A 16-year-old girl presents with recurrent stroke-like episodes, partial seizures, and sensorineural hearing loss. Serum lactate is elevated, and muscle biopsy shows ragged red fibers. Her mother had similar episodic headaches and weakness. Her younger brother is asymptomatic despite carrying the same mtDNA variant. Which principle best explains the brother's lack of symptoms?

• A Genomic imprinting silences the maternal allele in males
• B Uniparental disomy causing mosaic loss of the mutated copy
• C Anticipation through expansion of a CTG repeat between generations
• D Heteroplasmy: variable proportions of mutated versus normal mtDNA among tissues determine expression ✓

Explanation

This is MELAS, a mitochondrial DNA point mutation disorder, classically the m.3243A>G change in tRNA-leucine. Because each cell contains many copies of mtDNA and replication segregates randomly at mitosis, the fraction of mutant genomes, the heteroplasmic load, differs across tissues and individuals. A threshold proportion must be exceeded before symptoms appear, explaining why a sibling sharing the same variant can remain well. Maternal-only transmission reflects exclusive maternal inheritance of mitochondria.

Reference: Robbins and Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.