio-MDGC-MS), we could demonstrate that 4,5-dimethyl-3-hydroxy-2[5H]-furanone (sotolone), a well-known flavour impact compound present in fenugreek and lovage, was present in urine from seven patients with maple syrup urine disease. Urine samples from healthy control persons lacked sotolone. We have shown that sotolone is responsible for the characteristic odour of maple syrup urine disease and, since maple syrup also contains sotolone, the naming of this disease appears to be correct.

Hyperinsulinaemic hypoglycaemia—Leading symptom in a patient with congenital disorder of glycosylation Ia (phosphomannomutase deficiency)

AbstractA male infant is described who presented with persistent hyperinsulinaemic hypoglycaemia, responding to diazoxide treatment. However, this therapy was discontinued because of seizures as a consequence of disturbed water and electrolyte balance. Glucose homeostasis could only be maintained by subtotal pancreatectomy, which was performed at 3