PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
A.N. Emami R.
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Saturday, April 8, 2023 Total slide : 45 3
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Case 1Patrick
Birth History: Full Term, 3,620 gmUncomplicated Pregnancy, Labor & DeliveryMother 24 yr old, healthyNo Prenatal exposure to alcohol, drugs, infection, known teratogensDischarged home on day of life 2
Saturday, April 8, 2023 Total slide : 45 4
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Case 1 (CONTINUED)
Developmental HxRolled over – 3 monthsSocial smile - 4 mStand alone – 14 mFirst word – 18 mPhrases – not yetWalk alone – 2 yr
Seizure HistoryFirst – 11 mGeneralized, tonic/clonicTotal – 4 seizuresMRI – decreased grey/white differentiation and cortical atrophy
Saturday, April 8, 2023 Total slide : 45 5
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Case 1 (Cont)
Physical ExamGrowthBlond hair, blue eyesNon-dysmorphic childNeurological exam:
Decreased tone, brisk reflexes
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PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
PatrickNormal• Abnormal high intensity signal in deep white matter• Leucodystrophy and Cortical atrophy
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PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Case 2
Jeremy newborn maleFull Term: 3,100 gmUncomplicated P,L & DNo perinatal infection, no alcohol, no drugs, no known teratogens
Mother - 19 yr oldFirst PregnancyFather -18 yr oldHealthy
Saturday, April 8, 2023 Total slide : 45 8
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Case 2Physical Exam and Labs
Ht & Wt = 70% General exam normalHC< 5% Neurological exam - normalUrine Ferric Chloride (FeCl3) is positive
Saturday, April 8, 2023 Total slide : 45 9
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Case 2
Jeremy is now 13 years old and exhibits
Persistent microcephalySpasticityMental retardation
Coarctation of Aorta
Saturday, April 8, 2023 Total slide : 45 10
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
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
Saturday, April 8, 2023 Total slide : 45 11
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Case 4
Hannah: 6 month old female Diagnosed with metabolic disorder on abnormal newborn metabolic screenNormal growth / developmentNormal physical examOn treatment with metabolic formula
Saturday, April 8, 2023 Total slide : 45 12
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
All four cases
Examples of hyperphenylalanemiaDefects in metabolism of phenylalaninePrototype – PKU
Elevation of PHE > 20 mg/dlNormal < 2 mg/dl
Saturday, April 8, 2023 Total slide : 45 13
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
PKUClinical Findings
Mousy or musty odorExzemaFair coloring (decreased hair and skin
pigmentation)Behavior Problems
Mental RetardationLose ~ 1 IQ point per week of non-treatment
Saturday, April 8, 2023 Total slide : 45 14
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Phenylalanine Metabolism
PhenylalanineEssential AAMajor interconversions through tyrosine
PHE
TYRBody Protein
Melanin
DOPA
NE / EPI
Food Catabolism
50%
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PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
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PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Conditionally Essential AA
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PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Essential Amino Acids
HistidineIsoleucineLeucineLysineMethionine (and/or cysteine)Phenylalanine (and/or tyrosine)ThreonineTryptophanValine
Saturday, April 8, 2023 Total slide : 45 18
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Phenyl lactatePhenylacetatePhenylethylaminePhenylacetyl glutamine
Alternate Disposal Urine
Mousy or mustyodor
Saturday, April 8, 2023 Total slide : 45 19
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
PKU
Autosomal Recessive disorder caused by mutation in PAH geneNewborn screening started in 1963Incidence: 1 in 15,000Subtypes and heterogeneity
ClassicModerate and mildNon-classical or non-PKU hyperphenylalaninemia
Saturday, April 8, 2023 Total slide : 45 20
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
PKU
Autosomal Recessive disorder caused by mutation in PAH geneNewborn screening started in 1963Incidence: 1 in 15,000Subtypes and heterogeneity
ClassicModerate and mildNon-classical or non-PKU hyperphenylalaninemia
% enzyme activity determines clinical severity
Saturday, April 8, 2023 Total slide : 45 21
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
PKU
Autosomal Recessive disorder caused by mutation in PAH geneNewborn screening started in 1963Incidence: 1 in 15,000Subtypes and heterogeneity
ClassicMildHyperphenylalaninemia
% enzyme activity determines clinical severity
Saturday, April 8, 2023 Total slide : 45 22
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
PKU
Autosomal Recessive disorder caused by mutation in PAH geneNewborn screening started in 1963Incidence: 1 in 15,000Subtypes and heterogeneity
ClassicModerateMildHyperphe
Tetrahydrobiopterin (BH4) responsive Hyperphenylalaninemia
• Urine pterins• blood dihydropteridine reductase
Saturday, April 8, 2023 Total slide : 45 23
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Saturday, April 8, 2023 Total slide : 45 24
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Saturday, April 8, 2023 Total slide : 45 25
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Saturday, April 8, 2023 Total slide : 45 26
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
BH4 Responders
PAH mutation62% catalytic21% regulatory
Allelic pattern1 mild + 1 severe2 mild2 severe (rare)
Diet – BH4 without protein restriction
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PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Biological Effects
HyperPhe inhibits transport of large, neutral AA into the brain (as does Leucine)
Inhibition of protein and neurotransmitters Deficiencies of dopamine, serotonin
Saturday, April 8, 2023 Total slide : 45 28
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Major Neuropathologic changes
1. Hypomyelination (Phe-sensitive oligodendrocytes)
2. White matter degeneration (leucodystrophy)3. Developmental delay/arrest cerebral cortex
Microcephaly Mental retardation Seizures
Saturday, April 8, 2023 Total slide : 45 29
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Non-Neuro pathology
Hypomelanosis – Why ?
Saturday, April 8, 2023 Total slide : 45 30
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Non-Neuro pathology
HypomelanosisBlond hair, blue eyes, pale Deficient Tyrosine production (precursor of Melanin)
CardiacCoarctation of the Aorta
Saturday, April 8, 2023 Total slide : 45 31
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Maternal PKU syndrome
First mentioned in literature in 1937First 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’s1983 – MPKUCS begun
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PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Maternal PKU Collaborative Study
Untreated women92% risk of mental retardation73% risk of microcephaly40% risk of low birth weight12% risk of congenital heart disease
Reduced risk if maternal plasma phe levels are normalized pre-conceptually
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PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Maternal PKU syndrome
Dose-Response Relationship Goal: Phe level between 2-6 mg/dl by 8 weeks
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PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Maternal PKU syndrome
The longer ittakes to get Phelevel < 8 mg/dlthe lower the IQof the baby
Saturday, April 8, 2023 Total slide : 45 35
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Balancing Metabolic Control
Exposure to normal
PHE intake
Elimination of PHE
from the diet
Saturday, April 8, 2023 Total slide : 45 36
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Balancing Metabolic Control
Exposure to normal PHE intake:Elevations of PHEElevations of PHE-ketonesDeficient TYR, DOPA, NE, EPIMental retardation / seizures
Saturday, April 8, 2023 Total slide : 45 37
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Balancing Metabolic Control
Exposure to normal PHE intake:Elevations of PHEElevations of PHE-ketonesDeficient TYR, DOPA, NE, EPIMental retardation / seizures
= Bad
Saturday, April 8, 2023 Total slide : 45 38
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Balancing Metabolic Control
Elimination of PHE from the diet:Decreases PHEDecreases PHE-ketonesDeficient TYR, DOPA, NE, EPIDEATH from essential AA deficiency
Saturday, April 8, 2023 Total slide : 45 39
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Balancing Metabolic Control
Elimination of PHE from the diet:Decreases PHEDecreases PHE-ketonesDeficient TYR, DOPA, NE, EPIDEATH from essential AA deficiency
= Bad
Saturday, April 8, 2023 Total slide : 45 40
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Optimal Therapy of PKU
Initiate treatment by 7 days of lifePhenylalanine levelsAge Level Freq of Testing
0-12 months 2-6 mg/dl 1x/week1-12 years Same 2x/month> 12 years 2-15 mg/dl 1x/month
Pregnancy 2-6 mg/dl* 2x/week
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PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
summery
HyperphenylalanemiaAn abnormal lab finding Several defects may result in hyperphe
Specific Dx is criticalPHE restriction in
BH4 deficiency is lethal
Treatment isEffective if begun early and continued for lifeAggressive management during growth and during illness
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PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
What about our cases??
Patrick – case 1 Dx ?
3 yr old with developmental delay and seizures…..
Jeremy – case 2 Dx ?• Newborn with
microcephaly and + FeCl3
• Now mentally retardedChoices1. Classic PKU – treated or untreated2. Maternal PKU3. Hyperphe
Saturday, April 8, 2023 Total slide : 45 43
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
What about our cases??
Patrick – case 1 Classic PKU (mod)• 3 yr old with
developmental delay and seizures…..
• Patrick has permanent disabilities
Jeremy – case 2 Maternal PKU syndrome• Newborn with
microcephaly and + FeCl3• Now mentally retarded• He is metabolically
normal… but his mother had PKU
• His mother wants more children but is not on diet
Saturday, April 8, 2023 Total slide : 45 44
PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Our Cases
Luis - Case 3Dx ? • 8yo with learning
disability and hyperactivity
Hannah - Case 4 Dx ?• 6 month old• Normal growth and
developmentChoices1. Classic PKU – treated or untreated2. Maternal PKU3. Hyperphe
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PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
Our Cases
Luis - Case 3 Classic PKU (Mexico)• On treatment• His hyperactivity has
improved• He will not regain
normal intellect
Hannah - Case 4 Classic PKU, treated• Continues to do well
on therapy• Growth, development
and intellectual situation are normal
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PhenyiketonuriaMetabolic & Molecular Basis of Inherited Disease
The End