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Inbornerrorsofmetabolism

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Inborn Erros of Metabolism

Inborn Erros of Metabolism

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  • 1. Inborn Errors of Metabolism Namrata Singh M.D
  • 2. Introduction to IEM
    • Usually a single gene defect that causes a block in metabolic pathways.
    • Problems are because of accumulation of enzyme substrate behind the metabolic block or deficiency of the reaction product.
  • 3. Intro. Contd…
    • In some instances the substrate is diffusible & affects distant organs & in some there is just a local effect ( lysosomal storage disease ).
  • 4. Intro. Contd…
    • Clinical presentation is varied  mild to severe forms ( mutations even in the same gene may be different in different people ).
    • Can present at any time.
    • Can affect any organ system.
  • 5. IEM ~~ General approach
    • DIAGNOSIS : Some clinical presentations:-
      • Consider in DDx . when dealing with :-
        • Critically ill infant
        • Seizures
        • Encephalopathy (Reyes like syndrome )
        • Liver disease
        • MR or developmental delay or regression
        • Recurrent vomiting
        • Unusual odor
        • Unexplained acidosis
        • Hyperammonemia
        • hypoglycemia
  • 6. IEM~~ General approach
    • Some clues to look for :-
      • *Symptoms accompany changes in diet.
      • *Developmental regression.
      • *History of food preferences or aversions.
      • *History of consanguinity in parents.
      • *Family history of MR , unexplained deaths in cousins or siblings etc.
  • 7. IEM ~~ General approach
    • Physical exam:- common findings—
      • Alopecia or abnormal hair
      • Retinal cherry red spot
      • Cataracts or corneal opacities
      • Hepatosplenomegaly
      • Coarse features
      • Skeletal changes ( gibbus)
      • Ataxia
      • FTT
      • Micro or macrocephaly
      • Rash / jaundice /hypo or hypertonia
  • 8. IEM ~~ General approach
    • Lab tests:- almost always needed—
      • Serum electrolytes
      • Ph ( anion gap & acidosis )
      • Se lactate
      • Se pyruvate
      • Ammonia
  • 9. IEM ~~ General approach
    • Labs:- more specific labs—
      • Serum & urine amino acids
      • Urine organic acids
      • DNA probes
      • Glycine in CSF (glycine encephalopathy)
      • Urine ketones
        • If + in neonates  IEM
        • If – in older child  IEM ( defect in f.a. oxidation )
  • 10. IEM – Clinical situations
    • MR or dev delay 
      • Can occur alone.
      • Seen in urea cycle ,a.a disorders.
      • Also in organic acidemias ,peroxisomal & lysosomal storage disorders.
      • Serum & urine a.a .
      • Urine for mucopolysacchiduria.
  • 11. IEM – Clinical situations
    • Ill neonate :-
      • Clinically indistinguishable from sepsis.
      • Usually disorders of protein & CHO metabolism.
      • Acidosis or altered mental status out of proportion to systemic symptoms.
      • Labs:
        • Lytes , NH3, gluc , ketones , urine ph ,glycine in CSF.
        • Se & urine for a.a & o.a (* before oral intake is stopped or pt is transfused)
  • 12. IEM – Clinical situations
    • Vomiting & encephalopathy :-
      • Same studies !!
  • 13. IEM – Clinical situations
    • Hypoglycemia :-
      • Seen in fatty acid oxid defects ,glycogen storage diseases ,hereditary fructose intolerance & organic acidemias.
      • Other labs:-
        • Urine ketones ~(+) in GSD & organic acidemias. ~(-) in HFI & f.a. oxidation disorders
  • 14. IEM Clinical situations
    • Hypoglycemia contd…
      • Other labs:-
        • NH3  elevated in organic acidemias & fatty acid oxidation defects.
        • Urine reducing subst.– (+) in galactosemia ,HFI.
        • Urine organic acids
  • 15. IEM Clinical situations
    • Hyperammonemia :-
      • initially – poor appetite , irritability . Then , vomiting , lethargy , seizures & coma.
      • Tachypnea – direct effect on resp. drive.
      • Seen in (1)- urea cycle disorders (2)- organic acidemias (3)- transient hyperammonemia of the newborn.
      • Resp alkalosis : urea cycle disorders & transient hyperammonemia of newborn.
      • Acidosis : organic acidemias
  • 16. HYPERAMMONEMIA RESP ALKALOSIS ACIDOSIS UREA CYCLE DEFECTS TRANSIENT HYPERAMMONEMIA OF NEWBORN ORGANIC ACIDEMIAS SE CITRULLINE—LOW– EARLY UREA CYCLE DEFECT SLIGHTLY ELEV– TRANSIENT HYPERAMMONEMIA OF NB MARKEDLY ELEV– CITRULLINEMIA & ARGINOSUCCINIC ACIDEMIA
  • 17. IEM Contd…
      • Early urea cycle defects :
        • OTC Defect 
          • incr. Urine orotic acid levels
          • Fam hx of male newborn deaths
          • X- linked trait
  • 18. IEM Contd…
    • Acidosis :-
      • With recurrent vomiting.
      • With elevated NH3.
      • Out of proportion to clinical picture.
      • Difficult to correct.
      • Seen in organic acidemias , MSUD ,GSD , disorders of gluconeogenesis.
      • Increased anion gap (ketoacids ,lactic acid , methylmalonic acid.)
  • 19. IEM Contd…
    • Acidosis :- additional tests—
      • Se glucose
      • NH3
      • Urine pH
      • Ketones
      • Amino & organic acids
      • Blood lactate & pyruvate
  • 20. IEM Contd…
    • Lactate & pyruvate—
      • Measure in arterial blood.
      • Normal Ratio is 10:1 to 20:1.
      • High ratio 
        • Mitochondrial disorders.
        • Pyruvate carboxylase deficiency.
      • Normal or low ratio 
        • Glycogen storage disease.
        • Pyruvate dehydrogenase deficiency
  • 21. IEM~~ Management
    • Broad management :-
      • Problems  severe acidosis , hypoglycemia , hyperammonemia . Can lead to coma & death!
      • Stop all oral intake.
      • Give I/V glucose to stop catabolism.( most respond favorably to glucose – some do not eg. Primary lactic acidosis in pyruvate dehydrogenase deficiency .)
      • Bicarb.
      • Hyperammonemia – may need dialysis .
  • 22. IEM ~~ Management
    • Specific interventions :-
      • Urea cycle disorders-
        • * preventing protein catabolism ( high calorie diet , arginine supplementation )
        • * decreasing NH3 load (protein restriction )
        • * utilizing NH3 scavengers ( benzoate ,phenylbutyrate)
  • 23. IEM~~ Management
      • PKU-
        • *Avoid enzyme substrate in diet.
        • *Diet low in phenylalanine ( Lofenelac , Phenylfree, Analog XP , Maxamaid XP )
        • *Protein restriction.
      • Galactosemia-
        • *galactose free diet ( soy formulas contain sucrose rather than lactose )
  • 24. IEM~~Management
      • Isovaleric acidemia-
        • Pharmacotherapy to remove accumulated substrate –( glycine treatment).
      • Methylmalonic acidemia-
        • Provide co-enzyme ( vit B12)
      • Gauchers disease-
        • Provide normal enzyme (enzyme infusions)
  • 25. IEM~~Management
      • Wilsons disease-
        • Liver transplantation.
      • HFI-
        • Restriction of fruits & fruit juices .
  • 26. IEM  Some associations
    • Sweaty feet odor  only 2 disorders !!
      • Isovaleric acidemia
      • Glutaric acidemia type 2
    • Glutaric acidemia type 1 
      • Extra pyramidal movement disorders
      • Retinal hemorrhages /IC bleeding (like shaken baby syndrome)
  • 27. IEM  Associations
    • Fatty acid oxidation defects –
      • LC Acyl CoA dehydrogenase deficiency  cardiomyopathy!!
      • MC Acyl CoA dehydrogenase deficiency  no cardiomyopathy!!
      • Both have hypoketotic hypoglycemia.
    • Carnitine deficiency  cardiomyopathy ( carnitine is essential for transportation of LCFA into mitochondria for metabolism )
  • 28. IEM  Associations
    • All are AR inherited other than 
      • Lesch Nyhan syndrome – XLR.
      • OTC deficiency – XLR.
      • Fabry’s disease – XLR.
      • Hunter’s syndrome – XLR ( vs Hurler’s syndrome – AR)
  • 29. IEM  Associations
    • Odors :-
      • Glutaric acidemia type 2– sweaty feet
      • Isovaleric acidemia – sweaty feet
      • Hawkinsuria – swimming pool
      • MSUD – maple syrup
      • Methionine malabsorption – cabbage
      • Multiple carboxylase deficiency – tomcat urine
      • Oasthouse urine disease– hops like
      • PKU – mousy or musty
      • Trimethlyaminuria – rotting fish
      • Tyrosinemia – rancid fishy or cabbage like
  • 30. IEM  Associations
    • Cherry red spot 
      • Sialidosis
      • Nieman –Pick’s disease
      • Gaucher’s disease (flank shaped osteolytic lesions)
      • GM1 gangliosidosis
      • Tay- Sach’s disease ( eastern european Jews)
      • Sandoff’s disease ( pan ethnic)
  • 31. IEM  Associations
    • Wolman’s syndrome  adrenals enlarged & calcified.
    • Farber’s disease  arthropathy , painful joints .subcutaneous nodules.
    • Metachromatic leukodystrophy  ataxia , dementia.
    • Lesch-Nyhan’s  self mutilation , hyperuricemia , hyperuricosuria , gouty arthritis , urate ureterolithiasis)
  • 32. IEM  Associations
    • Corneal clouding 
      • Seen in mucopolysaccharidosis.
      • Seen in Hurler’s, Scheie’s & Morquio’s.
      • Hurler’s – AR, HSM, umbilical hernia , coarse facies , corneal clouding , gibbus , heart disease).
      • Hunter’s – X –linked ( all the above but no corneal clouding & no gibbus.)
  • 33. INITIAL FINDINGS ( POOR FEEDING , VOMITING , LETHARGY, CONVULSIONS ,COMA ) METABOLIC DISORDER INFECTION OBTAIN PL. NH3 HIGH NORMAL OBTAIN BLOOD Ph & CO2 OBTAIN BLOOD Ph & CO2 NORMAL ACIDOSIS NORMAL UREA CYCLE DEFECTS ORGANIC ACIDEMIAS AMINOACIDOPATHIES GALACTOSEMIA