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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 – PowerPoint PPT presentation

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Title: Inborn Errors of Metabolism


1
Inborn Errors of Metabolism
  • An inherent deficiency in a key metabolic pathway
    resulting in
  • Cellular Intoxication
  • Energy deprivation
  • Mixture of the two

2
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
  • Dont be fooled--other diagnoses like sepsis,
    ICH, pulm. hem. may accompany IEM
  • Remember some IEMs are dysmorphic!

3
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4
When to suspect an IEM
  • Infants have only a limited repertoire of
    symptoms--sxs non-specific
  • Vomiting, lethargy, FTT, szs, 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).

5
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.

6
  • 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

7
Importance of history
  • Catabolic state induction (sepsis,fasting,dehydrat
    ion)
  • Protein intake
  • Change or addition of PO proteins, carbs, etc in
    formula
  • Consanguinity
  • FHx of SIDS

8
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

9
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

10
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

11
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

12
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)

13
Therapeutic Measures for IEM
  • D/C oral intake temporarily
  • Usually IVFs 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

14
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

15
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

16
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

17
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20
Stable Patient, Now what?
21
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 dont exactly fit, resort back to
    categories of IEMs and Neurodegenerative
    Disorders.

22
Quick References
23
Fatty Acid Oxidation Defects
  • Autosomal recessive inheritance
  • Examples are MCAD, LCAD, VLCAD
  • Defect in acyl-CoA Dehydrogenase, a mitochondrial
    duty, and important in fasting state.
  • KEY features
  • Acute attack of life-threatening coma with
    Hypoglycemia
  • Absence of urine 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

24
Glycogen Storage Disorders
  • Type 2- Pompes 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.

25
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

26
Leighs 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, Lebers HON

27
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

28
Random Questions for the Boards
  • Amino Acids responsible for MSUD?
  • Valine, Leucine, Isoleucine
  • Name 1 of the 3 classic Metal Storage disorders?
  • Menkes Kinky Hair Syndrome (X-link recessive)
  • Wilsons Disease
  • Neonatal Hemachromatosis

29
Menke Syndrome
30
Board questions
  • Name some classic Mucopolysaccharidosis?
  • Hunters (X-linked, no corneal clouding)
  • Hurlers (presence of Corneal clouding)
  • Morquio Syndrome (nl IQ, short, cloudy cornea)
  • -How are mucopolysaccharidoses Diagnosed?
  • Urine MPSs, definite with Skin Fibroblast Bx

31
Hurler syndrome
  • Boy and brother Liver

32
  • Smith-Lemli-Opitz Syndrome due to defect in
    cholesterol synthesis.

33
Smith Lemli Opitz syndrome
34
For the Boards
  • Most common Urea cycle defect and also only
    X-linked
  • Ornithine Transcarbamylase Deficiency

35
Whats 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)
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