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
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 metabolism1
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
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
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
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
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 disease1
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 disease2
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 disease3
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
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
Therapeutic Measures for IEM Metabolism

  • 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/citrate Carnitine/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
Treatment of the Acutely Sick Child Metabolism

General Therapy

  • Maintain vital functions

    • Oxygenation

    • Hydration

    • Acid/Base balance

      Specific Therapy

  • Treat infection

  • High dose I.V. glucose

  • Carnitine supplementation


Treatment of genetic diseases

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

  • 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

Patient is stabilized now what
Patient is stabilized. Now what: Metabolism

  • 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
Quick References: Metabolism

Fatty acid oxidation defects
Fatty Acid Oxidation Defects: Metabolism

  • **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
Glycogen Storage Disorders: Metabolism

  • 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
Mitochondrial Disorders: Metabolism

  • 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
Leigh’s Disease Metabolism

  • 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
Peroxisomal Metabolism 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
Random Questions for the Boards: Metabolism

  • 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
Menke Syndrome Metabolism

Board questions
Board questions Metabolism

  • 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
Hurler syndrome Metabolism

  • Boy and brother Liver

For the boards
For the Boards: Metabolism

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

  • Ornithine Transcarbamylase Deficiency

What s that smell

Musty or Mousy: Metabolism


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?