The Physician’s Guide to Urea Cycle Disorders · the first few days of life. Infants with a urea cycle disorder often ... • Rapid deterioration of neurologic status. ... This

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NORD Guides for Physicians

The Physician’s Guide to

Urea Cycle Disorders

Visit website at:nordphysicianguides.org/urea-cycle-disorders/

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Contents ©2012 National Organization for Rare Disorders®

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What are Urea Cycle Disorders?The urea cycle disorders (UCD) result from genetic mutations causing defectsinthemetabolismoftheextranitrogenproducedbythebreakdownofproteinandothernitrogen-containingmolecules.Severedeficiencyortotalabsenceofactivityofanyofthefirstfourenzymes(CPSI,OTC,ASS,ASL)intheureacycleorthecofactorproducer(NAGS)resultsin the accumulation of ammonia and other precursor metabolites during thefirstfewdaysoflife.Infantswithaureacycledisorderofteninitiallyappear normal but rapidly develop cerebral edema and the related signs oflethargy;anorexia;hyperventilationorhypoventilation;hypothermia;seizures;neurologicposturing;andcoma.Inmilder(orpartial)ureacycleenzyme deficiencies, ammonia accumulation may be triggered by illness or stress at almost any time of life, resulting in multiple mild to moderately severe elevations of plasma ammonia concentration. The hyperammonemia isusuallylesssevereandthesymptomsmoresubtle.PatientswithArginasedeficiency may present with hyperammonemia with severe stress, but are morelikelytopresentwithprogressiveneurologicsymptomsunrelatedtohyperammonemic episodes.

The urea cycle was first described in 1932 by Krebs and Henseleit. Classic urea cycle deficiency with no enzyme activity invariably presents with overwhelming hyperammonemia in the newborn period with little effect fromtheenvironment.Patientswithresidualactivitymaygodecadesbefore encountering an environmental stress strong enough to overwhelm their marginal ureagenesis capacity and resulting in a hyperammonemic episode. Commonly distributed, functional polymorphisms in the urea cycle may not result in hyperammonemia, but instead affect the production ofdownstreammetabolicintermediates(suchasarginine)duringkeyperiods of need. These variations in intermediate molecule supply can affectothermetabolicpathwayssuchastheproductionofnitricoxide(NO)fromcitrulline/arginineandpotentiallythetricarboxylicacidcyclethroughaspartate and fumarate.

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Asshowninfigure1,theureacycleiscomposedoffiveprimaryenzymes, one cofactor producer and two transport molecules across the mitochondrialmembrane.Inbornerrorsofmetabolismareassociatedwith each step in the pathway and have been well described over the years. The cycle has the interesting property of having a subset of the enzymes participate in another metabolic pathway which produces nitric oxide.Theureacycleasanitrogenclearancesystemislimitedprimarilyto the human liver and intestine with carbamyl phosphate synthetase andornithinetranscarbamylaselimitedexclusivelytothosetissues.Theenzymes downstream which process citrulline into arginine are ubiquitous intheirdistribution.Astherate-limitingenzymeintheureacycle,CPSIfunctional changes would have the greatest impact on cycle function fromenvironmentalandpharmacologicstress(likevalproicacidandcyclophophamide).Hepatotoxins,bothchronicandacute,havelongbeenknowntoaffecttheclearanceofammoniafromthebloodstream.Throughloss of liver tissue and direct effects on the enzymes of the urea cycle, the abilitytoclearexcessnitrogeniscompromised.Thisoftenresultsinhepaticencephalopathy which compromises the neurologic integrity of the patient. Alcoholisoneoftheleadingcausesofhepaticencephalopathy,andchronichyperammonemia one of the more debilitating results of chronic cirrhosis. Thepointatwhichthesetoxinsresultinelevatedammonialevelsisafactoroftheextentoftheliverdamagebutalsothegeneticallydeterminedbaseline capacity of the cycle. Other agents such as the seizure medication, valproicacid,arealreadyestablishedasureacycletoxins.

Figure 1

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Symptoms & SignsSymptomsprogressfromirritabilitytosomnolencetolethargyandcoma.Abnormalposturingandencephalopathyareoftenrelatedtothedegreeof central nervous system swelling and pressure upon the brainstem. Asignificantportionofneonateswithseverehyperammonemiahaveseizures. Hyperventilation, secondary to cerebral edema, is a common early findinginahyperammonemicattack,whichcausesarespiratoryalkalosis.Hypoventilation and respiratory arrest follow as pressure increases on the brainstem.

SymptomsofNewbornswithUreaCycleDefects •Normalappearanceatbirth •Irritabilityprogressingtosomnolence,lethargy,thencoma •Lossofthermoregulation(hypothermia) •Feedingdisruption(increasescatabolism) •Neurologicposturing(fromcerebraledema) •Seizures •Hyperventilationandthenhypoventilation

Inmilder(orpartial)ureacycleenzymedeficiencies,ammoniaaccumulationmay be triggered by illness or stress at almost any time of life, resulting in multiple mild to moderately severe elevations of plasma ammonia concentration. The hyperammonemia is usually less severe and the symptomsmoresubtlethaninsevereureacycleenzymedeficiencies.Inpatients with partial enzyme deficiencies, the first recognized clinical episodemaybedelayedformonthsoryears.Althoughtheclinicalabnormalities vary somewhat with the specific urea cycle disorder, inmostthehyperammonemicepisodeismarkedbylossofappetite,cyclicalvomiting,lethargy,andbehavioralabnormalities.Sleepdisorders,delusions,hallucinations,andpsychosismayoccur.Anencephalopathic(slowwave)EEGpatternmaybeobservedduringhyperammonemiaandnon-specificbrainatrophymaybeseensubsequentlyonMRI.

CommonClinicalFeaturesforLateOnsetUreaCycleDisorders •DramaticandrapidIncreaseinNitrogenLoadfrom - Trauma - Rapid weight loss and auto-catabolism -Increaseinproteinturnoverfromsteroids •Tendtoavoidproteinintheirdiet •Oftenhavehistoryofbehavioralorpsychiatricillnesses

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•Rapiddeteriorationofneurologicstatus. •Severeencephalopathyinconsistentwithmedicalcondition. •Usuallyinvolvedefectsinfirstpartofureacycle. •Evidenceforcerebraledemabyclinicalexamorradiograph •Seizuresinsomecases. •Decreaseinoralintakeleadinguptodecompensation

PresentingSymptomsin260PatientsatFirstPresentationofHyperammonemia •Neurologicsymptoms(100%) •Decreasedlevelofconsciousness(63%) •Abnormalmotorfunctionortone(30%) •Seizures(10%) •Vomiting(19%) •Infection(30%) •Subjective:Decreasedappetite,fussy •Physiologic:Respiratoryalkalosis(secondarytocerebraledema)followed by apnea

CausesAbriefreviewofdisordersoftheoftheureacyclefollows:Table1liststhegenes of the cycle associated with disease.

Gene Name Gene Symbol Location Protein Name Carbamylphosphate CPS1 2q25 Carbamoyl-phosphate synthetaseI synthaseammonia

Ornithine transcarbamylase OTC Xp21.1 Ornithine carbamoyltransferase

Argininosuccinatesynthase ASS 9q34 Argininosuccinate synthase

Argininosuccinatelyase ASL 7cen- Argininosuccinate q11.2 lyase

Arginase ARG1 6q23 Arginase1

N-acetylglutamate NAGS 17q21.3 N-acetylglutamate synthase synthetase

Ornithine Transporter ORNT1 13q14 Ornithine Transporter Mitochondrial1 Mitochondrial1

Citrin Citrin 7q21.3 Proposedhepatic mitochondrial

asparatate transporter

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DeficienciesofCPS1,ASS,ASL,ARG,NAGS,ORNT1andCitrinareinheritedin an autosomal recessive manner. OTC deficiency is inherited in an X-linkedmanner.

N-Acetylglutamate Synthetase Deficiency (NAGS) N-acetylglutamate synthetase deficiency affects the body’s ability to maken-acetylglutamate(NAG)whichisarequiredcofactorforthefunctionofcarbamylphosphatesynthetaseI.WithoutNAG,CPSIcannotconvertammoniaintocarbamylphosphate.AlongwithOTCdeficiencyandCPSI,deficiencyofN-acetylglutamateisthemostsevereoftheureacycledisorders.PatientswithcompleteNAGSdeficiencyrapidlydevelophyperammonemiainthenewbornperiod.Patientswhoaresuccessfullyrescuedfromcrisisarechronicallyatriskforrepeatedboutsofhyperammonemia.

Carbamoylphosphate Synthetase I Deficiency (CPSI Deficiency) CarbamylphosphatesynthetaseIdeficiencyaffectstheliver’sabilitytoconvertnitrogentourea.ThisenzymetakesammoniaandthroughtheuseofbicarbonateandATPproducescarbamylphosphate.Thisenzymerequiresthepresenceofitscofactorn-acetylglutamate.AlongwithOTCdeficiencyandNAGS,deficiencyofCPSIisthemostsevereoftheureacycledisorders.PatientswithcompleteCPSIdeficiencyrapidlydevelophyperammonemiainthenewbornperiod.Patientswhoaresuccessfullyrescuedfromcrisisarechronicallyatriskforrepeatedboutsofhyperammonemia.PatientswithpartialCPSIdeficiencycanpresentatalmost any time of life with a stressful triggering event.

CPSIisthefirstenzymeintheureacycleandisfoundprimarilyintheliver.ItrequiresthecofactorN-acetylglutamatetofunction.Currently,diagnosisisbasedonenzymaticassayoflivertissue.Sequenceanalysisisavailableona research basis only.

Ornithine Transcarbamylase (OTC) Deficiency Ornithine transcarbamylase deficiency affects the liver’s ability to convert ammonia into urea. OTC combines carbamyl phosphate with ornithine tomakecitrullinewhichissubsequentlyprocessedtourea(see:cyclediagram).AlongwithCPSIandNAGSdeficiency,OTCdeficiencyisthemostsevereoftheureacycledisorders.PatientswithcompleteOTCdeficiency rapidly develop hyperammonemia in the newborn period. Patientswhoaresuccessfullyrescuedfromcrisisarechronicallyatriskforrepeated bouts of hyperammonemia. OTC is located on the X-chromosome whichresultsinthemajorityofseverepatientsbeingmale.Femalescan

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also be affected but tend to present outside the neonatal period. Carrier femalescanalsobeaffected(unliketheotherureacycledisorders)duetoswitchingoffononeoftheXchromosomesinfemales.Patientswithpartial OTC deficiency can present at almost any time of life with a stressful triggering event.

Argininosuccinate Synthetase Deficiency (ASSD) (Citrullinemia I) Defectsinargininosuccinatesynthetase(ASS)affecttheabilitytoincorporate ammonia into urea. This enzyme combines citrulline with aspartatetoformargininosuccinate.PatientswithcompleteASSDpresentwith severe hyperammonemia in the newborn period. The use of arginine in these patients allows some nitrogen (ammonia) to be incorporated into theureacyclewhichmakestreatmentsomewhateasierthanotherdefectsin the cycle. Citrulline levels in these patients can be 100s of times the normalvalues.UnlikeCPSI,NAGS,andOTC,thisenzymeisdistributedthroughout the body. Diagnosis is by enzymatic assay of fibroblasts. PrenataltestingisperformedbyenzymaticanalysisofamniocytesorCVSsample.

Citrin Deficiency (Citrullinemia II) CitrullinemiaIIisanautosomaldisorderthatresultsindecreasedactivity in the liver of a transport molecule for aspartate. This results in limitation of activity for the enzyme argininosuccinic acid synthase which combinesaspartateandcitrullinetomakeargininosuccinicacid.Citrin(the defective protein) is an aspartate glutamate transporter across the mitochondrial membrane. This defect can present with classic newborn hyperammonemia,intrahepaticcholestatis,jaundiceandfattyliver,butismorelikelytopresentwithinsidiousneurologicfindings,hyperammonia,hypercitrullinemiaandhyperlipidemiainadulthood.ThemajorityofpatientsreportedhavebeenJapaneseorAsianwhoshareacommonmutation. These patients can also have the dietary peculiarity of avoiding carbohydrates rather than protein. This probably is due to the overlap of this disorder with glucose metabolism. Treatment for hyperammonemia is the same as the other urea cycle disorders.

Argininosuccinate Lyase Deficiency (Argininosuccinic Aciduria)Argininosuccinatelyasedeficiencyaffectsthebody’sabilitytoclearthenitrogen already incorporated into the urea cycle as argininosuccinate. Thiscauseshyperammonemia.Severedefectsoftenpresentwithrapid-onset hyperammonemia in the newborn period. This enzyme defect is

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past the point in the metabolic pathway at which all the waste nitrogen has been incorporated into the cycle as argininosuccinate (see figure). Treatmentofthesepatientsisbasedonareductioninnitrogenintakeandsupplementation with arginine to complete a partial cycle. This disorder ismarkedbychronichepaticenlargementandelevationoftransaminases.Biopsyofthelivershowsenlargedhepatocytes,whichmayovertimeprogress to fibrosis, the etiology of which is unclear. These patients can alsodeveloptrichorrhexisnodosa,anode-likeappearanceoffragilehair,whichusuallyrespondstoargininesupplementation.Reportsexistofaffected patients who have never had prolonged coma, but nevertheless have significant developmental disabilities. Clinical trials are underway to determine if the use of nitrogen scavengers will improve the outcome in these patients.

Deficiency of this enzyme prevents the conversion of argininosuccinate to the amino acid arginine which affects the urea cycle and other biochemical pathways.

Diagnosis is based on the presence of large amounts of argininosuccinic acid in the bloodstream and direct enzymatic analysis of fibroblasts. PrenataldiagnosisisavailablebyenzymaticanalysisofamniocytesorCVSsample.

Arginase Deficiency (Hyperargininemia) Arginasedeficiencyisnottypicallycharacterizedbyrapid-onsethyperammonemia. These patients often present with the development of progressive spasticity with greater severity in the lower limbs. They also developseizuresandgraduallyloseintellectualattainments.Growthisusually slow and without therapy they usually do not reach normal adult height. Other symptoms that may present early in life include episodes of irritability,anorexiaandvomiting.Severeepisodesofhyperammonemiaareseen infrequently with this disorder, but can be fatal.

Diagnosis is made by the elevated levels of arginine in the blood and by analysis of enzymatic activity in red blood cells.

Treatment is similar to other urea cycle disorders (limitation of protein, use of essential amino acid supplements, diversion of ammonia from urea cycle )withtheexceptionthatargininesupplementationisnotindicatedduetotheexcessiveargininelevelsalreadypresentinthiscondition.

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Ornithine Translocase Deficiency (HHH Syndrome) The HHH (hyperornithinemia, hyperammonemia, homocitrullinuria) syndrome is an autosomal recessive inherited disorder described in morethan50patients.Theclinicalsymptomsarerelatedtothehyperammonemia and resemble those of the urea cycle disorders. Plasmaornithineconcentrationsareextremelyhigh.Thedefectinornithine translocase results in diminished ornithine transport into the mitochondria with ornithine accumulation in the cytoplasm and reduced intramitochondrial ornithine causing impaired ureagenesis and orotic aciduria. Homocitrulline is thought to originate from transcarbamylation of lysine.Mostpatientshaveintermittenthyperammonemiaaccompaniedbyvomiting,lethargyandcoma(inextremecases).Growthisabnormalandintellectualdevelopmentisaffected.Spasticityiscommonasareseizures.Adultpatientsarefoundwithpartialactivityoftheenzyme.Theytypicallyself-select low protein diets.

CommonStressorsthataffectureacyclefunction •Geneticdefectinanenzyme •Damagetotheliver(bothchronicandacutely) •Chemicaltoxins(ETOH,industrialetc.) •Infectiousorviralprocesses •Drugeffectsonthecycle -DirectInterferencewithEnzymes -Valproicacid(Depakote) - Chemotherapy (particularly cyclophosphamide) - Damage or general disruption of hepatic function -Systemicantifungals -Chemotherapyfromhepatotoxiceffects -Acetaminophen - Corticosteroids (catabolic effects) •OtherMetabolicDiseases - Organic acidemias (such as methylmalonic, propionic, etc.) -Pyruvatecarboxylasedeficiency -Fattyacidoxidationdefects -Galactosemia - Tyrosinemia -Glycogenstoragedisease •Vascularbypassoftheliverbyscarringorvascularbypass

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•NitrogenoverloadoftheSystem -Massivehemolysis(suchaslargebonefractureortrauma) - Total parenteral nutrition -Proteincatabolismfromstarvationorbariatricsurgery -Postpartumstress -HeartLungTransplant - Renal Disease -GIbleeding

DiagnosisThe most important step in diagnosing urea cycle disorders is clinical suspicionofhyperammonemia.Abloodammonialevelisthefirstlaboratory test in evaluating a patient with a suspected urea cycle defect. Particularcareshouldbetakenindrawingabloodammoniasincethereissignificant variability depending on proper technique and handling. The clinician should remember that treatment should not be delayed in efforts to reach a final diagnosis, and that later stages of treatment should be tailored to the specific disorder.

Inadditiontoplasmaammonia,laboratorydatausefulinthediagnosisofUCDs include pH, CO2, the anion gap, blood lactate, plasma acylcarnitine profile acylcarnitines, plasma and urine amino acids, and urine organic acid analysesincludingthespecificdeterminationoforoticacid.Patientswithtrue urea cycle defects will typically have normal glucose and electrolyte levels. The pH and CO2 can vary with the degree of cerebral edema and hyper- or hypo-ventilation.

Inneonatesitshouldberememberedthatthebasalammonialeveliselevatedoverthatofadults,whichtypicallyislessthan35µmol/L(lessthan110µmol/Linneonates).Anelevatedplasmaammonialevelof150µmol/L(>260µg/dl)orhigherinneonatesand>100µmol/l(175µg/dl)inolder children and adults, associated with a normal anion gap and a normal blood glucose level, is a strong indication for the presence of a urea cycle defect. Quantitative plasma amino acid analysis can be used to evaluate these patients and arrive at a tentative diagnosis. Elevations or depressions of the intermediate amino-containing molecules arginine, citrulline, and argininosuccinate (Figure 2, Diagnostic Flow Chart) will give clues to the point of defect in the cycle.

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Theaminoacidprofileinsicknewbornscanbequitedifferentfromthoseinchildrenandadults,whichshouldbetakenintoaccount.Thelevelsofthe nitrogen buffering amino acid glutamine will also be quite high and canserveasconfirmationofthehyperammonemia.IfadefectinNAGS,CPSI,orOTCissuspected,thepresenceoftheorganicacidoroticacidin the urine can help distinguish the diagnosis. Orotic acid is produced when there is an overabundance of carbamyl phosphate which spills into the pyrimidine biosynthetic system. The determination of urine organic acids and plasma acylcarnitines will also herald the presence of an organic aciduria.Othergeneticdefectsthataffectammoniadetoxificationarelysinuric protein intolerance, the hyperinsulinism-hyperammonemia syndrome,hypoprolinemia(paradoxicalfastinghyperammonemia)andpyruvatecarboxylasedeficiency.Allofthemareveryrareandimportanthints would be obtained through the investigations outlined above.

Figure 2

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Enzymatic and genetic diagnosis is available for all of these disorders. ForCPSI,OTC,andNAGS,enzymaticdiagnosisismadeonaliverbiopsyspecimenfreshlyfrozeninliquidnitrogen.EnzymatictestingforASS,ASLcanbedoneonfibroblastsamplesandarginasecanbetestedonredbloodcells.ClinicallyapprovedDNAsequenceanalysisisonlyavailableforOTC at the time of this printing, but its availability for the other disorders isanticipatedsoon,asitisavailableoutsidetheUS.AfrequentlyupdatedwebresourcefortestinginformationcanbefoundattheNIHsponsoredsite: http://www.geneclinics.org

TreatmentDisclaimer:Thetreatmentofthesedisordersiscomplexandbestconductedby a specialist in inborn errors of metabolism at a center equipped to do so. For the pediatrician, recognition, stabilization, and rapid transport are the surest way to achieve optimal outcome. Delays in treatment and failure to maximizeappropriatetreatmentwillhavepermanentanddamagingeffectson the patient.

This section provides an overview of UCD management. The treatment of these patients requires a highly-coordinated team of specialists trained in caring for patients with inborn errors of metabolism (Table). Emergency management of patients in hyperammonemic coma resulting from a UCD is based on three interdependent principles: first, physical removal of the ammonia by dialysis or some form of hemofiltration; second, reversal of thecatabolicstatethroughcaloricsupplementationandinextremecases,hormonal suppression (glucose/insulin drip); and third, pharmacologic scavengingofexcessnitrogen.Thesearenotconsecutivebutshouldbepursuedindependentlyinparallelasquicklyaspossible.

Treatment Team and Organization •MetabolicSpecialist - Coordinate treatment and management •Intensivecareteam -Assistwithphysiologicsupport -Ventilatormanagement -Sedationandpainmanagement •Nephrologistordialysisteam -Managedialysis -Managerenalcomplications

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•Surgicalteam -Largeborecatheterplacement -Liverbiopsyasnecessary -Gastrostomytubeplacement(ifindicated) •Pharmacystaff - Formulate nitrogen scavenging drugs -Crosscheckdosingordersincomplexmanagement •Laboratorystaff -Analyzelargevolumeofammoniasamplesinacutephase -Analyzeaminoacidsandotherspecialtylabs •Nursingstaff -Executecomplexandrapidlychangingmanagementplan - Closely monitor patient for signs of deterioration or change •Nutritionist -Maximizecaloricintakewithneutralnitrogenbalance -Educatefamilyinmanagementofcomplexverylow-proteindiet •Socialwork -Rapidlyidentifyresourcesforcomplexoutpatienttreatmentregimen -Workwithfamiliesinhighlystressfulclinicalsituation •GeneticCounselor - Educate family in genetics of rare metabolic disease -Identifyotherfamilymembersatpotentialrisk(OTCparticularly) - Ensure proper samples are obtained for future prenatal testing - Contact research/diagnostic centers for genetic testing

EmergencyManagement •Fluids,dextrose,andInterlipid®tomitigatecatabolismandtypical dehydration(attempt80cal/kg/day) •Antibioticsandsepticworkuptotreatpotentialtriggeringeventsor primary sepsis (continue through treatment course) •Contactandpossibletransporttotreatment-capableinstituteassoon as possible •Removeproteinfromintake(POorTPN) •Establishcentralvenousaccess •Providephysiologicsupport(pressors,bufferingagents,etc.). (Renal output is critical to long term success). •Stabilizeairwayascerebraledemamayresultinsudden respiratory arrest

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Ifammoniadoesnotfallwithhigh-calorieinfusionpluspharmaceuticalmeasures or ammonia is well over 700umol/l, central venous access should be established at once and dialysis/rapid hemofiltration begun immediately at the highest available flow rate. Dialysis is very effective for the removal of ammonia and the clearance is dependent on the flowthroughthedialysiscircuit.Inseverecasesofhyperammonemia,provision for hemofiltration should be made to follow the dialysis until thepatientisstabilizedandthecatabolicstateisreversed.Somepatientswill reaccumulate ammonia after their initial round of dialysis and may requireadditionalperiodsofdialysis.Mostpatientswillhaveaslightriseinammonia after dialysis since removal by scavengers and the liver will not be as effective. This slight rise usually does not necessitate repeat dialysis.

The importance of the management of the catabolic state cannot be overstressed.Sincethecatabolismofproteinstoresisoftenthetriggeringevent for hyperammonemia, the patient will not stabilize and ammonia will continuetoriseuntilitisreversed.Fluids,dextroseandIntralipid®shouldbegiventobluntthecatabolicprocess.Mostpatientsaredehydratedatinitialpresentationduetopoorfluidintake.Thepatientshouldbeassessedfordehydrationandfluidsreplaced.Sincethesepatientssufferfromcerebraledema,careshouldbetakentoavoidoverhydrationwhileavoidingdehydration. The nitrogen scavenging drugs are usually administered in a largevolumeoffluidwhichshouldbetakenintoconsideration.Aregimenof80-120kcal/kg/dayisareasonablegoal.Theadministrationofinsulinandglucoseareusefulbutalsorequireexperienceandshouldbereservedforthesickestpatients.Atthesametime,proteinmustbetemporarilyremovedfromintake(POorTPN).Supplementationofarginineservestoreplace arginine not produced by the urea cycle (in addition to the partial cycle function it can stimulate) and prevents its deficiency from causing additional protein catabolism. Refeeding the patient as soon as practicable is useful since more calories can be administered this way. The use of essential amino acid formulations in feeding can reduce the amount of proteinnecessarytomeetbasicneeds.Table1isextractedfromSinghetaland lists the proposed caloric needs for patients with urea cycle disorders.

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Emergency pharmacologic management with ammonia scavengers and arginine is initiated as soon as possible using the drug combination sodium phenylacetateandsodiumbenzoate(Ammonul,UcyclydPharma),ideallywhilethedialysisisbeingarrangedandthediagnosticworkupisunderway.Twoagentsareusedincombinationtotrapnitrogeninexcretableforms.Sodiumbenzoatecombineswithglycinetomakehippuratewhichisexcretedbythekidneys(orremovedinthedialysate),andsodiumphenylacetatecombineswithglutaminetomakephenacetylglutaminewhichisalsoexcretedintheurine.Thebodyreplacestheseaminoacidsusingexcessnitrogen.Itissuspectedthattheremovalofglutamineby phenylacetate has the additional benefit of removing a compound suspectedofhavingamajorroleintheneurotoxicityofthesedisorders.Currently administering a second loading dose to the patient after the initialphaseisnotrecommended.Argininemustalsobeadministeredcontinuouslyintheacutephaseoftreatmentofureacycledisorders.Inaddition to replenishing circulating amino acid levels, arginine can utilize thosepartsofthecyclenotaffectedbygeneticblocksandincorporatesomenitrogen.Sincearginineistheprecursorfornitricoxideproduction,it is worth considering modification of the arginine dose downward if the patient develops vasodilation and hypotension. Table 2 lists doses for the acute management of these patients according to the diagnosis at the time oftreatment(informationextractedfromFDApackageinsert).Duetothe

Table 1

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potentialfortoxicity(lethalinextremecases)ofthesedrugsconsultationwithanexperiencedmetabolicphysicianisrecommendedbeforestartingtreatment.Aresourceforfindingthesephysiciansandothertreatmentsuggestions is found in the home page for this web site at: http://www.rarediseasesnetwork.org/ucdc

Table 2

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Aftertheinitialloadingphaseanddialysis,thepatient’sdoseshouldbeconverted to the maintenance doses of the ammonia scavengers listed in themanufacturerspackaginginsert(Table1).Iftheexactenzymedefectisknowntheamountofarginineadministeredcanbeadjusteddownward.Ifchronictherapyiswarranted,thepatientcanthenbeswitchedtotheoralpro-drugofphenylacetate,phenylbutyrate(Buphenyl).TheusualtotaldailydoseofBuphenylTabletsandPowderforpatientswithureacycledisordersis450–600mg/kg/dayinpatientsweighinglessthan20kg,or9.9–13.0g/m²/dayinlargerpatients.Thetabletsandpowderaretobetakeninequallydividedamountswitheachmealorfeeding(i.e.,threetosixtimesperday).Citrullinesupplementationisrecommendedfor patients diagnosed with deficiency of n-acetylglutamate synthase, carbamylphosphate synthetase or ornithine transcarbamylase; citrulline dailyrecommendedintakeis0.17g/kg/dayor3.8g/m2/day.Argininesupplementation is needed for patients diagnosed with deficiency of argininosuccinicacidsynthetase;arginine(freebase)dailyintakeisrecommendedat0.4–0.7g/kg/dayor8.8-15.4g/m2/day.Inpatientswith n-acetylglutamate synthetase, the use of carbamyl glutamate has beendemonstratedtobeveryeffective,andisnowFDAapprovedforthisdisorder.Thepackageinsertshouldbeconsultedfordosing.

Inallinstancesintensivecaretreatmenthastobemeticulous.Ventilatororcirculatorysupportmayberequired.Anticonvulsivemedicationtocontrolseizures and sedation or head cooling to reduce cerebral activity could be of benefit to these patients but has not been clinically evaluated for effect. Antibiotictherapyandevaluationforsepsisisrecommendedbecausesepsis is an important consideration in the primary presentation and if present may lead to further catabolism. Electrolytes and acid-base balance aretobecheckedevery6hoursduringtheinitialphaseoftreatment.The use of osmotic agents such as mannitol is not felt to be effective in treating the cerebral edema from hyperammonemia but this is mainly anecdotal.Incanines,openingthebloodbrainbarrierwithmannitolresulted in cerebral edema by promoting the entry of ammonia into the brainfluidcompartment.Intravenoussteroidsandvalproicacidshouldbeavoided. Other measures include physiologic support (pressors, buffering agents to maintain pH and buffer arginine HCl, etc.) and maintenance of renal output, particularly if ammonia scavengers are being used. Finally, it is imperative to reassess continuation of care after the initial phase of treatment.

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Rapid response to the hyperammonemia is indispensable for a good outcome.Acutesymptomatologycentersaroundcerebraledema,disruptions in neurochemistry and pressure on the brainstem. The resulting decrease in cerebral blood flow plus prolonged seizures, when they occur, arepoorprognosticfactors.Inadults,becausethesuturesoftheskullarefused, sensitivity to hyperammonemia appears considerably greater than in children. Thus treatment should be aggressive and intensified at a lower ammonia concentration than in children.

Neurologic Evaluation Cerebral studies should be conducted to determine the efficacy of treatmentandwhethercontinuationiswarranted.EEGshouldbeperformed to assess both cerebral function and evidence of seizure activity. Ifavailable,MRI-determinedcerebralbloodflowcanbeusedtoestablishifvenous stasis has occurred from cerebral edema. Evaluation of brainstem function and higher cortical function are useful to assess outcome. Finally, the decision for continuation is based on baseline neurologic status, duration of the patient’s coma and potential for recovery, and whether the patientisacandidatefortransplantation.Ifthebasicureacycledefectis severe enough, liver transplantation should be considered. Criteria for transplantationareofcourselinkedbacktoneurologicstatus,durationofcoma,andavailabilityofdonororgans.DiagnosticsamplesofDNA,liver,andskinshouldbeobtainedsincetheycanbecentralinfamilycounselingand future treatment issues.

Long-Term Management Everyeffortshouldbemadetoavoidtriggeringevents.Itisimperativetopreventorquicklyinterruptacatabolicstateatanearlystageofimpendingdecompensation during subsequent illnesses or surgeries, as well as during anyeventresultinginsignificantbleedingortissuedamage.Asthisusually happens at home, it is essential to educate the family about how to reactadequately.Allpatientsshouldcarryanemergencycardorbraceletcontaining essential information and phone numbers as well as instructions on emergency measures. Every patient should relate to physicians and a hospital with a dedicated team of metabolic specialists who can be reached at any time. For vacations it is usually prudent to enquire about metabolic services in the respective destination.

Long-termdietmodificationwithnutritionaloversightisnecessaryinpatientswithureacycleenzymedefects.Patientsshouldalsoavoid

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dehydration, an especially common occurrence among adults in connection withalcoholintake,excessiveexercise,hiking,andairlineflights.Notall adult patients who recover from a hyperammonemic episode require chronic nitrogen scavengers, but they ought to be considered since many ofthesepatientscanbecomemorebrittleastimegoeson.Inparticular,IVsteroids for asthma and administration of valproic acid are contraindicated.

Shouldpsychiatricproblemsoccuroverthelongterm,caregiversshouldbealerttothepossibilityofhyperammonemia.Inaddition,manypatientswithcitrullinemia type 2, in particular, have presented with mental disturbance.

Clinical observations of patients with argininosuccinic acid lyase deficiency demonstrate a high incidence of chronic progressive cirrhosis with eventual fibrosis of the liver. This finding is not commonly seen in the other urea cycledisordersandstudiesareunderwaytobetterdeterminetheexactpathophysiology.Itisimportanttoprovidegeneticcounselinginordertoassessrisktootherfamilymembers.

Clinical Testing and Work-Up: For patients with UCD during initial presentation the following are suggested: •HeadUltrasound •MRIoftheheaduponstabilization •HearingScreenatDischarge •VisionScreenatDischarge

For long term management the following are suggested: •Developmentaltesting •ForASS,ASLpatientsechocardiogramevery2yearslookingfor pulmonary hypertension •ForpatientswithallUCD:annualabdominalultrasoundand alpha-fetoprotein after age 20.

For routine clinic visits: •Dietaryhistory •Aminoacidprofile •Growthparameters •Ammonia

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Investigational Therapies

Informationoncurrentclinicaltrialsispostedatwww.clinicaltrials.govAllstudiesreceivingU.S.governmentfunding,andsomesupportedbyprivateindustry, are posted on this government web site.

For information about clinical trials sponsored by private sources, contact: www.centerwatch.com

NORD does not endorse or recommend any particular studies.

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51.Seminara,J.,Tuchman,M.,Krivitzky,L.,Krischer,J.,Lee,H.S.,Lemons,C.,Baumgartner,M.,Cederbaum,S.,Diaz,G.A.,Feigenbaum,A.,Gallagher,R.C.,Harding,C.O.,Kerr,D.S.,Lanpher,B.,Lee,B.,Lichter-Konecki,U.,McCandless,S.E.,Merritt,J.L.,Oster-Granite,M.L.,Seashore,M.R.,Stricker,T.,Summar,M.,Waisbren,S.,Yudkoff,M.,andBatshaw,M.L.Establishingaconsortiumforthestudyofrarediseases:TheUreaCycleDisordersConsortium.Mol.Genet.Metab.100Suppl1:Pages:S97-105.2010.PM:20188616

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24

Resources

NIHRareDiseasesClinicalResearchNetwork:UreaCycleDisordersConsortium (treatment, studies, education): http://rarediseasesnetwork.epi.usf.edu/ucdc/index.htm

National Urea Cycle Disorders Foundation (information, referrals, resources, patient/family education and support) http://www.nucdf.org/75S.GrandAve. Pasadena,CA91105 Phone:(626)578-0833 TollFree:(800)386-8233 Email: [email protected]

EuropeanNetworkandRegistryforIntoxicatingMetabolicDiseases http://www.e-imd.org/en/index.phtml

GeneTests:http://www.ncbi.nlm.nih.gov/sites/GeneTests/

Acknowledgements

NORDisgratefultothefollowingmedicalexpertforservingasauthorofthisPhysicianGuide:

MarshallSummar,MD DivisionChief,GeneticsandMetabolism CenterforNeuroscienceandBehavioralMedicine Children’sNationalMedicalCenter WashingtonDC

NORDalsogratefullyacknowledgestheassistanceofCynthiaLeMons,ExecutiveDirector,NationalUreaCycleDisordersFoundation,inthepreparationofthisGuide.

This NORD Physician Guide was made possible by an educational grant from Cytonet.

Patient Support and Resources National Organization for Rare Disorders (NORD) 55KenosiaAvenue POBox1968 Danbury,CT06813-1968 Phone:(203)744-0100 Toll free: (800) 999-NORD Fax:(203)798-2291

www.rarediseases.org [email protected]

NORD gratefully acknowledges the assistance of the following medical expert in the preparation of this booklet:

Marshall Summar, MD DivisionChief,GeneticsandMetabolism Center for Neuroscience and BehavioralMedicine Children’sNationalMedicalCenter WashingtonDC

NORD Guides for Physicians

#1 The Pediatrician’s Guide to Tyrosinemia Type 1

#2 The Pediatrician’s Guide to Ornithine Transcarbamylase Deficiency...and other Urea Cycle Disorders

#3 The Physician’s Guide to Primary Lateral Sclerosis

#4 The Physician’s Guide to Pompe Disease

#5 The Physician’s Guide to Multiple System Atrophy

#6 The Physician’s Guide to Hereditary Ataxia

#7 The Physician’s Guide to Giant Hypertrophic Gastritis and Menetrier’s Disease

#8 The Physician’s Guide to Amyloidosis

#9 The Physician’s Guide to Medullary Thyroid Cancer

#10 The Physician’s Guide to Hereditary Angioedema (HAE)

#11 The Physician’s Guide to The Homocystinurias

#12 The Physician’s Guide to Treacher Collins Syndrome

These booklets are available free of charge. To obtain copies, call or write to NORD or download the text from www.rarediseases.org.

This booklet was made possible through an educational grant from Cytonet.

For information on rare disorders and the voluntary health organi-zations that help people affected by them, visit NORD’s web site at www.rarediseases.org or call (800) 999-NORD or (203) 744-0100.

NORD helps patients and families affected by rare disorders by providing:

• Physician-reviewedinformation in understandable language

• Referralstosupportgroupsand other sources of help

• Networkingwithotherpatients and families

• Medicationassistanceprograms

• Grantsandfellowshipsto encourage research on rare diseases

• Advocacyforhealth-related causes that affect the rare- disease community

• Publicationsforphysiciansand other medical professionals

Contact NORD at [email protected].

National Organization for Rare Disorders (NORD)POBox1968Danbury,CT06813-1968Phone:(203)744-0100Toll free: (800) 999-NORDFax:(203)798-2291