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 eyed, and pale complexion because of deficient melanin production from tyrosine.

Musty Odor, Blue Eyes, Microcephaly & Mental Retardation

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APhenylalanine → Tyrosine

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↓Valine MaleylacetoacetateLeucine ↓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

AbstractPKU 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.

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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

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“Dr P KUMAR_BIOGEN INNO-VISION 2015”e-CONCEPT MAP ON PHENYLKETONURIA

(PKU)

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Bridge to GeneticsPrenatal Diagnosis of PKU

Bridge to Genetics

Bridge to Behavioural Science

Phenylalanine Metabolism

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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

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Ferric Ferric ChlorideTest ChlorideTest Patients With Patients With

PKUPKU

Pleotropy-Abnormalities Associated with Metab Pleotropy-Abnormalities Associated with Metab DisordersDisorders

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.Abdo Abdo – HEPATOMEGALY. – HEPATOMEGALY. SkinSkin – Jaundice. Cataracts, retinitis – Jaundice. Cataracts, retinitis

pigmentosa. 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 the 15. 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 classical new field of metabolomics, you assess a 21-year-old with classical phenylketonuria (PKU).phenylketonuria (PKU). Phenylalanine is fed with a label in the phenyl Phenylalanine is fed with a label in the phenylring. 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 p Phenylketonutria (PKU) is a defect in phenylalanine hydroxylase, resulting in a block in the conversion of pHenylalanine to tyrosine. Henylalanine to tyrosine. PhenylalaninePhenylalanine accumulates in in both disorders and to converted to accumulates 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 very whose 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 eonatal deaths, fetal

losses. losses. Maternal family history. males - X-linked disorders. All-Maternal family history. males - X-linked disorders. All-

mitochondrial mitochondrial DNADNA is is maternallymaternally inherited inherited. A positive family history may be . A positive family history may be

helpful!. helpful!. Timing of onset of symptoms. Timing of onset of symptoms. AfterAfter feeds were started?. feeds were started?. Response to therapies. Response to therapies.

USMLE STEP 1 MCQ

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What Are The Common Signs & Symptoms of Metabolic Diseases in the What Are The Common Signs & Symptoms of Metabolic Diseases in the Neonate?Neonate?.Acute life threatening illness. encephalopathy - lethargy, irritability, coma. .Acute life threatening illness. encephalopathy - lethargy, irritability, coma. Vomiting, & respiratory distress. Seizures, Hypertonia, Hepatomegaly. Hepatic dysfunction / Vomiting, & respiratory distress. Seizures, Hypertonia, Hepatomegaly. Hepatic dysfunction / jaundice. Odour, jaundice. Odour, DysmorphismDysmorphism, failure to thrive (FTT), Hiccoughs. , failure to thrive (FTT), Hiccoughs.

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“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

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