Inbornerrorsofmetabolismturningpoint10_2012.pdf

Diagnosis of IEM And Emergency Management Susan Sklower Brooks, M.D., F.A.C.M.G. Professor of Pediatrics Professor of Obstetrics, Gynecology and Reproductive Sciences Robert 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? An infectious disease? 2. A congenital heart disease? 3. An inborn error of metabolism? 4. Who cares? 1.

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The 2 year old child became Case Reportwhile traveling with unresponsive her parents on the New Jersey 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? Inborn Error of Metabolism? 2. Still not sure? 3. Who cares?

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Inborn Errors of Metabolism ƒ ƒ ƒ ƒ ƒ ƒ ƒ ƒ ƒ ƒ ƒ

Amino acid disorders Organic acidemias Urea cycle disorders Carbohydrate metabolism disorders Mitochondrial disorders Mitochondrial fatty acid oxidation disorders Peroxisomal disorders Lysosomal storage disorders Purine and pyrimidine disorders Porphyrias Metal metabolism disorders

Major Presentation Categories for Inborn Errors of Metabolism „ Intoxication „ Energy

Metabolism „ Complex Molecules

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

Intoxication „ Symptom

free interval-Æ vomiting, lethargy coma, liver failure, etc „ Often treatable with diet or cofactor „ Small molecule disease – amino acids, organic acids, fatty acid

Disorders of Energy Metabolism „ Hypoglycemia,

failure to thrive, lactic acidemia, hypotonia, myopathy, SIDS „ Mitochondrial Disorders

Complex Molecules „ Permanent

and progressive symptoms „ Lysosomal, peroxisomal „ For Some Enzyme Replacement Therapies

Amino/Organic Acid Disorders „ Disorders

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-acute „ Various symptoms dependent on disorder – Homocystinuria – thrombosis – Tyrosinemia – liver disease – PKU – hypopigmentation, seizures, intellectual disability

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

PRESENTATION: Neonatal to Adult onset „

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

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 - 72hrs Vomiting Hypothermia Tachypnea and apnea Seizures Cerebral edema Metabolic alkalosis Death

Urea Cycle Disorders - Late Onset 1 yr through adulthood „ Hyperammonemic episodesÆconfusionÆcoma „ Associated 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 „ „ „ „

Cardiomyopathy Myopathy Encephalopathy Sudden death

„ „ „ „

Hypoketotic hypoglycemia Elevated transaminases Elevated uric acid Elevated CK

Full Term 4 Day Old „A

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 negative Mother adequately treated with 2 doses of antibiotics ROM = 12 hours, no maternal fever NSVD at 37 weeks gestation BW = 2.3 kg Discharged from nursery on DOL # 2 Newborn screen sent on DOL # 2 Formula feeding Q3 hours upon discharge

Physical Exam „ Weight

2.0 kg (down 14% from BW) „ Length and HC: 50th percentile „ Temp=92o, BP=56/28, HR=120, RR=36 „ Hypoactive infant with poor interaction „ AF sunken and dry mucous membranes „ Normal facies

Clinical Course „ Patient

became less responsive and developed worsening respiratory distress „ Progressed to cardio-pulmonary arrest „ Resuscitated, and maintained on mechanical ventilation and vasoactive medications „ Developed seizure activity and was maintained on anticonvulsants

What are you thinking? Sepsis 2. Cardiac 3. Metabolic 4. Inexperienced parent 1.

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What laboratory studies should you order?

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Blood Gas CBC Ammonia Electrolytes LFTs UA Lactic acid All of the above B lo od

1.

146 6.3

113 27 <5 2.4

pH 7.13

7.6 (Ca2+) 38 (Gluc)

pCO211

17.2 3.9 380 55.9

HCO3<5

pO2 236

Lactate 0.8 Ammonia = >1190 UA: 5.5 / 1.025 / 2+ Ketones and Protein

TP 5.6 Alb 3.1 TB 12.4

AP 108 AST 50 ALT 36

What do we know… „ Neonate

in coma „ Hypoglycemia „ Severe metabolic acidosis „ Hyperammonemia „ Ketonuria

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

Blood: NH3, pH, Electrolytes, Urine: Ketones

NH3 No Acidosis

NH3 +/Acidosis + Ketones ++ Anion gap

NH3 normal No Acidosis

Amino acidemia Organic acidemia Urea cycle defect HHH syndrome Transient hyperammonemia of the newborn Amino Acids

Organic acidemia (propionic, isovaleric, etc Organic Acids

Organic Acids Amino Acids

Treatment „ „ „ „ „ „ „ „

Airway Correct dehydration and acidosis Prevent 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 tests Check newborn screen results

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

Diagnosis?

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Fatty acid oxidation disorder Amino acidemia Organic acidemia Mitochondrial Urea cycle defect Fa tty

1.

Further Studies Help Make the Specific Diagnosis „

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

„

Acylcarnitine profile confirmed elevated C3carnitine „ Urine 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 C3 „ Differential: Propionic vs Methylmalonic acidemia „ FINAL DIAGNOSIS: Propionic Acidemia „ Long term treatment: restrict propiogenic amines (methionine, valine, isoleucine,threonine) by special diet; antibiotics to decrease gut bacteria

Case Report A 2 year old child became unresponsive while traveling with her parents on the New Jersey 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 History „

Past 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 talking Family Hx: Parents 1st cousins

Exam „ Patient

sedated and intubated „ Normal facies „ No liver or spleen enlargement „ No skin lesions

Initial labs on Arrival „ „ „ „ „

„ „ „

pH 6.997 pCO2 5.0 pO2 59 HCO3 1.2 Na 146 Cl 112 HCO3 10 CA 8.9 K 4.5 BUN 17 Glu 227 Urine Ketones 2+ NH4 37 AST 32 ALT 17 Lactate 1.9 Anion Gap = Na+ - (Cl-+HCO3) Normal =10 +/- 4 146 – (112+10) = 24

What do we know… „ Acute

episodic decompensation „ Prolonged air flight – poor feeding, dehydration, high protein, lactose+ feed „ Parental

consanguinity „ Severe metabolic acidosis „ Raised anion gap, ketone + „ Normal ammonia, lactate, LFT, glucose

Treatment „ „ „ „ „ „ „

Airway Correct dehydration and acidosis – always D10 or higher Prevent catabolism by providing calories Stop 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 - intubation „ Hypotension requiring vasopressin „ Seizure-like activity – CT scan – large basal ganglia hypodensities, mildly enlarged ventricles

Diagnosis „ Amino

acids – essentially normal „ Organic 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 Thymine uracil valine isoleucine methionine threonine cholesterol odd chain fatty acids BIOTIN Propionyl-CoA

D-CH3malonyl-CoA

Propionyl CoA Carboxylase

PROPIONIC ACID

ADENOSYL COBALAMIN (B12) L-CH3malonyl-CoA Succinyl CoA

Methylmalonyl CoA racemase

Methylmalonyl CoA mutase

METHYLMALONIC ACID

Methylmalonic Acidemia „

B12 Responsive Cobalamin Defects – Cbl A, B, H - faulty cobalamin synthesis – Cbl C, D, cobalamine impaired methyl and adenosylcobalamin production – CblF – impaired transport

„

B12 Unresponsive Mutase defects – Mut0 – no mutase activity – Mut+- some mutase activity

A Case of CblC MMA/HCYs Before treatment: Neonatal Coma requiring ventilator support

With treatment No metabolic crisis Gaining milestones

Metabolic Acidosis from IEM Glycogen Storage Disease, Gluconeogenesis defect

Metabolic Acidosis

No

Yes Hypoglycemia?

Normal Yes Anion Gap >16

No +Hyperchloremia : GI losses, RTA, galactosemia,

Yes +Ketones

No +Hypoglycemia, Fatty acid oxidation defect Chart adapted from Dr. S. Lowe

Normal Amino & Organic Acids

Abnormal

Amino Aciduria Organic Aciduria

Lactate/Pyruvate

Elevated

Mitochondrial Energy Defect

Pyruvate Dehydrogenase, Pyruvate Carboxylase

When Should You Consider An IEM? „

Newborn period – Acute neurological decline • • • •

„ „ „ „

Lethargy Decreased feeding Vomiting, diarrhea, dehydration Seizures

Acidosis (especially if elevated anion gap) Tachypnea Hypo (or hyper) glycemia Hyperammonemia

Neonate’s response to severe illness „ Respiratory

distress

„ Hypotonia „ Poor

suck „ Vomiting/diarrhea „ Lethargy/Coma

Work-up of sick neonate „ CXR „ CSF „ Cultures „ Head

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 feeding Unusual odors – Sweet (MSUD), sweaty feet, barn-like

„ „ „

Dystonia, choreoathetosis, myoclonus,hypotonia, unexplained seizures Hepatosplenomegaly MR or CP without a clear etiology

How Common Are IEM?

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More common than childhood leukemia Rare as hen’s teeth Less than 1:10,000 Less than 1:20,000 M or e

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How Common and Why? „ „

Individually rare but collectively numerous: 1:2500 newborns Genetics – Most autosomal recessive – Few X-linked

„

Pathogenesis – Enzyme deficiencies – Cofactor binding • problems with transport, absorption, enzyme action

Incidence of Childhood Disorders vs. Inborn Errors of Metabolism Disease

Incidence

IEM

Incidence

Meningitis

1:3,700

1:4,000

Leukemia

1:10,000

Intermediary Metabolism PKU

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

1:10,000

1:100,000

History and Physical Findings Suggestive of IEM History „ „ „ „ „

„

Physical Findings

Aversion to specific „ foods „ Untoward reaction to „ childhood illnesses Psychomotor „ retardation „ Growth failure „ Pertinent family „ historyconsanguinity Early neonatal deaths

Rapid breathing Exfoliative dermatitis Seizures and/or coma often with hypotonia Unusual odor Hepatomegaly Cataracts Microcephaly

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 Escapade ƒ An 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.

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

ƒ

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

Transferred to tertiary pediatric center

Suspected Diagnosis? 100%

Tick-borne encephalitis 2. New onset seizure disorder 3. Reye Syndrome 4. Urea Cycle Defect 1.

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Past Medical History „ „ „ „ „ „

Recurrent episodes of vomiting as toddler Soft neurological findings and learning disability Hospitalized in infancy twice with gastroenteritis and dehydration. Took longer than usual to recover Learning disability Picky eater – likes sweets and pasta, dislikes milk and meat Ate 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?

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Amino acids Organic Acids Ketones Acylcarnitine profile Amino acids and organic acids

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Hyperammonemia Acquired Disorders Inherited Disorders „ Transient „ Urea cycle defects hyperammonemia of „ Defects of urea the newborn cycle intermediate „ Reye Syndrome transport (HHH, LPI) „ Liver Failure „ Organic Acidurias „ Valproate therapy „ FAOD „ Infection with urease „ „

positive bacteria Leukemia therapy Severe systemic illness

Back to Patient: Additional Laboratory Studies ƒAmino acids – increased glutamine ƒOrganic acids – increased orotic acid ƒDiagnosis: Partial Ornithine transcarbamoylase deficiency (OTC)

The Urea Cycle

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

Urea Cycle Disorders Neonatal Presentation „ Normal

at birth „ Develop poor feeding, vomiting, lethargy, irritability, tachypnea after protein feed (about 24 hrs) „ Same presentation as Sepsis „ Respiratory alkalosis „ Family history of unexplained neonatal death

Urea Cycle Infantile Presentation to Adult „ Variable

anorexia, lethargy, failure to thrive, migraine/headache „ Mental status change after protein „ Self selected low protein diet „ Normal ÆDevelopmental delay „ Irritability, behavior problems „ Intermittent encephalopathy

OTC Deficiency „ „

X-Linked Urea Cycle Defect In Males – Severe defect Æ neonatal coma • massive hyperammonemia

– Partial defect Æ later onset • variable hyperammonemia

„

In Females – May or may not be symptomatic depending on Lyonization – Often avoid protein

Genetic Hyperammonemia Differential ALKALOSISÆ primary urea cycle defect ACIDOSIS Æ organic acidemia,

mitochondrial, lactic acidosis HYPOGLYCEMIA CARDIAC +/Æ FAOD LIVER +/-,MUSCLE +/-

Treatment „ „ „ „

„

Stop all protein intake Maintain Anabolism – high glucose infusion with insulin (If FAOD not suspected add Lipid) Remove Ammonia – Hemodialysis Activate 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 Findings Vital 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 Uric acid=11.2 U/A neg.

Anion gap 19

Suspected Diagnosis Alcohol intoxication 2. Drugs 3. Post-ictal state 4. IEM 1.

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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 stupor Hypotension Alcohol within legal limit No glucose obtained initially but improved with glucose infusion Acidosis Increased uric acid

Assuming a metabolic disease is likely what tests should be ordered? Acylcarnitine profile 2. Amino acids 3. Porphyrins 4. Purines and pyrimidines 1.

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Tests you would order? Acylcarnitine profile – increased C8

Urine Organic Acid – increased dicarboxylic acids (adipic, suberic, sebacic), hexanoylglycine

Consistent with MCAD deficiency

FAOD „ „ „ „ „

Hypoglycemia, lethargy, hepatomegaly, cardiomyopathy, liver failure, arrhythmia Lab Findings: no ketosis, ↑ CK, ↑ Uric Acid Acute Treatment: Glucose infusion 10-12 mg/kg/min til stable, then Continuous enteral feeding low-fat, high glucose, normal protein L 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 meals „ When 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 metabolism „ If undiagnosed, mortality rate of 25% „ Autosomal recessive transmission „ MCAD is necessary for mitochondrial beta-oxidation of fatty acids

MCAD Presentation „ „ „ „ „

Classic presentations SIDs/near-miss SIDs Vomiting and lethargy after a period of fasting in a child 3-15 months of age Few present after 4 years of life Decompensate 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 4

5

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

Fatty acid oxidation disorders Organic Acidemias Urea Cycle Defects Amino acid disorders Biotinidase CAH CF Galactosemia Hemoglobinopathies Hypothyroidism

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 circulation Avoid catabolism – high glucose infusion 7-10 mg/kg/min (D10 1.5 X Maintenance) Stop intake of potential toxin Correct Electrolytes Correct acidosis R/O Infection/treat Consult/Transfer Æ 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 Removal „ Consider

for intoxication states (branch

chain organic acidurias, urea cycle defects) „ Exchange

transfusion – least effective „ Peritoneal 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 overhydration „ Hemodialysis

– most effective

Vitamin Cofactors Biotin 10-20 mg/day

Propionic, MCD, PC

Carnitine 50-100 mg po, 400 mg IV BCOA, Primary hyperammonemia, hyperlacticacidemia 100 mg po, iv FAOD 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

Hyperammonemia „

Lab findings: ammonia >400 μmol/l respiratory

„

alkalosis May have significant handicap despite treatment

„

Treatment: – – – –

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.