X-Linked Vacuolar Myopathy with Excessive Autophagic Vacuoles
Background Histopathology & Immunohistochemistry Differential Diagnosis Reference
BACKGROUND AND CLINICAL INFORMATION:
Summary: This is a rare form of
X-linked recessive myopathy and cases are identified mostly, if not exclusively,
in Finland, France and Canada. The clinical course is characterized by childhood
onset slow progression of muscle weakness without loss of ambulation with no
evidence of cardiac, respiratory, or central nervous system involvement.
Patients have normal life expectancy. Female carriers are usually asymtomatic or
only very mildly affected. Muscle fibers are not necrotic and show excessive
autophagic activity and exocytosis of the phagocytosed material. These vacuoles
are strongly reactive for dystrophin. Membrane bound vacuoles and balls of dense
material under the basal lamina are present. Deposition of C5b-9 complement
attack complex, subsarcolemmal deposition of calcium, and expression of MHC1
complex are also features of this disease. The gene is probably on chromosome
levels: The serum CK level may be
elevated during the first years of life by 2.5 to 3 times normal and may, during
adolescence, rise to 10 to 15 times normal.
Onset: Usually around 18-20 years old but cases with early
onset at 5 years old have also been reported.
symptoms: It is usually a very slowly progressive muscle
weakness that is mainly proximal and affects the legs more than the arms.
Atrophy of the thigh may be apparent.
heart, central nervous system, and other organs are not affected.
The candidate gene may be
located in chromosome Xq28. The gene appears to be close to the Emery-Dreifuss
injury based theory: The vacuoles are
autophagosomes clearing up sarcoplasmic debris after a sublethal injury to the
attack complex based theory: The
injury is induced by deposition of membrane attack complex of complement on
myofibers with secondary invagination and/or endocytosis.
HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY:
Morphology: The cardinal feature is
sarcoplasmic vacuoles that is bound by a dystrophin positive membrane.
Marked variation in fiber size: Fibers have increased
variation in size and are predominantly composed of round small and hypertrophic
fibers. Necrotic fibers are uncommon. Some fibers may be partially split.
Vacuoles: The vacuoles may have granular content that is blue
with HE stain (rimmed vacuoles) or may be optically clear. These vacuoles are
PAS(-) and do not contain lipid. Acid phosphatase reactivity is present in some
fibers. Calcium deposition can also be seen in the vacuoles. The vacuoles have
immunoreactive for dystrophin, laminin and MHC I.
Subsarcolemmal calcium: They often occur as irregular deposition along the
surface and can be well demonstrated by alizarin red. Although some fibers may
appear normal with HE stain, calcium deposition can also be demonstrated in
Dystrophin: Strongly positive at the rim of the vacuoles.
Complement membrane attack complex: They can be demonstrated
on the membrane in all fibers including those that appear normal. The membrane
attack complex is also present in the walls of capillaries and perimysial
Immunoreactivity for MHC I can be seen in the surface of the fibers and in some
LAMP-2: This is a protein that is found in the vacuoles. This
protein is normally found in lysosomal membranes and is considered to be
important in autophagy.
Balls of dense material: This is the most characteristic finding. These balls
of dense material are outside the basement membrane but under the basal lamina
which often appear mulilaminated. A lot of calcium is present in these sites.
Membrane bound vacuoles: These vacuoles may contain remains of mitochondria,
membrane whorls, and calcium apatite crystals.
disease: X-linked (the gene is on
Xq24) vacuolar myopathy and cardiomyopathy7 with mental retardation. Danonís
disease and vacuolar myopathy and
excessive autophagy are two different conditions. [Nishino
I et al., 2000; Danon
MJ et al., 1981; Hart
ZH et al., 1987; Valeros
et al., 1997].
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