Neuromuscular

CENTRONUCLEAR (MYOTUBULAR) MYOPATHY

General features
Infantile
  MTM1 mutation
Childhood
Juvenile
  Necklace fibers
  Abnormal fiber types
  Punctate, Small fibers
  DNM2 mutations: Myopathic
    Muscle fibers
Adult
  Titin mutations

General: Pathologic differential diagnosis

Centronuclear myopathy: Infantile

A single central nucleus in many muscle fibers

   
From: T Mozaffar


H&E stain

H&E stain

H&E stain

H&E stain

Toluidine blue stain
Central nuclei & abnormal internal architecture



Toluidine blue stain

Toluidine blue stain

Toluidine blue stain

Electron microscopy from T Mozaffar


Type I (light) muscle fibers tend to be smaller than type II.
Clear regions occur in center of some fibers.


ATPase stain, pH 9.4

ATPase stain, pH 9.4


Internal architecture: Small "Halo" muscle fibers.
  Darker staining: Central regions
  Clear rim around edge
  Common in MTM1 mutations


NADH stain

NADH stain




NADH stain

Centronuclear myopathy: Childhood


H&E stain

H&E stain

NADH stain

ATPase stain, pH 9.4
Some smaller muscle fibers
  Central nuclei
Other muscle fibers
  Central regions are basophilic.
Abnormal internal architecture.
  Central dark staining.
  Coarse
  Radial strands
Type I (light) muscle fibers
  Smaller than type II
  Clear central regions

Muscle fibers with abnormal internal architecture, including "radial" strands and necklace fibers
NADH stain

Centronuclear myopathy: Juvenile with Necklace fibers



H&E stain
H+E
H&E stain
Muscle fiber sizes: Bimodal distribution
Central nuclei: Especially in smaller fibers
Clefts: In center of other muscle fibers


H&E stain


Gomori trichrome stain
Central nuclei: Especially in smaller fibers
Clefts: In center of other muscle fibers
Rings (Necklaces): In some muscle fibers


Gomori trichrome stain

Necklace fibers
  Dark fibers: Rings
  Light fibers: Irregular internal architecture

NADH stain

NADH stain

  ATPase, pH 9.4
ATPase pH 9.4 stain
Small muscle fibers
  Most are type 1
  Contain central clear regions


ATPase pH 4.3 stain


Esterase stain

Centronuclear myopathy: Juvenile with many Central nuclei & Type 2C fibers


H&E stain
Many muscle fibers have single central nuclei


H&E stain


VvG stain


NADH stain
Abnormal internal architecture around central nuclei


ATPase pH 9.4 stain


ATPase pH 4.3 stain
Many abnormal, intermediate-staining (type 2C), muscle fibers

Centronuclear myopathy: Juvenile with Small muscle fibers & Punctate central NADH stain



H&E stain
Many muscle fibers have single central nuclei


H&E stain stain


NADH stain
Punctate central staining in many muscle fibers


ATPase pH 9.4 stain
Type 1 muscle fibers are smaller than type 2


ATPase pH 4.3 stain

Centronuclear myopathy: Teenage, DNM2 mutation


H&E stain
Myopathic muscle
Central nuclei: Single; In most muscle fibers
Endomysial connective tissue: Increased between muscle fibers
Fat: Replaces perimysium and some muscle


Gomori trichrome stain

H&E stain

NADH stain
Abnormal internal architecture
Muscle fibers may have radial strands, necklace formations or central "dots"

NADH stain

NADH stain


ATPase pH 9.4 stain
Fiber type pathology
Type 1 fibers: Small, Predominant


ATPase pH 4.3 stain
Fiber types: All type I

Acid phosphatase stain

Cytochrome oxidase stain
Central abnormalities in internal architecture
Lysosomal (Acid phosphatase positive; Above)
Mitochondrial (COX positive; Left)
Endoplasmic reticulum (Caveolin-3 positive; Below)




Caveolin-3 stain

Cytoplasmic abnormalities: Dystrophin & Desmin staining


Dystrophin stain

Desmin stain

Nuclei: Large central nuclei with irregular emerin

Emerin stain

Centronuclear Myopathy, DNM2 mutations: Individual muscle fibers


H&E stain stain
Central Nuclei: Often large

H&E stain


stain
Central Nuclei: Often large with pale centers

Congo red stain


H&E stain
Other Central Pathology
  Multiple central nuclei
  Central pallor

VvG stain
Internal Architecture
  Abnormal internal regions

VvG stain


NADH stain
Internal Architecture
  Radial strands
  Central clustering

NADH stain

NADH stain
Internal Architecture
  Radial strands

NADH stain

Centronuclear myopathy: Infant (1 year), MTM1 mutation 1



H&E stain
Central nuclei: Single; Large; In many muscle fibers
Muscle fiber size: Moderately varied
Perimysium: Replaced by fat in some regions

Congo red stain


H&E stain
Central nuclei: Single; Large; In many muscle fibers
Muscle fiber size: Moderately varied
Endomysial connective tissue: Normal to slightly increased

Congo red stain

Abnormal Muscle Fibers
  Many fibers have central nuclei
  A few smaller muscle fibers have basophilic cytoplasm & clustered, irrregular-shaped nuclei

H&E stain


Acid phosphatase stain
Acid phosphatase staining: Around central nuclei; Central regions in other muscle fibers


VvG stain
Peripheral halos: Pale; Subsarcolemmal

Gomori trichrome stain

PAS stain


SDH stain
Peripheral halos: Mitochondria concentrated in center of muscle fibers

COX stain

Peripheral halos: SR concentrated in center of muscle fibers

NADH stain

VvG stain


ATPase pH 9.4 stain
Fiber types
  Type 1 predominance
  Central clear regions
  No halos
  Some small muscle fibers are type 2C (Below)

ATPase pH 4.3 stain

Neuromuscular junctions: Dark stained; Large

Esterase stain

Perimysial Vein & Artery
  Normal structure

VvG stain

Centronuclear Myopathy:
  Titin


VvG stain

H&E stain

H&E stain

VvG stain

Congo red stain

Congo red stain

NADH stain

NADH stain

NADH stain

NADH stain

Desmin stain

COX stain

Acid phosphatase stain

ATPase ph 9.4 stain

ATPase ph 4.3 stain

Also see: Congenital fiber type size disproportion
Return to Centronuclear myopathy

References
1. J Neuropathol Exp Neurol 2016 Jan 28

1/10/2019