2. Neurologic presentation of PKU
Dr.Pirzadeh
Child neurologist

3. Oslo, Norway, the Late 1920s
Harry (a young dentist) and his wife Borgny Egeland were concerned that their 3 year old daughter was very slow in speaking. While dealing with this concern, Borgny recognized she was pregnant this time with a son, later named Dag. He was early found to be very delayed
The Egelands detected a strange musty odor which they thought might be causing their children’s retardation. The father who had severe asthma was said to be unable to stay in a closed room with the children due to the odor
They sought the help of a Chemistry Professor that had taught Harry in Dental School, Dr. Asbjørn Følling (he was teaching there while in medical school). The Følling medical thesis was written on “Mechanisms of Acidosis”

4. Borgny was asked to bring urine samples to the Følling laboratory; routine tests were normal but when ferric chloride was added (a test for ketones which produces a red-brown color) the girl’s urine turned a dark green color which faded in a few minutes
Could the positive test be drugs or herbs? All these were eliminated, still the evanescent dark green color was present
Dr. Følling asked Mrs. Egeland to bring daily urine samples which soon totaled about 20 liters. Using laborious chemical precipitation procedures he recrystallized the compound (he could follow its presence by the positive FeCl3 test) six times and identified this compound as phenylpyruvic acid
Følling screened 434 mentally-retarded children using the urinary FeCl3 test and found 8 with the same abnormality, which he termed phenylpyruvic oligophrenia, and identified it as a defect in phenylalanine metabolism
In 1934, he published these findings, approximately 6 months after the Egelands had contacted him!

5. Neurologic presentation of PKU
Asbjorn Fölling Lecture
Fölling had originally called the disorder “oligophrenia phenylpyruvica”)

6. Transient Green Color seen by Følling

7. PHENYLALANINE HYDROXYLASE
The normal metabolism of phenylalanine (pathways a and b)
BREAKDOWN
Dietry sources, particularly plant proteins
PHENYLALANINE HYDROXYLASE
PHENYLALANINE
TYROSINE
(b)
(a)
BODY PROTEINS
© 2008 Paul Billiet ODWS

8. PHENYLALANINE HYDROXYLASE
The abnormal metabolism in phenylketonuric subjects
(pathway c)
HYDROXYPHENYLACETIC ACID
(c)
PHENYLALANINE*
Dietry sources, particularly plant proteins
BODY PROTEINS
(b)
(a)
PHENYLALANINE HYDROXYLASE
(c)
PHENYLACETIC ACID*
*Agents, thought to be responsible for mental retardation
© 2008 Paul Billiet ODWS

9. phenylalanin
1- classic hyperphenylalanimia ( classic pku 2 – milder forms of (non-pku ) hyperpheny… 3 – hyperphenylalaninemia from def of BH4 4 – BH4 defects without hyperphenylalaninemia ( hereditary progressive dystonia , AD dopa-responsive dystonia , segawa disease)

10. Neurologic presentation of PKU
Normal neonates
Developmental delay
Microcephaly
Mental retardation
autism
Seizures
Movement disorder
Hyperactivity

11. Maternal PKU= phenylketonuric fetopathy
Normal phenylalanine levels
Microcephaly
Cardiac defects
Motor-mental retardation

12. Neurologic presentation of PKU
No consistent finding on neurologic examination.

13. Presentation of PKU Unpleasant musty/ mousy body odor
Severe vomiting (misdiagnosis of PS)
Light hair, eyes, and skin
Eczema-like rash

14. Phenylketoneuria (PKU)

16. Case presentation 15 years old male Refractory epilepsy
Onset : 3 months
Types:
Drop attacks
GTC (nocturnal)
Frequency : /day

17. Case presentation NVD G4 P4 Ab 0 HC: ??? 52 cm W: ???  50 kg
No positive history of HIE or Icter
Relative parents
His older sister : MR + epileptic

18. Case presentation Cognition: class 3 No organomegaly No specific odor
No cerebellar signs
DTR : ++ / +++
No clonus
No skin lesions

19. Case presentation
TFT: nl Lactate ,Ammonia :NL VBG: nl

24. Testing and Diagnosis
Cleary, M. A. (2011). Phenylketonuria. Paediatrics and Child Health, 21(2),

25. History of PKU
1934: Asbjorn Folling described an inherited metabolic disorder characterized by severe intellectual impairment, motor problems and skin abnormalities - affected individuals identified by abnormal excretion of phenylpyruvic acid (high frequency of consanguinity in parents of PKU patients; Mendelian disease)
1950s: PKU patients shown to have deficient activity of PAH
1960s: treatment of PKU with low phenylalanine diet shown to be effective

26. History of PKU 1980s: mapping and cloning of PAH gene
1990s: PKU more than a simple Mendelian trait; also behaves as complex, multifactorial disorder
2000s: Non-dietary treatments for PKU developed

27. یک نفس یاد خدا
یک سبد اطلس عشق و صفا
یک هزار آیه از جنس دعا
همه تقدیم شما

28. PKU
Newborn mass Screening: Ferric chloride test:??? Guthrie test: Tandem mass spectrometry (TMS) All must be investigated for BH4 def(urinary Neopterine & Biopterine)

29. GENETICS
AR Prevalence in usa : 1/14000 to 1 /20000 More in turkey , Arabs , Yemenians jews IRAN: 1/10000

30. treatment
Goals of therapy : Correct hyperphenylalaninemia Restore neurotransmitter deficiencies in CNS DHBR needs more BH4 therapy than others L-dopa 5-hydroxytryptophan DHBR def needs to folinic acid too. PROLACTIN levels may be a convenient method for monitoring adequacy of neurotransmitter replacement therapy.

31. Hyperphenylalaninemia from deficiency of cofactor BH4
BH4 is cofactor for phenylalanine , tyrosine & tryptophan hydroxylases. The latter 2 hydroxylases are essential for biosynthesis of the neurotransmitters DOPAMINE & SEROTONINE. BH4 is cofactor for NITRIC OXIDE SYNTHASE , which catalizes the generation of nitric oxide from arginine. BH4 is synthesized from GTP through several enzymatic reaction.

32. Clinical manifestation of BH4 def
Are identified during newborn pku screening Plasma phe level may be as high as those of classic or milder forms of hyperphenylalaninemia. Neurologic manifestations , such as loss of head control , truncal hypotonia , drooling , swallowing difficulties & myoclonus seizure , develops after 3 months of age despite adequate diatery therapy.

33. Diagnosis of BH4 def.
Measurement of NEOPTERIN (oxidative product of dihydroneopterine triphosphate) & BIOPTERIN (oxidative product of BH2 and BH4 in body fluids ,especially URINE. GTP cyclohydrolase def :low N &B PTPS def: increased N & decreased B DHPR def: normal N & very high B CDH def : increased 7-B

34. BH4 loading test
An oral dose of BH4 ( 20 mg/kg) normalizes plasma phe in patients with BH4 def in 4-8 hr. the blood phe should be elevated (6.6 mg/dl ) to enable interpretation of the results. This may be achieved by D/C diet therapy for 2 days before test or by administering a loading dose of phe (100mg/kg ) 3 hr before the test.

35. Enzyme assay in BH4 def
DHBR can be measured in dry blood spot PTPS activity can be measured in the LIVER & KIDNEY &RBC. CDH activity can be …(LIVER&KIDNEY) GTP hydrolase : LIVER & cytokine stimulated mononuclear cells or fibroblasts

36. PKU
Through Newborn Screening almost all affected newborns are diagnosed and treated early.
Untreated PKU causes mental retardation
At least 1 baby in 25,000 is born with PKU in the United States

37. Treatment for PKU
A special diet can help prevent PKU. ( very restricted)
In 2007 the FDA approved KUVAN as the first drug to help manage PKU.