WBR0302

Author	[[PageAuthor::William J Gibson (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Biochemistry
Sub Category	SubCategory::General Principles
Prompt	[[Prompt::A 4-month-old girl is brought to the emergency department following a seizure. Her mother had an uncomplicated pregnancy and had regular follow-ups with her obstetrician. The patient was delivered abroad and had a normal neonatal course. The family immigrated to USA only 3 weeks ago. Ever since the family moved, her mother has noticed that the girl has not been the same anymore. She does not seem to develop like her 2 sisters did before her; she appears lethargic all the time and feeds poorly. Upon further questioning, the mother adds that the patient's urine has an unusual musty odor. On physical examination, the patient has a pale skin with blonde hair and blue eyes. Her skin appears dry with eczematous lesions. Administration of which amino acid is required to relieve this patient's symptoms?]]
Answer A	AnswerA::Glycine
Answer A Explanation	AnswerAExp::Glycine is not usually supplemented in patients with PKU.
Answer B	AnswerB::Cysteine
Answer B Explanation	[[AnswerBExp::Folic acid and cysteine are supplemented in homocystinuria.]]
Answer C	AnswerC::Phenylalanine
Answer C Explanation	AnswerCExp::Phenylalanine supplementation would be disastrous for a patient with phenylketonuria. The deleterious effects of phenylketonuria are caused by the accumulation of phenylalanine, leading to toxic concentrations in the body.
Answer D	AnswerD::Tryptophan
Answer D Explanation	AnswerDExp::Glutamate
Answer E	AnswerE::Glutamate is not usually supplemented in patients with PKU.
Answer E Explanation	AnswerEExp::Tyrosine supplementation is essential for patients with phenylketonuria.
Right Answer	RightAnswer::E
Explanation	[[Explanation::Phenylketonuria (PKU) is an autosomal recessive inborn error of amino acid metabolism characterized by a loss-of-function mutation in the PAH gene the encodes the hepatic enzyme, phenylalanine hydroxylase. Phenylalanine hydroxylase is necessary to hydroxylate phenylalanine to tyrosine, a precursor for thyroxine, melanin, and catecholamines. Newborns do not exhibit symptoms at birth, and symptoms often develop a few weeks/months later (3-6 months). In USA, patients are usually screened for PKU using the Guthrie test, a semi-quantitative bacterial inhibition assay that detects hyperphenylalaninemia (HPA) at day 2-3 after birth. Neonatal screening may help in the early management and the prevention of irreversible neurological damage. The most common early manifestation of PKU includes failure to thrive and failure to meet developmental milestones. Patients typically appear fair-skinned (pale skin, blonde hair, and blue eyes) due to low levels of melanin, which is derived from phenylalanine and tyrosine. They also have dry, eczematous skin and a musty/mousy odor of the skin and urine due to build-up of phenylalanin. If left untreated, PKU can result in mental retardation, seizures, and neuropsychiatric complications. Classical PKU is defined as the total or near-total deficiency of the phenylalanine hydroxylase enzyme. Classical PKU should always be distinguished from other diseases that have similar presentations and cause HPA, including deficiency of tetrahydrobiopterin (malignant PKU), tyrosinemias, and milder forms (non-classical) of HPA. Patients with classical PKU are managed with restriction of dietary phenylalanine (including aspartame sweeteners that contains phenylalanine) and supplementation of other amino acids. Tyrosine (and some other amino acids such as tryptophan, valine, histidine, leucine, and isoleucine) is a necessary protein source for patients with PKU. In contrast to mandatory neonatal screening, prenatal screening is only required for pregnant women who already have a family member affected by PKU. Prenatal screening may be performed using detection of the PAH gene. Educational Objective: Phenylketonuria (PKU) is an autosomal recessive inborn error of amino acid metabolism characterized by a loss-of-function mutation in the PAH gene the encodes the hepatic enzyme, phenylalanine hydroxylase. Manifestations begin at 3-6 months of age with failure to thrive, seizures, and neuropsychiatric symptoms. Patients often appear fair-skinned with eczema and may have a musty/mousy odor of the skin and urine. Tyrosine, a precursor for thyroxine, melanin, and catecholamines, is an essential source of proteins among patients with phenylketonuria. References: MacLeod EL, Ney DM. Nutritional management of phenylketonuria. Ann Nestle Eng. 2010;68(2):58-69. van Spronsen FJ. Phenylketonuria: a 21st century perspective. Nat Rev Endocrinol. 2010; 6(9):509-14. First Aid 2014 page 111]]
Approved	Approved::Yes
Keyword	WBRKeyword::Biochemistry, WBRKeyword::Pathway, WBRKeyword::Phenylketonuria, WBRKeyword::Genetics, WBRKeyword::Metabolism, WBRKeyword::Tyrosine, WBRKeyword::Amino acid, WBRKeyword::Amino acid metabolism, WBRKeyword::Phenylalanine, WBRKeyword::Seizure, WBRKeyword::Musty odor, WBRKeyword::Mousy odor, WBRKeyword::Fair skinned, WBRKeyword::Blonde, WBRKeyword::Blue eyes, WBRKeyword::Inborn error of metabolism
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