4 Level 3 Case report Variable clinical and biochemical presentation of OTCD in one family

Transcription

1 Type of Results reported Comment Adams S et al, 2010 presentation of the current dietary management of UCD na Level 4 Expert presentation of the current practice of dietary management of UCD in the UK Abstract from a conference presentation in the UK Aebi H, 1976 enzyme studies of the urea cycle under varying dietary na Level 4 Expert, Description of UCD enzyme studies in the pre-genetic era conditions book chapter Ah Mew N et al, 2010 to test whether carbamylglutamate increases function of 3 Level 3 Case reports 3-day trial of oral CG increases ureagenesis and decreases plasma ammonia in 3 CPS1 Abstract from a conference presentation Ahrens M et al, 2001 to find a consensus on the management of UCD in the US na Level 4 Expert Comprehensive summary of recommendations on the management of UCD Study reports only US experience Ahrens MJ et al, 1996 to report on the heterogeneity of OTC in OTC females 13 Level 3 Case series report Higher than expected rate of clinical and biochemical abnormalities in this series of OTC females Al-Hassnan ZN et al, description of stroke in with HHH syndrome 3 Level 3 Case reports work presents a yet unreported CNS involvement pattern in HHH syndrome not yet reported finding Alonso EM et al, 2003 to determine the functional status and HRQOL in children 55 Level 2- Case control Children who have survived LT have functional outcomes in the physical domain that are lower published normal population served as control after liver transplantation than those of normal children Anderson JM & Brodsky To report an unusual clinical finding in OTC 1 Level 3 Case report isolated cortical visual loss was reported in a patient with OTCD not yet reported finding MC, 2010 Ash DE et al, 1998 To describe the molecular basis of hyperargininemia na Level 4 Expert Mutations identified in hyperargininemia affect the structure and function of the enzyme Ausems MG et al, 1997 Bachmann C, 2003c Bachmann C, 2003b To describe asymptomatic and late-onset OTC in a four-generation family 4 Level 3 Case report Variable clinical and biochemical presentation of OTCD in one family to compare conservative longterm management using 88 Level 2- Case control initial plasma ammonia levels > 300, peak > 480 umol/l do not result in normal outcome protein restriction versus protein restriction combined with drugs to question the role of NBS for UCDs in the light of na Level 3 Case series report 56% of UCD pts. were symptomatic within 4 days of age, thus NBS comes too late for prevention classical Wilson & Jung criteria & Review of irreversible damage large cohort, retrospective, questionnaire, high variation of treatment modalities raises the important question, suggests to first think an then introduce an available method, retrospective, in part historical cohort Bachmann C et al, 1982 to report the clinical and laboratory findings in a patient 1 Level 3 Case report and this report describes in more detail the findings in the first known NAGS patient with NAGS review Bachmann C, 1992 To describe the current knowledge on OTCD na Level 4 Expert increased lethal outcome in OCT-deficient between 12 and 15 years of age Bachmann C, 2002 to review the mechanisms of hyperammonemia na Level 4 Expert Nice overview on all currently discussed pathyphysiological models of the effect of hypermmonemia in the acute and chronic state Bachmann C, 2003a Review on inherited hyperammonemias na Level 4 Book chapter Description of pathophysiology, biochemistry and diagnostic strategies for inherited hyperammonemic conditions Bachmann C, 2006 Review on current management of hyperammonemia na Level 4 Expert, Overview on the current treatment strategies mainly due to UCDs book chapter Bachmann C, 2008 to highlight the role of compartmentation in interpretation of plasma amino acids na Level 4 Expert comprehensive review of the role of compartmentation when plasma amino acids have to be interpreted Bachmann C & Colombo JP, 1988 To report on the acid-base status in with hereditary UCDs before treatment 51 Level 2- Cohort Acidosis as well as alkalosis were found in UCD ; acid-base status is of no use in the differential diagnosis of with hyperammonemia Ballard RA et al, 1978 to describe and discuss transient hyperammonemia of preterm infants 5 Level 3 Case reports different outcome with 4 survivors and 1 fatal, normal UC enzyme analysis in 3 highlights a new entity of unknown etiology Barsotti RJ, 2001 Description of all aspects of the measurement of ammonia na Level 4 Expert Nice overview on preanalytical problems of ammonia measurement and methodological aspects in blood of ammonia determination Batshaw ML et al, 2001 Safety and efficacy of PA, PB and benzoate na Level 4 Review PB/benzoate decrease mortality/morbidity from UCDs, report on overdosage in single cases, differences newborn/children nice and very competent review, review of current practice, but no controlled studies available Baumgartner MR et al, 2005 Belanger-Quintana A et al, 2003 Berning C et al, 2008 Berry GT & Steiner RD, 2001 To describe delta1-pyrroline-5-carboxylate synthase as differential diagnosis of UCDs 1 Level 3 Case report extensive clinical, biochemical and molecular geentic studies in a single family with P5CS novel disease to report on hyperammonaemia as a cause of psychosis in 1 Level 3 Case report description of a rare complication of UCDs in an adolescent an adolescent development of a bacterial expression system for ASS na Level 3 Case series report with mild citrullinemia need a lifelong awareness for their disorder mainly To provide an overview on the long-term treatment of na Level 4 Review treatment must be tailored for each individual nice overview, also for monitoring, "just" an expert with UCDs, focussed on US practice (benzoate not part of recommendations)

2 Bosch AM et al, 2004 Bourdeaux C et al, 2007 Braissant O, 2010 Braissant O et al, 2002 Brosnan JT & Brosnan ME, 2010 Brown GW & Cohen PP, 1959 investigates galactosemia patient's HRQUOL and cognitive performance 63 Level 3 prospective, non randomised, non controlled 235 Level 2- multivariate analysis Type of Results reported Comment HRQUOL and cognitive outcome are impaired, assessment allows focused individualized interventions Lto living-related versus deceased donor pediatric liver transplantation for UCDs LT with LD provided similar patient and graft outcome, when compared to DD; higher rate of artery thrombosis and a lower rate of rejection were observed in group DD to discuss current concepts in the pathogenesis of urea na Level 4 Expert nice, comprehensive overview on the current concepts cycle disorders To describe ammonium-induced impairment of axonal na Level 4 Experimental The ammonium-induced impairment of axonal growth is prevented through glial creatine growth To review the creatine metabolism and the urea cycle na Level 4 Expert with urea cycle disorders also have altered creatine metabolism to describe methods for the quantitative assay of urea cycle enzymes in liver na Level 4 Expert & first report on enzymatics for UC enzymes Brumm VL et al, 2010 review on psychiatric problems in PKU na Level 4 review, expert more research on the issue required recommendations Brunetti-Pierri N et al, 2008 Brusilow S & Horwich A, 2001 to report the phenotypic correction of OTC using low dose helper-dependent adenoviral vectors na Level 4 Expert & Textbook chapter na Level 4 Textbook chapter The standard textbook chapter the vectors used in the present will likely permit application for the treatment of OTC reporting exclusively lab findings; possibly basic work for later clinical application Brusilow SW 1984 The role of arginine for pts. with UCDs; no controls 4 Level 3 Case series report arginine is an indispensable amino acid for children with inborn errors of ureagenesis convinicing design, clear result of utmost importance, homogeneuos age group, no controls, small number, 4 disorders Brusilow SW & Maestri Overview na Level 4 Review general overview on UCD management very nice overview on UCD in general Brusilow SW, 1991 to the role of phenylacetylglutamine for waste nitrogen excretion 16 Level 2- Case series report PAG may replace urea as waste nitrogen product; high doses result in normal glutamine levels Brusilow SW & Batshaw Description of arginine therapy for argininosuccinase 2 Level 3 Case reports Arginine supplementation may be effective therapy for argininosuccinase M, 1979 Bucuvalas JC et al, 2003 single-center cross-sectional of 77 pediatric liver transplantation recipients 77 Level 2- Cohort HRQOL in pediatric liver transplant recipients was lower than that reported for healthy children but similar to that for children with other chronic illness Burlina AB et al, 2001 Safety and efficacy of PB in OTCD; no control 9 Level 3 Case series report use of phenylbutyrate in with OTC is safe very early report, heterogeneous group, small number, no cognitive, retrospective Burlina AB, 2004 Review on hepatocyte transplantation for inborn errors of metabolism na Level 4 Expert use of isolated hepatocytes might offer a unique opportunity for treating inborn errors of metabolism and should be evaluated in studies Burlina AB et al, 1992 to determine normal values for the allopurinol test 6 Level 2- Case-control normal values were established; the allopurinol test may help in diagnosis of OTC females Burton BK 1998 Differential diagnosis of IEM; a chapter is dedicated to hyperammonemia na Level 4 Review discussion of differential diagnosis of IEM including hyperammonemia Most causes of hyperammonemia encountered in emergency situations are cited, not exhaustive, some causes of chronic hyerammonemia are missing Busuttil AA et al, 1998 Liver transplantation OTCD 3 Level 3 Case series report Successful OLT Well defined indication and outcome measures Caldovic L et al, 2004 to the restoration of ureagenesis in NAGS by N-carbamylglutamate to report on null mutations in the N-acetylglutamate synthase gene to report late onset N-acetylglutamate synthase caused by hypomorphic alleles 1 Level 3 Case report incorporation of an isotopic label from ammonium chloride into urea was markedly reduced before treatment with N-carbamyl-L-glutamate and completely normalized following treatment Caldovic L et al, Level 3 Case reports The finding of deleterious mutations in the NAGS gene confirms the genetic origin of NAGS Caldovic L et al, Level 3 Case reports Studies of the purified recombinant mutant proteins revealed deleterious effects on NAGS affinity for substrates, and on the rate of catalysis Caldovic L et al, 2007 update on NAGS gene mutations na Level 4 Expert comprehensive description of mutations and polymorphisms in the NAGS gene Campeau PM et al, 2010 Early orthotopic liver transplantation in UCDs: Follow up of a combination of early liver transplantation, aggressive metabolic management and early a developmental outcome childhood intervention improve the neurologic outcome of children with UCDs Cavicchi C et al, 2009 Role of low citrulline in NBS for early detection of OTCD pts.; controls 5 Level 3 Case series report, prospective developmental 6 Level 3 Case control Hypocitrullinemia is not a reliable marker for newborn screening of OTCD, hypocitrullinemia can indicate OTC with a low FP rate (0,003%) thorough analysis of NBS data, false-negatives remain unknown

3 Type of Results reported Comment Cederbaum JA et al, 2001 questionnaire sent out to UCD families 180 Level 3 uncontrolled questionnaire parents worry mostly on financial / insurance issues and lack of knowledge in emergency hospitals Cederbaum SD et al, to report on the treatment of hyperargininaemia due to 2 Level 3 Case reports diet improved biochemical and clinical situation 1982 arginase with a chemically defined diet Chadefaux-Vekemans B et al, 2002 improving prenatal diagnosis by using ratio; 74 controls 87 Level 2+ Case control citrulline/ornithine + arginine ratio is better than citrulline level alone new method Choi CG & Yoo HW, 2001 Study of localized proton MR spectroscopy in infants with urea cycle defect 2 Level 3 Case reports Proton MRS provided useful information for the diagnosis and understanding of the pathophysiology of urea cycle enzyme defect Choi JH et al, 2006 cases of citrullinemia presenting with stroke 2 Level 3 Case reports UCDs should be included in the differential diagnosis of unexplained stroke during infancy and childhood Christodoulou J et al, Report on OTC presenting with strokelike 1 Level 3 Case report novel observation of recurrent strokelike episodes in a heterozygous OTC-deficient girl novel finding in OTCD 1993 episodes Clay AS & Hainline BE, 2007 Differential diagnosis of hyperammonemia in adults na Level 4 Review differential diagnosis for hyperammonemia including non metabolic causes quite complete for differential diagnosis of hyperammonemia in the acute phase, citrullinemia type I wrong defined, single mistakes in biochemical Colombo JP et al, 1982 Colombo JP & Richterich R, 1968 Comte B et al, 2002 Description of a novel enzyme assay for NAGS in human liver Study on urea cycle enzymes in the developing human fetus report on the identification of phenylbutyrylglutamine, a new metabolite of phenylbutyrate metabolism in humans na Level 3 Expert & na Level 3 Expert & na Level 3 Expert & Description of a novel enzyme assay for the rare NAGS Basic scientific describing liver urea cycle enzymes After administration of PBA to normal humans, the cumulative urinary excretion of phenylacetate, PBA, phenylacetylglutamine and phenylbutyrylglutamine amounts to about half of the dose of PBA Connelly A et al, 1993 report on MRS showing increased brain glutamine in OTC 2 Level 3 Case reports intracerebral accumulation of glutamine contributes to the encephalopathy associated with hyperammonemia Cowley DM et al, 1998 Caes report on adult-onset arginase 1 Level 3 Case report First reported case of adult-onset disease resulting from hyperargininaemia and arginase Crombez EA & Cederbaum SD, 2005 article summarizes the clinical course of selected with arginase diagnosis and 5 Level 4 Expert With adherence to the dietary and drug regimen, a favorable outcome can be expected, with cessation of further neurological deterioration and in some instances, of improvement Das AM et al, 2009 to the efficacy of prenatal benzoate treatment in 2 fetuses with citrullinemia and OTC 2 Level 3 Case reports Benzoate infusion of the mother shortly before birth is safe and results in therapeutic levels of benzoate in umbilical cord blood de Groot MJ et al, 2011 to report the metabolic investigations in two young children 2 Level 3 Case reports acute liver failure can be caused by ASS and other UCDs; thus metabolic with citrullinemia type I that could prevent liver investigations are mandatory in ALF and might safe from liver transplantation de Keijzer MH et al, 1997 to the effect of dilution of capillary plasma samples on feasibility of ammonia measurements statistically significant correlation to enzymatic assay extending the measuring range of ammonia on the BAC II analyzer from 286 mumol/l to about 700 mumol/l Dhawan A et al, 2006 to review the current status of hepatocyte transplantation for liver-based metabolic disorders na Level 4 Expert Clinical improvement and partial correction of the metabolic abnormality was observed in most cases, progress has been made in developing the technique Dionisi-Vici C et al, 2002 To estimate at the national level (in Italy) the overall and diseasespecific incidence of inborn errors of metabolism not mass screened at birth na Level 2+ Retrospective survey Inborn errors of metabolism constitute a highly heterogeneous category of rare diseases, incidence of UCDs 1: Dionisi-Vici C et al, 1987 to assess the effect of citrulline, arginine and ornithine 2 Level 3 Case reports low creatine could be normalized by arginine or citrulline, recommendation to combine diet and supplementation in HHH syndrome citrulline supplementation Dixon M, 2007 review on dietary management of UCD na Level 4 Expert, Overview on the current dietary strategies book chapter Dixon M & Leonard JV, 1992 Dixon M et al, 2000 to review the current knowledge on dietary treatment in acute and chronic management and to outline practical details of the treatment to comment on papers presented at the Fifth Dietitians Meeting at the VIII International Congress of Inborn Errors of Metabolism na Level 4 Expert na Level 4 Expert nice overview and outline of the principles and practice of dietary regimens for IEM including emergency treatment to review the current evidence on the usefulness of breat feeding in IEMs probably no full coverage of IEM focus on IEM and less on UCDs Drogari E & Leonard JV, Case series OTC late onset males 6 Level 3 Case reports variable outcome in late onset OTC males 1988 Duran M, 2008 book chapter on lab diagnostics of amino acids na Level 4 Expert, book chapter overview on laboratory aspects of UCDs and other amino acidopathies including reference ranges and preanalytics Ellaway CJ et al, 2002 Diagnostic clues and management in neonates with IEM na Level 4 Review Description of main causes of hyperammonemia in newborns Covers most of differential diagnosis of hyperammonemia in newborns, covers only hyperammonemia in the neonatal period

4 Type of Results reported Comment Engel K et al, 2009 to summarize the molecular genetic backgroound of ASS1 na Level 4 Expert comprehensive description of mutations and polymorphisms in the ASS1 gene Engel K et al, 2008 to report the genetic background in 5 otc pateints with 5 Level 3 Case series report of OTC transcript can help identifying OTC mutations, RNA from liver needed negative exon screening Enns GM et al, 2007 reports outcome and survival according to age at presentation; no controls 299 Level 2+ Case series report nice overview over a large chohort large cohort, long observation time, retrospective Enns GM, 2008 reviews neurological and neurocognitive outcome in UCD na Level 3 Review neurological and cognitive outcome of UCD still poor and pathogenesis Enns GM & Millan MT, to review the current status of cell-based therapies for na Level 4 Expert overview on an emerging new therapy possibly also for UCD 2008 metabolic liver disease Enns GM et al, 2005 to report on postpartum complications in woman with citrullinemia 1 Level 3 Case report recommendation to obtain metabolic studies in women with neurologic or severe psychiatric symptoms in the postpartum period Ensenauer R et al, 2005 Liver transplantation 1 Level 3 Case report Successful transplantation at 60 days early transplant, successful Faghfoury H et al, 2011 to report transient fulminant liver failure as an initial presentation in citrullinemia type I 2 Level 3 Case reports in some cases of CTLN1 with acute liver failure, emergency intervention such as transplantation is not warranted despite evidence of severe hepatotoxicity Fecarotta S et al, 2006 to report a case of HHH syndrome with fulminant hepatitislike 1 Level 3 Case report The diagnosis of HHH syndrome should be considered in with fulminant hepatitis-like presentation presentations, early identification and treatment of these can be life-saving and can avoid liver transplantation Feillet F & Leonard JV, to review current evidence of alternative pathway therapy na Level 4 Expert nice overview on nitrogen scavengers for UCDs 1998 for UCDs Feillet F et al, 2010 evaluate psychosocial / psychological issues in PKU na Level 4 review, expert psychosocial care for PKU patiens and families recommended management Felipo V & Butterworth to review evidence that mitochondrial dysfunction occurs na Level 4 Expert acute hyperammonemia results in alterations of mitochondrial and cellular energy function RF, 2002 in acute hyperammonemia Fensom AH et al, 1980 na na Level 2- Case control Mycoplasma contamination can result in false negative indirect enzyme analysis important observation Feoli-Fonseca JC et al, 1996 Effect of benzoate on carnitine metabolism and ammonia nitrogen removal; no control 16 Level 2+ Cohort benzoate leads to inconstant hippurate elimination and carnitine ; broad inter- and intraindividual variability important issue, inhomogeneous patient groups, HHH included Ficicioglu C et al, 2009 to report the longterm outcome of 13 ASL deficient detected by newborn screening 13 Level 3 Case series report early diagnosis and treatment can contribut to the relatively mild clinical course of the group Fleisher LD et al, controls 2 Level 2- Case control ASA level was elevated in an affected pregnancy (not in non-affected); indirect enzymatics in only 1 affected pregnancy cultured AFC cells is feasible Fletcher JM et al, 1999 Liver transplantation 1 Level 3 Case report improved intellectual function, successful transplant Intellectual outcome not objectively assessed Fulgoni VL, 2008 na na Level 4 Expert summary of the current protein intake in America derived from an analysis of the National Health and Nutrition Examination Survey Gao HZ et al, 2003 to report novel mutations in the argininosuccinate synthetase gene and genotype-phenotype correlation 38 Level 3 Case series report adds to the understanding of the genetic background of ASS1, however, still difficult to prove the genotype phenotype correlation, because many were compound heterozygotes 1 Level 3 Case report early treated NAGSD results in a favourable outcome Gessler P et al, 2010 to describe the long-term outcome of a NAGS deficient patient Gorker I & Tuzun U, 2005 To report on a case with autism in OTCD 1 Level 3 Case report introduction of treatment (protein restriction and benzoate) improves psychiatric symptoms in OTCD Griffith AD et al, 1989 to the effect of benzoate on mitochondrial function inhibition of pyruvate carboxylase occurred primarily by depletion of the activator, acetyl CoA, through sequestration of coenzyme A during benzoate metabolism Gropman A, 2010 to review brain imaging in urea cycle disorders na Level 4 Expert nice review on the current state of the art Gropmann AL et al, 2007 to report features of a ucd cohort na Level 4 Review nice overview on neurological implications Gropmann AL & Batshaw review studies on cognitive outcome in UCD na Level 4 review, expert good overview on cognitive outcome in different UCD populations M, 2004 Gropmann AL et al, 2008 To evaluate brain metabolism in subjects with partial OTC 25 Level 2+ Case control Brain metabolism is impaired in partial OTCD utilizing 1H MRS; 22 controls Gropmann AL et al, 2010 to whether white matter microstructure in OTCD correlates with cognitive deficits; 18 controls 19 Level 2+ Case control DTI was more sensitive than FSE T2-weighted imaging for detecting abnormalities in normalappearing white matter, the extent of abnormality correlated with cognitive deficits no detailed analysis of effect of treatment, diagnosis correctly established (OTC versus ARG1 ) Grünewald S et al, 2004 to evaluate the reliability of the allopurinol test in at-risk OTC females of known genotype; 20 controls 22 Level 2- Retrospective highest sensitivity of allopurinol test (91%) was given by orotidine alone or in combination with case-control orotic acid, but specificity was only 70% and 65%, respectively

5 Type of Results reported Comment Guffon N et al, 2011 to report retrospective data on 23 NAGSD treated 23 Level 3 Case series report Carglumic acid is safe and efficient for treatment of primary NAGS with carglumic acid over 16 years Guffon N et al, 2005 to evaluate the role of the N-carbamoyl-L-glutamic acid test for neonatal hyperammonemia 8 Level 3 Case series report, In with subsequently confirmed NAGS, hyperammonemia normalized within 8 hours, this test may be useful in the early diagnosis of with suspected UCD prospective Guffon N et al, 1995 case report on a NAGS patient 1 Level 3 Case report successful treatment of a new neonatal case of NAGS by carbamylglutamate Gyato K et al, 2004 relate neurocogniteve indices with clinical status, mutations in hetreozyg OTC females 19 Level 3 Case control specific neurocognitive phenotype in OTC females, asymptomatic subjects outperformed symptomatic subjects Häberle J & Koch, 2004 genetic approach in prenatal testing; no controls 15 Level 3 Case series report Genetic testing is feasible if mutation is known basis for standardazation Häberle J & Lachmann, 2010 to perform a cross-sectional observational on female OTC in large European centres 110 Level 2- Cohort high proportion of symptomatic OTC females, also high proportion of adult choice of participating centres was based on workshop participation Häberle J, 2011 to summarise current management of hyperammonemia na Level 4 Review, expert comprehensive review on diagnosis and treatment of hyperammonemia in pediatric, no new data Häberle J et al, 2003a to the molecular background of with mild citrulline levations in blood 21 Level 3 Case series report Mild citrullinemia is an allelic variant of classical citrullinemia type 1 most from newborn screening, most from Europe and Turkey Häberle J et al, 2003b to elucidate the gene structure of CPS1 and to investigate additional 6 Level 3 Case series report gene structure of CPS1 was presented plus additional novel mutations Häberle J et al, 2010 report on postpartum hyperammonemia in a small series of 3 Level 3 Case reports primary hyperammonemia should be considered as differential diagnosis of neurological changes only 3 cases, heterogeneous management in the postpartum period Hackbarth R et al, 2007 To decribe the effect of vascular access location and size on circuit survival in pediatric continuous renal replacement therapy na Level 4 Review, expert detailed description of vascular access requirements to perform extracorporeal detoxification Harada E et al, 2006 to report on late-onset OTC in male 10 Level 3 Case series report the plasma amino acid profile of the late-onselt OTC was unique, in comparison to other liver diseases with increases in glutamine, proline, lysine, valine and methionine, and decreases in serine, ornithine and arginine Hatzmann J et al, 2008 assess HRQuOL in parents of chronically ill children; Level 2- controlled trial Parents of chronically ill children have impaired HRQuOL controls Hatzmann J et al, 2009a to explore the influence of demographic and disease related factors on parental HRQoL na Level 3 cross-sectional Main factors explaining parental HRQoL seemed to be emotional support, care dependency, days on holiday and being chronically ill as a parent Hatzmann J et al, 2009b to examine medical, socio-demographic and psychosocial determinants of health-related quality of life (HRQoL) of parents of children with metabolic diseases na Level 3 Survey Mainly psychosocial determinants were predictive for parental HRQoL Hauser ER et al, 1990 to describe a new test for identification of OTC carriers 24 Level 3 Case series report measurement of urine orotidine is simple and reliable to identify OTC females Heckmann M et al, 2005 to report the false positive NAGS diagnosis in 3 newborns from one family 3 Level 3 Case report The enzyme assay for NAGS is not entirely reliable in neonatal age due to unknown factors Hermenegildo C et al, 1996 to the relationship of acute ammonia toxicity and activation of NMDA receptors this in mice shows that acute ammonia toxicity is mediated by activation of NMDA receptors Hiroma T et al, 2002 report on four cases of neonatal-onset hyperammonemia due to metabolic disorders treated with continuous 4 Level 3 Case reports CHDF is an extremely effective and safe treatment for fluminant neonatal-onset hyperammonemia due to metabolic disorders hemodiafiltration Horslen SP et al, 2003 to report on isolated hepatocyte transplantation in an infant with a severe UCD 1 Level 3 Case report Isolated hepatocyte transplantation can be an effective additional means for severe UCDs Hudak ML et al, 1985 to report on the difference between transient hyperammonemia and UCDs 33 Level 3 Case series report Distinctive laboratory findings in with THAN included abnormal chest radiographic, findings and plasma ammonium concentrations that were higher at an earlier age retrospective Huner G et al, 2005 to report the breastfeeding experience in inborn errors of na Level 4 Review, expert nice overview on breast-feeding in metabolic diseases metabolism other than phenylketonuria Ihara K et al, 2005 Discussion of the potential mechanisms of hyperammonemia in HI/HA syndrom; no control 1 Level 3 Case report HI/HA syndrom presented as differential diagnosis of CPS1 Interesting discussion of pathophysiological mechanisms in HI/HA syndrome, single case report; incomplete procedures (CPS1 measurement without variation of NAG concentration) Ito S et al, 2003 Allopurinol challenge before and after LTx 1 Level 3 Case report Normalisation of diet, metabolic stability Metabolic normalisation demonstrated Jacoby LB et al, 1981 Measure ASS activities in cultured AFC to perform prenatal testing; 25 controls 2 Level 2+ Cohort ASS activity varies in AFC cultures: low in epithelial-like, high in fibroblast-like cultures highlights another possible problem in prenatal enzymatic ASS testing, only 2 probands at risk; no true citrullinemia patient / positive control

6 Jalan R & Rose C, 2004 Kamoun P et al, 1995 to define the role of hypothermia as a treatment modality for increased intracranial pressure in with acute survey of European experience with prenatal testing in UCDs na Level 4 Review, expert 247 Level 3 retrospective survey Type of Results reported Comment nice overview on the role of hypothermia in acute liver failure, this new methods is promising and should be further explored Report of different techniques of prenatal testing complete survey of European situation by 1995, no general new information Kasumov T et al, 2004 to explore metabolites of phenylbutyrate identification of additional metabolites of PBA in humans Kawagishi N et al, 2005 to report the QoL in an OTC patient after liver 1 Level 3 Case report the quality of life (QOL) improved greatly after a living donor liver transplantation transplantation Keegan CE et al, 2003 to report on acute extrapyramidal syndrome in mild OTC 1 Level 3 Case report presenting with unexplained neurological insults might benefit from an for an inborn error of metabolism Keskinen P et al, 2008 Retrospective of incidence and courses of UCD in Finland; no controls 55 Level 3 Case series report lower incidence of UCDs than in other countries, better outcome of recent retrospective of UCDs in one country, large number of, long observation time, incomplete data, heterogeneous group Kim S et al, 1972 to in rats whether N-carbamoyl-L-glutamate plus L- arginine does protect from ammonia toxicity findings reported provide a rational basis for the use of N-carbamoyl-L-glutamate plus L-arginine in the prevention and treatment of hyperammonemia Klaus V et al, 2009 to report two CPS1 from one family with highly 2 Level 3 Case reports allelic imbalance may explain clinical variability in CPS1 in some families divergent clinical course Kleijer WJ et al, 1984 Indirect enzyme assay in intact CVS; no control 1 Level 3 Case report ASS enzymatics is feasible in intact CVS new method Kleijer WJ et al, 1984b prenatal testing for citrullinemia using amniotic fluid 3 Level 3 Case report indirect ASS assay can/should be combined with citrulline measurement in AF new method, small numbers Kölker S et al, 2006 to the role for the blood-brain barrier for neurological Treatment should be aimed at preventing the accumulation of toxic compounds complications of organic acidaemias Krivitzky L et al, 2009 characterize cognitive, emotional, adaptive behaviour in 92 Level 2- Case series good overview on cognitive skills UCD subjects Kuchler G et al, 1996 to reoprt the therapeutic use of carbamylglutamate in the case of CPS1 1 Level 3 Case report carbamylglutamate might be effective in CPS1 Kurokawa K et al, 2008 case series CPS1; no controls 25 Level 3 Case series report description of onset and death large cohort, long observation time, retrospective Kvedar JC et al, 1991 to report the hair findings in 2 with ASL 2 Level 3 Case report Dietary management reverses grooving and abnormal polarization of hair shafts in ASL Lee B et al, 2005 To describe common problems in treatment of UCD pts. 2 Level 3 Review and case reports Lee B et al, 1999 report on hepatocyte gene therapy in a neonatal bovine model of citrullinemia Lee B et al, 2000 studiy of control subjects,, and their relatives with different enzymatic deficiencies affecting the urea cycle while consuming a low protein diet; 26 controls 22 Level 2+ Case control no novel findings but nice overview near-complete (albeit "US" biased, i.e. benzoate not listed/discussed) overview on longterm treatment, results show the clinical efficacy of treating a large-animal model of an inborn error of hepatocyte metabolism The 15N-ureay15N-glutamine ratio is a sensitive index of in vivo urea cycle activity and correlates with clinical severity Leonard JV & McKiernan, to review current knowledge on liver transplantation for 59 Level 4 Expert Recommendations for LTx Best available review so far 2004 UCDs Leonard JV & Morris AA, 2006 IEM in the neonatal period na Level 4 Review Discussion around the differential diagnosis of IEM in the neonate Comprehensive, causes of hyperammonemia of the neonate only, not exhaustive Leonard JV, 2001 current understanding of nutritional management of UCDs na Level 4 Review no added proven value of citrate or carnitine, protein requirements vary with age and metabolic nice overview, not based on controlled studies status Leonard JV & Morris AA, 2002 review on neonatal aspects of urea cycle disorders na Level 4 Review nice overview but no novel findings Leonard JV et al, 2008 considerations on the postnatal management of suspected na Level 4 Expert intersting suggestions for clinical research directions UCD Linnebank M et al, 2000 genetic background in an ASL patient 1 Level 3 Case report frequent finding of alternative splicing in the ASL gene MacArthur RB et al, 2004 to describe the pharmacokinetics of PA and BZ 20 Level 2+ Cohort slower elimination of PA, non-linear pharmacokinetics by PA and BZ, present dosing regimens need to be optimized Maestri NE et al, 1991 Prospective treatment of UCD; no controls 32 Level 2+ Cohort PA/PB (better than benzoate) reduce risk of hyperammonemia, improve survival, stabilize cognitive function Maestri NE et al, 1996 to treatments designed to activate new pathways of 32 Level 2+ Cohort PA/PB (better than benzoate) reduce risk of hyperammonemia, improve survival, stabilize waste-nitrogen excretion in OTCDs; no controls cognitive function Maestri NE et al, 1999 retrospective analysis of 74 cases of neonatal-onset ornithine transcarbamylase (OTC) 74 Level 3 Case series report OTC should be suspected in term infants who have early signs of encephalopathy, severe developmental delay is the usual outcome of OTC done in healthy subjects, not in UCD relatively large cohort, same cohort as in Maestri, NEJM 1996 results are limited to symptomatic girls, no comparison between period before and after treatment

7 Maestri NE et al, 1998 Maestri NE et al, 1992 Majoie CB et al, 2004 to describe the phenotype of ostensibly healthy OTC females to describe the plasma glutamine concentrations in an OTC over a period of 2 years to different neuroradiological tools in a patient with citrullinemia Type of Results reported Comment 79 Level 3 Case series report wide range of phenotypic variability of OTC females, carriers had significantly higher levels of fasting plasma glutamine and alanine 1 Level 3 Case report A correlation coefficient of 0.77 (p less than ) was found suggesting that one goal of therapy is the maintenance of plasma glutamine levels at or near normal values 1 Level 3 Case report Diffusion-weighted and DTI are valuable techniques for the detection of irreversible brain damage and for the characterization of hyperintense lesions on T2-weighted MR images in citrullinemia Mandell R et al, 1996 prenatal testing by use of amniotic fluid; no control 15 Level 3 Case series report ASLD: just biochemical reliable; ASSD: both, biochemical plus enzyme analysis required other methods (CVS indirect enzyme testing) already available, better suited because earlier Marin-Valencia I et al, 2010 To assess the efficacy of the perimortem protocol in neonates with suspected inborn errors of metabolism (IEM) na Level 3 Case series report protocol was especially useful for collecting all biological samples in with rapidly fatal evolution with a non-specific diagnostic suspicion, and to collect special tissues in previously diagnosed Mayatepek E et al, 1991 Carnitine in OTCD; no control 1 Level 3 Case report carnitine def. can occur, cause unknown, maybe treatment with benzoate/pa, carnitine def. may enhance hyperammonemia important report, single case McBride KL et al, 2004 OLT 5 Level 3 Case series report mild-moderate developmental delay in Tx < 1 y, moderate-severe delay in historical control historical control, objective measures used Mendez-Figueroa H et al, to report six cases of OTC during pregnancy 6 Level 3 Case series report Although risk to women with OTC during the intra- and postpartum period exists, 2010 multidisciplinary management and a coherent plan usually result in successful labor, delivery, and postpartum Meyburg J et al, 2009 to report further cases with liver cell transfusion 4 Level 3 Case series report Successfull LCT First such description, no detailed outcome Meyburg J & Hoffmann GF, 2008 to report cases with liver cell transfusion 6 Level 3 Case series report Successfull infusion in 5 of 6 First comprehensive review Meyburg J & Hoffmann review on liver, liver cell and stem cell transplantation for na Level 4 Review nice review on liver (cell) transplantation GF, 2010 the treatment of urea cycle defects Mhanni AA et al, 2008 to report on HHH syndrome presenting with acute fulminant hepatic failure 2 Level 3 Case reports The diagnosis of HHH syndrome should be considered in with unexplained fulminant hepatic failure Midgley DE et al, 2000 to the health-related quality of life in long-term survivors of pediatric liver transplantation; 293 controls to report a case with enzyme replacement therapy in a patient with hyperargininemia, no control 51 Level 2- Case control majority of pediatric liver transplant recipients have mild functional deficits, utility scores reflected a high level of HRQOL but were significantly less than those of a reference population Mizutani N et al, Level 3 Case report erythrocyte exchange transfusion is considered to be effective for the control of clinical and biochemical abnormalities in hyperargininemia Monneret C, 2005 Review on histone deacetylase inhibitors na Level 4 Review nice review on HDAC inhibitors represent a new class of targeted anticancer agents relevant for judgement on PBA Morgan TM et al, 2011 to assess the risk of hyperammonemia that required urgent care or hospitalization after routine vaccinations in pediatric with underlying UCDs; 38 controls Morini C et al, 2009 to report on severe ophthalmological manifestations in a patient with HHH syndrome Morioka D et al, 2005a Liver transplantation in 13 own UCD and in 51 from the literature Morioka D et al, 2005b to evaluate the outcome of LDLT for noncirrhotic inheritable metabolic liver disease (NCIMLD) to clarify the effects of using a heterozygous carrier as a donor Morris AA et al, 1998 to report the favourable experience with carbamylglutamate in a NAGS patient Moscioni D et al, 2006 to determine the efficacy of AAV vector constructs in correcting metabolic defects in the liver in two strains of OTC-deficient mice 74 Level 2+ controlled retrospective, analytical no statistically significant association between childhood immunizations and hyperammonemic events in children with UCDs 1 Level 3 Case report important to include a careful ophthalmological with electrophysiological testing in the general assessment of HHH syndrome 13/51 Level 3 Case series report 93% one year survival Large cohort 21 Level 3 Case series report cumulative survival rate of the recipients was 85.7%, use of heterozygous donors in LDLT for NCIMLD has no negative impact 1 Level 3 Case report third report of a NAGSD patient who is neurologically intact, successful treatment with CG Long-term correction of ammonia metabolism and prolonged survival could be achieved Msall M et al, 1984 to the neurologic outcome in children with UCDs 26 Level 3 Case series report prolonged hyperammonemic coma is a major prognostic indicator associated with poor outcome Mustafa A & Clarke JT, 2006 to report an OTC case presenting with acute liver failure 1 Level 3 Case report OTC should be considered in the differential diagnosis of infants presenting with acute hepatocellular dysfunction Nagasaka H et al, 2001 Living donor liver transplantation 1 Level 3 Case report successful transplantation from asymptomatic OTC carrier unique report, no cognitive data Nagasaka H et al, 2006 To investigate the effects of arginine on nutrition, growth and urea cycle function in boys with late-onset OTCD; no control 7 Level 3 Case series report arginine replacement exerts beneficial effects on growth and metabolism in boys with late-onset OTCD Nasser M et al, 2009 review on carnitine supplementation for inborn errors of metabolism na Level 4 Cochrane Metaanalysis there were not any good quality trials to include in the review, individuals receiving carnitine should be carefully observed and monitored, decision to prescribe carnitine should be based on clinical experience together with individual preferences elative large effect of intervention, very homogeneous group

8 Nassogne MC et al, 2005 review of the clinical presentation of 217 with UCDs including long-term outcome of these Naylor EW & Chase DH, 1999 new method for NBS na Level 2+ Retrospective analysis Type of Results reported Comment 217 Level 3 Case series report Patients with late-onset forms may present at any age and carry a 28% mortality rate and a subsequent risk of subsequent disabilities TMS is able to detect pts. with metabolic disorders, TMS is cost effective report on the retrospective analysis of the results in NBS of individuals Newnham T et al, 2008 Liver transplantation 1 Level 3 Case report Improved clinical an chemical outcome Single case, objective assessment Nicolaides P et al, 2002 To determine the long term neurological and cognitive outcome of continuously treated surviving. 28 Level 3 Case series report most neurological complications could be attributed to hyperammonaemic encephalopathy but other mechanisms may also contribute to the neurological abnormalities Nordenstrom A et al, 2007 Noujaim HM et al, 2002 to report the use of carbamylglutamate in a neonatal patient with NAGS 1 Level 3 Case report A trial with N-carbamylglutamate may not detect all with NAGS and neonatal onset retrospective analysis of technical aspects and outcome of 15 Level 3 Case series report Overall survival rate is 60% (median follow-up, 34 months), which compares favourably with 15 liver transplantations in infants weighing less than 5 kg older patient groups one of two such studies Numata S et al, 2008 to report on paternal transmission of mutant alleles associated with late-onset OTC in male 20 Level 3 Case series report father-to-daughter transmission and mother-to-offspring transmission occurred in five (25%) and 15 (75%), respectively, and mutant alleles associated with the late-onset phenotype were eliminated more slowly Nuzum CT & Snodgrass to describe assays of the 5 urea cycle enzymes in human on of the first descriptions of enzyme assays for UCD enzymes PJ, 1976 liver homogenates Ohtani Y et al, 1988 carnitine status in UCD, longterm; no control 12 Level 3 Case report Secondary carnitine can occur in OTC investigated during hyperammemia large group of Oyanagi K et al, 1980 Palmieri F, 2008 Pascual JC et al, 2007 Patejunas G et al, 1998 Patel HP & Unis ME, 1985 Pekkala S et al, 2010 Picca S et al, 2008 Picca S et al, 2001 Levels of enzyme activities in fetuses, infants, children, adults; no control review paper on diseases caused by defects of mitochondrial carriers OTC case with acrodermatitis-enteropathica like dermatosis; no control paper on gene therapy for citrullinaemia using murine and bovine models to report a rare finding: pili torti in association with 67 Level 3 Case series report OTC & ARG activities increase during fetal development; CPS1, ASS & ASL are not different in fetal stages (increase later) na Level 4 Review up-to-date review on mitochondrial carrier defects broad variation (4 hours) in sampling liver tissue; nonfetal probands were somewhat sick 1 Level 3 Case report amino acids can lead to acrodermatitis-like picture, think of this in similar cases caloric and protein intake over time is not well explained use of adenoviral vectors in the treatment of citrullinaemia is a viable approach to therapy 1 Level 3 Case report novel association of a hair finding with citrullinemia citrullinemia on an expression system for determing the effects of this novel CPS1 expression/purification system does help to identify CPS1 possibly nine clinical mutations and one polymorphism on CPS1 responding to NAG analogues treatment solubility, stability, activity, and kinetic parameters to discuss the dialytic therapy options for neonates with na Level 4 Review review paper on dialysis for neonatal hyperammonemia to investigate the prognostic indicators in ten 10 Level 3 Case series report CVVHD to be the optimal modality for extracorporeal ammonium detoxification hyperammonemic neonates treated with different modalities; no control Potter M et al, 2001 to investigate the effects of different foods as the protein load and of different analytical methods in order to develop another diagnostic tool; 18 controls 18 Level 2- Case control Praphanphoj V et al, 2000 case reports on intravenous sodium benzoate and sodium phenylacetate toxicity Prietsch V et al, 2002 review on emergency management of inherited metabolic diseases Puppi J et al, 2008 report on hepatocyte transplantation followed by auxiliary liver transplantation The new test appears at least as sensitive and specific as the allopurinol test and is more convenient 3 Level 3 Case reports three accidentally received the drugs far in excess of recommended doses, thus, intoxication with sodium benzoate and sodium phenylacetate can occur na Level 4 Review review paper on emergency treatment, no new data but practical overview 1 Level 3 Case report hepatocyte transplantation can be used in conjunction with APOLT as an effective treatment for severe OTC-deficient Qureshi IA et al, 1984 to report on the treatment of hyperargininemia with sodium na Level 4 Review to discuss treatment of hyperargininemia and suggest use of sodium benzoate and an argininerestricted benzoate and arginine-restricted diet diet Rabier D et al, 1991 to report on hypocitrullinaemia observed in 5 with 5 Level 3 Case series low citrulline levels might be caused by mitochondrial disease good statistics Rabinstein AA, 2010 to review treatment of brain edema in acute liver failure na Level 4 Review extensive review on the subject with many examples, thorough work not specific for UCDs Raiha NC & Suihkonen J, on development of urea-synthesizing 1968 enzymes in human liver Raper SE et al, 2002 Pilot Study of In Vivo Liver-Directed Gene Transfer with an 18 Level 3 Case series Adenoviral Vector in Partial OTC Deficiency report, phase I clinical trial basic science, work describing the developmental changes of UCD enzymes in liver This clinical trial defines potentially important issues of liver-directed adenovirus vectors in humans that were not entirely predicted on the basis of animal models, and may be useful in the design of other applications of systemically administered adenovirus vectors

9 Rashed MS, 2001 Riudor E et al, 2000 Rudman D et al, 1973 Sadowski RH et al, 1994 Review of the clinical applications of tandem mass spectrometry in diagnosis and screening for inherited metabolic disorders to define the influence of dose and age on the response of the allopurinol test for OTC in control infants to determine maximal rates of excretion and synthesis of urea in normal and cirrhotic subjects; 10 controls to report the outcome of acute hemodialysis of infants weighing less than five kilograms Type of Results reported Comment na Level 4 Review NBS for metabolic disorders is feasible and cost effective nice review, discussion on pitfalls 36 Level 3 Case series report dose-normalized responses should be used in the allopurinol test and there is no need for careful age-matching of the controls. 19 Level 2- Case control doses of protein do not further accelerate urea excretion, but prolong the duration of urinary urea N excretion 33 Level 3 Case series report Only nine treatments were discontinued prematurely: six for intractable hypotension and three for technical problems, survival rates for the infants with hyperammonemia (75%) and primary renal disease (71%) were better than those for infants with acute renal failure (33%) Sakiyama T et al, 1984 to report the successful trial of enzyme replacement therapy in a case of argininemia 1 Level 3 Case report replacement of red blood cells improves not only the clinical and biochemical conditions, but the general condition of the patient as well Salvi S et al, 2001 to report the clinical and molecular findings in eight with HHH syndrome. 8 Level 3 Case series report the most consistent neurologic finding was spastic paraparesis, all showed signs of pyramidal tract involvement Sander J et al, 2003 to report on a single centre experience of neonatal screening for citrullinaemia 15 Level 3 Case series report neonatal screening for citrullinaemia is more complex than expected and results may be obtained too late in severe forms Sanjurjo P et al, 1997 to the effect of a protein-restricted diet on polyunsaturated fatty acids 13 Level 3 Case series report long-chain polyunsaturated fatty acids are semi-essential in infant nutrition far beyond the breastfeeding period Santos Silva E et al, 2001 Liver transplantation 1 Level 3 Case report Successful OLT in argininemia, normal neurological outcome clear outcome Saudubray JM et al, 2006 Differential diagnosis of IEM na Level 4 Review discussion of differential diagnosis of IEM including hyperammonemia Most causes of hyperammonemia encountered in emergency situations are cited, not exhaustive, some causes of chronic hyerammonemia are missing Saudubray JM et al, 1999 Liver transplantation 5 Level 3 Case series report Successful transplantation No cognitive data, no discussion of indication Scaglia F & Lee B, 2006 to review the clinical, biochemical, and molecular spectrum na Level 4 Review nice review of hyperargininemia due to arginase I Scaglia F, 2010 to of the role of BCAA in UCD subjects; 11 controls 11 Level 2- Case control Scaglia F et al, 2004 Schaefer F et al, 1999 Scheuerle AE et al, 1993 Schmidt J et al, 2006 Sedel F et al, 2007 Serrano M et al, 2009 Shchelochkov OA et al, 2009 Shi D et al, 1998 Shih VE et al, 1982 Singh RH et al, 2005 to measure steady state plasma branched chain and other essential non-branched chain amino acids in control subjects and UCD ; 11 controls to report the experience with CVVHD in neonates suffering from hyperammonemic coma case reports on cerebral palsy in arginase to discuss on anesthetic management of with OTC and to describe a case report IEMs may present in adolescence or adulthood as a psychiatric disorder to report 9 followed up in our hospital presenting late-onset UCDs To elucidate the molecular etiology in with clinical signs of OTCD and negative OTC sequencing to solve the crystal structure of human ornithine transcarbamoylase to some aspects of ornithine metabolism in cultured skin fibroblasts from two from two with the HHH syndrome To outline the nutrition management of urea cycle disorders 5 Level 2- Case control Branched chain amino acid levels were significantly lower in treated with UCDs, better titration of protein restriction can be achieved with branched chain amino acid supplementation Steady-state leucine levels were noted to be significantly lower in treated UCD, PBA treatment has substantial impact on the metabolism of branched chain amino acids 6 Level 3 Case series report CVVHD is the most effective therapy for neonatal hyperammonemic coma, an adequate sized vascular access is important 2 Level 3 Case reports Arginase should be considered in infants with acute lethargy, hypotonia, feeding difficulties, vomiting, and/or in older children and adults with lower limb spasticity 2 Level 3 Case report and expert General anesthesia with midazolam, s-ketamine, fentanyl and isoflurane in combination with surgical field infiltration with ropivacaine did not lead to an excessive increase of ammonia levels above normal values elegant design na Level 4 Review IEM can present as psychiatric disorder nice classification of IEMs according to their psychiatric symptoms 9 Level 3 Case series report unexplained or nonresponsive neuropsychiatric/neurodevelopmental symptoms appearing during childhood or adolescence be followed by a of ammonia and amino acid plasmatic levels to rule out a urea cycle disorder 70 Level 3 Case series report approximately half of the with negative OTC sequencing may have OTC gene deletions readily identifiable by the targeted oligonucleotide-based acgh description of the human OTC structure at at 1.85-Å resolution 2 Level 3 Experimental 2 Level 3 Case report & review fibroblasts failed to incorporate 14C-label from ornithine into protein, thus, fibroblasts are suitable for further ing the underlying metabolic defect in HHH syndrome no novel findings reported but nice recommendation Singh RH, 2007 nutritional management of UCD pts. na Level 4 Expert Nice and near-complete summary of nutritional aspects of UCD treatment nice overview Many practical recommendations for daily problems