Inborn Errors of Metabolism

Aka: Inborn Errors of Metabolism, Neonatal Metabolic Emergency

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II. Labs: Metabolic disorders tested on Newborn Screen

  1. See Newborn Screen

III. Pathophysiology

  1. All Metabolism (Glucose, Lipid and Protein)
    1. Path: Acetyl-CoA to Krebs Cycle
    2. Disrupted pathway results in build up of Ketones
  2. Glucose Metabolism (Glycolysis)
    1. Path: Glycogen (and fructose, galactose) to Glucose to pyruvate to actetyl-CoA (and Krebs Cycle)
    2. Disrupted pathway results in build-up of Lactic Acid and Ketones
    3. Brain may use Ketones for fuel by 12-24 hours and Lactic Acid in chronic elevations
  3. Lipid Metabolism
    1. Path: Fat to free Fatty Acids to acetyl CoA (via beta oxidation)
    2. Fatty Acid Metabolism abnormalities results in hypoketotic Hypoglycemia
  4. Protein Metabolism
    1. Path: Protein to Amino Acids (with ammonia by product) to organic acids to pyruvate and acetyl CoA
    2. Aminoacidopathy
      1. Amino Acid deamination (removal of amine group) to keto-acid fails to occur
      2. Specific Amino Acids insidiously accumulate (e.g. phenyketonuria)
    3. Organic acidemia
      1. Amino Acid deamination to keto-acid occurs, but keto-acid metabolism fails to occur
      2. Accumulation of organic acids (keto-acids), as well as ammonia
      3. Presents with severe Metabolic Acidosis with Anion Gap in an ill appearing child
  5. Urea Cycle (nitrogen processing from Protein Metabolism)
    1. Path: Protein Metabolism to ammonia to urea cycle
    2. Disrupted pathway leads to build-up of ammonia without acidosis
    3. Hyperammonia (from urea cycle disorders) is a significant Neurotoxin and must be managed emergently
  6. Energy production
    1. Path: Krebs Cycle to NADH to ATP (via electron transport)
    2. Disrupted pathway leads to build-up of lactate (driven by excess NADH)

IV. Classification

  1. Inborn Errors of Small Molecule Metabolism
    1. Example: Galactosemia
  2. Lysosomal Storage Diseases
    1. Example: Gaucher's Disease
  3. Disorders of Energy Metabolism
    1. Oxidation defects
    2. Disorders of Fatty Acid mobilization and metabolism
      1. Medium-chain-acyl-CoA Dehydrogenase Deficiency
    3. Glycogen Storage Diseases
      1. Type 1: von Gierke's Disease
      2. Type 2: Pompe's Disease
      3. Type 3: Forbes Disease
      4. Type 4: Andersen's Disease
      5. Type 5: McArdle's Disease
      6. Type 6: Hers Disease
      7. Type 7: Tarui's Disease
  4. Other more rare classes of metabolism error
    1. Paroxysmal disorders
    2. Transport disorders
    3. Defects in Purine and Pyrimidine metabolism
    4. Receptor Defects

V. Symptoms: Presentations of Inborn Errors of Metabolism

  1. Cardiopulmonary changes
    1. Exercise intolerance
    2. Familal vascular disease
    3. Tachycardia
    4. Abnormal breathing
  2. Gastrointestinal changes
    1. Diarrhea
    2. Poor feeding
    3. Recurrent Emesis
    4. Pancreatitis
  3. Neurologic changes
    1. Somnolence or irribility
    2. Increased Muscle tone or hypotonia
    3. Muscle cramping or spasticity
    4. Peripheral Neuropathy
    5. Upward Gaze Paralysis
    6. Seizures
    7. Temperature dysregulation

VI. Signs: Presentations of Inborn Errors of Metabolism

  1. Cardiopulmonary changes
    1. Cardiomyopathy
  2. Endocrine
    1. Refractory Hypoglycemia
  3. Neurologic changes
    1. Cerebrovascular Accident or stroke-like events
    2. Encephalopathy
    3. Altered Level of Consciousness (lethargy to coma)
    4. Cerebral calcifications
    5. Agenesis of corpus callosum
    6. Macrocephaly
    7. Seizures (esp. Status Epilepticus)
  4. Eye changes
    1. Lenticular Cataracts
    2. Corneal Opacity
    3. Cherry red Macule
    4. Lens discoloration
    5. Optic atrophy
  5. Skin changes
    1. Angiokeratoma
    2. Non-specific dermatitis or hair changes
    3. Ichthyosis
    4. Inverted nipples
    5. Xanthomas
  6. Musculoskeletal changes
    1. Arthrosis
    2. Dystosis multiplex
    3. Osteoporosis
  7. Renal Changes
    1. Renal Calculi
    2. Renal Fanconi Syndrome
  8. Gastrointestinal Changes
    1. Hepatomegaly
  9. Dysmorphic Features (Lysosomal Storage Disorders)
    1. Hunter Syndrome
    2. Hurler Syndrome
  10. Body odor
    1. Musty odor
      1. Hereditary Tyrosinemia
      2. Phenylketonuria (PKU)
    2. Tom cat's urine
      1. 3-Methylcrotonyl CoA Carboxylase Deficiency
    3. Sweaty feet
      1. Isovaleric Acidemia
    4. Burnt Sugar
      1. Maple Syrup Urine Disease (MSUD)

VII. Causes: Inborn Errors of Metabolism with Presentations in the pregnant mother

  1. Ornithine transcarbamylase
    1. Hyperammonemia
    2. Coma
    3. Psychiatric findings
  2. Long-chain hydroxyacyl dehydrogenase deficiency
    1. Acute Fatty Liver
    2. Hyperemesis
    3. HELLP Syndrome

VIII. Causes: Inborn Errors of Metabolism with Presentations in Adolescents and Adults

  1. Hemochromatosis (1:200 to 1:400 caucasian)
    1. Diabetes Mellitus
    2. Cirrhosis
    3. Hyperpigmentation
    4. Cardiomyopathy
  2. Gaucher Disease Type I (1:855 Ashkenazi Jewish)
    1. Anemia
    2. Thrombocytopenia
    3. Parkinsonism
    4. Osteoporosis
  3. X-Linked Adrenoleukodystrophy (<1:20,000)
    1. Spastic Paraparesis
    2. Peripheral Neuropathy
    3. Dementia and Psychosis (males)
    4. Adrenal Insufficiency (males)
  4. Wilson Disease (1:30,000)
    1. Kaiser-Fleischer rings (Corneal green ring)
    2. Hyperpigmentation
    3. Cirrhosis
    4. Tremor
    5. Dysarthria
    6. Dementia
  5. Fabry Disease (<1:50,000, less severe, and later presentation in Heterozygous females)
    1. Acroparesthesia
    2. Angiokeratoma
    3. Heart Disease
    4. Renal Disease
  6. Ornithase Transcarbamylase Deficiency (1:70,000, lethal in newborn males, presents in teen females)
    1. Abdominal Pain
    2. Headache
    3. Dietary Protein avoidance
  7. Homocystinuria (1:200,000)
    1. Osteoporosis
    2. Ocular Lens Dislocation
    3. Thrombophilia
  8. Carnitine Palmitoyltransferase II Deficiency
    1. Rhabdomyolysis
    2. Muscle Weakness
    3. Myopathy after Exercise
  9. GM2 Gangliosidosis (Tay-Sachs, Sandhoff Disease, rare)
    1. Motor Neuron disorder
    2. Dystonia
    3. Cerebellar degeneration
    4. Bipolar Disorder
  10. Porphyria (rare)
    1. Seizures
    2. Chest Pain
    3. Photosensitivity
    4. Extremity pain
  11. References
    1. Gray (2000) J Neurol Neurosurg Psychiatry 69(1): 5-12 [PubMed]

IX. Labs

  1. See Newborn Screening
  2. Initial presentation
    1. Bedside Glucose (Hypoglycemia)
      1. Glycogen Storage Disease
        1. Hypoglycemia after 4-6 hours of Fasting
      2. Fatty Acid Oxidation Disorders
        1. Hypoglycemia after 8-12 hours of Fasting
      3. Hypoglycemia is is often due to non-metabolic disorders (e.g. poor feeding without disorder)
    2. Complete Blood Count with Peripheral Smear
    3. Basic Chemistry Panel (Electrolytes, Serum Creatinine)
      1. Organic Acidemia (Metabolic Acidosis with Anion Gap)
    4. Liver Function Tests (ALT, AST)
      1. Fatty Acid Oxidation Disorders
      2. Mitochondrial Disorders
      3. Tyrosinemia Type I
      4. Hereditary Fructose Intolerance
    5. Creatine Kinase (Cardiomyopathy)
      1. Fatty Acid Oxidation Disorders
      2. Organic Acidemia
      3. Mitochondrial Disorders
      4. Glycogen Storage Disorders
    6. Serum Ammonia (normal <50 umol/L, significant if levels >200 umol/L; associated with encephalopathy)
      1. Urea Cycle Disorders
      2. Organic Acidemia
      3. Fatty Acid Oxidation Disorders
    7. Serum lactate
      1. Sepsis
      2. Mitochondrial Disorders
      3. Pyruvate Dehydrogenase
      4. Carboxylase Deficiency
      5. Organic Acidemia
      6. Glycogen Storage Disease
    8. Serum Ketones
      1. More than trace Ketones is suggestive of a metabolic disorder
    9. Uric Acid
      1. Poor Test Sensitivity and Test Specificity, but when positive in newborns, is suggestive of metabolic disease
    10. Venous Blood Gas
      1. Metabolic Acidosis with Anion Gap (Ketosis, Lactic Acidosis) is typical for most congenital metabolic disorders
      2. Organic Acidemia
      3. Urea Cycle Disorders (increased pH)
      4. Hyperammonemia induces Hyperventilation beyond acidosis compensation (Respiratory Alkalosis)
    11. Urinalysis
      1. Urine Ketones in organic acidemia, Fatty Acid oxidation disorder
      2. Expect Urine pH <5 in Metabolic Acidosis with appropriate renal compensation
        1. Consider Renal Tubular Acidosis if Urine pH >5
  3. Diagnosis (typically as directed by metabolic specialist)
    1. Plasma carnitine
    2. Acylcarnitine profile (esterified carbon chains to carnitine)
      1. Organic Acidemia
      2. Fatty Acid Oxidation Disorder
    3. Quantitative Amino Acid Profile (increased levels)
      1. Maple Syrup Urine Disease
      2. Phenylketonuria
      3. Tyrosinemia Type I
      4. Urea Cycle Disorders
      5. Organic Acidemia (increased Glycine)
    4. Biotinidase
    5. Urine organic and Amino Acids
      1. Amino Acid Disorder
      2. Organic Acidemia
    6. Urine Acylglycines
      1. Fatty Acid Oxidation Disorder
      2. Organic Acidemia

X. Imaging: Second Trimester Prenatal Ultrasound Findings

  1. Intrauterine Growth Retardation (IUGR)
    1. Cholesterol synthesis disorders
    2. Organic Acidemia
    3. Amino Acid Disorders
    4. Glycosylation Disorders
  2. Brain Abnormalities
    1. Peroxisomal Disorders
    2. Fatty Acid Oxidation Disorders
    3. Organic Acidemia
    4. Amino Acid Disorders
  3. Hydrops fetalis (Ascites, Pleural Effusions, Pericardial Effusions, extremity edema)
    1. Lysosomal Storage Disease
    2. Glycogen Storage Disease Type IV
    3. Congenital Disorders of Glycosylation
  4. Renal Abnormality
    1. Peroxisomal Disorders
    2. Fatty Acid Oxidation Disorders
  5. Hyperechogenic colon
    1. Organic Acidemia
    2. Amino Acid Disorders
  6. Polyhydramnios
    1. Glycogen Storage Disease Type IV
  7. Liver Steatosis
    1. Fatty Acid Oxidation Disorders
  8. Left Ventricular Noncompaction
    1. Organic Acidemia
  9. References
    1. Vianey-Saban (2016) J Inherit Metab Dis 39(5):611-24 [PubMed]

XI. Differential Diagnosis: Neonatal Metabolic Emergency

  1. See Crashing Newborn

XII. Management: Immediate management priorities

  1. ABC Management
  2. Rehydration with Normal Saline in small boluses (10 cc/kg)
  3. Discontinue feeds
    1. Avoid Carbohydrates and Amino Acids until disorder is identified
  4. Correct Hypoglycemia and maintain caloric support
    1. Emergent dextrose replacement for Hypoglycemia
      1. See Neonatal Hypoglycemia
      2. See Rule of 50
      3. Administer 8-10 mg/kg/min of D10W via peripheral IV
    2. Maintain normoglycemia
      1. Goal Blood Glucose 100 to 120 mg/dl
      2. Glucose bypasses most disordered metabolic pathways
      3. D10 at 1.5x the calculated maintenance rate for weight
      4. Consider mitochondrial disorder If Lactic Acid increases on infusion
        1. Decrease to D5 infusion or consider Insulin
  5. Correct excess ammonia emergently (significant if ammonia levels >200 umol/L, and very severe at >300 umol/L)
    1. Neurologic outcomes are best with early treatment initiation for elevated ammonia levels
    2. Supply dextrose as alternative energy source (instead of Protein)
    3. Stop all Protein intake (excess nitrogen)
    4. Arrange emergent Dialysis
    5. Ammonia scavengers
      1. Sodium Benzoate
      2. Sodium Phenylacetate
      3. Arginine Hydrochloride
  6. Metabolic Acidosis
    1. Manage with hydration and supportive measures
    2. Bicarbonate is NOT first-line, but may be considered in shock or cardiac dysfunction
  7. Review Newborn Screen if available
    1. Newborn Screens do not have perfect Test Sensitivity or Test Specificity
    2. Newborn Screen does not identify Glycogen Storage Diseases or mitochondrial disorders
  8. Consultation
    1. Metabolic Physician (tertiary center)
    2. State Newborn Screening lab

XIII. Resources

  1. Low (1996) Inborn Errors of Metabolism
    1. http://www.hkmj.org/article_pdfs/hkm9609p274.pdf
  2. Vademecum Metabolicum: Diagnosis and Treatment of Inborn Errors of Metabolism (EVM)
    1. http://evm.health2media.com/#/menu

XIV. References

  1. Mason and Woods in Herbert (2019) EM:Rap 19(7):10-12
  2. Homme (2016) Inborn Errors of Metabolism, ACEP PEM Conference, Orlando, attended 3/9/2016
  3. Kruszka (2019) Am Fam Physician 99(1): 25-32 [PubMed]
  4. Raghuveer (2006) Am Fam Physician 73(11):1981-90 [PubMed]

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