1. Inborn Errors of Metabolism Emergencies in Neonates
Joseph Melvin, D.O. St. Christopher’s Hospital for Children Drexel University College of Medicine
“I had nothing to offer anybody except my own confusion” Jack Keurouac

2. Financial Disclosures
I am a principal investigator for a PKU treatment drug study conducted by Biomarin.
I have no financial interest in any Pharmaceutical or medical device Company.
I have not served on a Speaker’s Bureau for any Pharmaceutical Company
I deeply distrust banks, do not have a credit card, and keep my cash in a pillow case.

3. Overview Introduction Classification Approach Investigation Management
“Born under a bad sign, been down since I began to crawl
If it wasn't for bad luck, I wouldn't have no luck at all"
William Bell

4. General Classification
Urea Cycle Defects
Amino Acidopathies
Organic Acidopathies
Fatty Acid Oxidation Defects
Mitochondrial Defects
Peroxisomal Disorders
Lysosomal Disorders
Disorders of Carbohydrate Metabolism
Vitamin/Cofactor Deficiencies
Congenital Disorders of Gylcosylation
Neurotransmitter Disorders
And of course, the famous OTHER

5. General Principals of Evaluation
Commonality of clinical expression in acute presentation in Neonates.
Neurological symptoms (seizures, lethargy, and coma)
Dyspnea, vomiting, and poor feeding.
Identical symptoms can occur with the more frequent HIE, sepsis, and duct-dependent heart disease.
Typically, metabolic disorders are seen in children born normally at full term with no problems in the immediate post-partum period.

6. HIE vs Metabolic Disease
Meconium staining
Immediate appearance of neurologic symptoms at birth
Abnormalities of labor and delivery
Typical ultrasound or MRI abnormalities
APGAR
Metabolic Disease
Uneventful pregnancy and normal birth
Usually full term
Symptom free interval
Certain types of facial dysmorphism may be seen.

7. Family History Parental consanguinity History of other neonatal deaths
Affected males on the maternal side
Caveat: Most newborns who have proven inborn errors of metabolism have a negative family history
HELLP syndrome or Acute Fatty Liver of Pregnancy associated with FAO

8. Newborn Screening Fatty Acid Oxidation Disorders
Organic Acid Disorders
Amino Acid Disorders
Biotinidase Deficiency
Galactosemia
Sickle-cell disease
Congenital adrenal hyperplasia
Primary congenital hypothyroidism
Cystic Fibrosis
Severe Combined Immunodeficiency
Critical Congenital Heart Disease

9. Newborn Screen new additions
Lysosomal storage disorders
Fabry Disease
Gaucher Disease
Krabbe Disease
MPS 1 (Hurler Syndrome)
Niemann Pick Disease
Pompe Disease

10. Newborn Screening Metabolic Disorders Biotinidase deficiency
Galactosemia
Amino acid disorders
Phenylketonuria (PKU) / Hyperphenylalaninemia
Maple syrup urine disease (MSUD)
Tyrosinemia, type 1 and possibly type 2 or type 3 - tyrosine levels may not be sufficiently elevated for detection
Homocystinuria / Hypermethioninemia
5-oxoprolinuria (glutathione synthetase deficiency) - may not be reliably detected in first days of life
Urea cycle disorders
Citrullinemia (argininosuccinate synthetase deficiency)
Argininosuccinic aciduria (argininosuccinate lyase deficiency)
Argininemia - extremely rare
Organic acid disorders
2-methylbutyryl-CoA dehydrogenase deficiency (2MBD)
3-methylcrotonyl-CoA carboxylase deficiency (3MCC)
3-hydroxy-3-methylglutaric-CoA lyase deficiency (3HMG)
3-methylglutaconic aciduria (3MGA)
Glutaric aciduria, type 1 (GA1)
Propionic acidemia (PA)
Isovaleric acidemia (IVA)
Methylmalonic acidemia (MMA)
Malonic aciduria (MA) - may not be reliably detected in first days of life
Beta-ketothiolase deficiency (BKT)
Multiple carboxylase deficiency (MCD)
Fatty acid oxidation disorders
Short chain acyl-CoA dehydrogenase deficiency (SCAD)
Medium/Short chain L-3-hydroxyacyl-CoA-dehydrogenase deficiency (M/SCHAD)
Isobutyryl-CoA dehydrogenase deficiency (IBCD)
Medium chain acyl-CoA dehydrogenase deficiency (MCAD)
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD)
Very long chain acyl-CoA dehydrogenase deficiency (VLCAD)
Trifunctional protein deficiency (TFPD)
Carnitine palmitoyl transferase deficiency type 2 (CPT2) - neonatal form, extremely rare
Carnitine palmitoyl transferase deficiency type 1 (CPT1A) - may not be reliably detected in first days of life
Carnitine/acylcarnitine translocase deficiency (CACT) - neonatal form, extremely rare
Carnitine uptake defect (CUD) - may not be reliably detected in first days of life
Multiple acyl-CoA dehydrogenase deficiency (MADD) / Glutaric aciduria, type 2 (GA2)

11. Laboratory Evaluation Possibilities
Start with- Electrolytes, glucose, CBC, ammonia, urine for ketones, and lactic acid
Check the newborn screen
Plasma amino acids, Urine organic acids, Acyl carnitine profile, and free and total carnitine.
CSF cell count, glucose, protein, cultures, amino acids, lactate, pyruvate, neurotransmitters (P5P, 5-MTHFR), and glycine. Watch out for the dreaded FOLP syndrome.
Creatine/GAA, pipecolic acid, alpha aminoadipic semialdehyde, copper/ceruloplasmin, homocysteine, biotinidase, uric acid, and glycine
Consider Urine sulfites; VLCFAs; glycosylation panel

12. Basic Labs Red Flags Gapped Metabolic acidosis Hyperammonemia
Hypoglycemia
Increased Lactate
Urinary Ketones

13. Laboratory Evalaution
Ketosis
Ketones are a normal part of physiology, but not when they generate acidosis
Organic acidemias
Hyperammonemia
Urea cycle defects- elevated to micro moles
Fatty acid oxidation defects
Hypoglycemia
Hyperinsulinism
Liver failure
Glycogen storage disease, tyrosinemia, galactosemia, Niemann-Pick
Fatty acid oxidation defect

14. First Steps
1. Determine if there is metabolic acidosis/respiratory alkalosis
2. Is there an anion gap >16?
3. Is lactate elevated?
4. Is there hypoglycemia?
5. Ketones in the urine?
6. Is there hyperammonemia?
Within 24 HOL?
After 24 HOL?

15. Hyperammonemia Normal ammonia level- < 50 umol/l
If >  Think IEM ; If > 500 Really Really think IEM especially
If within 24 hours of life; preterm, RD THAN
After 24 hours- IEM
Noooooo Heel sticks when testing ammonia.

16. Copyright ©1998 American Academy of Pediatrics

19. Summary of Important Clues
Normal birth with subsequent deterioration
Gapped Acid base problems
Hyperammonemia > 200 micromoles
Hypoglycemia
Ketonuria
Increased Lactate
Dysmorphic features
Severe Hypotonia
Eye Abnormalities- Nystagmus, Cataracts, Retinitis Pigmentosa, and Optic atrophy.
Refractory Seizures/Burst suppression EEG
Unexplained Liver disease
Cardiomyopathy
MRI abnormalities

20. Clinical signs Dysmorphism Liver Disease Cardiac Disorders
E.g. Glutaric aciduria type II, storage diseases, Zellweger, Smith- Lemli-Opitz and CDGS, PDH, and PC
Liver Disease
Galactosemia, Niemann -Pick C, Fatty acid oxidation disorders, Tyrosinemia Type 1 and Mitochondrial disorders
Cardiac Disorders
Fatty Acid Oxidation Disorders, Mitochondrial Disease, Pompe’s disease, and CDGS
Hydrops Fetalis
Lysosomal Disorders
Renal Cysts
Mitochondrial disease and Zwellweger

21. Ophthalmology Cataract Fabry’s disease Galactosemia Homocystinuria
Retinitis Pigmentosa
Cockayne’s syndrome
Hallervorden-Spatz disease
Kearns-Sayre syndrome
Neuronal ceroid lipofuscinoses
Zellweger syndrome
Nystagmus
Ataxia telangiectasia
Gaucher’s disease, types 2 and 3
Niemann-Pick disease type C
Pelizaeus-Merzbacher disease
Pendular
Zwellengers
Cataract
Fabry’s disease
Galactosemia
Homocystinuria
Lowe syndrome
Myotonic dystrophy
Optic Atrophy
Canavan disease
Globoid cell leukodystrophy
Metachromatic leukodystrophy
Pelizaeus-Merzbacher disease
GM2 Gangliosidosis juvenile type

22. Cardiac Hypertrophic highest % of association with IEM
Fatty acid oxidation defects, most commonly VLCAD and LCHAD deficiencies, and oxidative phosphorylation defects ( Mitochondrial ) each accounted for approximately 25% of IEM
Within the dilated cardiomyopathy group,
oxidative phosphorylation defects
systemic carnitine deficiency
most common causes accounting for 40% of cases each.

23. Hypertrophic Cardiomyopathy
Nearly half the cases of hypertrophic cardiomyopathy caused by IEM were due to glycogen storage diseases
Most commonly seen in Pompe’s disease
Lysosomal storage disorder caused by a deficiency of the α- glucosidase.
Infantile form often presents as Cardiac Failure
Big Heart, Big Tongue, and usually big Liver
Hypotonia Muscle weakness and areflexia
The ECG characteristically reveals a short PR interval with tall QRS waves.

24. MRI Characteristics
In general, symmetric abnormalities in the area of the Basal Ganglia and/or White Matter abnormalities are suspicious for metabolic disease
Glutaric Aciduria Type I- Widened sylvian fissures
PDH-Defect of corpus callosum, heterotopias, and cystic necrosis of white matter and basal ganglia
Molybdenum cofactor deficiency-Multicystic necrosis of white matter
MSUD-White matter changes with edema more severe in cerebellum and brainstem

25. MRI changes
Maple syrup urine disease (MSUD): brainstem and cerebellar edema
Propionic & methylmalonic acidemia: basal ganglia signal change
Glutaric aciduria: frontotemporal atrophy, subdural hematomas
Pyruvate Dehydogenase Complex (PDHC) -Defect of corpus callosum, heterotopias, and cystic necrosis of white matter and basal ganglia

26. Case
2 day old newborn develops feeding difficulties and progressive lethargy. APGARs were 8 and 9. Septic work-up is negative. Metabolic acidosis with Gap of 18, elevated lactate, glucose low, serum ammonia level is 225 micro mol/L (normal-50), and urine was positive for ketones. No dysmorphic features and no seizures. Which IEM would you suspect?
1. Urea Cycle Defect
2. Amino Acidopathies
3. Organic Acidopathies
4. Fatty Acid Oxidation Defect
5. Mitochondrial Defect
6. Peroxisomal Disorder

27. First Steps
1. Determine if there is metabolic acidosis/respiratory alkalosis
2. Is there an anion gap >16?
3. Is lactate elevated?
4. Is there hypoglycemia?
5. Ketones in the urine?
6. Is there hyperammonemia?
Within 24 HOL?
After 24 HOL?

28. Summary of Important Clues
Normal birth with subsequent deterioration
Gapped Acid base problems
Hyperammonemia > 200 micromoles
Hypoglycemia
Ketonuria
Increased Lactate
Dysmorphic features
Severe Hypotonia
Eye Abnormalities- Nystagmus, Cataracts, Retinitis Pigmentosa, and Optic atrophy.
Refractory Seizures/Burst suppression EEG
Unexplained Liver disease
Cardiomyopathy
MRI abnormalities

29. Lets go to the algorithms

30. Organic Acidemias Important features
High anion gap metabolic acidosis
Ketonuria (in the NB)- pathognomonic of IEM
Elevated lactate
+/- hypoglycemia
+/- hyperammonemia
Neutropenia
Common Types of Organic Acid Defects
Methylmalonic acidemia
Propionic acidemia
Isovaleric acidemia - odor of “sweaty feet”
Glutaric aciduria type II
Dicarboxylic aciduria

31. Treatment of Lactic acidosis
1) Supportive care: hydration, treatment of sepsis, seizures, ventilation. Avoid sodium valproate.
Discontinue all feeds. Provide adequate calories by intravenous glucose and lipids. Maintain glucose infusion rate 8-10 mg/kg/min. Start intravenous lipid day 2 or 3 at 0.5 g/kg/day (up to 3g/kg/day). After stabilization gradually add protein 0.25 g/kg till 1.5 g/kg/day.
2) Treat acidosis: sodium bicarbonate mEq/kg/hr
(max 1- 2mEq/kg/hr)
3) Thiamine: up to 300 mg/day in 4 divided doses.
4) Riboflavin: 100 mg/day in 4 divided doses.
5) Add co-enzyme Q: 5-15 mg/kg/day
6) L-carnitine: mg/kg orally.
7) Biotin 10 mg/day. (Biotin responsive Multiple carboxylase deficiency may present with unexplained lactic acidosis)

32. Case
A 3 day old infant was initially vigorous at birth but now has poor feeding, tachypnea, and progressive lethargy. Septic work-up is negative. There is no metabolic acidosis. Serum electrolytes, glucose, and lactate are normal. An ABG shows: pH 7.53, pCO2 20, HCO3 25. Serum ammonia level is 565 micro mol/L (normal-50). Urine ketones are negative. What is the most likely diagnosis?
A. Fatty acid oxidation defect
B. Urea cycle defect
C. Organic acidemia
D. Glycogen Storage Disease Type I
E. Amino acid disorder

33. Summary of Important Clues
Normal birth with subsequent deterioration
Gapped Acid base problems
Hyperammonemia > 200 micromoles
Hypoglycemia
Ketonuria
Increased Lactate
Dysmorphic features
Severe Hypotonia
Eye Abnormalities- Nystagmus, Cataracts, Retinitis Pigmentosa, and Optic atrophy.
Refractory Seizures/Burst suppression EEG
Unexplained Liver disease
Cardiomyopathy
MRI abnormalities

34. Lets go to the algorithms

35. Urea cycle disorder No acidosis (usually respiratory alkalosis)
No ketones (unlike organic acidemia)
No hypoglycemia
First few days of life: poor feeding, vomiting, tachypnea, lethargy  coma
But with hyperammonemia usually in range

36. Which Urea Cycle Disorder?

37. Treatment of Neonatal Urea Cycle Defects
Avoid Nitrogen intake; kcal/kg/day; Parenteral glucose and insulin ; N/G feeds with protein-free formula
IV 10% Arginine HCL(600 mg/kg/day)
IV Sodium Phenylacetate 250 mg/kg/day
IV Sodium Benzoate 250 mg/kg/day
Combination Drug- Ammonul
If does not work in 4-6 hours- CVVHD
Arginie lack increases protoen catabolism excessive amonts can cause spasdtcityTreatment:
Remove ammonia
Hydration with D10 + electrolytes
D/C all protein x 24 hours—calories from CHO and fat
Na phenylacetate/Na benzoate
Give arginine
Protein restriction for life

38. Treatment for Ammonia Levels >300
CONSIDER DIALYSIS
Dialysis will clear ammonia at ml/min with ECMO based dialysis. Osmotic shifts have NOT been observed with this rapid rate of clearance.
10-30 ml/min for Hemodialysis
3-5 ml/min for Peritoneal Dialysis
This rate will take several days to significantly reduce the ammonia load. Brain Damage is related to duration of hyperammonemia

39. Case Which IEM would you suspect?
Mother’s pregnancy was uncomplicated with Apgars of 9 and 9. Over the next 3 days, the baby became lethargic and developed severe hypotonia with apnea requiring intubation. During the transport to SCHC, she was noted to have episodes of synchronous twitching of the extremities concerning for seizures. EEG was performed at SCHC and revealed burst suppression. Newborn screen normal.
Sepsis evaluation normal
Her urine ketones were normal
No metabolic acidosis
No hypoglycemia
Normal Ammonia
Normal Newborn Screen
Which IEM would you suspect?

40. Summary of Important Clues
Normal birth with subsequent deterioration
Gapped Acid base problems
Hyperammonemia > 200 micromoles
Hypoglycemia
Ketonuria
Increased Lactate
Dysmorphic features
Severe Hypotonia
Eye Abnormalities- Nystagmus, Cataracts, Retinitis Pigmentosa, etc
Refractory Seizures/Burst suppression EEG
Unexplained Liver disease
Cardiomyopathy
MRI abnormalities

41. Lets go to the Lab Algorithms

42. Burst Suppression EEG
The presence of burst suppression on neonatal EEG suggests severe encephalopathy due to:
Significant hypoxic-ischemic insult
Metabolic disorder
Epileptic Encephalopathy

43. Metabolic epilepsy syndromes
Non-ketotic hyperglycinemia
Biotinidase Deficiency ( Multiple Carboxylase Deficiency) months-Myoclonic seizures, hypotonia, skin rash, allopecia. Later- Optic atrophy, deafness, and Developmental delay Treatment is 5-10 mg of Biotin lifelong.
Molybendum- Sulfite oxidase/xanthine oxidase deficiency Intractable seizures, decreased uric acid, cerebral dysgenesis Dipstick Urine for sulfite at bedside; No metabolic abnormalities
Pyridoxine- Burst Suppression EEG with intractable seizures. Absence of other clinical or metabolic abnormalities. B6 100mg IV stops sz and normalizes EEG. CSF for neurotransmitters can make diagnosis.

44. Nonketotic Hyperglycinemia
Develop Hypokinesia, hypotonia, and hyporeflexia, with refractory seizures after 48 hrs. Progresses to lethargy, apnea and coma. Not on newborn screen.
Seizures are usually myoclonic in nature with burst suppression pattern on EEG. Hiccuping is often seen.
Biochemical marker is increased glycine in CSF; ratio of CSF to plasma is >.09
MRI diffusion images were significant for abnormal signal intensity are confined to the white matter tracts that are usually myelinated at birth.
Nonketotic hyperglycinemia was originally named to
distinguish it from ketotic hyperglycinemia, which
is now known to be propionic acidemia. Glycine encephalopathy has an estimated incidence of 1 in 60,000, making it the second most common disorder of amino acid metabolism after phenylketonuria.
It is caused by a defect in the glycine cleavage system (GCS), which is made up of four protein subunits

45. Summary Remember- usually normal APGARs and initial period of normal.
Check the newborn screen
Check labs in logical order-Noooooo heel sticks for ammonia or lactate.
Check those helpful algorithms- they can guide your choice of secondary labs.
MRI and EEG’S may be helpful while you wait for the labs
If you are worried, discontinue all feeds. Provide adequate calories by intravenous glucose and lipids. Maintain glucose infusion rate 8-10 mg/kg/min. Start intravenous lipid day 2 or 3 at 0.5 g/kg/day (up to 3g/kg/day). After stabilization gradually add protein 0.25 g/kg till 1.5 g/kg/day.
Treat acidosis and increased ammonia as detailed above.

46. Questions
Some problems are so complex that you have to be highly intelligent and well informed just to be undecided about them.” ― Laurence J. Peter

47. Bibliography
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48. Bibliography
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