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Zürich, Switzerland

Morell B.K.,Kantonsspital Munsterlingen | Teichler J.,Kinderspital Zurich | Budak K.,Universitatsspital Zurich | Vollenweider J.,Alleestrasse 20 | Pavlicek V.,Klosterhofstrasse 1
BMJ Case Reports | Year: 2010

We report the case of a young man with a history of attention deficit/hyperactivity disorder and mild cognitive impairment who presented with chronic fatigue, anorexia and progressive darkening of the skin. On laboratory testing, severely depressed concentrations of morning cortisol, along with highly elevated values of adrenocorticotropic hormone (ACTH) revealed primary adrenal insufficiency as the primary cause of the patient's symptomatology. Imaging of the brain showed altered signal intensities in the parieto-occipital regions of the brain. The demonstration of increased very long chain fatty acids (VLCFA) established the diagnosis of adolescent X-linked adrenoleukodystrophy (X-ALD). Presenting at an advanced yet slowly progressive stage the patient was not a suitable candidate for haematopoietic stem cell transplantation (HSCT), and treatment focused on hormone replacement therapy, family counselling and supportive care. On follow-up visits within the following year, fatigue had diminished and there was no evidence of progressive neurological deficits. However, exacerbation of the psychiatric symptomatology resulted in admittance to a psychiatric ward. Source


Bertram H.,Hannover Medical School | Emmel M.,Universitatsklinik Cologne | Ewert P.,Deutsches Herzzentrum Berlin | Grohmann J.,Albert Ludwigs University of Freiburg | And 7 more authors.
Journal of Interventional Cardiology | Year: 2015

Objective To assess feasibility, safety and effectiveness of right ventricular outflow tract (RVOT) stenting in symptomatic young infants. Methods Multicentre evaluation of 35 patients intended to undergo RVOT stenting in 11 pediatric cardiac centres from 2009 to August 2011. Results Median age and weight at the time of first stent implantation were 8 weeks and 3.3 kg, with 40% of patients <3 kg. 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. Conclusions 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. © 2015, Wiley Periodicals, Inc. Source


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. Source


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. Source


Haack T.B.,Helmholtz Center Munich | Haack T.B.,TU Munich | Haberberger B.,Helmholtz Center Munich | Haberberger B.,TU Munich | And 29 more authors.
Journal of Medical Genetics | Year: 2012

Background Next generation sequencing has become the core technology for gene discovery in rare inherited disorders. However, the interpretation of the numerous sequence variants identified remains challenging. We assessed the application of exome sequencing for diagnostics in complex I deficiency, a disease with vast genetic heterogeneity. Methods Ten unrelated individuals with complex I deficiency were selected for exome sequencing and sequential bioinformatic filtering. Cellular rescue experiments were performed to verify pathogenicity of novel disease alleles. Results The first filter criterion was 'Presence of known pathogenic complex I deficiency variants'. This revealed homozygous mutations in NDUFS3 and ACAD9 in two individuals. A second criterion was 'Presence of two novel potentially pathogenic variants in a structural gene of complex I', which discovered rare variants in NDUFS8 in two unrelated individuals and in NDUFB3 in a third. Expression of wild-type cDNA in mutant cell lines rescued complex I activity and assembly, thus providing a functional validation of their pathogenicity. Using the third criterion 'Presence of two potentially pathogenic variants in a gene encoding a mitochondrial protein', loss-of-function mutations in MTFMT were discovered in two patients. In three patients the molecular genetic correlate remained unclear and follow-up analysis is ongoing. Conclusion Appropriate in silico filtering of exome sequencing data, coupled with functional validation of new disease alleles, is effective in rapidly identifying disease-causative variants in known and new complex I associated disease genes. Source

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