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

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.

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

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

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.

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.

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

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

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

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)

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

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

Laboratory Evalaution Ketosis Ketones are a normal part of physiology, but not when they generate acidosis Organic acidemias Hyperammonemia Urea cycle defects- elevated to 500-1000 micro moles Fatty acid oxidation defects Hypoglycemia Hyperinsulinism Liver failure Glycogen storage disease, tyrosinemia, galactosemia, Niemann-Pick Fatty acid oxidation defect

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?

Hyperammonemia Normal ammonia level- < 50 umol/l If > 200 -- 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.

Copyright ©1998 American Academy of Pediatrics

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

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

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

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.

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.

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

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

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

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?

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

Lets go to the algorithms

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

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 0.35-0.5mEq/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: 50-100 mg/kg orally. 7) Biotin 10 mg/day. (Biotin responsive Multiple carboxylase deficiency may present with unexplained lactic acidosis)

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

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

Lets go to the algorithms

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 500 -1000 range

Which Urea Cycle Disorder?

Treatment of Neonatal Urea Cycle Defects Avoid Nitrogen intake;120-130 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

Treatment for Ammonia Levels >300 CONSIDER DIALYSIS Dialysis will clear ammonia at 170-200ml/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

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?

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

Lets go to the Lab Algorithms

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

Metabolic epilepsy syndromes Non-ketotic hyperglycinemia Biotinidase Deficiency ( Multiple Carboxylase Deficiency) 0-3 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.

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

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.

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

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