Inborn errors of metabolism
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Inborn Errors of Metabolism. An inherent deficiency in a key metabolic pathway resulting in Cellular Intoxication Energy deprivation Mixture of the two. Inborn Errors of Metabolism. IEM as a group are not rare: occur 1 in 5000 births collectively Often treatable if diagnosed

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Inborn Errors of Metabolism

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Inborn Errors of Metabolism

  • An inherent deficiency in a key metabolic pathway resulting in

    • Cellular Intoxication

    • Energy deprivation

    • Mixture of the two

Inborn Errors of Metabolism

  • IEM as a group are not rare: occur 1 in 5000 births collectively

  • Often treatable if diagnosed

  • Most difficult task for clinician is to know when to consider IEM and which tests to order for evaluation

  • Don’t be fooled--other diagnoses like sepsis, ICH, pulm. hem. may accompany IEM

  • Remember some IEMs are dysmorphic!

When to suspect an IEM

  • Infants have only a limited repertoire of symptoms--sxs non-specific

    • Vomiting, lethargy, FTT, sz’s, resp (tachypnea, hyperpnea, apnea), coma, cardiomyopathy

    • Odor, abnormal hair, dysmorphology

  • Labs: metabolic acidosis, hypoglycemia, hyperammonemia, reducing substances in urine, ketonuria, pancytopenia

  • Not all infants with life threatening IEM have either acidosis or hyperammonemia (i.e. non-ketotic hyperglycinemia, mild lactate elev).

When to suspect an IEM p.2

  • Rapid deterioration in an otherwise well infant.

  • Septic appearing infant or abnl sepsis such as E.coli.

  • Failure to thrive.

  • Regression in milestones.

  • Recurrent emesis or feeding difficulty, alterations in respirations, abnl urine/body smell, changing MS/lethargy, jaundice, sz, intractable hiccups.

  • Can masquerade like pyloric stenosis.

  • Dietary aversion- proteins, carbs.

  • Every child with unexplained . . .

    • Neurological deterioration

    • Metabolic acidosis

    • Hypoglycemia

    • Inappropriate ketosis

    • Hypotonia

    • Cardiomyopathy

    • Hepatocellular dysfunction

    • Failure to thrive

      . . . should be suspected of having a metabolic disorder

Importance of history

  • Catabolic state induction (sepsis,fasting,dehydration)

  • Protein intake

  • Change or addition of PO proteins, carbs, etc… in formula

  • **Consanguinity

  • FHx of SIDS

Metabolic Disorders Presenting as Severe Neonatal Disease

  • Disorders of Carbohydrate Metabolism

    • Galactosemia - presents with severe liver disease, gram negative sepsis, and/or cataracts

      • Enz deficiency: Gal-1-phos uridyl transferase, UDP-gal-4-epimerase

    • Glycogen storage disease type 1a & 1b - presents as hypoglycemia

      • Enz deficiency: Glucose-6 phosphatase

      • Lactic Acidosis - presents as lactic acidosis +/- hypoglycemia

      • Enz deficiency: Pyruvate carboxylase, Pyr dehydrogenase, etc.

    • Fructose intolerance - Needs fructose exposure, hypoglycemia and acidosis

Metabolic Disorders Presenting as Severe Neonatal Disease

  • Amino Acid Disorders

    • Maple syrup urine disease - presents with odor to urine and CNS problems

      • Enz deficiency: Branched chain ketoacid decarboxylase

    • Nonketotic hyperglycinemia - presents with CNS problems

      • Enz deficiency: Glycine cleavage system

    • Tyrosinemia - Severe liver disease, renal tubular dysfunction

      • Enz deficiency: Fumaryl acetate

      • Transient tyrosinemia of prematurity - progressive coma following respiratory distress

Metabolic Disorders Presenting as Severe Neonatal Disease

  • Urea Cycle Defects and Hyperammonemia

  • All present with lethargy, seizures, ketoacidosis, neutroenia, and hyperammonemia

  • Ornithine carbamyl transferase (OTC) deficiency

  • Carbamyl phosphate synthetase deficiency

  • Citrullinemia

  • Arginosuccinic Aciduria

  • Argininemia

  • Transient tyrosinemia of prematurity

Metabolic Disorders Presenting as Severe Neonatal Disease

All present with lethargy, seizures, ketoacidosis, neutropenia, hyperammonemia, and/or hyperglycinemia

  • Organic Acid Defects

    • Methylmalonic acidemia

    • Proprionic acidemia

    • Isovaleric acidemia - odor of “sweaty feet”

    • Glutaric aciduria type II

    • Dicarboxylic aciduria

  • Miscellaneous

    • Peroxisomal disorders

    • Lysosomal storage disease

    • Pyridoxine dependent seizures

First Steps in Metabolic Therapy for Inborn Errors of Metabolism

  • Reduce precursor substrate load

  • Provide caloric support

  • Provide fluid support

  • Remove metabolites via dialysis

  • Divert metabolites

  • Supplement with cofactor(s)

Therapeutic Measures for IEM

  • D/C oral intake temporarily

  • Usually IVF’s with glucose to give 12-15 mg/kg/min glu and at least 60 kcal/kg to prevent catabolism (may worsen PDH)

  • Bicarb/citrateCarnitine/glycine

  • Na benzoate/arginine/citrulline

  • Dialysis--not exchange transfusion

  • Vitamins--often given in cocktails after labs drawn before dx is known

    • Biotin, B6, B12, riboflavin, thiamine, folate

Treatment of the Acutely Sick Child

General Therapy

  • Maintain vital functions

    • Oxygenation

    • Hydration

    • Acid/Base balance

      Specific Therapy

  • Treat infection

  • High dose I.V. glucose

  • Carnitine supplementation



  • MODIFY ENVIRONMENT, e.g., diet, drugs

  • SURGICAL, correct or repair defect or organ transplantation

  • MODIFY OR REPLACE DEFECTIVE GENE PRODUCT, megadose vitamin therapy or enzyme replacement



What to do for the Dying Infant Suspected of Having an IEM

  • Autopsy--pref. performed within 4 hours of death

  • Tissue and body fluid samples

    • Blood, URINE, CSF (ventricular tap), aqueous humour, skin biopsy, muscle and liver--frozen in liquid nitrogen

  • Filter paper discs from newborn screen--call lab and ask them not to discard

Stable Patient, Now what?

Patient is stabilized. Now what:

  • Broad DDx for IEMs scares people.

  • You can group into KEY features.

  • Can focus on initial labs = Hyperammonia, hypoglycemia,metabolic acidosis.

  • Can focus on Prominent neurologic features.

  • Can focus on Dysmorphic features.

  • If these don’t exactly fit, resort back to categories of IEMs and Neurodegenerative Disorders.

Quick References:

Fatty Acid Oxidation Defects:

  • **Autosomal recessive inheritance**

  • Examples are MCAD, LCAD, VLCAD

  • Defect in acyl-CoA Dehydrogenase, amitochondrial duty, and important in fasting state.

  • KEY features:

  • Acute attack of life-threatening coma with Hypoglycemia

  • Absence ofurine ketones, and reducing substances, nl serum AAs.

  • +/- mild acidosis, or hyperammonemia, elevated LFTs, abnl coags. +/-Hepatomegaly-/+

  • Dx with serum Acylcarnitine Profile or fibroblast enzyme assay

Glycogen Storage Disorders:

  • Type 2- Pompe’s disease:

  • Normal Glucose

  • Do to an accumulation of glycogen in lysosomes.

  • **Ancient city of Pompeii was destroyed by Mt. Vesuvius- 79 AD**

  • Manifested by massive Cardiomegaly, Hepatomegaly, Macroglossia.

  • Fatal If results in CHF.

  • Limited therapies in Neonatal Variant.

    • Attempts at enzyme replacement ongoing.

Mitochondrial Disorders:

  • Spectrum of diseases with life-time variation of presentation.

  • Infantile/Neonatal: may present with encephalopathic picture, regressed milestones, cerebral cortical atrophy.

  • Generally lab findings of:

    • Lactic Acidosis

    • Nl to low serum pyruvate, incomparison to Lactate

    • Nl organic acids.

    • *** Important to check CSF values of the above***

Leigh’s Disease

  • AKA- Subacute necrosing encephalopathy

  • Due to defects in the mitochondrial electron transport chain.

  • May have devastating presentation with significant developmental regression.

  • Unfavorable natural history.

  • May respond to host of supplements.

  • **Other Mitochondrial disorders for completion sake**

    • MELAS, MERRF, Leber’s HON

Peroxisomal Disorders

  • Zellweger Syndrome

  • aka: Cerebro-hepato-renal syndrome

  • Typical and easily recognized dysmorphic facies.

  • Progressive degeneration of Brain/Liver/Kidney, with death ~6 mo after onset.

  • When screening for PDs. obtain serum Very Long Chain Fatty Acids- VLCFAs

Random Questions for the Boards:

  • Amino Acids responsible for MSUD?

  • Valine, Leucine, Isoleucine

  • Name 1 of the 3 classic Metal Storage disorders?

  • Menke’s Kinky Hair Syndrome (X-link recessive)

  • Wilson’s Disease

  • Neonatal Hemachromatosis

Menke Syndrome

Board questions

  • Name some classic Mucopolysaccharidosis?

  • Hunter’s (X-linked, no corneal clouding)

  • Hurler’s (presence of Corneal clouding)

  • Morquio Syndrome (nl IQ, short, cloudy cornea)

  • -How are mucopolysaccharidoses Diagnosed?

  • Urine MPSs, definite with Skin Fibroblast Bx

Hurler syndrome

  • Boy and brother Liver

  • Smith-Lemli-Opitz Syndrome: due to defect in cholesterol synthesis.

Smith Lemli Opitz syndrome

For the Boards:

  • Most common Urea cycle defect and also only X-linked:

  • Ornithine Transcarbamylase Deficiency

Musty or Mousy:


Boiled Cabbage

Tyrosinemia or hypermethioninemia

Maple Syrup

maple syrup urine disease

Sweaty feet:

isovaleric acidemia or glutaric acidemia type II

Cat urine

multiple carboxylase deficiencies (Biotin deficiency)

What’s that smell?

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