An 18-month-old boy is brought to the office due to language regression. He said several words at his 1-year appointment but now no longer speaks any words at all. His moods have also become more unpredictable over the past 4 months with frequent tantrums. The parents tried to bring him in sooner for evaluation, but they live in an impoverished part of the city and experienced financial difficulties with transportation to the office. On physical examination, the boy is quiet and maintains appropriate eye contact throughout the visit. Hemoglobin is 9 g/dL. Which of the following enzymes is most likely inhibited in this patient?
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This child's language regression and anemia are most likely due to lead poisoning. Lead toxicity is most prevalent among impoverished children residing in deteriorating urban housing built before 1978. Young children are particularly susceptible to lead poisoning via inhalation and ingestion of lead-based paint dust or chips due to normal crawling and mouthing behaviors. The incomplete blood-brain-barrier in children is vulnerable to the neurotoxic effects of lead, which include long-standing behavioral problems and developmental delay or regression.
Anemia in lead poisoning results from inhibition of ferrochelatase and δ-aminolevulinic acid (ALA) dehydratase in the heme biosynthesis pathway. Because protoporphyrin IX cannot combine with iron (Fe2+) to form heme due to ferrochelatase inhibition, it instead incorporates a zinc ion, leading to elevated zinc protoporphyrin levels. In addition, ALA levels are increased. Lead poisoning also commonly coexists with iron deficiency anemia, and severe lead poisoning can also induce hemolytic anemia.
(Choice B) Glucuronyl transferase (uridine 5'-diphospho-glucuronosyltransferase) is necessary for hepatic bilirubin conjugation. Gilbert syndrome, a condition marked by jaundice (elevated unconjugated bilirubin levels) during times of stress, results from mutations in the gene encoding glucuronyl transferase.
(Choice C) Defects in porphobilinogen deaminase result in acute intermittent porphyria (AIP), a disorder characterized by acute attacks of abdominal pain, neuropsychiatric symptoms, and red or brown urine. The chronicity of symptoms, lack of abdominal pain, and anemia make AIP unlikely in this patient.
(Choice D) Pyruvate kinase deficiency is typically inherited in an autosomal recessive pattern and leads to hemolytic anemia. Pyruvate kinase deficiency can present with pallor, scleral icterus, and splenomegaly, but it does not present with behavioral regression or language difficulties.
(Choice E) Defects in uroporphyrinogen decarboxylase cause porphyria cutanea tarda (PCT), the most common form of porphyria. Patients with PCT exhibit chronic photosensitivity with blistering in areas of sun exposure and elevated levels of uroporphyrinogen in the urine.
Educational objective:
Young children who reside in homes built before 1978 are at significant risk for lead toxicity. Lead directly inhibits ferrochelatase and δ-aminolevulinic acid (ALA) dehydratase, resulting in anemia, ALA accumulation, and elevated zinc protoporphyrin levels. Neurotoxicity is also a significant long-term complication.