A 1-day-old boy is diagnosed with hyperphenylalaninemia by newborn screening. He is placed on a special phenylalanine-restricted diet with tyrosine supplementation. The parents are extensively counseled on the boy's condition and informed of the necessary dietary restrictions. They are also instructed to return to his physician for regular follow-up visits. Several months later, laboratory test results indicate that the infant has a normal serum phenylalanine level. Careful examination, however, reveals some neurological abnormalities, including axial hypotonia and microcephaly. Further workup is notable for elevated prolactin, and his physician suspects a cofactor deficiency. Which of the following enzymes is most likely deficient in this patient?

Question

A 1-day-old boy is diagnosed with hyperphenylalaninemia by newborn screening.  He is placed on a special phenylalanine-restricted diet with tyrosine supplementation.  The parents are extensively counseled on the boy's condition and informed of the necessary dietary restrictions.  They are also instructed to return to his physician for regular follow-up visits.  Several months later, laboratory test results indicate that the infant has a normal serum phenylalanine level.  Careful examination, however, reveals some neurological abnormalities, including axial hypotonia and microcephaly.  Further workup is notable for elevated prolactin, and his physician suspects a cofactor deficiency.  Which of the following enzymes is most likely deficient in this patient?

Quizplus · Accepted Answer

11ec160b_36b7_0d0e_9249_99d45685fbc5_MD0001_00 This patient with phenylketonuria (PKU) most likely has a deficiency of dihydrobiopterin reductase (reduces BH₂ to BH₄) based on the combination of hyperphenylalaninemia and elevated prolactin. Phenylalanine is converted to tyrosine by phenylalanine hydroxylase using BH₄ as a cofactor. Tyrosine is converted to DOPA via the enzyme tyrosine hydroxylase, which also uses BH₄ as a cofactor. Once DOPA is synthesized, it is decarboxylated to dopamine by DOPA decarboxylase. Dopamine ultimately serves as the precursor molecule to the catecholamines epinephrine and norepinephrine. In classic PKU, supplementation of tyrosine allows for normal catecholamine production due to intact function of tyrosine hydroxylase. However, deficiency of dihydrobiopterin reductase results in both hyperphenylalaninemia from impaired phenylalanine hydroxylase activity and low dopamine levels from impaired tyrosine hydroxylase activity. Although phenylalanine levels can be controlled by dietary restriction, downstream deficiencies of neurotransmitters (eg, dopamine, norepinephrine, epinephrine, serotonin) lead to progressive neurologic deterioration in these patients. Normally, dopamine from the tuberoinfundibular system tonically inhibits prolactin release. Decreased BH₄ causes lower levels of dopamine, resulting in increased prolactin levels. (Choice B) The enzyme dopamine β-hydroxylase catalyzes the biosynthesis of norepinephrine from dopamine. It does not use BH₄ as a cofactor. (Choice C) Phenylalanine hydroxylase deficiency is the most common cause of PKU. This patient's phenylalanine levels have normalized with dietary therapy, but he has low dopamine levels (as indicated by elevated prolactin). Patients with classic PKU or phenylalanine hydroxylase deficiency do not have any difficulty producing dopamine with adequate levels of dietary tyrosine. (Choice D) Phenylethanolamine N-methyltransferase (PNMT) converts norepinephrine to epinephrine. It requires S-adenosyl-methionine (SAM) as a cofactor. (Choice E) Tyrosinase deficiency causes albinism, characterized by a lack of pigment in skin and hair due to absent melanin production. Melanin is synthesized in melanocytes from tyrosine by tyrosinase. Educational objective: Dihydrobiopterin reductase deficiency results in impaired tetrahydrobiopterin (BH₄) levels. BH₄ is an important cofactor for both phenylalanine hydroxylase and tyrosine hydroxylase. Although phenylalanine levels can be corrected with dietary restriction, downstream deficiencies of dopamine, norepinephrine, epinephrine, and serotonin lead to progressive neurologic deterioration. __________ References: Tyrosine, phenylalanine, and catecholamine synthesis and function in the brain. (http://www.ncbi.nlm.nih.gov/pubmed/17513421) Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies. (http://www.ncbi.nlm.nih.gov/pubmed/21937252) Serum prolactin as a tool for the follow-up of treated DHPR-deficient patients. (http://www.ncbi.nlm.nih.gov/pubmed/18425437)

A 1-Day-Old Boy Is Diagnosed with Hyperphenylalaninemia by Newborn Screening