Which of the following is Mitochondrial inheritance disorder

Explanation

## Correct Answer: A. Kearns-Sayre syndrome Kearns-Sayre syndrome (KSS) is a classic example of **mitochondrial inheritance disorder** caused by large deletions (typically 4.9–7.6 kb) in mitochondrial DNA (mtDNA). The hallmark triad includes progressive external ophthalmoplegia (PEO), pigmentary retinopathy, and cardiac conduction abnormalities (heart block). Critically, KSS demonstrates **maternal inheritance**—all mitochondria are inherited exclusively from the mother, as sperm contribute negligible mitochondria during fertilization. The disease manifests when the proportion of mutant mtDNA exceeds a threshold (heteroplasmy), explaining variable penetrance and severity even within families. Onset is typically before age 20. In Indian clinical practice, KSS presents with progressive ptosis, ophthalmoplegia, and cardiac arrhythmias requiring pacemaker insertion in severe cases. The diagnosis is confirmed by mtDNA deletion analysis and muscle biopsy showing ragged-red fibers on Gomori trichrome staining. Unlike nuclear inheritance patterns, KSS cannot be inherited from affected fathers—only mothers transmit the mutation. This maternal-only transmission pattern is the discriminating feature that identifies it as a mitochondrial disorder. ## Why the other options are wrong **B. Achondroplasia** — Achondroplasia is an **autosomal dominant disorder** caused by mutations in the FGFR3 gene on chromosome 4, not mitochondrial DNA. It follows Mendelian inheritance with 50% transmission from affected parents to offspring, regardless of parent sex. The condition causes short stature with characteristic features (short limbs, frontal bossing, lumbar lordosis). NBE may pair this with genetic disorders to trap students who confuse all genetic conditions as mitochondrial. **C. Cystic fibrosis** — Cystic fibrosis is an **autosomal recessive disorder** caused by mutations in the CFTR gene on chromosome 7, affecting chloride channel function in epithelial cells. It requires two mutant alleles for disease expression and follows Mendelian recessive inheritance. In India, CF is less common than in Caucasian populations but presents with pancreatic insufficiency, chronic lung infections, and elevated sweat chloride. This is nuclear DNA inheritance, not mitochondrial. **D. Williams syndrome** — Williams syndrome is caused by a **microdeletion on chromosome 7q11.23** involving the elastin gene and adjacent genes, inherited in an autosomal dominant pattern. It presents with characteristic facies (elfin features), supravalvular aortic stenosis, intellectual disability, and hypercalcemia. This is nuclear chromosomal inheritance with Mendelian transmission, not maternal-only mitochondrial inheritance. ## High-Yield Facts - **Kearns-Sayre syndrome** = mtDNA deletion (4.9–7.6 kb) + maternal inheritance + PEO + pigmentary retinopathy + cardiac conduction block - **Mitochondrial inheritance** is **maternal-only** because sperm contribute <100 mitochondria vs. egg's ~100,000; paternal transmission is virtually absent - **Heteroplasmy** in KSS means mutant and wild-type mtDNA coexist; disease manifests when mutant load exceeds ~60–70% threshold - **Ragged-red fibers** on Gomori trichrome staining of muscle biopsy are pathognomonic for mitochondrial myopathy including KSS - **Onset before age 20** with progressive ophthalmoplegia and cardiac arrhythmias requiring pacemaker is classic KSS presentation in Indian patients ## Mnemonics **KSS Triad: PRC** **P**rogressive external ophthalmoplegia (ptosis, ophthalmoplegia) + **R**etinopathy (pigmentary) + **C**ardiac conduction block (heart block, pacemaker needed) **Mitochondrial Inheritance = MOM** **M**itochondria from **O**nly **M**other—paternal mitochondria are destroyed in the zygote; this is the key discriminator for all mtDNA disorders ## NBE Trap NBE groups all genetic disorders together to trap students who confuse autosomal dominant (achondroplasia, Williams), autosomal recessive (cystic fibrosis), and mitochondrial inheritance patterns. The key discriminator is **maternal-only transmission**—only KSS shows this pattern because mitochondria come exclusively from the egg. ## Clinical Pearl In Indian practice, a young patient presenting with progressive ptosis, ophthalmoplegia, and syncope (from heart block) should immediately raise suspicion for KSS—especially if the mother is affected but the father is unaffected. Genetic counseling must emphasize that all children of an affected mother carry the mutation, while children of an affected father are unaffected, a pattern unique to mitochondrial disorders. _Reference: Robbins Ch. 5 (Genetic Disorders); Harrison Ch. 462 (Mitochondrial Diseases); KD Tripathi Ch. 35 (Genetics)_