A 16-year-old boy has episodes of stroke-like cortical blindness, lactic acidosis, and sensorineural deafness. Muscle biopsy shows ragged red fibers on modified Gomori stain. His mother had mild hearing loss; his father and maternal grandfather are entirely normal. The inheritance pattern and reason for variable severity among his siblings is best explained by:

• A Autosomal dominant inheritance with incomplete penetrance
• B X-linked recessive inheritance with skewed lyonization
• C Autosomal recessive inheritance with uniparental disomy in affected siblings
• D Maternal inheritance with varying proportions of mutant mitochondrial DNA (heteroplasmy) ✓

Explanation

This is MELAS (mitochondrial encephalopathy, lactic acidosis, and strokelike episodes), typically from the m.3243A>G mutation in MT-TL1. All mitochondrial DNA is inherited from the mother, so fathers never transmit the trait. Severity varies among siblings because each ovum carries a different proportion of mutant versus wild-type mitochondrial genomes (heteroplasmy), and symptoms appear only above a tissue-specific threshold proportion of mutated genomes.

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.