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
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
