Phenylketonuria

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Phenylketonuria

  1. 1. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria A.N. Emami R.
  2. 2. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria
  3. 3. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Case 1 Patrick Birth History: Full Term, 3,620 gm Uncomplicated Pregnancy, Labor & Delivery Mother 24 yr old, healthy No Prenatal exposure to alcohol, drugs, infection, known teratogens Discharged home on day of life 2Tuesday, June 26, 2012 Total slide : 45 3
  4. 4. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Case 1 (CONTINUED) Developmental Hx Seizure History Rolled over – 3 First – 11 m months Generalized, Social smile - 4 m tonic/clonic Total – 4 seizures Stand alone – 14 m MRI – decreased First word – 18 m grey/white Phrases – not yet differentiation and Walk alone – 2 yr cortical atrophyTuesday, June 26, 2012 Total slide : 45 4
  5. 5. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Case 1 (Cont) Physical Exam Growth Blond hair, blue eyes Non-dysmorphic child Neurological exam: Decreased tone, brisk reflexesTuesday, June 26, 2012 Total slide : 45 5
  6. 6. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Normal Patrick• Abnormal high intensity signal in deep white matter• Leucodystrophy and Cortical atrophyTuesday, June 26, 2012 Total slide : 45 6
  7. 7. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Case 2 Jeremy newborn Mother - 19 yr old male First Pregnancy Full Term: 3,100 gm Father -18 yr old Uncomplicated P,L Healthy &D No perinatal infection, no alcohol, no drugs, no known teratogensTuesday, June 26, 2012 Total slide : 45 7
  8. 8. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Case 2 Physical Exam and Labs Ht & Wt = 70% General exam normal HC< 5% Neurological exam - normal Urine Ferric Chloride (FeCl3) is positiveTuesday, June 26, 2012 Total slide : 45 8
  9. 9. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Case 2 Jeremy is now 13 years old and exhibits Persistent microcephaly Spasticity Mental retardation Coarctation of AortaTuesday, June 26, 2012 Total slide : 45 9
  10. 10. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Case 3 Luis (8yo) referred to Developmental Pediatrics clinic Chief Complaint: Hyperactivity and Learning Disabilities Patient and his Brother •Self selects diet •low in meat, eggs, cheese •enriched in fruits / vegetables •Similar pigmentation to his brotherTuesday, June 26, 2012 Total slide : 45 10
  11. 11. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Case 4 Hannah: 6 month old female Diagnosed with metabolic disorder on abnormal newborn metabolic screen Normal growth / development Normal physical exam On treatment with metabolic formulaTuesday, June 26, 2012 Total slide : 45 11
  12. 12. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria All four cases Examples of hyperphenylalanemia Defects in metabolism of phenylalanine Prototype – PKU Elevation of PHE > 20 mg/dl Normal < 2 mg/dlTuesday, June 26, 2012 Total slide : 45 12
  13. 13. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria PKU Clinical Findings Mousy or musty odor Exzema Fair coloring (decreased hair and skin pigmentation) Behavior Problems Mental Retardation Lose ~ 1 IQ point per week of non-treatmentTuesday, June 26, 2012 Total slide : 45 13
  14. 14. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Phenylalanine Metabolism Phenylalanine Food Catabolism Essential AA PHE 50% Body Protein Major TYR interconversions Melanin through tyrosine DOPA NE / EPITuesday, June 26, 2012 Total slide : 45 14
  15. 15. Metabolic & Molecular Basis of Inherited Disease PhenyiketonuriaTuesday, June 26, 2012 Total slide : 45 15
  16. 16. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Conditionally Essential AATuesday, June 26, 2012 Total slide : 45 16
  17. 17. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Essential Amino Acids Histidine Isoleucine Leucine Lysine Methionine (and/or cysteine) Phenylalanine (and/or tyrosine) Threonine Tryptophan ValineTuesday, June 26, 2012 Total slide : 45 17
  18. 18. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Urine Alternate Disposal Phenyl lactate Phenylacetate Phenylethylamine Phenylacetyl glutamine Mousy or musty odorTuesday, June 26, 2012 Total slide : 45 18
  19. 19. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria PKU Autosomal Recessive disorder caused by mutation in PAH gene Newborn screening started in 1963 Incidence: 1 in 15,000 Subtypes and heterogeneity Classic Moderate and mild Non-classical or non-PKU hyperphenylalaninemiaTuesday, June 26, 2012 Total slide : 45 19
  20. 20. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria PKU Autosomal Recessive disorder caused by mutation in PAH gene Newborn screening started in 1963 Incidence: 1 in 15,000 Subtypes and heterogeneity Classic Moderate and mild Non-classical or non-PKU hyperphenylalaninemia  % enzyme activity determines clinical severityTuesday, June 26, 2012 Total slide : 45 20
  21. 21. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria PKU Autosomal Recessive disorder caused by mutation in PAH gene Newborn screening started in 1963 Incidence: 1 in 15,000 Subtypes and heterogeneity Classic Mild Hyperphenylalaninemia  % enzyme activity determines clinical severityTuesday, June 26, 2012 Total slide : 45 21
  22. 22. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria PKU Autosomal Recessive disorder caused by mutation in PAH gene Newborn screening started in 1963 Incidence: 1 in 15,000 Subtypes and heterogeneity Classic Moderate Tetrahydrobiopterin (BH4) responsive Mild Hyperphenylalaninemia • Urine pterins Hyperphe • blood dihydropteridine reductaseTuesday, June 26, 2012 Total slide : 45 22
  23. 23. Metabolic & Molecular Basis of Inherited Disease PhenyiketonuriaTuesday, June 26, 2012 Total slide : 45 23
  24. 24. Metabolic & Molecular Basis of Inherited Disease PhenyiketonuriaTuesday, June 26, 2012 Total slide : 45 24
  25. 25. Metabolic & Molecular Basis of Inherited Disease PhenyiketonuriaTuesday, June 26, 2012 Total slide : 45 25
  26. 26. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria BH4 Responders PAH mutation 62% catalytic 21% regulatory Allelic pattern 1 mild + 1 severe 2 mild 2 severe (rare) Diet – BH4 without protein restrictionTuesday, June 26, 2012 Total slide : 45 26
  27. 27. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Biological Effects HyperPhe inhibits transport of large, neutral AA into the brain (as does Leucine) Inhibition of protein and neurotransmitters  Deficiencies of dopamine, serotoninTuesday, June 26, 2012 Total slide : 45 27
  28. 28. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Major Neuropathologic changes Hypomyelination (Phe-sensitive oligodendrocytes) White matter degeneration (leucodystrophy) Developmental delay/arrest cerebral cortex Microcephaly Mental retardation SeizuresTuesday, June 26, 2012 Total slide : 45 28
  29. 29. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Non-Neuro pathology Hypomelanosis – Why ?Tuesday, June 26, 2012 Total slide : 45 29
  30. 30. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Non-Neuro pathology Hypomelanosis Blond hair, blue eyes, pale Deficient Tyrosine production (precursor of Melanin) Cardiac Coarctation of the AortaTuesday, June 26, 2012 Total slide : 45 30
  31. 31. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Maternal PKU syndrome First mentioned in literature in 1937 First mentioned as a complication of PKU in 1956 Women with MR and PKU has 3 children, all retarded despite not having PKU Microcephaly and cardiac defects reported in 1960’s 1983 – MPKUCS begunTuesday, June 26, 2012 Total slide : 45 31
  32. 32. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Maternal PKU Collaborative Study Untreated women 92% risk of mental retardation 73% risk of microcephaly 40% risk of low birth weight 12% risk of congenital heart disease Reduced risk if maternal plasma phe levels are normalized pre-conceptuallyTuesday, June 26, 2012 Total slide : 45 32
  33. 33. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Maternal PKU syndrome Dose-Response Relationship Goal: Phe level between 2-6 mg/dl by 8 weeksTuesday, June 26, 2012 Total slide : 45 33
  34. 34. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Maternal PKU syndrome The longer it takes to get Phe level < 8 mg/dl the lower the IQ of the babyTuesday, June 26, 2012 Total slide : 45 34
  35. 35. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Balancing Metabolic Control Exposure to Elimination normal of PHE PHE intake from the dietTuesday, June 26, 2012 Total slide : 45 35
  36. 36. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Balancing Metabolic Control Exposure to normal PHE intake: Elevations of PHE Elevations of PHE-ketones Deficient TYR, DOPA, NE, EPI Mental retardation / seizuresTuesday, June 26, 2012 Total slide : 45 36
  37. 37. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Balancing Metabolic Control Exposure to normal PHE intake: Elevations of PHE Elevations of PHE-ketones Deficient TYR, DOPA, NE, EPI = Bad Mental retardation / seizuresTuesday, June 26, 2012 Total slide : 45 37
  38. 38. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Balancing Metabolic Control Elimination of PHE from the diet: Decreases PHE Decreases PHE-ketones Deficient TYR, DOPA, NE, EPI DEATH from essential AA deficiencyTuesday, June 26, 2012 Total slide : 45 38
  39. 39. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Balancing Metabolic Control Elimination of PHE from the diet: Decreases PHE Decreases PHE-ketones Deficient TYR, DOPA, NE, EPI = Bad DEATH from essential AA deficiencyTuesday, June 26, 2012 Total slide : 45 39
  40. 40. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Optimal Therapy of PKU Initiate treatment by 7 days of life Phenylalanine levels Age Level Freq of Testing 0-12 months 2-6 mg/dl 1x/week 1-12 years Same 2x/month > 12 years 2-15 mg/dl 1x/month Pregnancy 2-6 mg/dl* 2x/weekTuesday, June 26, 2012 Total slide : 45 40
  41. 41. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria summery Hyperphenylalanemia Treatment is An abnormal lab – Effective if begun finding early and continued for Several defects may life result in hyperphe – Aggressive Specific Dx is critical management during PHE restriction in growth and during BH4 deficiency is lethal illnessTuesday, June 26, 2012 Total slide : 45 41
  42. 42. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria What about our cases?? Patrick – case 1 Jeremy – case 2  Dx ?  Dx ? 3 yr old with • Newborn with developmental delay microcephaly and + FeCl 3 and seizures….. • Now mentally retarded Choices 2. Classic PKU – treated or untreated 3. Maternal PKU 4. HyperpheTuesday, June 26, 2012 Total slide : 45 42
  43. 43. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria What about our cases?? Patrick – case 1 Jeremy – case 2  Classic PKU (mod)  Maternal PKU syndrome • Newborn with • 3 yr old with microcephaly and + FeCl3 developmental delay • Now mentally retarded and seizures….. • He is metabolically • Patrick has permanent normal… but his mother disabilities had PKU • His mother wants more children but is not on dietTuesday, June 26, 2012 Total slide : 45 43
  44. 44. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Our Cases Luis - Case 3 Hannah - Case 4 Dx ?  Dx ? • 8yo with learning • 6 month old disability and • Normal growth and hyperactivity development Choices 2. Classic PKU – treated or untreated 3. Maternal PKU 4. HyperpheTuesday, June 26, 2012 Total slide : 45 44
  45. 45. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Our Cases Luis - Case 3 Hannah - Case 4  Classic PKU (Mexico)  Classic PKU, treated • On treatment • Continues to do well • His hyperactivity has on therapy improved • Growth, development • He will not regain and intellectual normal intellect situation are normalTuesday, June 26, 2012 Total slide : 45 45
  46. 46. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria The EndTuesday, June 26, 2012 Total slide : 45 46

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