Transcript Neurologic presentation of PKU

Dr.Pirzadeh
Child neurologist
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”
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!
Neurologic presentation of PKU
Asbjorn Fölling Lecture
Fölling had originally called
the disorder “oligophrenia
phenylpyruvica”)
Transient Green Color seen by Følling
The normal metabolism of phenylalanine
(pathways a and b)
BREAKDOWN
Dietry
sources,
particularly
plant
proteins
PHENYLALANINE
PHENYLALANINE
HYDROXYLASE
(a)
TYROSINE
(b)
BODY
PROTEINS
© 2008 Paul Billiet ODWS
The abnormal metabolism in phenylketonuric subjects
(pathway c)
HYDROXYPHENYLACETIC
ACID
Dietry
sources,
particularly
plant
proteins
(c)
PHENYLALANINE
HYDROXYLASE
PHENYLALANINE*
(a)
(c)
(b)
PHENYLACETIC
ACID*
*Agents, thought to be responsible for mental retardation
© 2008 Paul Billiet ODWS
BODY
PROTEINS
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 doparesponsive dystonia ,
segawa disease)
Neurologic presentation of PKU
 Normal neonates
 Developmental delay
 Microcephaly
 Mental retardation
 autism
 Seizures
 Movement disorder
 Hyperactivity
Maternal PKU= phenylketonuric
fetopathy
 Normal phenylalanine levels
 Microcephaly
 Cardiac defects
 Motor-mental retardation
Neurologic presentation of PKU
No consistent
finding on
neurologic
examination.
Presentation of PKU
 Unpleasant musty/
mousy body odor
 Severe vomiting
(misdiagnosis of PS)
 Light hair, eyes, and skin
 Eczema-like rash
Phenylketoneuria (PKU)
Case presentation
15 years old male
Refractory epilepsy
Onset : 3 months
Types:
Drop attacks
GTC (nocturnal)
Frequency : 10-20 /day
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
Case presentation
Cognition: class 3
No organomegaly
No specific odor
No cerebellar signs
DTR : ++ / +++
No clonus
No skin lesions
Case presentation
TFT: nl
Lactate ,Ammonia :NL
VBG: nl
Testing and Diagnosis
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
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
PKU
Newborn mass Screening:
Ferric chloride test:???
Guthrie test:
Tandem mass spectrometry (TMS)
All must be investigated for BH4 def(urinary
Neopterine & Biopterine)
GENETICS
AR
Prevalence in usa : 1/14000 to
1 /20000
More in turkey , Arabs , Yemenians jews
IRAN: 1/10000
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.
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.
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.
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
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.
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
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
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.