A 9-year-old boy presents with progressive spastic gait, lower-limb spasticity, hyperreflexia, bilateral extensor plantar responses, and adducted thumbs held tightly across the palms. MRI reveals agenesis of the corpus callosum and hydrocephalus. His pedigree shows affected maternal uncles and male cousins (through carrier females), but NO affected females and NO male-to-male transmission. Every affected male is connected through a carrier mother or grandmother. The inheritance pattern marked **A** in the diagram is most consistent with this presentation. Which of the following genetic mechanisms best explains why affected fathers CANNOT transmit this condition to their sons?
A. Affected fathers have mutations in autosomal genes that show incomplete penetrance in male offspring
B. Affected fathers transmit the mutation through mitochondrial DNA, which is maternally inherited, so sons do not inherit the paternal mitochondrial mutation
C. Affected fathers pass their X chromosome only to daughters; sons inherit the Y chromosome from fathers and are therefore unaffected
D. Affected fathers produce sperm with both X and Y chromosomes, but Y-bearing sperm are preferentially selected during fertilization
Explanation
Why "Affected fathers pass their X chromosome only to daughters; sons inherit the Y chromosome from fathers and are therefore unaffected" is right
This is the defining feature of X-linked recessive inheritance. Affected males (hemizygous for the mutation on their single X chromosome) pass their X chromosome to all daughters (making them obligate carriers) and their Y chromosome to all sons. Since sons receive the Y from their father, they do not inherit the paternal X-linked mutation and are therefore unaffected—even if the father is severely affected. This explains the absence of male-to-male transmission in the pedigree and is pathognomonic for X-linked inheritance. The clinical presentation (CRASH syndrome with adducted thumbs, corpus callosum agenesis, hydrocephalus, and spastic paraplegia) is consistent with SPG1 (L1CAM mutations on Xq28), a classic X-linked recessive form of hereditary spastic paraplegia.
Why each distractor is wrong
Affected fathers have mutations in autosomal genes that show incomplete penetrance in male offspring: Autosomal dominant inheritance (like SPG4 due to SPAST mutations) would show male-to-male transmission, which is explicitly absent in this pedigree. Incomplete penetrance does not explain the complete absence of transmission to sons.
Affected fathers produce sperm with both X and Y chromosomes, but Y-bearing sperm are preferentially selected during fertilization: This is biologically incorrect. Sperm carry either an X or a Y chromosome (not both), and there is no preferential selection of Y-bearing sperm in X-linked inheritance. The absence of male-to-male transmission is due to the segregation of sex chromosomes, not sperm selection.
Affected fathers transmit the mutation through mitochondrial DNA, which is maternally inherited, so sons do not inherit the paternal mitochondrial mutation: Mitochondrial inheritance is maternal only, but this pedigree shows affected males connected through carrier females in a pattern inconsistent with mitochondrial transmission. Additionally, mitochondrial disorders would show affected mothers transmitting to ALL offspring, not the "knight's move" pattern seen here through maternal uncles.
High-YieldNEET PG
No male-to-male transmission is the single most reliable feature to diagnose X-linked inheritance and exclude autosomal dominant forms of hereditary spastic paraplegia.
Fink, GeneReviews — Hereditary Spastic Paraplegia Overview; L1CAM mutations cause SPG1/CRASH syndrome with X-linked recessive inheritance
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