Spinal Muscular Atrophy

SPINAL MUSCULAR ATROPHY (5q)

SMA
Mechanisms of pathology
General features
SMA Types
Related to Severity
SMA, Congenital (Type 0)
SMA, Type 1
SMA, Type 2
SMA, Type 3
Age 2 years
Age 6 years
Age 27 years

Also see
Spinal Muscular Atrophy, 5q
XBSMA pathology

H&E stain

SMA: Mechanisms Underlying Pathology

Initial innervation
- By reduced nubers of motor axons
Functional axons
- Innervate, & maintain size of, larger muscle fibers
- Abnormal patterns of activity produce
  - Hypertrophy: Larger muscle fibers have
    - Very increased size for age
    - Type 1 fiber predominance
  - Atrophy
    - Some muscle fibers may be innervated by non-functioning axons
    - Esterase stain: NMJs are preserved with Strongly staining on some small & large muscle fibers
    - Younger patients: Many 2C fibers
    - ATPase pH 4.6: No 2A fibers; Many degrees of staining of 2B fibers
  - Abnormal fiber types
    - Type I fibers by ATPase: May be pale on COX or dark on PAS
    - Darker fibers on COX: May also be dark on PAS
Disease progression
- Axon loss: Not proven
- Axons may become progressively dysfunctional or lost

SMA 5q: General Features

VvG stain

Muscle fibers
Small fibers: Large groups
Large fibers: Clustered; Hypertrophied, especially for age

H&E stain
Grouped atrophy
Small muscle fibers: Often rounded
Pyknotic nuclear clumps: None
Large muscle fibers: Hypertrophy

VvG stain

Gomori trichrome stain

H&E stain

Larger muscle fibers
Hypertrophied
Commonly type I
Clustered

Smaller muscle fibers
Round
Commonly type II,
May also be I or IIC
Clustered

ATPase pH 9.4 stain

ATPase pH 4.3 stain

SMA, Congenital (Type 0)

H & E	H & E
Only small muscle fibers are present. Small fibers have moderate variation in size.

VvG

SMA0: Fiber type properties

Many small fibers are Type 2C. (Intermediate stained at ATPase pH 4.3)

ATPase pH 4.3

Most muscle fibers are dark (Like type 2C) on ATPase pH 9.4

ATPase pH 9.4

Most muscle fibers are intermediate stained (Like type 2C) on ATPase pH 4.3

ATPase pH 4.3

Muscle fibers are variably intermediate stained (Like type 2B) on ATPase pH 4.6
There are no 2A muscle fibers

ATPase pH 4.6

COX
Mitochondrial stains are pale

SDH

SMA, Type 1

H & E	H & E
Many muscle fibers are small. A few hypertrophied fibers are present

NADH

Some large & small muscle fibers have reduced or absent glycogen

PAS

SMA Type 2

Age: 9 months

H&E stain
Large groups of atrophic muscle fibers

H&E stain

Patterns of fiber size changes: Varied among fascicles
Hypertrophic muscle fibers with scattered small angular fibers (Top; Left)
Intermediate, variably sized fibers (Bottom; Left)
Very small fibers: No pyknotic nuclear clumps (Middle)
Large & Small fibers with grouped atrophy (Right)

H&E stain

Esterase

Esterase

Neuromuscular junctions on large & small muscle fibers.

Esterase stain

VvG

Intramuscular nerves: Unremarkable

Toluidine blue
Sensory nerve
Normal numbers of large & small myelinated axons
Thinly myelinated larger axons: Consistent with young age.

VvG

NADH

NADH

Small muscle fibers
Stain darkly on NADH
Large muscle fibers
Coarse internal architecture

NADH

SMA 2: Fiber type properties

ATPase pH 9.4

Small muscle fibers: May be varied types or mostly type II
Large muscle fibers: Hypertrophied; Clustered; Type I or Abnormal intermediate staining

ATPase pH 4.3

ATPase, pH 9.4	ATPase, pH 9.4	ATPase, pH 4.3
Small muscle fibers: May be varied types (Left) or mostly type II (Middle) Large muscle fibers: Clustered; Type I or Abnormal intermediate staining		Many small fibers are type 2C

ATPase, pH 4.3

Incomplete Fiber Type Switching (Abnormal fiber types): ATPase doesn't entirely correspond to COX & PAS

ATPase, pH 9.4

Large muscle fibers: Mostly type I (Intermediate staining)
Small muscle fibers: Mostly type II (Dark staining)

ATPase, pH 4.3

Large muscle fibers: Mostly type I (Dark staining)
Small muscle fibers (Bottom left): Many type IIC (Varied degrees of intermediate staining)

ATPase, pH 4.6

Large muscle fibers: Mostly type I (Dark staining)
Small muscle fibers (Bottom left): Many type IIB (Varied degrees of intermediate staining); Few, or no IIA (Pale staining)

Cytochrome oxidase

COX: Clusters of larger fibers that have Type I staining on ATPase are pale (Usual Type II pattern)
Large muscle fibers
Clusters of type I (Dark staining) & Type II (Pale staining)
Some pale stained fiber clusters (Type II pattern) are Type I patterns on ATPase
Small muscle fibers: Intermediate & Pale staining

PAS

PAS: Similar to, instead of opposite of, COX stain in larger fibers Large muscle fibers
Clusters of abnormal type II pattern (Dark staining) in type I fibers on ATPase & COX
Some clusters have Type I pattern (Pale staining)
Fiber types are opposite of COX pattern
Small muscle fibers: Type 2 pattern (Darker staining)

SMA Type 3, Age 2 years

H & E
Grouped atrophy. Larger muscle fibers are not promiently hypertrophied.

ATPase pH 9.4	NADH
Variable involvement of fascicles. Top: Scattered small fibers. Large fibers are type 1. Bottom: Few small fibers. Type 2 predominance. Abnormal intermediate-staining fibers.	Variable involvement of fascicles. Top: Scattered small fibers. Most fibers are dark-stained. Bottom: Few small fibers. Most fibers are pale-stained.