A 4-year-old boy from Kerala presents with acute jaundice, dark urine, and pallor 2 days after receiving sulfamethoxazole for a urinary tract infection. His mother is clinically well but has a brother with a history of neonatal jaundice. The pedigree pattern shown in the diagram is marked **A**, indicating the inheritance pattern of G6PD deficiency. Which of the following best explains why the mother is phenotypically normal despite carrying the mutation?

Question

Accepted Answer

C. X-linked recessive inheritance with random X-inactivation (lyonisation) in heterozygous females, resulting in mosaic red-cell enzyme activity. ## Why X-linked recessive inheritance with random X-inactivation (lyonisation) in heterozygous females, resulting in mosaic red-cell enzyme activity is right

The pedigree pattern marked **A** depicts X-linked recessive inheritance: affected hemizygous males (the boy) with disease transmitted through phenotypically normal carrier females (the mother), and male-to-male transmission absent. Heterozygous females like the mother are typically clinically normal because random X-inactivation (lyonisation) results in a mosaic population of red cells—roughly half expressing the normal allele and half the mutant allele. This intermediate enzyme activity is usually sufficient to prevent haemolysis under routine conditions. The mother's brother (maternal uncle) being affected confirms the X-linked pattern: he inherited the same mutant X chromosome from their mother. The boy's acute haemolytic episode was triggered by the oxidative stress of sulfamethoxazole, a known G6PD precipitant, overwhelming his deficient NADPH-dependent antioxidant defences (Harrison's 21e Ch 99; Nelson 21e Ch 489).

## Why each distractor is wrong

- **Autosomal recessive inheritance requiring two mutant alleles for clinical expression**: G6PD deficiency is definitively X-linked, not autosomal recessive. The pedigree pattern—affected males with carrier mothers and no male-to-male transmission—is pathognomonic for X-linked inheritance and rules out autosomal recessive disease.

- **Autosomal dominant inheritance with incomplete penetrance in female carriers**: G6PD is not autosomal dominant; it is X-linked recessive. Autosomal dominant disorders typically show vertical transmission and affect both sexes equally, neither of which applies here. The mother's normal phenotype is explained by X-inactivation, not incomplete penetrance.

- **Mitochondrial inheritance with maternal transmission to all offspring regardless of sex**: Mitochondrial disorders are maternally inherited and affect all children of an affected mother. The pedigree pattern here (affected son, normal mother, affected maternal uncle) is incompatible with mitochondrial inheritance and is characteristic of X-linked recessive disease.

**High-Yield:** G6PD deficiency is X-linked recessive; heterozygous females are typically asymptomatic due to lyonisation but can rarely present clinically if X-inactivation is severely skewed. The pedigree signature is unmistakable: affected males, carrier mothers, no male-to-male transmission, and affected maternal uncles.

[cite: Harrison's 21e Ch 99; Nelson 21e Ch 489]

Answer

A. Mitochondrial inheritance with maternal transmission to all offspring regardless of sex

Answer

B. Autosomal dominant inheritance with incomplete penetrance in female carriers

Answer

D. Autosomal recessive inheritance requiring two mutant alleles for clinical expression

Explanation

Why X-linked recessive inheritance with random X-inactivation (lyonisation) in heterozygous females, resulting in mosaic red-cell enzyme activity is right

Why each distractor is wrong

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