Dr. Kumar Ponnusamy and colleagues aim to delineate the molecular and biochemical basis of phenylketonuria (PKU), its diagnosis and management, and facilitate online teaching about it. PKU is an autosomal recessive genetic disorder caused by a mutation that renders the enzyme phenylalanine hydroxylase nonfunctional. This prevents the conversion of phenylalanine to tyrosine, leading to accumulation of phenylalanine and its toxic byproducts in the central nervous system, which can cause severe mental retardation if left untreated. Management of PKU involves a low-phenylalanine diet, avoiding aspartame, and careful control of phenylalanine levels during pregnancy to prevent adverse effects on fetal development.

1. Dr Kumar Ponnusamy1,2
Ms Jegathambigai1 RN1
and Ms Sindhu B3
Objective: To delineate the molecular and biochemical basis of PKU, diagnosis and management as well to facilitate “USMLE
preparatory Course: BIOGEN Reusable On-Line Resources for Large Group Teaching-Learning in Relatively Short Time”.
Biochemistry & Genetics, International Medical School (IMS) Management & Sciencne University,
AIMST University School of Medicine, 08100 Kedah, Malaysia1
ST Matthew’s University School of Medicine (SMU), Grand Cayman, Cayman Islands, BWI2
Department of Biomedical Engineering, Vellore Institute of Technology (VIT) Vellore, India3
Bridge to Genetics / Inheritance: Autosomal recessive
(AR), metabolic genetic disorder, characterized by a
mutation in the gene for the hepatic enzyme PAH,
rendering it nonfunctional.
Clinical Signs & Symptoms
References: Kaplan & Google.com
Bridge to Pharmacology-Toxicology / Management of
PKU: Diet low in Phenylalanine, avoid aspartame, diet important
during pregnancy. Contraindications: Aspartame (N-aspartyl-
phenylalanine methyl ester), which is widely used as an artificial
sweetner, must be strictly avoided by “Phenylketonurics”. Women
with PKU who become pregnant must be especially careful about
the phenyl alanine level in their blood so as not to adversely affect
neuorologic development in the fetus. Infants born to with phenyl
ketonuric mothers without metabolic control during pregnency have a
high risk of mental retardation, microcephaly and low birth weight.
Behavioural Science / Community Medicine / Ethics: PKU
Support Society / Genetic counseling-Prenatal Screening in
Chorionic Villi Sampling / Referral to PKU Specialty Care Centres.
Molecular-Biochemical Basis of PKU: PKU is a
metabolic disease characterized by accumulation of
PA and its by-products in the blood of fetuses and
newborns. PKU results from a defect in the enzyme
Phenylalanine Hydroxylase (PAH), such that PA is
not converted to Tyrosine. The alternative conversion
of PA to PPA causes accumulation of the latter as a
toxin in the CNS, which can lead to severe mental
retardation.
Laboratory Diagnosis: Infants are routinely screened a
few days after birth for blood PA level as well as urinary
phenyl pyruvic acid and phenyl acetic acids levels.
PHENYLKETONURIA (PKU) e-COGNITIVE CONCEPT MAP
Diffusion-Weighted Imaging of White Matter
Abnormalities in Patients with PKU
DEFICIENCY Dysmorphic Features
in Maternal PKU
MCQ: A child with white-blond hair, blue eyes, and pale
complexion is on a special diet in which one of the essential
amino acids is severely restricted. He has been told to avoid
foods artificially sweetened with aspartame.
Ans: A. The child has PKU; aspartame
Contains PA. These children may be blond, blue e
yed, and pale complexion because of deficient
melanin production from tyrosine.
Musty Odor, Blue Eyes,
Microcephaly & Mental Retardation
Klung&Cummings1997
A
Phenylalanine → Tyrosine
↓B
Homogentisate
↓
Valine Maleylacetoacetate
Leucine ↓C
↓D
Methylmalonyl CoA → TCA Cycle
↑E ↑F
Acetyl-CoA Glutamate
↑G
Alanine → Pyruvate
PKU
“Dr PK_BIOGEN INNO-VISION 2015. Doc1”
Pathophysiology of PKU
PKU
Phenotype
Pleiotropy of PKU
Abstract
PKU is a inborn error of Phenylalanine (PA) metabolism, the occurrence of PKU varies among ethnic groups and geographic regions worldwide. In the
United States, PKU occurs in 1 in 10,000 to 15,000 newborns. Infants with classic PKU are normal at birth but if untreated show slow development,
severe mental retardation, autistic symptoms, and loss of motor control. Children may have pale skin and white-blonde hair. The neurotoxic effects
relate to high levels of PA and not to the phenylketones (PK) from which the name of the disease derives. Key Words: Phenylketonuria,
phenylalanine hydroxylase (PHA)-deficiency, inheritance and complications of PKU, pleiotropy, laboratory diagnosis-prenatal-diagnosis and
management of PKU.
3
5
6
7
89
10
2A
2
1
4
Preventive &
Community
Medicine
PKU Management: “Synthetic Diet
Enriched With Antioxidants, Devoid
of PA”
http://www.iwk.nshealth.ca/sites/default/files/PL-0841-PKU-Done-forWEB-Apr2014_0.pdf
PKU Inheritance
Dysmorphism
of PKU
Research Component on PKU

2. 2
“Dr P KUMAR_BIOGEN INNO-VISION 2015”
e-CONCEPT MAP ON PHENYLKETONURIA
(PKU)
√
☻√ USMLE STEP 1 Q-2
USMLESTEP1Q-1
Bridge to Genetics
Prenatal Diagnosis of PKU
Bridge to
Genetics
Bridge to
Behavioural Science
Phenylalanine Metabolism
Epidemiology
PKU &
Neuroscience
PKU Biochemistry
Prenatal Screening & Genetic Counselling on PKU
Acknowledgements: Lippincott, Google.com & All On-Line Resources
Bridge to Molecular
Biology & Genetics
Dr Kumar Ponnusamy*
& Dr Jegathambigai RN
XX
Ferric ChlorideTestFerric ChlorideTest
Patients With PKUPatients With PKU
Pleotropy-Abnormalities Associated with Metab DisordersPleotropy-Abnormalities Associated with Metab Disorders
GeneralGeneral – Dysmorphisms (abnormality in shape or size), ODOUR.– Dysmorphisms (abnormality in shape or size), ODOUR.
H & NH & N - Cata- CataCNSCNS - Tone, seizures, tense fontanelle.- Tone, seizures, tense fontanelle.
RespResp - Kussmaul’s, tachypnea.- Kussmaul’s, tachypnea. CVSCVS - Myocardial dysfunction.- Myocardial dysfunction.
AbdoAbdo – HEPATOMEGALY.– HEPATOMEGALY. SkinSkin – Jaundice. Cataracts, retinitis pigmentosa.– Jaundice. Cataracts, retinitis pigmentosa.
15. A new test is developed that can non-radioactively “label” compounds in the human body. As a physician with a back-ground In the15. A new test is developed that can non-radioactively “label” compounds in the human body. As a physician with a back-ground In the
new field of metabolomics, you assess a 21-year-old with classicalnew field of metabolomics, you assess a 21-year-old with classical phenylketonuria (PKU).phenylketonuria (PKU). Phenylalanine is fed with a label in the phenylPhenylalanine is fed with a label in the phenyl
ring.ring. In the urineIn the urine, in which of the following compounds would you expect to find the, in which of the following compounds would you expect to find the greatest amount of label?.greatest amount of label?.
A.A. Tyrosine.Tyrosine.
B.B. Tryptophan.Tryptophan.
C.C. Epinephrine.Epinephrine.
D.D. Phenylketone.√Phenylketone.√
E. Acetate.E. Acetate. Answer: D.Answer: D. Phenylketonutria (PKU) is a defect in phenylalanine hydroxylase, resulting in a block in the conversion of pPhenylketonutria (PKU) is a defect in phenylalanine hydroxylase, resulting in a block in the conversion of p
Henylalanine to tyrosine.Henylalanine to tyrosine. PhenylalaninePhenylalanine accumulates in in both disorders and to converted toaccumulates in in both disorders and to converted to phenylketonesphenylketones. Tyrosine is the product. Tyrosine is the product
whose formation is blocked, and epinephrine, a product of tyrosine, would not be made or “labelled’. Acetate and tryptophan are verywhose formation is blocked, and epinephrine, a product of tyrosine, would not be made or “labelled’. Acetate and tryptophan are very
far downstream from tyrosine.far downstream from tyrosine.
1.1. Which of the metabolites below is aWhich of the metabolites below is a
precursor of tyrosine.precursor of tyrosine.
A.A. L-Dihydroxyphenylalanine (dopa).L-Dihydroxyphenylalanine (dopa).
B.B. Dopamine.Dopamine.
C.C. Norepinephrine.Norepinephrine.
D.D. Epinephrine.Epinephrine.
E.E. Phenylalanine.√Phenylalanine.√ Ans: EAns: E..
Family History Helpful to Rule Out IEMFamily History Helpful to Rule Out IEM..
CONSANGUINITYCONSANGUINITY,, ethnicity, inbreeding. Nethnicity, inbreeding. Neonatal deaths, fetal losses.eonatal deaths, fetal losses.
Maternal family history. males - X-linked disorders. All-Maternal family history. males - X-linked disorders. All-mitochondrialmitochondrial
DNADNA isis maternallymaternally inheritedinherited. A positive family history may be helpful!.. A positive family history may be helpful!.
Timing of onset of symptoms.Timing of onset of symptoms. AfterAfter feeds werefeeds were
started?.started?. Response to therapies.Response to therapies.
USMLE STEP 1 MCQ
BridgetoETHICS
Bridge to
Behavioural
Science
What Are The Common Signs & Symptoms of Metabolic Diseases in the Neonate?What Are The Common Signs & Symptoms of Metabolic Diseases in the Neonate?.Acute life.Acute life
threatening illness. encephalopathy - lethargy, irritability, coma. Vomiting, & respiratory distress.threatening illness. encephalopathy - lethargy, irritability, coma. Vomiting, & respiratory distress.
Seizures, Hypertonia, Hepatomegaly. Hepatic dysfunction / jaundice. Odour,Seizures, Hypertonia, Hepatomegaly. Hepatic dysfunction / jaundice. Odour, DysmorphismDysmorphism, failure, failure
to thrive (FTT), Hiccoughs.to thrive (FTT), Hiccoughs.
DIAGNOSIS
“What you have brought while coming, and what you
are going to take away while going?. The Only Thing
What You Are Going to Take Away is Karma_
Just Educate The Society”_Dr P Kumar, BIO-GEN.
Mother: The ONLY Visible GOD I Know
3
5
4
6
7
8
9
10
11
12
2
13
1
LabDiagnosis
PA Metabolism
Patho
physiology