Page 819 - Robbins Basic Pathology by Vinay Kumar, Abul K. Abbas, Jon C. Aster

defect and the disease phenotype is not known. Most
patients become symptomatic by the age of 20 years,
usually owing to weakness in the facial muscles and the
shoulder. Patients also exhibit weakness in the lower
trunk and the dorsiflexors of the foot. Most affected
persons have a normal life expectancy.
Channelopathies, Metabolic Myopathies,
and Mitochondrial Myopathies
Other important inherited disorders of skeletal muscle are
the result of defects in ion channels (channelopathies),
metabolism, and mitochondrial function.
• Ion channel myopathies are a group of familial disorders
characterized by myotonia, relapsing episodes of hypo-
tonic paralysis associated with abnormal serum potas-
sium levels, or both. As implied by their name, these
diseases stem from inherited defects in genes encoding
ion channels. Hyperkalemic periodic paralysis results from
mutations in the gene encoding the skeletal muscle
sodium channel protein SCN4A, which regulates sodium
entry during contraction. Malignant hyperthermia is a rare
syndrome characterized by a dramatic hypermetabolic
state (tachycardia, tachypnea, muscle spasms, and
finally hyperpyrexia). It is triggered when patients car-
rying mutations in the ryanodine receptor, a calcium
release channel protein, are given halogenated anes-
thetic agents or succinylcholine during surgery. Some of
these patients also show features of a congenital myopa-
thy referred to as central core disease, so called because
the center of the myofiber contains a collection of disor-
ganized myofibrils.
• Myopathies due to inborn errors of metabolism include
disorders of glycogen synthesis and degradation
(Chapter 6), and abnormalities in lipid handling. The
latter include disorders of the carnitine transport system
or deficiencies of the mitochondrial dehydrogenase
enzyme system, both of which can lead to significant
accumulation of lipid in myocytes (lipid myopathies).
These storage disorders can manifest as systemic disease
or result in a muscle-specific phenotype. Some are
associated with ongoing muscle damage and weakness.
Others manifest with recurring episodes of massive
exercise- or fasting-induced muscle damage, sometimes
associated with acute renal failure and myoglobulinuria
(rhabdomyolysis).
• Mitochondrial myopathies can stem from mutations in
either the mitochondrial or nuclear genomes, the latter
because some mitochondrial enzymes are encoded in
nuclear DNA. The forms caused by mitochondrial muta-
tions show maternal inheritance (Chapter 6). Mitochon-
drial myopathies usually manifest in early adulthood
with proximal muscle weakness and sometimes with
severe involvement of the ocular musculature (external
ophthalmoplegia). There can also be neurologic signs and
symptoms, lactic acidosis, and cardiomyopathy. Some
mitochondrial diseases are associated with normal
muscle morphology, whereas others show aggregates of
abnormal mitochondria; the latter impart a blotchy red
appearance in special stains—hence the term ragged red
fibers. On ultrastructural examination, these correspond
to abnormal aggregates of mitochondria with abnormal
shape and size, some containing paracrystalline parking
lot inclusions.
Disorders of Skeletal Muscle 805
Acquired Disorders of Skeletal Muscle
A diverse group of acquired disorders can manifest with
muscle weakness, muscle cramping, or muscle pain. These
include inflammatory myopathies, toxic muscle injuries,
postinfectious rhabdomyolysis, and muscle infarction in
the setting of diabetes. In most instances these are dis­
orders of adults with acute or subacute onsets.
Inflammatory Myopathies
Polymyositis, dermatomyositis, and inclusion body myosi-
tis are the most important primary inflammatory myopa-
thies. Other immune disorders (e.g., SLE, sarcoidosis) also
can involve skeletal muscle.
• Polymyositis is an autoimmune disorder associated
with increased expression of MHC class I molecules on
myofibers and predominantly endomysial inflamma-
tory infiltrates containing CD8+ cytotoxic T cells. The
autoimmune attack leads to myofiber necrosis and sub-
sequent regeneration (Fig. 21–6, A). Patients with poly-
myositis are often successfully treated with corticosteroids
or other immunosuppressive agents.
• Dermatomyositis is the most common inflammatory
myopathy in children, in whom it appears as an isolated
entity. In adults, it can manifest as a paraneoplastic dis-
order. In both contexts, it is believed to have an autoim-
mune basis. On microscopic examination, it is associated
with perivascular mononuclear cell infiltrates, “dropout”
of capillaries, the presence of so-called tubuloreticular
inclusions in endothelial cells, and myofiber damage in
a paraseptal or perifascicular pattern (Fig. 21–6, B). Type
1 interferon-induced gene products are strongly upregu-
lated in affected muscles. Some patients have autoanti-
bodies that are relatively specific for dermatomyositis;
these include antibodies against Mi-2 (a nuclear heli-
case) and p155 and p140, proteins with uncertain
functions.
• Inclusion body myositis is the most common inflammatory
myopathy in patients older than 60 years of age. It
is lumped in with other forms of myositis, but it has yet
to be determined whether inflammation is cause or
effect in this disorder. The morphologic hallmark of
inclusion body myositis is the presence of rimmed vacu-
oles (Fig. 21–6, C) that contain aggregates of the same
proteins that accumulate in the brains of patients with
neurodegenerative diseases—hyperphosphorylated tau,
amyloid derived from β-amyloid precursor protein and
TDP-43 (Chapter 20)—leading some to speculate that
this is a degenerative disorder of aging. Other features
typical of chronic inflammatory myopathies, including
myopathic changes, mononuclear cell infiltrates, endo-
mysial fibrosis, and fatty replacement, also are evident.
The disease follows a chronic, progressive course and
generally does not respond well to immunosuppressive
agents, another feature suggesting that inflammation is
a secondary event.
Toxic Myopathies
A number of insults can cause toxic muscle injury, includ-
ing intrinsic factors (e.g., thyroxine) and extrinsic factors
(e.g., acute alcohol intoxication, various drugs).