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Phenylketonuria
- 1. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria A.N. Emami R.
- 2. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria
- 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 2 Tuesday, June 26, 2012 Total slide : 45 3
- 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 atrophy Tuesday, June 26, 2012 Total slide : 45 4
- 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 reflexes Tuesday, June 26, 2012 Total slide : 45 5
- 6. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Normal Patrick • Abnormal high intensity signal in deep white matter • Leucodystrophy and Cortical atrophy Tuesday, June 26, 2012 Total slide : 45 6
- 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 teratogens Tuesday, June 26, 2012 Total slide : 45 7
- 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 positive Tuesday, June 26, 2012 Total slide : 45 8
- 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 Aorta Tuesday, June 26, 2012 Total slide : 45 9
- 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 brother Tuesday, June 26, 2012 Total slide : 45 10
- 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 formula Tuesday, June 26, 2012 Total slide : 45 11
- 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/dl Tuesday, June 26, 2012 Total slide : 45 12
- 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-treatment Tuesday, June 26, 2012 Total slide : 45 13
- 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 / EPI Tuesday, June 26, 2012 Total slide : 45 14
- 15. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Tuesday, June 26, 2012 Total slide : 45 15
- 16. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Conditionally Essential AA Tuesday, June 26, 2012 Total slide : 45 16
- 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 Valine Tuesday, June 26, 2012 Total slide : 45 17
- 18. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Urine Alternate Disposal Phenyl lactate Phenylacetate Phenylethylamine Phenylacetyl glutamine Mousy or musty odor Tuesday, June 26, 2012 Total slide : 45 18
- 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 hyperphenylalaninemia Tuesday, June 26, 2012 Total slide : 45 19
- 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 severity Tuesday, June 26, 2012 Total slide : 45 20
- 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 severity Tuesday, June 26, 2012 Total slide : 45 21
- 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 reductase Tuesday, June 26, 2012 Total slide : 45 22
- 23. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Tuesday, June 26, 2012 Total slide : 45 23
- 24. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Tuesday, June 26, 2012 Total slide : 45 24
- 25. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Tuesday, June 26, 2012 Total slide : 45 25
- 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 restriction Tuesday, June 26, 2012 Total slide : 45 26
- 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, serotonin Tuesday, June 26, 2012 Total slide : 45 27
- 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 Seizures Tuesday, June 26, 2012 Total slide : 45 28
- 29. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Non-Neuro pathology Hypomelanosis – Why ? Tuesday, June 26, 2012 Total slide : 45 29
- 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 Aorta Tuesday, June 26, 2012 Total slide : 45 30
- 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 begun Tuesday, June 26, 2012 Total slide : 45 31
- 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-conceptually Tuesday, June 26, 2012 Total slide : 45 32
- 33. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Maternal PKU syndrome Dose-Response Relationship Goal: Phe level between 2-6 mg/dl by 8 weeks Tuesday, June 26, 2012 Total slide : 45 33
- 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 baby Tuesday, June 26, 2012 Total slide : 45 34
- 35. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria Balancing Metabolic Control Exposure to Elimination normal of PHE PHE intake from the diet Tuesday, June 26, 2012 Total slide : 45 35
- 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 / seizures Tuesday, June 26, 2012 Total slide : 45 36
- 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 / seizures Tuesday, June 26, 2012 Total slide : 45 37
- 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 deficiency Tuesday, June 26, 2012 Total slide : 45 38
- 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 deficiency Tuesday, June 26, 2012 Total slide : 45 39
- 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/week Tuesday, June 26, 2012 Total slide : 45 40
- 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 illness Tuesday, June 26, 2012 Total slide : 45 41
- 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. Hyperphe Tuesday, June 26, 2012 Total slide : 45 42
- 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 diet Tuesday, June 26, 2012 Total slide : 45 43
- 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. Hyperphe Tuesday, June 26, 2012 Total slide : 45 44
- 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 normal Tuesday, June 26, 2012 Total slide : 45 45
- 46. Metabolic & Molecular Basis of Inherited Disease Phenyiketonuria The End Tuesday, June 26, 2012 Total slide : 45 46