Diagnosis of IEM

AndEmergency Management

Susan Sklower Brooks, M.D., F.A.C.M.G.Professor of Pediatrics

Professor of Obstetrics, Gynecology and Reproductive SciencesRobert Wood Johnson Medical School

What do they have in common?

A full term 4 day old?A 2 year old from Pakistan?An 8 year old at summer camp?An 18 year old college student?

What Do They Have In Common?

1. An infectious disease?

2. A congenital heart disease?

3. An inborn error of metabolism?

4. Who cares?

An infec

tious

dise

ase?

A cong

enita

l hea

rt di...

An inbor

n erro

r of m

e...

Who cares

?

0% 0%

100%

0%

Case ReportThe 2 year old child became The 2 year old child became unresponsive while traveling with unresponsive while traveling with her parents on the New her parents on the New JerseyJersey Turnpike. Turnpike.

Summer Camp Escapade

The 8 year old went to sleep-away camp for the first time. After several days she became increasing lethargic and was brought to a local ED. On arrival she was barely arousable.

College Binge?

The 18 year old college student was brought to the ED unresponsive. She had been at a prefinal party with friends where alcohol was served.

What is the likely diagnosis?

1. Inborn Error of Metabolism?

2. Still not sure?3. Who cares?

Inborn Erro

r of M

eta...

Still not

sure?

Who cares

?

94%

0%6%

Inborn Errors of MetabolismAmino acid disordersOrganic acidemiasUrea cycle disordersCarbohydrate metabolism disordersMitochondrial disordersMitochondrial fatty acid oxidation disordersPeroxisomal disordersLysosomal storage disordersPurine and pyrimidine disordersPorphyriasMetal metabolism disorders

IntoxicationEnergy MetabolismComplex Molecules

Major Presentation Categories for Inborn Errors of Metabolism

Saudubray, JM et al, Semin Neonatol 2002: 7:3-15

Intoxication

Symptom free interval- vomiting, lethargy coma, liver failure, etcOften treatable with diet or cofactorSmall molecule disease – amino acids, organic acids, fatty acid

Disorders of Energy Metabolism

Hypoglycemia, failure to thrive, lactic acidemia, hypotonia, myopathy, SIDSMitochondrial Disorders

Complex Molecules

Permanent and progressive symptomsLysosomal, peroxisomalFor Some Enzyme Replacement Therapies

Amino/Organic Acid DisordersDisorders of Intermediary Metabolism– Failure in breakdown pathways of amino

acids• Amino acid – Amine (NH2) = Organic Acid

– Examples of Amino acid disorders• PKU, Homocystinemia, Tyrosinemia

– Examples of Organic acid disorders• Methylmalonic acidemia, propionic acidemia

Amino Disorder Presentation

Generally non-acuteVarious symptoms dependent on disorder– Homocystinuria – thrombosis– Tyrosinemia – liver disease– PKU – hypopigmentation, seizures,

intellectual disability

Organic Acidemias

Neonatal presentation:– Uncomplicated pregnancy– Hypo or hypertonia– Feeding problems– Seizures– Lethargy– Unusual odors– Metabolic encephalopathy– Cerebral edema, coma, – Multi-organ failure and death

Lab Findings– Hypoglycemia– Metabolic acidosis– Hyperammonemia– Ketosis

Organic acids = Amino Acids with the Amine group (NH2) removed

PRESENTATION: Neonatal to Adult onset

Urea Cycle Disorders

Primary functions of Urea cycle:– elimination of waste nitrogen as urea to

avoid accumulation of toxic nitrogen compounds

– synthesis of arginine

Urea Cycle Disorders – Neonatal Onset

Lethargy by 48 - 72hrsVomitingHypothermiaTachypnea and apneaSeizuresCerebral edemaMetabolic alkalosisDeath

Urea Cycle Disorders - Late Onset

1 yr through adulthoodHyperammonemic

episodes confusion comaAssociated with change in diet,

illness (infection), surgery

Fatty Acid Oxidation Disorders

Fatty acid transport and mitochondrial oxidation plays major role in energy production→ times of fasting and metabolic stress

Presentation of FAOD

CardiomyopathyMyopathyEncephalopathySudden death

HypoketotichypoglycemiaElevated transaminasesElevated uric acidElevated CK

Full Term 4 Day OldA 4-day-old male is brought to an ER by his parents because of poor feeding

– Mother reports decreased feeding beginning on DOL # 3

– 2 episodes of vomiting on DOL # 3

– On DOL # 4, pt was less active, and went 6 hours without feeding or voiding

Birth History

Mother GBS+, all other labs negativeMother adequately treated with 2 doses of antibioticsROM = 12 hours, no maternal feverNSVD at 37 weeks gestationBW = 2.3 kg Discharged from nursery on DOL # 2Newborn screen sent on DOL # 2Formula feeding Q3 hours upon discharge

Physical Exam

Weight 2.0 kg (down 14% from BW)Length and HC: 50th percentileTemp=92o, BP=56/28, HR=120, RR=36Hypoactive infant with poor interactionAF sunken and dry mucous membranesNormal facies

Clinical CoursePatient became less responsive and developed worsening respiratory distressProgressed to cardio-pulmonary arrestResuscitated, and maintained on mechanical ventilation and vasoactive medicationsDeveloped seizure activity and was maintained on anticonvulsants

What are you thinking?

1. Sepsis2. Cardiac 3. Metabolic4. Inexperienced

parent

Sepsis

Cardiac

Meta

bolic

Inexperi

ence

d pare

nt

9%0%

91%

0%

What laboratory studies should you order?1. Blood Gas2. CBC3. Ammonia4. Electrolytes5. LFTs6. UA7. Lactic acid8. All of the above

Blood G

as

CBCAmmon

iaElec

trolyt

es

LFTs UA

Lacti

c acid

All of t

he ab

ove

0% 0% 0%

100%

0%0%0%0%

146 113 27 7.6 (Ca2+) 17.2 6.3 <5 2.4 38 (Gluc) 3.9 380

55.9

pH 7.13 pCO2 11 HCO3 <5 pO2 236

Lactate 0.8Ammonia = >1190

TP 5.6TP 5.6 AP 108AP 108Alb 3.1Alb 3.1 AST 50AST 50TB 12.4TB 12.4 ALT 36ALT 36UA: 5.5 / 1.025 /

2+ Ketones and Protein

What do we know…

Neonate in comaHypoglycemiaSevere metabolic acidosisHyperammonemiaKetonuria

Algorithm for the Diagnosis of the Neonate in ComaModified from Hoffmann et al, Inherited Metabolic Diseases, 2002

Blood: NH3 , pH, Electrolytes, Urine: Ketones

NH3

No AcidosisNH3 normalNo Acidosis

NH3 +/-Acidosis +Ketones ++Anion gap

Urea cycle defectHHH syndromeTransient hyperammonemia of the newborn

Organic acidemia (propionic, isovaleric, etc

Organic Acids

Organic AcidsAmino Acids

Amino acidemiaOrganic acidemia

Amino Acids

Treatment

AirwayCorrect dehydration and acidosisPrevent catabolism by providing calories (glucose at least 6 mg/kg/min; insulin if needed; intralipids)Stop potential toxins (Protein)Remove toxins (dialysis, activation of alternative pathways)Therapeutic cocktail (B12, folate, biotin, carnitine)Obtain urine and plasma for diagnostic testsCheck newborn screen results

Ogier de Baulny, H. Semin Neonatol 2002:7:17-26

Diagnosis?1. Fatty acid

oxidation disorder

2. Amino acidemia3. Organic

acidemia4. Mitochondrial5. Urea cycle

defect

Fatty a

cid oxid

ation d...

Amino acidem

ia

Organ

ic ac

idemia

Mitoch

ondrial

Urea cy

cle defe

ct

4% 8% 4%0%

83%

Further Studies Help Make the Specific Diagnosis

NBS contacted – increased C3 on screen – C3 elevation MMA, PA, Multiple CoA Carboxylase

DefAcylcarnitine profile confirmed elevated C3-carnitineUrine studies showed high levels of the following organic acids in his urine:• Methylcitrate which is formed from conjugation of

propionyl-coA with oxaloacetate– Propionylglycine, which results from conjugation of

propionyl-coA with glycine– Tiglylglycine, which results from incomplete isoleucine

catabolism

Diagnosis:

NBS reported elevated C3Differential: Propionic vs MethylmalonicacidemiaFINAL DIAGNOSIS: Propionic AcidemiaLong term treatment: restrict propiogenic amines (methionine, valine, isoleucine,threonine) by special diet; antibiotics to decrease gut bacteria

Case ReportA 2 year old child became unresponsive while A 2 year old child became unresponsive while traveling with her parents on the New Jersey traveling with her parents on the New Jersey Turnpike. Turnpike.

Initial treatment

EMS was called and took the child to the nearest emergency room where she was in coma and found to have pH of 6.9. – She was given IV hydration and

bicarbonate and transferred to the BMSCH

History

Mother and children flew into JFK on day of admission from Pakistan (18 hr flight). On the flight baby was given milk and juice. On arrival she was noted to be lethargic but family thought it was from the long travel.

Additional HistoryPast Medical History:– Born in Pakistan

Hospitalizations:– DOL 8 - persistent vomiting – 5 months - acidosis, apnea, bradycardia.

Intubated and treated with electrolyte solutions. When discharged parents told to give her ½ strength Good Start formula, no meat, no eggs or dairy.

Development: walking and talkingFamily Hx: Parents 1st cousins

Exam

Patient sedated and intubatedNormal faciesNo liver or spleen enlargementNo skin lesions

Initial labs on ArrivalpH 6.997pCO2 5.0 pO2 59 HCO3 1.2Na 146 Cl 112 HCO3 10 CA 8.9K 4.5 BUN 17 Glu 227Urine Ketones 2+NH4 37AST 32 ALT 17 Lactate 1.9

Anion Gap = Na+ - (Cl-+HCO3) Normal =10 +/- 4146 – (112+10) = 24

What do we know…

Acute episodic decompensationProlonged air flight – poor feeding, dehydration, high protein,

lactose+ feedParental consanguinitySevere metabolic acidosisRaised anion gap, ketone +Normal ammonia, lactate, LFT, glucose

Treatment

AirwayCorrect dehydration and acidosis – always D10 or higherPrevent catabolism by providing caloriesStop potential toxins (Protein)Remove toxins (consider dialysis, activation of alternative pathways)Therapeutic cocktail (B12, folate, biotin, carnitine)Obtain urine and plasma for diagnostic tests

Prolonged Hospital Course

Respiratory support - intubationHypotension requiring vasopressinSeizure-like activity – CT scan – large basal ganglia hypodensities, mildly enlarged ventricles

Diagnosis

Amino acids – essentially normalOrganic Acids – urine MMA very high

DX: METHYLMALONIC ACIDURIA Later testing showed:– CblA B12 responsive– mutation 433C>T (R145X) homozygote – a

common mutation in the MMA gene

Propionic and Methylmalonic Acidemia

Thymineuracilvalineisoleucinemethioninethreoninecholesterolodd chain fatty acids

Propionyl-CoA D-CH3 malonyl-CoA L-CH3 malonyl-CoA Succinyl CoA

Propionyl CoA Carboxylase

Methylmalonyl CoA racemase

Methylmalonyl CoA mutase

BIOTINADENOSYL

COBALAMIN (B12)

PROPIONIC ACID METHYLMALONIC ACID

Methylmalonic Acidemia

B12 Responsive Cobalamin Defects–– CblCbl A, B, H A, B, H -- faulty faulty

cobalamincobalamin synthesissynthesis–– CblCbl C, D, C, D, --

cobalaminecobalamine impaired impaired methyl and methyl and adenosylcobalaminadenosylcobalamin productionproduction

–– CblFCblF –– impaired impaired transporttransport

B12 Unresponsive Mutase defects–– Mut0 Mut0 –– no no mutasemutase

activityactivity–– MutMut++-- some some mutasemutase

activityactivity

A Case of CblC MMA/HCYsBefore treatment:

Neonatal Coma requiring ventilator support

With treatmentNo metabolic crisisGaining milestones

Metabolic Acidosis from IEMMetabolic Acidosis from IEM

Metabolic Acidosis

Anion Gap >16

+Hyperchloremia : GI losses, RTA, galactosemia,

NoNo

YesYes+Ketones

NoNo

+Hypoglycemia, Fatty acid oxidation defect

YesYes NormalNormal

AbnormalAbnormal ElevatedElevated

Amino & Organic Acids

Lactate/Pyruvate

Amino Aciduria

Organic Aciduria

Mitochondrial Energy Defect

NormalNormal

Hypoglycemia?

YesYesGlycogen Storage Disease, Gluconeogenesis defect

Pyruvate Dehydro- genase, Pyruvate Carboxylase

NoNo

Chart adapted from Dr. S. Lowe

When Should You Consider An IEM?Newborn period– Acute neurological decline

• Lethargy• Decreased feeding• Vomiting, diarrhea, dehydration• Seizures

Acidosis (especially if elevated anion gap)TachypneaHypo (or hyper) glycemiaHyperammonemia

Neonate’s response to severe illness

Respiratory distressHypotoniaPoor suckVomiting/diarrheaLethargy/Coma

Work-up of sick neonate

CXRCSFCulturesHead ultrasound

If the above are normal, in an infant who was initially well and then deteriorated, ….

THINK INBORN ERROR OF METABOLISM

Further Presentations

Up to the seventh decade of life“Recurrent syndromes”– Stupor, lethargy– Emesis; often with dehydration

Failure to thrive , poor feedingUnusual odors– Sweet (MSUD), sweaty feet, barn-like

Dystonia, choreoathetosis, myoclonus,hypotonia, unexplained seizuresHepatosplenomegalyMR or CP without a clear etiology

How Common Are IEM?1. More common

than childhood leukemia

2. Rare as hen’s teeth

3. Less than 1:10,000

4. Less than 1:20,000

More c

ommon

than

ch...

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s hen

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an 1:

10,00

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an 1:

2000

0

20%

44%

32%

4%

How Common and Why?Individually rare but collectively numerous: 1:2500 newbornsGenetics– Most autosomal recessive– Few X-linked

Pathogenesis– Enzyme deficiencies– Cofactor binding

• problems with transport, absorption, enzyme action

Disease Incidence IEM Incidence Meningitis 1:3,700 Intermediary

Metabolism 1:4,000

Leukemia 1:10,000 PKU 1:10,000

Retinoblastoma 1:20,000 MMA 1:20,000

JRA 1:40,000 Galactosemia 1:35,000

CNS Tumor 1:42,000 Urea Cycle Defects 1:70,000

Chronic Renal Failure

1:100,000 MSUD 1:100,000

Incidence of Childhood Disorders vs. Inborn Errors of Metabolism

History and Physical Findings Suggestive of IEMHistory

Aversion to specific foodsUntoward reaction to childhood illnessesPsychomotor retardationGrowth failurePertinent family history-consanguinityEarly neonatal deaths

Physical FindingsRapid breathingExfoliative dermatitisSeizures and/or coma often with hypotoniaUnusual odorHepatomegalyCataractsMicrocephaly

ED Presentation

Review of 53 pediatric patients who presented to the ED and ultimately were diagnosed with IEM– 85% presented with neurological signs– 58% presented with GI complaints– 51% presented with both neuro and GI

Diagnostic approach to inborn errors of metabolism in an emergency unit.Pediatric Emergency Care. 16(6):405-408, December 2000.CALVO, M. MD, PhD; ARTUCH, R. MD, PhD; MACIA, E. MD; LUACES, C. MD, PhD; VILASECA, M. A. PhD; POU, J. MD, PhD; PINEDA, M. MD, PhD

Keep Your Index of Suspicion High for IEM

Obtain labs during acute episode– CBC with differential and platelets– Chemistries (lytes, ABG, Mg, Ca, LFT,

Glucose, ammonia, lactate, U/A with Ketones)

– Metabolic labs (amino acids plasma, urine, CSF?, plasma acylcarnitine, urine organic acids, urine acylglycine, urine orotic acid

– Freeze urine and plasma for further studies

Summer Camp EscapadeAn 8 year old went to sleep-away camp for the first time. After several days she became increasing lethargic and was brought to a local ED. On arrival she was barely arousable.

She was afebrile, with normal vital signs. The physical examination was unremarkable.

Laboratory studies were normal with the exception of ammonia which was 350.

Transferred to tertiary pediatric center

Suspected Diagnosis?

1. Tick-borne encephalitis

2. New onset seizure disorder

3. Reye Syndrome4. Urea Cycle Defect

Tick-born

e ence

phalitis

New onse

t seiz

ure d

i...Rey

e Syn

drome

Urea C

ycle

Defect

0%

100%

0%0%

Past Medical HistoryRecurrent episodes of vomiting as toddlerSoft neurological findings and learning disabilityHospitalized in infancy twice with gastroenteritis and dehydration. Took longer than usual to recoverLearning disabilityPicky eater – likes sweets and pasta, dislikes milk and meatAte more at camp due to policy of eat all foods on your plate and ask for more of what you like

Does this change your diagnosis? What other labs would you like to see?1. Amino acids2. Organic Acids3. Ketones4. Acylcarnitine

profile5. Amino acids and

organic acids Amino acids

Organ

ic Acid

sKeto

nes

Acylca

rnitin

e pro

file

Amino acids a

nd orga..

.

0%5%

71%

5%

19%

HyperammonemiaInherited Disorders

Urea cycle defectsDefects of urea cycle intermediate transport (HHH, LPI)Organic AciduriasFAOD

Acquired DisordersTransient hyperammonemia of the newbornReye SyndromeLiver FailureValproate therapyInfection with ureasepositive bacteriaLeukemia therapySevere systemic illness

Back to Patient: Additional Laboratory Studies

Amino acids – increased glutamine

Organic acids – increased oroticacid

Diagnosis: Partial Ornithinetranscarbamoylase deficiency (OTC)

The Urea Cycle

http://ureacycle.cnmcresearch.org/otc/

Urea Cycle Disorders - Neonatal Presentation

Normal at birthDevelop poor feeding, vomiting, lethargy, irritability, tachypnea after protein feed (about 24 hrs)Same presentation as SepsisRespiratory alkalosis Family history of unexplained neonatal death

Urea Cycle - Infantile Presentation to Adult

Variable anorexia, lethargy, failure to thrive, migraine/headacheMental status change after proteinSelf selected low protein dietNormal Developmental delayIrritability, behavior problemsIntermittent encephalopathy

OTC Deficiency

X-Linked Urea Cycle DefectIn Males – Severe defect neonatal coma

• massive hyperammonemia– Partial defect later onset

• variable hyperammonemia

In Females– May or may not be symptomatic depending on

Lyonization– Often avoid protein

Genetic Hyperammonemia Differential

ALKALOSIS primary urea cycle defect

ACIDOSIS organic acidemia, mitochondrial, lactic acidosis

HYPOGLYCEMIACARDIAC +/- FAODLIVER +/-,MUSCLE +/-

Treatment

Stop all protein intakeMaintain Anabolism – high glucose infusion with insulin (If FAOD not suspected add Lipid)Remove Ammonia – HemodialysisActivate alternate pathways – sodium benzoate, sodium phenylacetate, arginine/ citrulline (Ammonul)Correct acidosis, fluid and electrolyte balance

College Binge?

An 18 year old college student was brought to the ED disoriented. She had been at a prefinal party with friends where alcohol was served.Friends reported that she didn’t eat all day because she didn’t want to gain weight from the party. She got to the party had one drink and became disoriented and ataxic. They brought her to the ED. She swore she only had one drink.

Initial FindingsVital Signs: Pulse 100, Respiration 20, Blood pressure 70/20, Temp: 98.6

General: drowsy but arousable

Neuro: ataxic gait

CT scan (head) normal

Electrolytes: CO2 18 Anion gap 19

Uric acid=11.2

U/A neg.

Suspected Diagnosis

1. Alcohol intoxication

2. Drugs3. Post-ictal state4. IEM

Alcoho

l intox

icatio

n

Drugs

Post-ic

tal st

ate IEM

0%

96%

0%4%

Received a liter of NS with dextrose with improvement of BP and mental status

Blood alcohol – within legal limit

Tox screen - negative

What do we know?

Fasted Ataxia and stuporHypotensionAlcohol within legal limitNo glucose obtained initially but improved with glucose infusionAcidosis Increased uric acid

Assuming a metabolic disease is likely what tests should be ordered?

1. Acylcarnitine profile

2. Amino acids3. Porphyrins4. Purines and

pyrimidines

Acylca

rnitin

e pro

fileAmino ac

idsPor

phyri

ns

Purines

and p

yrimidines

13%21%

0%

67%

Tests you would order?

Acylcarnitine profile –increased C8

increased dicarboxylic acids (adipic, suberic, sebacic), hexanoylglycine

Consistent with MCAD deficiency

Urine Organic Acid –

FAOD

Hypoglycemia, lethargy, hepatomegaly, cardiomyopathy, liver failure, arrhythmiaLab Findings: no ketosis, ↑ CK, ↑ Uric AcidAcute Treatment: Glucose infusion 10-12 mg/kg/min til stable, thenContinuous enteral feeding low-fat, high glucose, normal proteinL carnitine 100 mg/kg/day (controversial and should be avoided in long chain disorders)

Chronic Treatment of Fatty Acid Oxidation Defect

Avoid fasting!!!Frequent carbohydrate mealsWhen ill institute emergency protocol– Oral hydration if possible (not vomiting,

good appetite)– IV D10 solution 1.5 x maintenance

May decompensate rapidly –err on the side of treatment

MCAD

Most common inherited disorder of fatty acid metabolismIf undiagnosed, mortality rate of 25%Autosomal recessive transmissionMCAD is necessary for mitochondrial beta-oxidation of fatty acids

MCAD Presentation

Classic presentationsSIDs/near-miss SIDsVomiting and lethargy after a period of fasting in a child 3-15 months of ageFew present after 4 years of lifeDecompensate from fasting, febrile illness, stressors (surgery), or alcohol consumption … triggers a Reye’s syndrome like illness

Newborn Screening Revolution

Tandem Mass Spectrometry (MS/MS)– Organic acidopathies– Amino acidopathies– Fatty acid metabolism

MS/MS: Sorts and counts…10

5

4

Newborn Screening: NJ 54 disorders by MS/MS & other technologies

Fatty acid oxidation disordersOrganic AcidemiasUrea Cycle DefectsAmino acid disordersBiotinidaseCAHCFGalactosemiaHemoglobinopathiesHypothyroidism

Sisters with propionic acidemia (www.savebabiescanada.org/FamilyStories/Jennaa)

Glutatic Acidemia I (www.savebabies.org/familystori

es/NikkiGA1.php)

LCHAD www.savebabiescanada.org/.../Andrew_

LCHAD.htm

General Emergency Management for Suspected IEM

Maintain ventilation and circulationAvoid catabolism – high glucose infusion 7-10 mg/kg/min (D10 1.5 X Maintenance)Stop intake of potential toxinCorrect ElectrolytesCorrect acidosisR/O Infection/treatConsult/Transfer Metabolic Center

Some Specific Management of Suspected IEM

Prevent catabolism – IV Glucose 7-10 mg/kg/min +/-intralipid 2 g/kg/d (if FAOD not suspected) Hyperammonemia Suspected Urea Cycle Defect– 250 mg/kg arginine over 90 min, then 250 mg/kg/d via

central line– 250 mg/g NaBenzoate/NaPhenylacetate (ammonul) load

IV over 90-120 min via central line, then 250 mg/kg/d– hemodialysis

Ketotic Hypoglycemia Suspected Organic Acidemia– 50 mg/kg levocarnitine IV loading; 50-100 mg/kg/24 hr– 1 mg B12 IM (hydroxy B12)– Biotin 10 mg PO

Hypoketotic Hypoglycemia Suspected FAOD– Avoid lipid– Avoid fasting– Provide glucose IV or enteral feeding

Toxin RemovalConsider for intoxication states (branch chain organic acidurias, urea cycle defects)Exchange transfusion – least effectivePeritoneal dialysis – 40-50 mg/kg dialysate, 15 min fill, 30 min dwell, 15 min drainage over 24-36 hrs. Simple but complicated by poor drainage, leakage of dialysate, risk of overhydrationHemodialysis – most effective

Vitamin CofactorsBiotin 10-20 mg/day Propionic, MCD, PC

Carnitine 50-100 mg po, 400 mg IV

100 mg po, iv

BCOA, Primary hyperammonemia, hyperlacticacidemiaFAOD

Cobalamin, B12 1-2 mg/day MMA

Folinic acid 10-40 mg/day Folinic acid responsive sx

Pyridoxine 50-100 mg/day Pyridoxine responsive sx

Riboflavin 20-40 mg/day Glutaric acidemia, FAOD

Thiamine, B1 10-50 mg/day MSUD, hyperlacticacidemia

HyperammonemiaLab findings: ammonia >400 μmol/l respiratory alkalosisMay have significant handicap despite treatmentTreatment:– Hemodialysis– High energy, protein-free nutrition– When NH3 < 150 add protein (iv amino acids)– Sodium benzoate 250 mg/kg load over 90-120 min

and 250 mg/kg/day; sodium phenylbutyrate 250 mg/kg load over 90-120 min and 250 mg/kg/day (Ammonul = 10% solution of above)

– L arginine 200 mg/kg/day iv– L-carnitine 400 mg IV

REMEMBER…. Inborn Errors of Metabolism Individually rare….but collectively numerous. Keep your index of suspicion high.