Nelson Textbook of Pediatrics 22nd Edition — Mitochondrial disorders affecting muscle and brain. MELAS (m.3243A>G, stroke-like episodes, avoid valproate), MERRF (m.8344A>G, myoclonus, epilepsy, ragged red fibers), Kearns-Sayre (mtDNA deletion, PEO + retinopathy + heart block, onset <20y), Leigh syndrome (basal ganglia lesions, SURF1). Diagnosis: lactate, muscle biopsy (RRF, COX deficiency), mtDNA/nDNA sequencing.
🌐 paeds.online — Pakistan's Pediatric Platform| Syndrome | Gene/Mutation | Key Features | Muscle Biopsy | Inheritance |
|---|---|---|---|---|
| MELAS | m.3243A>G (tRNA-Leu) ~80% | Stroke-like episodes (not vascular), encephalopathy, lactic acidosis, seizures, myopathy, hearing loss, diabetes | Ragged red fibers (RRF), COX-deficient | Maternal |
| MERRF | m.8344A>G (tRNA-Lys) ~80% | Myoclonus, generalized epilepsy, ataxia, myopathy, ragged red fibers, dementia | RRF, COX-deficient | Maternal |
| Kearns-Sayre (KSS) | Large mtDNA deletion (1.1-10kb) | PEO (progressive external ophthalmoplegia), pigmentary retinopathy, heart block, onset <20y, cerebellar ataxia | RRF, COX-deficient | Sporadic (not inherited) |
| Chronic PEO (CPEO) | mtDNA deletion or nuclear (POLG, etc.) | Ptosis, ophthalmoparesis, ± proximal weakness | RRF, COX-deficient | Maternal or AD/AR |
| Leigh syndrome | SURF1 (COX), mtDNA ATP6, NDUFS4, etc. | Subacute necrotizing encephalomyelopathy, basal ganglia lesions (putamen), developmental regression, hypotonia, elevated lactate | Usually no RRF; COX deficiency | AR or maternal |
| NARP | m.8993T>G (MT-ATP6) | Neurogenic weakness, ataxia, retinitis pigmentosa, sensory neuropathy | Usually no RRF | Maternal |
| Mitochondrial DNA depletion syndrome | TK2, POLG, DGUOK, etc. | Progressive myopathy, hypotonia, respiratory failure, liver failure (TK2: muscle specific) | Depleted mtDNA copy number, COX deficiency | AR |
Sodium valproate inhibits mitochondrial function, can precipitate fatal hepatic failure and worsening encephalopathy, especially in POLG mutations and MELAS. Use alternative AEDs: levetiracetam, lamotrigine, topiramate.
Diagnostic clues: Elevated lactate (serum/CSF), ragged red fibers (modified Gomori trichrome), COX-negative fibers, abnormal MRS (lactate peak).
Supportive therapies (limited evidence): Coenzyme Q10, riboflavin, carnitine, creatine, thiamine, vitamin C/E.