Collaborative evaluation study on 18 candidate diseases for newborn screening in 1.77 million samples.

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.

Congenital disorders of glycosylation with defective fucosylation.

Fucosylation is essential for intercellular and intracellular recognition, cell-cell interaction, fertilization, and inflammatory processes. Only five types of congenital disorders of glycosylation (CDG) related to an impaired fucosylation have been described to date: FUT8-CDG, FCSK-CDG, POFUT1-CDG SLC35C1-CDG, and the only recently described GFUS-CDG. This review summarizes the clinical findings of all hitherto known 25 patients affected with those defects with regard to their pathophysiology and genotype. In addition, we describe five new patients with novel variants in the SLC35C1 gene. Furthermore, we discuss the efficacy of fucose therapy approaches within the different defects.

A Homozygous Splice Site Mutation in SLC25A42, Encoding the Mitochondrial Transporter of Coenzyme A, Causes Metabolic Crises and Epileptic Encephalopathy.

SLC25A42 is an inner mitochondrial membrane protein which has been shown to transport coenzyme A through a lipid bilayer in vitro. A homozygous missense variant in this gene has been recently reported in 13 subjects of Arab descent presenting with mitochondriopathy with variable clinical manifestations. By exome sequencing, we identified two additional individuals carrying rare variants in this gene. One subject was found to carry the previously reported missense variant in homozygous state, while the second subject carried a homozygous canonical splice site variant resulting in a splice defect. With the identification of two additional cases, we corroborate the association between rare variants in SLC25A42 and a clinical presentation characterized by myopathy, developmental delay, lactic acidosis, and encephalopathy. Furthermore, we highlight the biochemical consequences of the splice defect by measuring a mild decrease of coenzyme A content in SLC25A42-mutant fibroblasts.

An exceptional Albanian family with seven children presenting with dysmorphic features and mental retardation: maternal phenylketonuria.

BACKGROUND: Phenylketonuria is an inborn error of amino acid metabolism which can cause severe damage to the patient or, in the case of maternal phenylketonuria, to the foetus. The maternal phenylketonuria syndrome is caused by high blood phenylalanine concentrations during pregnancy and presents with serious foetal anomalies, especially congenital heart disease, microcephaly and mental retardation. CASE PRESENTATION: We report on an affected Albanian woman and her seven children. The mother is affected by phenylketonuria and is a compound heterozygote for two pathogenetic mutations, L48S and P281L. The diagnosis was only made in the context of her children, all of whom have at least one severe organic malformation. The first child, 17 years old, has a double-chambered right ventricle, vertebral malformations and epilepsy. She is also mentally retarded, microcephalic, exhibits facial dysmorphies and small stature. The second child, a girl 15 years of age, has severe mental retardation with microcephaly, small stature and various dysmorphic features. The next sibling, a boy, died of tetralogy of Fallot at the age of three months. He also had multiple vertebral and rib malformations. The subsequent girl, now eleven years old, has mental retardation, microcephaly and epilepsy along with facial dysmorphy, partial deafness and short stature. The eight-year-old child is slightly mentally retarded and microcephalic. A five-year-old boy was a premature, dystrophic baby and exhibits mental retardation, dysmorphic facial features, brachydactyly and clinodactyly of the fifth finger on both hands. Following a miscarriage, our index case, the youngest child at two years of age, is microcephalic and mentally retarded and shows minor facial anomalies. All children exhibit features of phenylalanine embryopathy caused by maternal phenylketonuria because the mother had not been diagnosed earlier and, therefore, never received any diet. CONCLUSION: This is the largest family suffering from maternal phenylketonuria reported in the literature. Maternal phenylketonuria remains a challenge, especially in woman from countries without a neonatal screening program. Therefore, it is mandatory to be alert for the possibility of maternal phenylketonuria syndrome in case of a child with the clinical features described here to prevent foetal damage in subsequent siblings.

Childhood obesity: concept, feasibility, and interim results of a local group-based, long-term treatment program.

OBJECTIVE: The authors performed a group-based program for obese children and adolescents in Bavaria, Germany to enable them to establish a health-oriented lifestyle and to reduce overweight. The authors compared this program with a control approach based on the patients' own initiative. DESIGN: This is a controlled clinical trial. SETTING: A nutrition program for outpatients in a German university hospital. PARTICIPANTS: Seventy-three obese patients aged 7 to 15 years (mean 11.2 years) were recruited by pediatricians and local newspaper reports and randomized into intervention and control groups. Children and adolescents in each group were divided into 3 groups according to age--7-8 years, 9-10 years, and 11-13 years. Children were classified overweight (defined as body mass index (BMI) > 90th percentile for age and gender), obese (BMI > 97th percentile), and extremely obese (BMI > 99.5th percentile), according to the European Childhood Obesity Group and the German Working Group on Pediatric Obesity, congruent with adult standards used to assess overweight and obesity. INTERVENTION: Thirty-seven patients (age 7-13 years, mean 10.9 years) for the 1-year intervention. This intervention consisted of modules for physical activity, nutritional education, and coping strategies. The program was performed twice each week and incorporated parental participation and medical supervision, including laboratory tests. The obese controls (n = 36, age 8-15 years, mean 11.6 years) received written therapeutic advice during a visit at 0 and 6 months in the outpatient clinic. MAIN OUTCOME MEASURE: The primary outcome variable was the body mass index (BMI) z score. ANALYSIS: Analysis of variance and t test were used, and a P value < .05 was considered significant. RESULTS: There was a reduction of BMI z score in the active treatment group (P < .05), but not for controls. Moreover, the active group showed beneficial effects for body mass index (BMI), fat mass, and systolic blood pressure 12 months after beginning the intervention. CONCLUSIONS AND IMPLICATIONS: Group-based programs for young, obese patients can be effective tools for establishing a health-oriented lifestyle and reducing the burden of obesity.

Transcriptional effects of hypoxia on fusiogenic syncytin and its receptor ASCT2 in human cytotrophoblast BeWo cells and in ex vivo perfused placental cotyledons.

OBJECTIVE: The purpose of this study was to test the hypothesis that hypoxia down-regulates placental syncytin, which could play a role in altered placentogenesis; we investigated the influence of hypoxia on syncytin and its receptor ASCT2 gene expression in BeWo cells and in ex vivo perfused human cotyledons. STUDY DESIGN: BeWo cells were incubated with deferoxamine or cobalt chloride under normoxia and hypoxia. Additionally, a model of dually ex vivo perfused cotyledons was applied. Under hypoxic and cobalt chloride stimuli syncytin, ASCT2, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), beta-actin, and beta(2)-microglobulin (beta(2)-MG) messenger RNAs were analyzed with the use of real-time polymerase chain reaction. RESULTS: Hypoxia, deferoxamine, and cobalt chloride markedly decreased syncytin messenger RNA in BeWo cells, whereas ASCT2 messenger RNA was not altered significantly. In isolated perfused cotyledons, hypoxia also reduced syncytin (P<.05) but not ASCT2 messenger RNA. CONCLUSION: Our data provide first evidence that syncytin gene expression is down-regulated by hypoxia, which strengthens the hypothesis that syncytin is reduced in disturbed pregnancies in the course of placental hypoxia.