Page 818 - Robbins Basic Pathology by Vinay Kumar, Abul K. Abbas, Jon C. Aster

804 C H A P T E R 21 Peripheral Nerves and Muscles

AB C

Figure 21–5 Duchenne muscular dystrophy. Histologic images of muscle biopsy specimens from two brothers. A and B, Specimens from a 3-year-old
boy. C, Specimen from his brother, 9 years of age. As seen in A, at a younger age fascicular muscle architecture is maintained, but myofibers show
variation in size. Additionally, there is a cluster of basophilic regenerating myofibers (left side) and slight endomysial fibrosis, seen as focal pink-staining
connective tissue between myofibers. In B, immunohistochemical staining shows a complete absence of membrane-associated dystrophin, seen as a
brown stain in normal muscle (inset). In C, the biopsy from the older brother illustrates disease progression, which is marked by extensive variation in
myofiber size, fatty replacement, and endomysial fibrosis.

clinical feature and may result in death in the absence of cataracts, early frontal balding, endocrinopathies, and
significant skeletal muscle weakness. testicular atrophy.

Other X-Linked and Autosomal Muscular Dystrophies • Limb-girdle muscular dystrophies. These autosomal mus-
cular dystrophies preferentially affect the proximal mus-
Other forms of muscular dystrophy share some features culature of the trunk and limbs. The genetic basis for
with DMD and BMD but have distinct clinical, genetic, and these is heterogeneous. The growing list includes at least
pathologic features. 6 dominant subtypes and 12 autosomal recessive sub-
• Myotonic dystrophy. Myotonia, the sustained involuntary types. Some of the responsible mutations affect compo-
nents of the dystrophin-glycoprotein complex other
contraction of a group of muscles, is the cardinal neuro- than dystrophin. Others affect proteins involved in
muscular symptom in myotonic dystrophy. Patients vesicle transport and repair of cell membrane after
often complain of stiffness and difficulty releasing their injury (caveolin-3 and dysferlin), cytoskeletal proteins,
grip, for instance, after a handshake. Myotonic dystro- or posttranslational modification of dystro­glycan, a
phy is inherited as an autosomal dominant trait. More component of the dystrophin-glycoprotein complex.
than 95% of patients with myotonic dystrophy have
mutations in the gene that encodes the dystrophia myo- • Emery-Dreifuss muscular dystrophy (EMD) is a rare but
tonica protein kinase (DMPK). In normal subjects, this fascinating disorder caused by mutations affecting
gene contains fewer than 30 repeats of the sequence structural proteins found in the nucleus. An X-linked
CTG, whereas in severely affected persons, several thou- form results from mutations in the gene encoding the
sand repeats may be present. Myotonic dystrophy thus protein emerin, while an autosomal dominant form is
falls into the group of disorders associated with trinu- caused by mutations in the gene encoding lamin A/C.
cleotide repeat expansions (Chapter 6). As is the case It is hypothesized that defects in these proteins compro-
with other disorders with similar mutations, myotonic mise the structural integrity of the nucleus in cells that
dystrophy exhibits the phenomenon of anticipation, char- are subjected to repetitive mechanical stress (e.g., cardiac
acterized by worsening of the disease manifestations and skeletal muscle). These proteins also may regulate
with each passing generation due to further trinucleo- chromatin structure. The clinical picture is characterized
tide repeat expansion. The CTG repeat expansion is by progressive muscle weakness and wasting, contrac-
located in the 3′ untranslated region of the DMPK tures of the elbows and ankles, and cardiac disease. The
mRNA, and the manner in which it produces disease is cardiac involvement is severe, being associated with car-
unclear. The disease often manifests in late childhood diomyopathy and arrhythmias that lead to sudden
with gait abnormalities due to weakness of foot dorsi- death in up to 40% of patients.
flexors, with subsequent progression to weakness of the
intrinsic muscles of the hands and wrist extensors, • Fascioscapulohumeral dystrophy is an autosomal dominant
atrophy of the facial muscles, and ptosis. Other tissues form of muscular dystrophy that is usually associated
may also be affected, presenting as cardiac arrhythmias, with deletions in chromosomal region 4q35. The patho-
physiologic relationship between this chromosomal