II. Labs: Metabolic disorders tested on 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
    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. Example: Glycogen Storage 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
  2. Gastrointestinal changes
    1. Diarrhea
    2. Poor feeding
    3. Recurrent Emesis
    4. Pancreatitis
  3. Neurologic changes
    1. Somnolence or irribility
    2. Increased muscle tone
    3. Muscle cramping or spasticity
    4. Peripheral Neuropathy
    5. Upward gaze paralysis

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. 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. Labs

  1. Initial presentation
    1. Bedside Glucose
    2. Complete Blood Count with Peripheral Smear
    3. Comprehensive metabolic panel
    4. Plasma ammonia
    5. Serum lactate
    6. Venous Blood Gas
    7. Urinalysis
  2. Diagnosis
    1. Plasma carnitine
    2. Acylcarnitine profile
    3. Quantitative Amino Acid Profile
    4. Biotinidase
    5. Urine organic and amino acids
    6. Urine Acylglycines

VIII. Management: Immediate management priorities

  1. Rehydration with Normal Saline in small boluses (10 cc/kg)
  2. Correct Hypoglycemia
    1. Emergent dextrose replacement
    2. Maintain normoglycemia
      1. D10 in Normal Saline (or 1/2NS in neonate) at 1.5x the calculated maintenance rate for weight
  3. Correct excess ammonia emergently
    1. Supply dextrose as alternative energy source (instead of protein)
    2. Stop all protein intake (excess nitrogen)
    3. Arrange emergent Dialysis
    4. Ammonia scavengers
      1. Sodium Benzoate
      2. Sodium Phenylacetate
      3. Arginine Hydrochloride

IX. Resources

  1. Low (1996) Inborn Errors of Metabolism
    1. http://www.hkmj.org/article_pdfs/hkm9609p274.pdf

X. References

  1. Homme (2016) Inborn Errors of Metabolism, ACEP PEM Conference, Orlando, attended 3/9/2016
  2. Raghuveer (2006) Am Fam Physician 73(11):1981-90 [PubMed]

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Ontology: Inborn Errors of Metabolism (C0025521)

Definition (NCI) A group of disorders present at birth that involve genetic defects leading to disturbances in carbohydrate, lipid, lysosomal storage or amino acid metabolism in the body.
Definition (MSH) Errors in metabolic processes resulting from inborn genetic mutations that are inherited or acquired in utero.
Definition (CSP) errors in metabolic processes resulting from inborn genetic mutations that are inherited or acquired in utero.
Concepts Congenital Abnormality (T019) , Disease or Syndrome (T047)
MSH D008661
SnomedCT 363205007, 86095007
English Error, Inborn Metabolism, Errors Metabolism, Inborn, Errors Metabolisms, Inborn, Errors, Inborn Metabolism, Inborn Errors Metabolism, Inborn Errors Metabolisms, Inborn Metabolism Error, Inborn Metabolism Errors, Metabolism Error, Inborn, Metabolism Errors, Inborn, Metabolism Inborn Error, Metabolism Inborn Errors, Metabolism, Inborn Errors, Metabolisms, Inborn Errors, inborn metabolism disorder, METAB ERR INBORN, INBORN ERR METAB, METAB INBORN ERR, IBEM - Inborn error of metabol, IEM - Inborn error metabolism, Congenital Metabolic Disorder, Inborn Errors of Metabolism, Inborn error of metabolism NOS, Metabolism, Inborn Errors [Disease/Finding], inborn error of metabolism, inborn error metabolism, errors inborn metabolism, inborn errors metabolism, inborn errors of metabolism, Congenital Metabolism Disorder, Metabolic hereditary disorder, Metabolic hereditary disorder (disorder), Metabolism, Inborn errors of, Inborn Error of Metabolism, Inborn errors of metabolism, Inborn error of metabolism, IBEM - Inborn error of metabolism, IEM - Inborn error of metabolism, Inborn error of metabolism (disorder), Inborn error of metabolism, NOS
Italian Errore congenito del metabolismo, Errore congenito del metabolismo NAS, Errori congeniti del metabolismo
Dutch metabolisme aangeboren afwijking NAO, aangeboren metabolismestoornissen, metabolisme aangeboren afwijking, Aangeboren afwijking van de stofwisseling, Afwijking, aangeboren, stofwisseling, Stofwisseling, aangeboren afwijking van de
French Erreur innée du métabolisme SAI, Erreur innée du métabolisme, Erreurs innées du métabolisme, Maladies métaboliques congénitales
German angeborene Stoffwechselstoerung NNB, Angeborene Stoffwechselstoerungen, angeborene Stoffwechselstoerung, Angeborene Stoffwechseldefekte, Angeborene Stoffwechselerkrankungen, Angeborene Stoffwechselstörungen, Stoffwechsel, angeborene Störungen
Portuguese Erro congénito do metabolismo NE, Erro congénito do metabolismo, Erros congénitos de metabolismo, Erros Inatos do Metabolismo
Spanish Error innato del metabolismo NEOM, trastorno hereditario del metabolismo, trastorno metabólico hereditario, metabolopatía hereditaria, trastorno hereditario del metabolismo (trastorno), metabolopatía congénita (trastorno), metabolopatía congénita, Errores innatos del metabolismo, Error innato del metabolismo, enzimopatía congénita, Errores Innatos del Metabolismo
Japanese 先天性代謝異常症NOS, 先天性代謝障害, 先天性代謝異常症, センテンセイタイシャイジョウショウ, センテンセイタイシャショウガイ, センテンセイタイシャイジョウショウNOS, 代謝異常-先天性, 先天性代謝異常, 先天代謝異常, 代謝-先天性異常
Swedish Ämnesomsättningsrubbningar, medfödda
Finnish Synnynnäiset aineenvaihduntahäiriöt
Czech Vrozené poruchy metabolismu, Vrozená vada metabolismu, Vrozená vada metabolismu NOS, vrozené poruchy metabolismu, dědičné metabolické poruchy, dědičné poruchy metabolismu, metabolismus - vrozené poruchy
Polish Choroby metaboliczne wrodzone
Hungarian Veleszületett anyagcserezavar k.m.n., Veleszületett anyagcserezavar, Metabolizmus veleszületett hibái
Norwegian Stoffskiftefeil, medfødte, Medfødte stoffskiftefeil, Medfødte feil i metabolismen, Medfødte metabolismedefekter, Medfødte feil i stoffskiftet