Zürich, Switzerland
Zürich, Switzerland

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PubMed | Northern General Hospital, Alderhey Childrens Hospital, Semmelweis University, Klinikum am Steinenberg and 56 more.
Type: Journal Article | Journal: Molecular genetics and metabolism | Year: 2015

There appears little consensus concerning protein requirements in phenylketonuria (PKU).A questionnaire completed by 63 European and Turkish IMD centres from 18 countries collected data on prescribed total protein intake (natural/intact protein and phenylalanine-free protein substitute [PS]) by age, administration frequency and method, monitoring, and type of protein substitute. Data were analysed by European region using descriptive statistics.The amount of total protein (from PS and natural/intact protein) varied according to the European region. Higher median amounts of total protein were prescribed in infants and children in Northern Europe (n=24 centres) (infants <1 year, >2-3g/kg/day; 1-3 years of age, >2-3 g/kg/day; 4-10 years of age, >1.5-2.5 g/kg/day) and Southern Europe (n=10 centres) (infants <1 year, 2.5 g/kg/day, 1-3 years of age, 2 g/kg/day; 4-10 years of age, 1.5-2 g/kg/day), than by Eastern Europe (n=4 centres) (infants <1 year, 2.5 g/kg/day, 1-3 years of age, >2-2.5 g/kg/day; 4-10 years of age, >1.5-2 g/kg/day) and with Western Europe (n=25 centres) giving the least (infants <1 year, >2-2.5 g/kg/day, 1-3 years of age, 1.5-2 g/kg/day; 4-10 years of age, 1-1.5 g/kg/day). Total protein prescription was similar in patients aged >10 years (1-1.5 g/kg/day) and maternal patients (1-1.5 g/kg/day).The amounts of total protein prescribed varied between European countries and appeared to be influenced by geographical region. In PKU, all gave higher than the recommended 2007 WHO/FAO/UNU safe levels of protein intake for the general population.

Haack T.B.,Helmholtz Center Munich | Haack T.B.,TU Munich | Gorza M.,Helmholtz Center Munich | Danhauser K.,Helmholtz Center Munich | And 28 more authors.
Molecular Genetics and Metabolism | Year: 2014

Defects of mitochondrial oxidative phosphorylation (OXPHOS) are associated with a wide range of clinical phenotypes and time courses. Combined OXPHOS deficiencies are mainly caused by mutations of nuclear genes that are involved in mitochondrial protein translation. Due to their genetic heterogeneity it is almost impossible to diagnose OXPHOS patients on clinical grounds alone. Hence next generation sequencing (NGS) provides a distinct advantage over candidate gene sequencing to discover the underlying genetic defect in a timely manner. One recent example is the identification of mutations in MTFMT that impair mitochondrial protein translation through decreased formylation of Met-tRNAMet.Here we report the results of a combined exome sequencing and candidate gene screening study. We identified nine additional MTFMT patients from eight families who were affected with Leigh encephalopathy or white matter disease, microcephaly, mental retardation, ataxia, and muscular hypotonia. In four patients, the causal mutations were identified by exome sequencing followed by stringent bioinformatic filtering. In one index case, exome sequencing identified a single heterozygous mutation leading to Sanger sequencing which identified a second mutation in the non-covered first exon. High-resolution melting curve-based MTFMT screening in 350 OXPHPOS patients identified pathogenic mutations in another three index cases. Mutations in one of them were not covered by previous exome sequencing.All novel mutations predict a loss-of-function or result in a severe decrease in MTFMT protein in patients' fibroblasts accompanied by reduced steady-state levels of complex I and IV subunits. Being present in 11 out of 13 index cases the c.626C. >. T mutation is one of the most frequent disease alleles underlying OXPHOS disorders. We provide detailed clinical descriptions on eleven MTFMT patients and review five previously reported cases. © 2013 Elsevier Inc.

PubMed | Universitares Herzzentrum Hamburg, Albert Ludwigs University of Freiburg, Medizinische Hochschule Hanover, Universitatsklinik Giessen and 7 more.
Type: Journal Article | Journal: Journal of interventional cardiology | Year: 2015

To assess feasibility, safety and effectiveness of right ventricular outflow tract (RVOT) stenting in symptomatic young infants.Multicentre evaluation of 35 patients intended to undergo RVOT stenting in 11 pediatric cardiac centres from 2009 to August 2011.Median age and weight at the time of first stent implantation were 8 weeks and 3.3kg, with 40% of patients <3kg. A total of 19 patients had suffered from hypoxemic spells, 8 patients were ventilated, 6 on inotropic support and 5 on prostaglandin infusion. Severe concomitant malformations were present in 11 patients, and acute infections in 2. Stenting of the RVOT was successfully performed in 33 patients, improving oxygen saturation from a median of 77 to 90% 2 days after intervention. Besides the 2 patients in whom RVOT stenting was not successful for technical reasons, there were no procedural complications. In 17 of 33 patients, 1-3 reinterventions were performed during follow-up, less than half of those were reinterventions in the RVOT. A total of 27 patients have undergone successful surgical repair 4-162 (median 19.5) weeks after initial RVOT stent implantation, 2 patients are still waiting. There were no perioperative deaths.Stenting of the RVOT provides a safe and effective management strategy for initial palliation in symptomatic young infants, including those patients not suitable or at higher risk for surgical therapy.

Faghfoury H.,University of Toronto | Faghfoury H.,Genomic Health | Baruteau J.,Robert Debre Hospital | Ogier de Baulny H.,University Children Hospital | And 2 more authors.
Molecular Genetics and Metabolism | Year: 2011

Citrullinemia type I (CTLN1) is a urea cycle disorder which typically presents in the neonatal period or infancy with hyperammonemia and concurrent neurologic deterioration. We report a 15-month-old female with CTLN1 who presented with encephalopathy and seizures with hyperammonemia requiring emergency treatment. Although there was a rapid resolution of her hyperammonemia, she developed fulminant liver failure. The severe increase of transaminases (aspartate aminotransferase and alanine aminotransferase levels peaking at 19,794. UI/L and 19,938. UI/L, respectively) and concurrent disturbances in her hepatic synthetic functions led to the consideration of a liver transplantation. However, there was a normalization of her liver function tests over the course of weeks with supportive therapy alone. Molecular analysis of the ASS1 gene confirmed the diagnosis of CTLN1 by revealing the known mutation c.1087. C > T (p.R363W) on the paternal allele and an intronic nucleotide exchange leading to an insertion of 69. bp on the transcript resulting in a frameshift and premature stop of translation on the maternal allele. We also briefly report another case of CTLN1 where liver failure was a prominent feature of the presentation. Fulminant liver failure has been described with a variety of other urea cycle disorders, but has been described in infantile onset presentation of CTLN1 in only two other cases recently. Our observation suggests that in some cases of CTLN1 with acute liver failure, emergency intervention such as transplantation is not warranted despite evidence of severe hepatotoxicity. © 2011 Elsevier B.V.

Gasser T.,University of Zürich | Molinari L.,Kinderspital Zurich | Largo R.,Kinderspital Zurich
Annals of Human Biology | Year: 2013

Background: Growth and pubertal development have each been studied in detail, but rarely in conjunction. Aim: The study aim was to determine what somatic and pubertal development have in common and how they differ and to quantify the association between milestones for growth and for pubertal development (in terms of pubic hair and genitalia/breast, Age of Peak Testes Velocity, APTV and menarche) in relation both to chronological (CA) and bone age (RUS). Subjects and methods: The data analysed are from the 1st Zurich Longitudinal Growth Study, with 120 boys and 112 girls with almost complete data from birth to adulthood. Results: Variability of pubertal milestones was somewhat reduced in terms of RUS, in particular in later phases. Pubic hair phase PH2 appeared ∼1 year after the onset of the pubertal spurt. Around the age of maximal deceleration (T9) an adult-like appearance of pubic hair, genitalia and breasts was reached in most cases. APTV occurred close to T8. Correlations were large between milestones for growth and PH stages and also with menarche or APTV. Conclusions: A successful modelling of testis growth led to a new pubertal milestone, APTV. The high correlations between the phenomenologically different domains "linear growth" and "pubertal development", and the high correlations between RUS and linear growth previously established allow the conclusion that these different domains develop along similar biological mechanisms, which are steered mainly by genetic factors. © 2013 Informa UK Ltd.

Molinari L.,Kinderspital Zurich | Gasser T.,University of Zürich | Largo R.,Kinderspital Zurich
Annals of Human Biology | Year: 2013

Background: Somatic and bone development have each been studied in detail, but rarely in conjunction. Aim: The aim of this study was to determine what somatic and bone development have in common and how they differ. A second aim was to check for a pubertal spurt in bone age (BA) and to quantify it in a similar way as has been done for height. The Preece-Baines model is used to fit longitudinal data for BA. Subjects and methods: The data analysed are from the 1st Zurich Longitudinal Growth Study comprising 120 boys and 112 girls with almost complete data from birth to adulthood. Results: Variability of somatic milestones was reduced in terms of BA and there was an aftergrowth after reaching adult RUS score 1000. A strong increase in the RUS score was seen at a late stage of the pubertal spurt (PS). Somatic milestones correlated with the RUS score attained at these ages and more so at an early stage of the PS. A PS for BA was clearly identified with a location at 14.2 years for boys and 12.2 years for girls. Age of peak bone development correlated highly with age of peak velocity of somatic variables. Conclusions: BA can be successfully modelled as a semi-quantitative entity. Bone development shows marked associations with somatic development, despite the fact that the latter reflects changes in size, while the former is essentially a maturity index and reflects changes in biochemical composition of tissues. © 2013 Informa UK Ltd.

Engel K.,Universitatsklinikum Munster | Vuissoz J.-M.,Clinique de Pediatrie | Vuissoz J.-M.,University of Bern | Eggimann S.,University of Bern | And 12 more authors.
Journal of Inherited Metabolic Disease | Year: 2012

Background The urea cycle defect argininosuccinate lyase (ASL) deficiency has a large spectrum of presentations from highly severe to asymptomatic. Enzyme activity assays in red blood cells or fibroblasts, although diagnostic of the deficiency, fail to discriminate between severe, mild or asymptomatic cases. Mutation/phenotype correlation studies are needed to characterize the effects of individual mutations on the activity of the enzyme. Methods Bacterial in-vitro expression studies allowed the enzyme analysis of purified mutant ASL proteins p.I100T (c.299 T>C), p.V178M (c.532 G>A), p.E189G (c.566A> G), p.Q286R (c.857A>G), p.K315E (c.943A>G), p.R379C (c.1135 C>T) and p.R385C (c.1153 C>T) in comparison to the wildtype protein. Results In the bacterial in-vitro expression system, ASL wild-type protein was successfully expressed. The known classical p.Q286R, the novel classical p.K315E and the known mutations p.I100T, p.E189G and p.R385C, which all have been linked to a mild phenotype, showed no significant residual activity. There was some enzyme activity detected with the p.V178M (5 % of wild-type) and p.R379C (10 % of wild-type) mutations in which Km values for argininosuccinic acid differed significantly from the wild-type ASL protein. © SSIEM and Springer 2011.

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