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Annual Symposium of the Society for the Study of Inborn Errors of Metabolism Birmingham, UK, 4 – 7 September 2012

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Annual Symposium of the Society for the Study of Inborn Errors of Metabolism Birmingham, UK, 4 – 7 September 2012 J Inherit Metab Dis (2012) 35 (Suppl 1):S1–S182 DOI 10.1007/s10545-012-9512-z ABSTRACTS Annual Symposium of the Society for the Study of Inborn Errors of Metabolism Birmingham, UK, 4 – 7 September 2012 This supplement was not sponsored by outside commercial interests. It was funded entirely by the SSIEM. 01. Amino Acids and PKU O-002 NATURAL INHIBITORS OF CARNOSINASE (CN1) O-001 Peters V1 ,AdelmannK2 ,YardB2 , Klingbeil K1 ,SchmittCP1 , Zschocke J3 3-HYDROXYISOBUTYRIC ACID DEHYDROGENASE DEFICIENCY: 1Zentrum für Kinder- und Jugendmedizin de, Heidelberg, Germany IDENTIFICATION OF A NEW INBORN ERROR OF VALINE 2Universitätsklinik, Mannheim, Germany METABOLISM 3Humangenetik, Innsbruck, Austria Wanders RJA1 , Ruiter JPN1 , Loupatty F.1 , Ferdinandusse S.1 , Waterham HR1 , Pasquini E.1 Background: Carnosinase degrades histidine-containing dipeptides 1Div Metab Dis, Univ Child Hosp, Amsterdam, Netherlands such as carnosine and anserine which are known to have several protective functions, especially as antioxidant agents. We recently Background, Objectives: Until now only few patients with an established showed that low carnosinase activities protect from diabetic nephrop- defect in the valine degradation pathway have been identified. Known athy, probably due to higher histidine-dipeptide concentrations. We deficiencies include 3-hydroxyisobutyryl-CoA hydrolase deficiency and now characterized the carnosinase metabolism in children and identi- methylmalonic semialdehyde dehydrogenase (MMSADH) deficiency. On fied natural inhibitors of carnosinase. the other hand many patients with 3-hydroxyisobutyric aciduria have been Results: Whereas serum carnosinase activity and protein concentrations described with a presumed defect in the valine degradation pathway. To correlate in adults, children have lower carnosinase activity although pro- identify the enzymatic and molecular defect in a group of patients with 3- tein concentrations were within the same level as for adults. The difference hydroxyisobutyric aciduria. in activity is caused by different carnosinase isoforms in children and Methods: Case Report: Fibroblasts were collected from several centres adults. Additionally we identified several natural compounds which influ- around the world from patients with 3-hydroxyisobutyric aciduria. The ence carnosinase activity. Carnosine degradation by carnosinase is inhibited patients investigated in this study showed a wide range of clinical signs by the carnosinase substrates anserine and homocarnosine but not by other and symptoms. The only parameter in common was the 3-hydroxyisobuty- histidine-dipeptides (e.g. leucine-histidine). We further measured the influ- ric aciduria. ence of amino acids on carnosinase activity. Whereas glutamine, ornithine, The activity of 3-hydroxyisobutyric acid dehydrogenase was measured as alanine or histidine had no effect on carnosinase activity, homocysteine, described in Loupatty et al. (2006) Mol. Genet. Metab. 87, 243–348). cysteine, methionine, citrulline, lysine and arginine inhibited carnosinase Results: We determined the activity of 3-hydroxyisobutyric acid dehydro- activities significantly, in concentrations found in homocystinuria or urea genase (HIBADH) in a series of patients with 3-hydroxyisobutyric aciduria cycle disorders. and found a full deficiency only in a single patient. Molecular analysis Conclusions: Carnosinase metabolism is highly regulated and controls revealed bona fide mutations in the gene encoding HIBADH. histidinedipeptide concentrations which seem to be important in oxidative Conclusions: We have now identified the first patient with 3-hydroxyisobutyric stress response. The protective function of carnosine and other histidine- acid dehydrogenase deficiency. The defect in the large group of patients with dipeptides and the regulation needs further investigations. 3-hydroxyisobutyric aciduria with normal HIBADH activity remains to establish in the future. S2 J Inherit Metab Dis (2012) 35 (Suppl 1):S1–S182 O-003 O-005 MELATONIN: A NEW BIOMARKER TO REFLECT BRAIN TETRAHYDROBIOPTERIN RESPONSIVENESS IN PKU: SEROTONIN METABOLISM IN PHENYLKETONURIA PREDICTION WITH THE 48-HOUR LOADING TEST AND Yano S1 , Moseley K1 , Azen C2 GENOTYPE 1Genetics, Pediatrics, USC, Los Angeles, United States Anjema K1 , van Rijn M1 , Hofstede FC2 , Bosch AM3 , Hollak CEM3 , 2Clinical & Translational Sci Inst, USC, Los Angeles, United States Rubio-Gozalbo ME4 , de Vries MC5 , Janssen MCH5 , Boelen CCA6 , Blau N7 , Heiner-Fokkema MR1 , van Spronsen FJ1 Background: Early diagnosis by newborn screening and phenylalanine 1Beatrix Child Hosp, Univ Med Center, Groningen, Netherlands (Phe) restriction has been successful in preventing intellectual disability in 2Wilhelmina Child Hosp, Univ Med Center, Utrecht, Netherlands the majority of PKU patients. However, current studies indicate that PKU 3Academic Medical Center, Amsterdam, Netherlands patients who were early diagnosed and maintained good blood Phe control 4Maastricht University Medical Center, Maastricht, Netherlands have lower executive function and a higher prevalence of depressive and 5Radboud Univ Nijmegen Med Center, Nijmegen, Netherlands anxiety disorders possibly due to deficiencies of neurotransmitters includ- 6Leiden University Medical Center, Leiden, Netherlands ing serotonin and dopamine. 7University Children's Hospital, Zürich, Switzerland Patients and Methods: We studied blood and urine melatonin, a serotonin metabolite in PKU patients, in a randomized double blind crossover study Background: It remains unclear how to efficiently diagnose tetrahydro- consisting of three 3-week phases in 10 adult PKU subjects: Phase 1 biopterin (BH4) responsiveness in patients with PKU. We compared the (washout), Phase 2 (supplementation of large neutral amino acid (LNAA) positive predictive value (PPV) of the 48-hour BH4 loading test and tablets or placebo), and Phase 3 (alternate supplementation). Study subjects genotype. stayed overnight to measure night time blood melatonin and urine 6- Methods: PAH deficient patients with ≥30 % phenylalanine reduction at ≥1 sulfatoxymelatonin and dopamine in first void urine specimens. The Phase time point(s) during the 48-hour BH4 loading test (20 mg/kg/day) were 1 protocol was also conducted in 10 control subjects. regarded potential responders and were invited for the BH4 extension Results and Conclusions: This study showed significantly lower concen- phase. True BH4 responsiveness was defined as long-term ≥30 % reduction trations of these neurotransmitter metabolites in PKU subjects compared to in mean phenylalanine concentration or >4 g/day and/or ≥50 % increase of controls in Phase 1, and significant increases with LNAA supplementation natural protein intake. compared to the washout and placebo phases. Urine 6-sulfatoxymelatonin Results: 177/183 patients successfully completed the 48-hour BH4 loading and dopamine may serve as biomarkers reflecting neurotransmitter metab- test. 80/177 were potential responders. 67/80 completed the BH4 extension olism in the brain, thus optimizing metabolic control. phase. 58/67 showed true BH4 responsiveness (PPV 87 %). Genotype was Conflict of Interest declared. complete in 65 % of 177 patients. 39/41 patients with ≥1 mutation associ- ated with long-term BH4 responsiveness in literature showed potential responsiveness. 31/32 participating in the BH4 extension phase showed true BH4 responsiveness (PPV 97 %). PPV of both methods was not O-004 significantly different (P00.16). Conclusions: Genotyping can be performed first. A genotype with ≥1 INHIBITION OF BRAIN PHENYLALANINE (PHE) TRANSPORT mutation associated with BH4 responsiveness is a good predictor for true IN PAHENU2 MICE WITH METHYL-AMINOISOBUTYRATE BH4 responsiveness. For patients with an unclassified or unknown geno- (MAIB): TREATMENT RAMIFICATIONS FOR type, the 48-hour BH4 loading test is a good alternative to detect BH4 PHENYLKETONURIA responsiveness. Vogel KR1 , Wasek BR2 , Arning EA2 , Bottiglieri T2 , Gibson KM1 Conflict of Interest declared. 1Clin Pharmacol, Wash State Univ, Spokane WA, United States 2Inst Metab Dis, Baylor Univ Med Center, Dallas TX, United States We documented the capacity of large neutral amino acid (LNAA) transport inhibitors (DL-norleucine (NL); 2-aminonorbornane (NB)) to lower brain phe in Pahenu2 mice [1], and extend this now to examine the effect of the system A transport inhibitor MAIB on brain phe levels in the same system. Pahenu2 mouse cohorts (mixed gender) were formed and fed an 18 % protein diet supplemented with 3 % MAIB (control, 3 % casein) for three weeks. At sacrifice, LNAAs and monoamine neurotransmitters were quan- tified using UPLC and/or tandem mass spectrometry. MAIB feeding did not alter weight or movement, or enhance morbidity, of subjects. Brain phe (782 +/- 18 (SEM; n05,-MAIB) : 671 +/- 19 (n06, +MAIB; p<0.01, two- tailed t test) and tyrosine (28 +/- 3 (-MAIB) vs. 21 +/- 1.3 (+MAIB; p<0.05) were lowered without alterations of other brain LNAAs. Dopamine and serotonin were unchanged in brain extracts, although turnover and metabolism of both was decreased. These results are the first to document inhibition of LNAA transport in Pahenu2 mice by MAIB. This inhibition, and the milder effects of MAIB in comparison to NL and NB, highlight the potential of MAIB as a therapeutic consideration for PKU. [1] Vogel KR (2012) Molec Genet Metab 105: 359. J Inherit Metab Dis (2012) 35 (Suppl 1):S1–S182 S3 O-006 02. Nutrition, Dietetics and Urea Cycle Defects (1) DISCOVERY OF NOVEL PHARMACOLOGICAL
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