Inbornerrorsofmetabolism

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Inborn Erros of Metabolism

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Inbornerrorsofmetabolism

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

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