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Basic Science
Pathology
10 notes available
1 Last Minute Review 2 Neuropathology Fundamentals 3 Embryology & Developmental Malformations 4 Neurocutaneous Syndromes (Phakomatoses) 5 CNS Tumors 6 Metabolic & Storage Diseases 7 Leukodystrophies 8 Mitochondrial Disorders 9 Neurotoxicology & Nutritional Deficiencies 10 Neurogenetics
Basic Science › Pathology

Mitochondrial Disorders

Mitochondrial Disorders

What You'll Learn

  • Maternal inheritance — mtDNA is exclusively inherited from the ovum; heteroplasmy (mixture of normal and mutant mtDNA) determines severity via a threshold effect
  • Ragged red fibers on Gomori trichrome stain and COX-negative fibers on cytochrome oxidase staining are the histopathologic hallmarks; SDH-positive/COX-negative = "ragged blue" fibers
  • Elevated lactate (serum, CSF) with elevated lactate:pyruvate ratio; MR spectroscopy shows a lactate doublet (inverted at TE 135 ms)
  • MELAS (m.3243A>G in MTTL1) — stroke-like episodes NOT following vascular territories, seizures, lactic acidosis, short stature, diabetes, hearing loss
  • MERRF (m.8344A>G in MTTK) — myoclonus epilepsy, ataxia, ragged red fibers, multiple symmetric lipomatosis
  • Kearns-Sayre syndrome (large mtDNA deletion) — onset before age 20, PEO + pigmentary retinopathy + cardiac conduction defects; sporadic
  • LHON — painless, sequential bilateral central vision loss in young males; three primary point mutations (m.11778G>A most common); NO ragged red fibers
  • Avoid valproate in known or suspected POLG-related disease (especially Alpers) — risk of fatal hepatotoxicity; use caution and individualize antiseizure choice in other mitochondrial disorders rather than treating “all mitochondrial disease” as an absolute valproate contraindication
HighYield Pearls
  • Maternal inheritance + heteroplasmy + threshold effect: mtDNA is exclusively from the ovum; affected mothers pass to ALL children but only daughters transmit; symptom expression depends on mutant load exceeding a tissue-specific threshold (typically 60–90%) — explains why siblings can be discordant
  • Avoid valproate in POLG/Alpers: precipitates fulminant hepatic failure; screen POLG before starting valproate in any young patient with unexplained epilepsy — this is a classic board "do not give" gotcha
  • IV L-arginine for acute MELAS stroke-like episodes: first-line acute therapy (improves NO availability, shortens episode); oral L-arginine ± citrulline for prophylaxis — do NOT treat as ischemic stroke
  • m.3243A>G in MTTL1 (tRNA-Leu) = MELAS (and the allelic MIDD phenotype) — ~80% of MELAS cases
  • m.8344A>G in MTTK (tRNA-Lys) = MERRF — myoclonus + epilepsy + ataxia + multiple symmetric lipomatosis
  • Single large mtDNA deletion (sporadic, de novo) = KSS / Pearson / sporadic CPEO: KSS triad = PEO + pigmentary retinopathy + cardiac conduction defects with onset before age 20 — all KSS patients need cardiac monitoring and often a pacemaker (arrhythmia is the leading cause of death)
  • m.11778G>A (ND4, Complex I) = LHON — most common mutation, worst prognosis; young male, painless sequential bilateral central vision loss; m.14484T>C has best recovery; NO ragged red fibers (selective retinal ganglion cell disease)
  • m.8993T>G in MT-ATP6 (Complex V) = NARP/Leigh spectrum: <70% mutant load asymptomatic, 70–90% NARP, >90% Leigh syndrome — textbook example of the heteroplasmy threshold
  • Leigh syndrome MRI = symmetric bilateral T2 hyperintensity in basal ganglia + brainstem (periaqueductal gray, substantia nigra); most common mitochondrial disease of infancy; SURF1 is the most common nuclear cause
  • MNGIE = TYMP (AR) → thymidine phosphorylase deficiency: GI dysmotility + cachexia + PEO + neuropathy + leukoencephalopathy; elevated plasma thymidine/deoxyuridine; treatable with allogeneic HSCT
  • Aminoglycosides + m.1555A>G (MT-RNR1): predisposes to aminoglycoside-induced sensorineural hearing loss — check before prescribing gentamicin in patients with mitochondrial family history
🔍 Quick ReferenceImaging · Clinical · Pathology / genetics
Imaging signs
  • Stroke-like lesion crossing vascular boundaries (cortical/subcortical T2/FLAIR hyperintensity, parieto-occipital predilection, migratory between studies) → MELAS
  • Symmetric bilateral T2 hyperintensity in basal ganglia and brainstem (putamen, caudate, periaqueductal gray, substantia nigra, inferior olivary nuclei) → Leigh syndrome
  • Lactate doublet at 1.33 ppm on MR spectroscopy, inverted at TE 135 ms / upright at TE 35 ms → mitochondrial disease (distinguishes lactate from lipid)
  • Bilateral optic nerve / disc pseudoedema with peripapillary telangiectatic microangiopathy (no leakage on fluorescein) → LHON
  • Diffuse leukoencephalopathy (often asymptomatic) in a cachectic patient with GI dysmotility → MNGIE
  • White matter T2 abnormalities + cerebellar atrophy in a teenager with PEO → Kearns-Sayre syndrome
Clinical signs
  • Painless sequential bilateral central vision loss in a young male (with male predominance and incomplete penetrance) → LHON
  • PEO + pigmentary ("salt-and-pepper") retinopathy + heart block, onset <20 years (KSS triad) → Kearns-Sayre syndrome
  • Myoclonus + generalized epilepsy + ataxia + multiple symmetric lipomatosis (Madelung-pattern lipomas of neck/shoulders) → MERRF
  • "Stroke" in a young patient with short stature, diabetes, and hearing loss, lesion not respecting a vascular territory → MELAS
  • Maternally inherited diabetes + sensorineural hearing loss without stroke-like episodes → MIDD (allelic to MELAS; same m.3243A>G)
  • Symmetric ptosis + ophthalmoplegia without diplopia, ragged red fibers on biopsy → CPEO (sporadic single mtDNA deletion or nuclear POLG/TWNK)
  • Infantile sideroblastic anemia + exocrine pancreatic insufficiency (survivors evolve to KSS) → Pearson syndrome
  • Childhood intractable seizures + encephalopathy + liver failure after valproate → Alpers (POLG)
  • GI pseudo-obstruction + cachexia + PEO + neuropathy → MNGIE
Pathology / genetics hallmarks
  • Ragged red fibers on modified Gomori trichrome (subsarcolemmal red deposits) → mtDNA disorders (MELAS, MERRF, KSS, CPEO; absent in LHON)
  • COX-negative fibers on cytochrome oxidase stain, mosaic pattern → mtDNA mutation exceeding threshold
  • SDH-positive / COX-negative ("strawberry red" / ragged blue) fibers on dual SDH-COX stain → most specific histochemical marker of mtDNA mutation (preserved nuclear-encoded SDH with loss of mtDNA-encoded COX)
  • Paracrystalline mitochondrial inclusions with abnormal cristae on electron microscopy → mitochondrial myopathy
  • Elevated lactate:pyruvate ratio (>20:1) with elevated serum/CSF lactate and elevated alanine → impaired oxidative phosphorylation
  • m.3243A>G (MTTL1, tRNA-Leu) → MELAS / MIDD
  • m.8344A>G (MTTK, tRNA-Lys) → MERRF
  • Single large-scale mtDNA deletion (~4,977-bp "common deletion", sporadic) → KSS / Pearson / sporadic CPEO
  • m.11778G>A / m.3460G>A / m.14484T>C (Complex I: ND4, ND1, ND6) → LHON (maternal inheritance with strong male predominance, incomplete penetrance)
  • m.8993T>G / m.8993T>C (MT-ATP6, Complex V) → NARP → Leigh (heteroplasmy-dependent)
  • m.1555A>G (MT-RNR1, 12S rRNA) → aminoglycoside-induced sensorineural hearing loss
  • Elevated plasma thymidine and deoxyuridine + TYMP mutation → MNGIE
  • POLG mutations → secondary multiple mtDNA deletions/depletion → Alpers / SANDO / MIRAS / MEMSA / PEO (valproate contraindicated)
  • SURF1 (Complex IV assembly factor, AR) → Leigh syndrome (most common nuclear cause)
Mitochondrial Genetics

mtDNA Structure

  • Circular, double-stranded DNA — 16,569 base pairs; located in the mitochondrial matrix
  • 37 genes: 13 encode respiratory chain protein subunits, 22 encode tRNAs, 2 encode rRNAs
  • No introns, no histones, limited DNA repair mechanisms → 10–17x higher mutation rate than nuclear DNA
  • Each cell contains hundreds to tens of thousands of mtDNA copies, with 2–10 mtDNA molecules per mitochondrion (oocytes harbor >100,000 copies)

Inheritance & Heteroplasmy

  • Maternal inheritance: mtDNA is transmitted exclusively from the ovum; paternal mitochondria are tagged with ubiquitin and destroyed after fertilization
  • An affected mother passes mutant mtDNA to all children, but only daughters transmit further; heteroplasmy levels (and therefore clinical severity) vary widely between siblings due to the genetic bottleneck
  • Heteroplasmy: coexistence of normal (wild-type) and mutant mtDNA within the same cell
    • Threshold effect: symptoms manifest when the proportion of mutant mtDNA exceeds a critical threshold (typically 60–90%, varies by tissue and mutation)
    • Tissues with high metabolic demand (brain, muscle, heart, retina) have lower thresholds → affected first
  • Mitotic segregation: during cell division, mitochondria are randomly distributed to daughter cells → heteroplasmy levels can shift between generations and tissues
  • Genetic bottleneck: during oogenesis, a small number of mtDNA molecules are selected → explains variable severity among siblings from the same mother

Nuclear-Encoded Mitochondrial Genes

  • >1,000 nuclear genes encode mitochondrial proteins (imported via translocase complexes TOM/TIM)
  • These follow Mendelian inheritance (autosomal recessive or autosomal dominant) — not maternal
  • Examples: POLG, SURF1, SUCLA2, COQ8A, TWNK, RRM2B
  • Genetic anticipation does NOT apply to mitochondrial disorders — that concept belongs to trinucleotide repeat expansions (e.g., Huntington disease, myotonic dystrophy)
Board Pearl

Not all mitochondrial diseases follow maternal inheritance. Nuclear-encoded mitochondrial gene mutations (POLG, SURF1, etc.) are inherited in autosomal recessive or dominant patterns. On the boards, if a pedigree shows father-to-child transmission of a "mitochondrial" phenotype, think nuclear gene rather than mtDNA mutation.

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