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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.
slide6
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
  • 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

General Therapy

  • Maintain vital functions
    • Oxygenation
    • Hydration
    • Acid/Base balance

Specific Therapy

  • Treat infection
  • High dose I.V. glucose
  • Carnitine supplementation

STRIVE TO IDENTIFY PRIMARY METABOLIC DISORDER

treatment of genetic diseases
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
  • REPLACE DEFECTIVE GENE
  • CORRECT ALTERED DNA IN DEFECTIVE GENE
what to do for the dying infant suspected of having an iem
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
patient is stabilized 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.
fatty acid oxidation defects
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
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
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
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
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
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
board questions
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
Hurler syndrome
  • Boy and brother Liver
for the boards
For the Boards:
  • Most common Urea cycle defect and also only X-linked:
  • Ornithine Transcarbamylase Deficiency
what s that smell
Musty or Mousy:

PKU

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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