Neuromuscular

mtRNA Leu (MTTL1) A3243G mutations: Pathology

MELAS Syndromes

Patients
Ages: 2nd & 3rd decades
  Brain
  Muscle
Age: 67 year old

Muscle Pathology: Young Adult

Muscle fibers
Perimysial vessels
Ragged Red Fibers: Scattered

Gomori trichrome stain
Scattered fibers with clear rim

H&E stain
 "Ragged red" fibers

Gomori trichrome stain

Gomori trichrome stain

Gomori trichrome stain

Mitochondrial Proliferation: Scattered muscle fibers with Increased SDH staining


SDH stain
Muscle Fibers: Increased SDH stain
  Scattered through muscle
  Variable degrees

 Muscle fiber: Increased SDH stain:
  Individual mitochondria within muscle fiber are enlarged
    compared to surrounding fibers

Mitochondrial Proliferation: Scattered muscle fibers with Increased COX staining


Cytochrome oxidase (COX) stain

Succinate dehydrogenase (SDH) stain

Cytochrome oxidase (COX) stain
Muscle fibers with Mitochondrial proliferation (Increased SDH stain)
Muscle fibers with increased SDH stain may also have increased COX stain

Succinic dehydrogenase (SDH) stain
Muscle fibers with increased SDH & COX stain

COX stain
Cytochrome Oxidase (COX) stain: Reduced or Increased
Muscle fibers may have reduced, normal or increased COX staining (Right)
 Lipid accumulation
  Increased Sudan black stain in muscle fiber
  with mitochondrial proliferation

COX stain

MELAS: Mitochondrial Ultrastructure


From: R Schmidt

From: R Schmidt

From: R Schmidt

From: R Schmidt

MELAS Vessels

SDH staining of intramuscular vessels is Increased

Succinic dehydrogenase (SDH) stain
MELAS
  Medium-sized perimysial vessels have increased SDH staining
  Contrast with normal staining in MNGIE & Control
 
Succinic dehydrogenase (SDH) stain
Normal: Mild SDH staining of medium sized perimysial vessels

MELAS: Capillaries


From: R Schmidt

From: R Schmidt

From: R Schmidt

From: R Schmidt

Brain pathology in MELAS

MRIs during "stroke-like" episodes
  • Cortical lesions (Posterior): Spares white matter
  • Lesion location
    • Not confined to territory of single vessel
    • Involves only part of territory of several vessels
  • Swelling
  • Mutation: A3243G

FLAIR image
T2 weighted image

From: Cindy Ly
CT during episode of homonymous hemianopia

Medial occipital lesion (Arrow)
Enlarged ventricles 		Late in disease course

MRI: Severe involvement
  of occipital cortex
Temporal gray matter: Severely abnormal
Temporal horn of Ventricles: Enlarged.

MELAS: 67 year-old female

  mtDNA A3243G 66% heteroplasmy
  Other disorders: Diabetes; Renal disease, End-stage
Capillaries
Larger vessels
Muscle fibers

Vessel Pathology


SDH stain
Perimysial Vessels
  Punctate dark stainin in walls

SDH stain

From: R Schmidt
Pericytes   Mitochondrial proliferation & enlargement (Black arrows)
Endothelial cells   Multiple small vacuoles (White arrows)

From: R Schmidt

From: R Schmidt
Large cells near vessels with
  Mitochondrial proliferation & enlargement
  Lipid droplets

From: R Schmidt

From: R Schmidt

From: R Schmidt
Large cells near vessels with cytoplasm nearly replaced by
  Mitochondrial proliferation & enlargement
  Lipid droplets

From: R Schmidt

From: R Schmidt
Large cells near vessels with cytoplasm nearly replaced by
  Mitochondrial proliferation & enlargement
  Lipid droplets

From: R Schmidt

From: R Schmidt
Endomysial vessels with
  Large endothelial cells with many vesicles
  No lumen
  Many smooth muscle cells in wall, some with mitochondrial proliferation (Arrow)
  Thick wall

From: R Schmidt

From: R Schmidt
Endomysial vessels with
  Large endothelial cell with many vesicles
  No lumen
  Scattered smooth muscle cells in wall
  Thick wall

From: R Schmidt

ATPase pH 4.3
Endomysial capillaries
  Pale staining by ATPase pH 4.3 (Arrows)
  Large size

ATPase pH 4.3

UEA-I
Endomysial capillaries
  Large size

From: R Schmidt
Endomysial capillaries
  Endothelial cells with many vesicles
  Large size
  Thick wall

From: R Schmidt

From: R Schmidt
Endomysial capillaries
  Endothelial cells with many vesicles
  Large size
  Thick wall

From: R Schmidt

From: R Schmidt

MELAS: Muscle Fibers


H&E stain
Fiber sizes
  Bimodal variation

SDH stain
SDH positive muscle fibers
  Dark stained cytoplasm

COX stain
COX reduced small muscle fibers
  Pale stained cytoplasm

Sudan black stain
Lipid droplets, small, in some muscle fibers

Sudan black stain

ATPase pH 9.4 stain
Type 2 muscle fiber atrophy

From: R Schmidt
Mitochondrial proliferation between sarcomeres

From: R Schmidt

From: R Schmidt

From: R Schmidt
Muscle fiber basement membrane
  Thick
  Undulating

From: R Schmidt

From: R Schmidt
Mitochondrial proliferation & enlargement: Beneath muscle fiber surface

From: R Schmidt
Return to Mitochondrial pathology
Return to Mitochondrial syndromes
Return to Muscle biopsies

12/1/2025