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SSIEM 2014 Annual Symposium: Abstracts Innsbruck, Austria, 2–5 September 2014

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SSIEM 2014 Annual Symposium: Abstracts Innsbruck, Austria, 2–5 September 2014 J Inherit Metab Dis (2014) 37 (Suppl 1):S27–S185 DOI 10.1007/s10545-014-9740-5 ABSTRACTS SSIEM 2014 Annual Symposium: Abstracts Innsbruck, Austria, 2–5 September 2014 This supplement was not sponsored by outside commercial interests. It O-002 was funded entirely by the SSIEM. Delineation of new IEM phenotypes via an integrated - omics approach Van Karnebeek C12, Tarailo M24, Horvath G12, Salvarinova R12, 01. Inborn errors of metabolism: general, adult Demos M23,LewisS4,RossC12, Stockler S12, Wasserman W W24 1 2 O-001 Div Biochem Dis, BC Child Hosp, UBC, Vancouver, Canada, TIDE- BC, Centre Molec Med Therap, Vancouver, Canada, 3Div Ped Neurol, BC Children's Hosp, UBC, Vancouver, Canada, 4Dept Med Genet, UBC, Suitability of nitisinone in alkaptonuria - a dose response study Vancouver, Canada Ranganath L1, Milan A M1, Hughes A T1, Dutton J J1, Fitzgerald R1, Briggs M1,BygottH1, Psarelli E E2,CoxT2, Gallagher J A2,JarvisJC2, Introduction: Genomic sequencing provides the exciting opportunity to Van Kan C 3, Hall A K3, Laan D3, Olsson B4,SzamosiJ4, Rudebeck M4, further delineate the clinical and biochemical spectrum of known inborn Kullenberg T4, Cronlund A4, Svensson L4, Junestrand C4, Ayoob H5, errors of metabolism, and to identify the etiology of IEM-mimics. Timmis O 5, Sireau N 5,LeQuanSangKH6, Genovese F 7, Braconi D8, Methods: As part of our TIDEX discovery study, 15 carefully character- Santucci A8, Nemethova M9, Zatkova A9, Imrich R10,RovenskyJ10 ized patients in 13 families with unexplained biochemical/mitochondrial phenotypes were selected according to our TIDEX criteria for whole 1Royal Liverpool University Hospital, Liverpool, United Kingdom, 2Uni- exome sequencing. Trio data were analyzed via our customized pipeline; versity of Liverpool, Liverpool, United Kingdom, 3PSR Group, Amster- candidate genes with rare, damage variants following Mendelian pattern dam, Netherlands, 4Swedish Orphan Biovitrum (SOBI), Stockholm, of inheritance validated via Sanger validation +/− in vitro studies. Sweden, 5AKU Society Ltd, Cambridge, United Kingdom, 6Hopital Results: Aside 7 novel genes, 6 novel phenotypes of recently discovered Necker, Paris, France, 7Nordic Biocsciences, Copenhagen, Denmark, human diseases were discovered: low HVA and 5-HIAA in SCN2A 8University of Siena, Siena, Italy, 9Instit Mol Physiol Genet,Slov Acad epileptic encephalopathy (dopamine/OH-tryptophan responsive); intermit- Sci, Bratislava, Slovakia, 10National Institute of Rheumatic Diseases, tent metabolic crises with status dystonicus, and respiratory chain complex Pieštany, Slovakia III deficiency in UQCRC2; renal failure, hearing loss, complex I & IV deficiency in RMND1; neonatal hypotonia with mitochondrial complex Background: Homogentisate-lowering therapy was investigated for I,II,IV deficiency in SCN4A; cortical neurodegeneration with infantile alkaptonuria (AKU). Nitisinone decreases homogentisic acid onset in AIMP1; atypical demyelination pattern in PLP1; myoclonic epi- (HGA) but the dose–response relationship has not been previously lepsy, retinitis pigmentosa, hearing loss, complex IV deficiency in PIGA. studied. Discussion: A combined phenomics-genomics approach identified novel Methods: SONIA 1 was an international, multicenter, randomized, phenotypes in 45 % of families studied (including respiratory chain open-label, no-treatment controlled, parallel-group, dose–response enzyme deficiencies secondary to non-mitochondrial gene defects) with study. The objective was to investigate the effect of different doses identification of 1 immediate treatment target. of once daily nitisinone on 24-h urinary HGA excretion (u-HGA24) in patients with AKU after 4 weeks of treatment. Forty patients were randomized to either no treatment, or 1, 2, 4 or 8 mg of nitisinone (8 per group). 02. Novel diagnostic/laboratory methods Findings: Nitisinone and u-HGA24 showed a clear dose–response. At 4 weeks, the adjusted mean u-HGA24 was 31152, 3846, 1668, 686 and O-003 327 mmol for the 0, 1, 2, 4 and 8 mg doses, respectively. The 8 mg daily dose, decreased mean u-HGA by 99.4 % compared to baseline. 24 Rapid quantification of underivatized amino acids in plasma Serum HGA was below limit of detection. Increased serum tyrosine by hydrophilic interaction chromatography (HILIC) coupled levels were seen at all doses to at least 10 times baseline values. No with tandem mass-spectrometry serious or severe adverse events were reported over the 4 weeks of nitisinone therapy. Prinsen H C M1, Schiebergen B G M1, Roeleveld M W1,JansJJM1,De Conclusion: In SONIA 1, nitisinone therapy significantly decreased u- Sain-van der Velden M G M1,VisserG2,Verhoeven-DuifNM1 HGA24 in a dose-dependent manner and was well tolerated within the studied dose range in AKU patients. 1Dept Med Genet, Metab Dis, UMC Utrecht, Utrecht, Netherlands, 2Dept Conflict of Interest declared. Metab Dis, UMC Utrecht, Utrecht, Netherlands S28 J Inherit Metab Dis (2014) 37 (Suppl 1):S27–S185 Background: Aminoacidopathies are a class of inborn errors of metabo- samples when the relevant marker metabolite is not available. The advan- lism (IEM) that can be diagnosed by analysis of amino acids (AA) in tages of UMSMS are exemplified by prospective diagnoses of disorders plasma. Current strategies for AA analysis include post-column such as cerebrotendinous xanthomatosis, creatine transporter defect, infan- ninhydrine derivatization or the use of perfluorinated acid such as ion- tile sialuria and deficiencies of steroid 21 hydroxylase (late onset), pairing agents. Major drawbacks are time-consuming procedures, costs, antiquitin, purine nucleoside phosphorylase, adenylosuccinase, GAMT problems with retentions and MS-sensitivity. Here we report a method for and FBP’ase. Early treatment of several of the above disorders was a analysis of 24 underivatized AA in plasma to detect defects in AA significant benefit. Most of these disorders were not suspected by referring metabolism. The presented method is adapted from Guo and co-workers clinicians and would not have been diagnosed during their work-up unless (J Agric Food Chem;61:2709–2719; 2013), who analyzed AA in fruit. UMSMS had been used. A rapid (~30 min) UMSMS modification has also Methods: A rapid, sensitive and specific method was developed for the been developed for the diagnosis of acutely presenting IEMs. analysis of AA in plasma without derivatization using hydrophilic interaction chromatography (HILIC) coupled with tandem mass-spectrometry (Xevo, O-006 Waters). Results: Excellent separation of 24 AA in plasma was achieved on an Acquity BEH Amide column (2.1 mm x 100 mm, 1.7 μm) in a single MS Hepatocyte transfection of naked DNA by hydrodynamic intraportal run of 12 min. Plasma samples of patients with a known IEM in AA injection in domestic pigs metabolism were analysed and patients were identified. The method was validated according to ISO-15189 accreditation for medical laboratories. Häberle J12,StollerF12,SchlegelA3, Viecelli H M12, Rüfenacht V12, Conclusion: The reported method is rapid, sensitive and specific and is Cesarovic N4,SidlerX5,DutkowskiP3,GrafR3, Thöny B12 applicable to study defects in AA metabolism in plasma. 1Div Metab Dis, Univ Child Hosp, Zurich, Switzerland, 2Child Res Cen, 3 O-004 Zurich, Switzerland, Lab Swiss HPB and Transpl, Univ Zurich, Zurich, Switzerland, 4Div Surg Res, Univ Hosp Zurich, Zurich, Switzerland, 5Vetsuisse Faculty, Univ Zurich, Zurich, Switzerland Zebrafish as a disease model for inborn errors of metabolism TuschlKKT12, Valdivia L E2, Clayton P T1, Wilson S W2,MillsPB1 Background: Liver is an attractive organ for gene delivery in order to correct several different genetic (metabolic) diseases. Hydrodynamic vein 1UCL Institute of Child Health, London, United Kingdom, 2Cell and injection of naked DNA/minicircles devoid of viral backbones was dem- Developmental Biology, UCL, London, United Kingdom onstrated (e.g. in murine PKU) to allow effective transduction of liver cells. We challenge here the hypothesis that successful hydrodynamic Background/Objectives: Next generation sequencing is increasingly pro- injection in mice via the tail vein can be adapted to portal vein injections viding candidate genes associated with human disease. Hence, it is imper- in newborn pigs after weaning. ative to uncover the role of these genes to understand disease pathogenesis. Materials and Methods: A surgical method allowing direct hydrodynamic We have chosen zebrafish to study inborn errors of metabolism with the portal vein injections of naked DNA in small pigs with long-term survival aim of using this experimentally tractable model organism to shed light on of the animals was developed. Efficiency at 10 and 28 days after portal disease mechanisms and provide a route for drug discovery. vein injections of naked DNA was evaluated by PCR in liver biopsies of Methods/Results: State of the art genome editing technologies such as sacrificed pigs. TALENs and the CRISPR/Cas system were used to target highly con- Results: Surgical procedure and intraportal hydrodynamic injectionsof served regions within zebrafish genes that are orthologues of human minicircles with portal vein pressure up to 90 mmHg were well tolerated disease genes. RNAs were injected into one cell stage embryos and the by newborn pigs (n=5) after weaning. PCR analysis showed that 25 % of rate of mutagenesis assessed using High Resolution Melting Analysis. liver samples were PCR-positive four weeks after the intervention. Heterozygous carriers from the F1 generation were selected
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