A 14-year-old boy from a consanguineous Kashmiri family presents with progressive tremor, dysarthria, and behavioral changes over 6 months. His parents are first cousins. Slit-lamp examination reveals golden-brown corneal deposits. Serum ceruloplasmin is 12 mg/dL (normal 20), and 24-hour urinary copper is 180 micrograms. The inheritance pattern marked **A** in the pedigree diagram is consistent with which genetic mechanism underlying this patient's condition?

Question

A 14-year-old boy from a consanguineous Kashmiri family presents with progressive tremor, dysarthria, and behavioral changes over 6 months. His parents are first cousins. Slit-lamp examination reveals golden-brown corneal deposits. Serum ceruloplasmin is 12 mg/dL (normal >20), and 24-hour urinary copper is 180 micrograms. The inheritance pattern marked **A** in the pedigree diagram is consistent with which genetic mechanism underlying this patient's condition?

Accepted Answer

D. Mutations in the ATP7B gene on chromosome 13q14.3 encoding a copper-transporting P-type ATPase, with both parents being heterozygous carriers. ## Why option 1 is right

Wilson disease (hepatolenticular degeneration) is an **autosomal recessive disorder** caused by mutations in the ATP7B gene on chromosome 13q14.3, which encodes a hepatocyte copper-transporting P-type ATPase. The pedigree pattern marked **A** — showing an affected individual with consanguineous parents (first cousins) — is the classic presentation of autosomal recessive inheritance. Consanguinity markedly increases the risk of two abnormal alleles meeting in offspring, which is why Wilson disease is over-represented in populations with high rates of consanguineous marriage, particularly in South Asian families. Both parents are obligate heterozygous carriers, and the affected child has inherited one mutant allele from each parent. ATP7B dysfunction results in failure of copper incorporation into apoceruloplasmin (lowering serum ceruloplasmin <20 mg/dL) and impaired biliary excretion of hepatocellular copper, leading to accumulation in the basal ganglia, cornea, and liver — explaining this patient's neurological presentation and Kayser-Fleischer rings.

## Why each distractor is wrong

- **Option 2 (X-linked recessive)**: X-linked inheritance would require the mother to be a carrier and the father to be unaffected; however, the pedigree marked **A** shows consanguineous parents (both autosomal carriers), not an X-linked pattern. Wilson disease is not X-linked.
- **Option 3 (Mitochondrial mutation)**: Mitochondrial inheritance shows maternal transmission to all offspring and no paternal contribution. The consanguineous pedigree pattern marked **A** is incompatible with mitochondrial inheritance, and Wilson disease is not a mitochondrial disorder.
- **Option 4 (Autosomal dominant ATOX1 haploinsufficiency)**: Autosomal dominant conditions typically appear in every generation and affect both sexes equally without consanguinity being protective. ATOX1 encodes a copper chaperone, not the primary transporter; mutations in ATOX1 are not the genetic basis of Wilson disease.

**High-Yield:** Consanguinity in a pedigree is a red flag for autosomal recessive inheritance; Wilson disease's over-representation in South Asian populations reflects high rates of consanguineous marriage, making family screening and early pre-symptomatic treatment critical.

[cite: Harrison's 21e Ch 442; Leipzig Criteria 2003]

Answer

A. Mutation in a single copy of an X-linked gene encoding a copper-binding protein, with the mother being an obligate carrier

Answer

B. Mitochondrial mutation affecting oxidative phosphorylation and copper-dependent cytochrome c oxidase assembly

Answer

C. Autosomal dominant mutation in the ATOX1 gene causing haploinsufficiency of the copper chaperone

Explanation

Why option 1 is right

Why each distractor is wrong

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