A 3-year-old boy who recently immigrated to the United States is brought to the physician by his parents because he has not yet begun to walk or speak. Assessment of his developmental milestones shows severe intellectual disability. He dies 6 months later from refractory seizures resulting in respiratory failure. Autopsy shows pallor of the substantia nigra, locus ceruleus, and vagal nucleus dorsalis. The underlying condition responsible for this patient's death is most likely caused by a deficiency of which of the following enzymes?

Question

A 3-year-old boy who recently immigrated to the United States is brought to the physician by his parents because he has not yet begun to walk or speak.  Assessment of his developmental milestones shows severe intellectual disability.  He dies 6 months later from refractory seizures resulting in respiratory failure.  Autopsy shows pallor of the substantia nigra, locus ceruleus, and vagal nucleus dorsalis.  The underlying condition responsible for this patient's death is most likely caused by a deficiency of which of the following enzymes?

Quizplus · Accepted Answer

11ec160b_36b5_866c_9249_d927f08fa323_MD0001_00 This patient's severe intellectual disability, history of seizures, and abnormal pallor of catecholaminergic brain nuclei on autopsy are suggestive of phenylketonuria (PKU). PKU results from the inability to convert phenylalanine into tyrosine, a reaction which is normally catalyzed by phenylalanine hydroxylase. This enzyme requires the cofactor tetrahydrobiopterin (BH₄), which is regenerated from dihydrobiopterin (BH₂) by the enzyme dihydropteridine reductase. Although neonatal hyperphenylalaninemia can be caused by deficiency of either enzyme, most cases are attributable to abnormalities in phenylalanine hydroxylase. It is believed that excess phenylalanine and the presence of large concentrations of phenylalanine metabolites (eg, phenyllactate & phenylacetate) contribute to the brain damage seen in PKU. Hypopigmentation involving the skin, hair, eyes, and catecholaminergic brain nuclei (which produce a dark pigment known as neuromelanin) results from the inhibitory effect of excess phenylalanine on melanin synthesis. The classic musty or mousy body odor is due to the accumulation of abnormal phenylalanine metabolites. (Choice A) Branched-chain ketoacid dehydrogenase catalyzes decarboxylation of the α-ketoacid derivatives of all 3 branched chain amino acids: leucine, isoleucine, and valine. Deficiency causes maple syrup urine disease, which is characterized by a burnt-sugar smell in the urine of affected patients. Hypopigmentation is not seen in the condition. (Choice B) Dopamine hydroxylase is the enzyme that catalyzes the biosynthesis of norepinephrine from dopamine. Deficiency of this enzyme causes a rare form of dysautonomia characterized by ptosis, orthostatic hypotension, hypoglycemia, and hypothermia. (Choice C) Alkaptonuria is an autosomal recessive disorder of tyrosine degradation caused by a deficiency of homogentisic acid oxidase. This condition results in the accumulation of large amounts of homogentisic acid, leading to connective tissue hyperpigmentation and degenerative joint disease. (Choice E) Albinism is an autosomal recessive disorder caused by defects in the biosynthesis and distribution of melanin. It is most commonly due to depressed or absent tyrosinase activity. Melanin synthesis begins with the conversion of tyrosine to DOPA and DOPA to dopaquinone by the enzyme tyrosinase in melanocytes. Albinism does not present with neurologic dysfunction. Educational objective: Deficiency of the enzyme phenylalanine hydroxylase or its cofactor tetrahydrobiopterin causes accumulation of phenylalanine in body fluids and the central nervous system. Homozygous infants are normal at birth but gradually develop severe intellectual disability and seizures if left untreated. Hypopigmentation of the skin, hair, eyes, and catecholaminergic brain nuclei is also frequently seen.

A 3-Year-Old Boy Who Recently Immigrated to the United States