A 35-year-old man presents with progressive distal weakness and atrophy of intrinsic foot muscles, pes cavus, and hammer toes over the past 10 years. Nerve conduction studies show motor velocities of 32 m/s with secondary axonal loss. His 28-year-old sister reports mild, intermittent distal paresthesias that began only recently. Their father is unaffected. The pedigree pattern shown in the diagram is marked **A**. Which of the following statements best characterizes the inheritance pattern and expected genetic counselling for this family?

Question

Accepted Answer

D. The father is unaffected but the mother is a heterozygous carrier; affected sons cannot transmit the condition to their sons, but all daughters of affected males are obligate carriers. ## Why option B is right

The pedigree pattern marked **A** is X-linked inheritance with the classic CMTX1 signature: the unaffected father has an affected son and a mildly affected daughter, indicating the mother is a heterozygous carrier. In X-linked inheritance, affected males (like the proband) cannot pass the X-chromosome to their sons—sons receive the Y from their father—but ALL daughters of affected males are obligate carriers (heterozygous), inheriting the mutant X. This no male-to-male transmission rule is the pathognomonic feature distinguishing CMTX1 from autosomal dominant CMT. The sister's mild, later-onset symptoms reflect random X-inactivation (lyonization) in heterozygous females, creating a mosaic Schwann cell population with variable connexin 32 expression. CMTX1 is caused by GJB1 mutations encoding connexin 32, a gap junction protein at nodes of Ranvier and Schmidt-Lanterman incisures critical for Schwann cell–axon communication (Bergoffen et al., Science 1993; GeneReviews CMTX1).

## Why each distractor is wrong

- **Option A**: Incorrectly states the father is a carrier (males cannot be carriers—they are either affected or unaffected) and wrongly predicts all sons will be affected and all daughters unaffected. In X-linked inheritance, an affected father passes his X to daughters (making them carriers/affected) and his Y to sons (making them unaffected).
- **Option C**: Violates the no male-to-male transmission rule. An affected father cannot transmit his X-chromosome to sons; sons receive only the Y chromosome from their father. This pattern would suggest autosomal dominant inheritance, which is not consistent with the pedigree marked **A**.
- **Option D**: Autosomal dominant inheritance would show male-to-male transmission (affected father → affected son), which is explicitly absent in CMTX1. The intermediate nerve conduction velocities (32 m/s) and secondary axonal loss also distinguish CMTX1 from autosomal CMT1A (uniformly slow, <38 m/s).

**High-Yield:** X-linked CMTX1 = NO male-to-male transmission; ALL daughters of affected males are obligate carriers; affected males typically more severe than heterozygous females (milder, later-onset due to X-inactivation).

[cite: Bergoffen J et al., Science 1993; GeneReviews — CMTX1]

Answer

A. The father is affected; his affected status will be transmitted to all his sons and daughters equally

Answer

B. The father is an obligate carrier; all his sons will be affected and all daughters will be unaffected

Answer

C. The father is unaffected; the condition follows autosomal dominant inheritance with male-to-male transmission

Explanation

Why option B is right

Why each distractor is wrong

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