Neurologic presentation of PKU Dr.Pirzadeh Child neurologist

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”

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

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

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

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)

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 Cleary, M. A. (2011). Phenylketonuria. Paediatrics and Child Health, 21(2), 61-64.

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

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

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.