Search

Analytical and therapeutic innovations led to a continuous but variable extension of newborn screening (NBS) programmes worldwide. Every extension requires a careful evaluation of feasibility, diagnostic (process) quality and possible health benefits to balance benefits and limitations. The aim of this study was to evaluate the suitability of 18 candidate diseases for inclusion in NBS programmes. Utilising tandem mass spectrometry as well as establishing specific diagnostic pathways with second‐tier analyses, three German NBS centres designed and conducted an evaluation study for 18 candidate diseases, all of them inherited metabolic diseases. In total, 1 777 264 NBS samples were analysed. Overall, 441 positive NBS results were reported resulting in 68 confirmed diagnoses, 373 false‐positive cases and an estimated cumulative prevalence of approximately 1 in 26 000 newborns. The positive predictive value ranged from 0.07 (carnitine transporter defect) to 0.67 (HMG‐CoA lyase deficiency). Three individuals were missed and 14 individuals (21%) developed symptoms before the positive NBS results were reported. The majority of tested candidate diseases were found to be suitable for inclusion in NBS programmes, while multiple acyl‐CoA dehydrogenase deficiency, isolated methylmalonic acidurias, propionic acidemia and malonyl‐CoA decarboxylase deficiency showed some and carnitine transporter defect significant limitations. Evaluation studies are an important tool to assess the potential benefits and limitations of expanding NBS programmes to new diseases. [ABSTRACT FROM AUTHOR]

Illsinger S, Janzen N, Lücke T, Bednarczyk J, Schmidt K-H, Hoy L, Sander J, Das AM. Cyclosporine A: impact on mitochondrial function in endothelial cells. Clin Transplant 2011: 25: 584-593. © 2010 John Wiley & Sons A/S. Abstract: Introduction: Although cyclosporine A (CSA) is considered to be an efficient immunosuppressive compound in transplantation, vascular side effects like arterial hypertension, neurologic complications and other adverse reactions occur. Interference of CSA with mitochondrial function may be responsible for these side effects. Methods: We evaluated the effect of CSA on mitochondrial and glycolytic function by measuring fatty acid oxidation (FAO), activities of respiratory chain complexes (RC) and citratesynthase (CS), lactate/pyruvate-ratios, energy-rich phosphates as well as activities of some glycolytic enzymes in human umbilical vein endothelial cells. Results: After 48 h of CSA incubation, global FAO, RC-complexes 1 + 3; 4 and 5 as well as CS were compromised while energy charges were not reduced. Lactate/pyruvate-ratios increased; cellular lactate dehydrogenase (LDH)-, hexokinase- and phosphofructokinase-activities were not impaired by CSA. Moderate cellular toxicity, assessed by LDH leakage, appeared only at the highest CSA concentration. Conclusion: Part of CSA toxicity may arise from alterations in mitochondrial function as judged by impaired FAO and respiratory chain enzymes. To some extent, energy balance seems to be maintained by cytosolic energy production. Although only demonstrated for endothelial cells, it is conceivable that such effects will alter energy metabolism of different organs with high oxidative energy demands. [ABSTRACT FROM AUTHOR]

In general, data regarding maturational processes of different metabolic pathways in the very vulnerable fetal and neonatal period are rare. This review is to substantiate the impact of selected inborn errors of metabolism on this critical period of life and their clinical manifestation. Significant adaptation of mitochondrial/energy-, carbohydrate-, lysosomal-, and amino acid-metabolism occurs during early prenatal and neonatal development. In utero, metabolic environment has an impact on the development of the fetus as well as fetal organ maturation. Defects of distinct metabolic pathways could therefore already be of significant relevance in utero and for clinical manifestations in the early fetal and neonatal period. Disturbances of these pathways may influence intrauterine growth and health. Production of a toxic intrauterine milieu, energy-deficiency, modification of membrane function, or disturbance of the normal intrauterine expression of genes may be responsible for fetal compromise and developmental disorders. Three categories of metabolic disorders will be discussed: the “intoxication type” (classical galactosemia, ornithine transcarbamylase deficiency, and “maternal phenylketonuria”), the “storage type” (Morbus Niemann Pick type C), and the “energy deficient type” (including long-chain fatty acid oxidation disorders, pyruvate dehydrogenase deficiency, and respiratory chain defects). For these disorders, the pathophysiology of early manifestation, special aspects regarding the prenatal and neonatal period, and diagnostic as well as therapeutic options are presented. © 2010 IUBMB IUBMB Life, 62(6): 403–413, 2010 [ABSTRACT FROM AUTHOR]

We report on a newborn male, born at term after an uneventful pregnancy presenting with a pathological acylcarnitine profile in routine newborn screening on the third day of life. The profile showed characteristic elevations of C14:0-, C16:0-, C16:1- and C18:1-acylcarnitines, while the ratio of (C16 + C18:1)/C2 was increased, suggesting CPT2- or carnitine-acylcarnitine-translocase- deficiency. The acylcarnitine profile in blood taken on day 9 was normal with breast milk feeding. No dicarboxylic aciduria was found. In fibroblasts, the activity of CPT2 was decreased to 25%, overall oxidation of the long-chain fatty acids was reduced to 10% of control values. Sequence analysis of the CPT2 gene showed heterozygosity for two previously undescribed mutations in exon 4: c.748-749delAA (truncating), and c.1436A > G (p.Tyr479Cys; missense) mutations. The asymptomatic parents were found to be heterozygous, the mother carries the c.748-749delAA and the father the c.1436A > G mutation. The boy is now 2.5 years old; no clinical symptoms associated with the marked impairment of long-chain fatty acid oxidation have occurred. Confirmation of mitochondrial fatty acid oxidation defects from an initial abnormal newborn-screening by tandem mass spectrometry should include enzyme and, if possible, molecular genetic analysis despite a normal 2nd screening. Biochemical testing of urine (organic acids) may be unrevealing., ((c) 2008 Wiley-Liss, Inc.)