WBR0345

Author	[[PageAuthor::Rim Halaby, M.D. [1] (Reviewed by Alison Leibowitz)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Pathophysiology
Sub Category	SubCategory::Hematology
Prompt	[[Prompt::A 2-year-old male is brought by his mother to the physician's office for delayed speech. The mother informs you that, unlike his older siblings at his age, the patient is irritable and hyperactive. Further questioning reveals that the patient's family lives in an old house with chipped paint. Physical examination is remarkable for pallor. Complete blood count (CBC) demonstrates hemoglobin levels of 9.8 g/dL and MCV: 68 fl. A peripheral smear of the patient's blood displays basophilic stippling. Based on the simplified diagram of heme synthesis shown below, which of the following steps is most likely inhibited in this patient? ]]
Answer A	AnswerA::A
Answer A Explanation	AnswerAExp::"A" corresponds to ALA-synthase, inhibited by B6 deficiency and in hereditary conditions, such as X-linked ALA-synthase deficiency.
Answer B	AnswerB::B
Answer B Explanation	AnswerBExp::See explanation.
Answer C	AnswerC::C
Answer C Explanation	AnswerCExp::"C" corresponds to porphobilinogen deaminase. Deficiency of this enzyme typically causes acute intermittent porphyria.
Answer D	AnswerD::D
Answer D Explanation	[[AnswerDExp::"D" corresponds to uroporphyrinogen III synthase. Uroporphyrinogen III synthase deficiency is associated with Gunther's disease.]]
Answer E	AnswerE::
Answer E Explanation	AnswerEExp::"E" corresponds to uroporphyrinogen decarboxylase, which is typically deficient in porphyria cutanea tarda.
Right Answer	RightAnswer::B
Explanation	[[Explanation::The patient in this scenario most likely has lead poisoning secondary to chronic exposure to lead-based paint flakes in the old house. Lead is readily absorbed and incorporated into the bone where it competes with calcium and causes impaired remodeling of cartilage and trabecular bone in the epiphyses, which is detected as radiodense lead lines. Central nervous system disturbances, manifesting as loss of short-term memory, delayed development, behavioral changes, or hearing impairment, are more common in children due to the relatively permeable blood-brain barrier, whereas demyelinating peripheral neuropathies predominate in adult patients. Other findings of chronic lead poisoning include abdominal pain, tubulointerstitial nephritis, and microcytic hypochromic anemia. Basophilic stippling, which represents precipitated ribosomes in reticulocytes, may be evident on the peripheral blood film. A definitive diagnosis is established by the detection of elevated serum levels of lead and protoporphyrin. Anemia in chronic lead poisoning is mediated by the inhibition of pyrimidine-5'-nucleotidase-1 (P5'N-1), ferrochelatase, and 5-aminolevulinate (ALA )dehydratase. Inhibition of P5'N-1 blocks the hydrolysis of uridine monophosphate (UMP) and cytidine monophosphate (CMP) resulting in reduced availability of nucleosides, which in turn leads to hemolytic anemia. In the heme biosynthesis pathway, lead inhibits the activity of ALA dehydratase, which converts ALA into porphobilinogen in the cytoplasm, and ferrochelatase, which incorporates the ferrous iron into protoporphyrin IX in the mitochondria. Anemia associated with chronic lead poisoning is typically microcytic and hypochromic. Educational Objective: Lead inhibits P5'N-1, ALA dehydratase, and ferrochelatase. References: First Aid 2014 page 380]]
Approved	Approved::Yes
Keyword	WBRKeyword::lead poisoning, WBRKeyword::lead toxicity, WBRKeyword::ALA dehydratase, WBRKeyword::ferrochelatase, WBRKeyword::anemia, WBRKeyword::microcytic, WBRKeyword::hypochromic, WBRKeyword::basophilic stippling
Linked Question	Linked::
Order in Linked Questions	LinkedOrder::