A 15-year-old boy presents with episodes of headache, vomiting, and lactic acidosis, followed over years by stroke-like episodes and seizures. Muscle biopsy shows ragged red fibers. His mother had similar episodes but her brother was unaffected. His mother's sister is asymptomatic despite carrying the same mtDNA mutation. This variability is best explained by:

• A Heteroplasmy, with the proportion of mutant mitochondrial DNA differing among family members and tissues ✓
• B Variable expressivity of an autosomal dominant nuclear gene mutation
• C Anticipation due to expansion of a trinucleotide repeat during oogenesis
• D X-linked dominant inheritance with random lyonization

Explanation

This is MELAS, a mitochondrial encephalomyopathy. Cells and individuals contain a mixture of wild-type and mutant mtDNA, called heteroplasmy. Symptoms appear only when the proportion of mutant genomes exceeds a tissue-specific threshold, which varies between relatives and between organs, explaining the asymptomatic aunt and variable severity down a maternal line. All mitochondria are inherited from the mother, so paternal transmission does not occur.

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.