Menkes disease (X-linked) causes severe neurodegeneration, kinky hair, seizures, and connective tissue defects in infant males due to copper deficiency despite adequate dietary intake. Which protein is defective, and how does its dysfunction cause the multi-system phenotype?

• A ATP7A (Menkes copper ATPase) — defective in intestinal cells, preventing copper export from enterocytes into portal circulation; copper trapped in gut causes deficiency in all copper-dependent enzymes (dopamine beta-hydroxylase, lysyl oxidase, cytochrome c oxidase, superoxide dismutase) ✓
• B Ceruloplasmin — copper cannot be incorporated into transport protein, so copper cannot be delivered to brain
• C ATP7B (Wilson ATPase) — copper accumulates in liver and brain due to defective biliary excretion
• D Metallothionein — copper cannot be stored in liver, causing deficiency and toxicity simultaneously

Explanation

Menkes disease is caused by mutations in ATP7A, a P-type ATPase copper transporter located in the trans-Golgi network of intestinal enterocytes and other cells. ATP7A exports copper from enterocytes into portal blood. Defective ATP7A traps copper in enterocytes (intestine), preventing systemic distribution. Copper-dependent enzymes that become deficient include: dopamine beta-hydroxylase (neurodegeneration, autonomic dysfunction), lysyl oxidase (kinky hair, connective tissue/vascular fragility), cytochrome c oxidase (energy failure), peptidylglycine alpha-amidating monooxygenase, and Cu/Zn-SOD. Wilson disease (ATP7B deficiency) causes copper overload — the opposite phenotype.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.