Review articleCongenital myopathies/dystrophies
Section snippets
Congenital myopathies
The congenital myopathies often present as the “floppy infant” syndrome [1], [2]. Clinically, they are nearly indistinguishable from one another. Most infants with congenital myopathy have a relatively benign course characterized by static or nonprogressive muscle weakness and hypotonia. Some infants, however, may have a rapidly progressive course leading to early death from respiratory insufficiency. Occasionally, congenital myopathies do not become manifest until later in childhood or even
Central core disease
Central core disease was the first congenital myopathy to be specifically recognized [4]. Infants with central core disease present as “floppy infants.” The afflicted children display weakness, hypotonia, and delayed motor development along with skeletal anomalies such as short stature, kyphoscoliosis, dislocated hips, and pes cavus. Adults with central core disease may be nearly asymptomatic or show varying degrees of proximal muscle weakness that is typically more pronounced in the lower
Nemaline myopathy
Nemaline myopathy was the second congenital myopathy to be delineated. This disorder was recognized in a hypotonic child whose muscle displayed a distinctive morphologic abnormality designated as “myogranules,” as well as in a 4-year-old boy with a morphologic abnormality described as “rods” [7], [8].
The spectrum of clinical manifestations of nemaline myopathy has expanded significantly since the original descriptions. Infants with nemaline myopathy can have severe weakness and hypotonia with a
Centronuclear myopathy
This condition was originally described in a 12-year-old boy with muscle weakness, including involvement of facial and extraocular muscles, and delayed motor development [18]. It was suggested that the disease resulted from arrested maturation of embryonic muscle, and the disorder was designated as myotubular myopathy. The term “centronuclear myopathy” was soon introduced to describe the disease in two teenage sisters who had weakness, also involving the extraocular muscles, and impaired motor
Multicore disease
Multicore disease is also referred to as minicore disease [30]. Although the histology is superficially similar to central core disease, this congenital myopathy is sufficiently distinct to warrant a separate nosologic classification.
Most patients with multicore disease are infants or young children with nonprogressive weakness of trunk and proximal limb muscles, reduced muscle bulk, and delayed motor development. Respiratory muscle weakness also has been reported [31]. As with central core
Congenital fiber-type disproportion
Brooke and Engel described a group of infants with uniform smallness of type 1 myofibers [33]. The term congenital fiber-type disproportion was later applied by Brooke.
Infants with congenital fiber-type disproportion display clinical features that are nonspecific and common to many congenital myopathies. These children are hypotonic and weak, especially during the first 2 years of life, often short, and have high-arched palates. Some have dislocated hips, kyphoscoliosis, and foot deformities.
Reducing body myopathy
This morphologically distinctive entity was originally described in two weak, hypotonic neonates who died in late infancy [38]. Subsequent reports described similar morphologic features in older individuals with varied clinical manifestations including a more benign course [39], [40].
The disease is characterized by the presence of a variable number of “reducing bodies.” These structures are round-to-ovoid masses, measuring 10 to 70 microns at maximal diameter. Reducing bodies are generally
Fingerprint body myopathy
This nonprogressive or slowly progressive congenital myopathy was originally delineated in 1972 [41]. The patients have weakness and hypotonia of limb and trunk muscles with sparing of cranial muscles. Motor development is delayed. Some patients may be intellectually impaired.
Muscle biopsy specimens show ill-defined ovoid inclusions measuring 1 to 10 microns in diameter. These structures are located beneath the subsarcolemma, predominantly in type 1 myofibers. The inclusions stain reddish with
Cytoplasmic body myopathy
Cytoplasmic bodies are small hyaline structures that have been encountered in the sarcoplasm in a wide variety of neuromuscular disorders including denervation, inflammatory myopathies, mitochondrial myopathies, and toxic myopathies. In addition to these acquired conditions, there is a heterogeneous congenital myopathy that is characterized by the presence of numerous cytoplasmic bodies [42], [43].
This congenital myopathy is manifested by proximal or generalized weakness that may be static or
Myopathies with tubular aggregates
Tubular aggregates are found in a wide variety of muscle diseases including the periodic paralyses, various myotonic disorders, and toxic and endocrine myopathies.
The presence of numerous tubular aggregates is also characteristic of certain familial myopathies. One form is manifest in infancy as a myasthenic syndrome [46]. Another tubular aggregate myopathy is apparently inherited as an autosomal dominant trait and produces slowly progressive proximal weakness with onset in childhood or
Type 1 myofiber predominance
Type 1 myofiber predominance commonly occurs in conjunction with more specific structural alterations seen in many of the congenital myopathies. Indeed, clinical weakness in the congenital myopathies, particularly in infants, often reflects type 1 myofiber predominance rather than other specific architectural changes in skeletal muscle. However, some patients, including both children and adults, have nonprogressive, apparently congenital myopathies with type 1 predominance as the only
Congenital dystrophies
The term congenital muscular dystrophy (CMD) is used to describe a heterogeneous group of disorders that are manifest at birth. The affected infants display hypotonia, weakness, or arthrogryposis. The diagnosis is substantiated by the demonstration of dystrophic myopathic features on muscle biopsy, elevation of serum creatine kinase, and exclusion of other recognizable myopathies of the newborn. CMD is commonly categorized by the presence or absence of clinically evident cerebral involvement.
Congenital dystrophies without clinical cerebral involvement
The clinical course of CMD without clinical cerebral involvement has long been recognized as highly variable. In those children with normal merosin, a milder and more slowly progressive course generally can be predicted. Over 90% of merosin-positive CMD children will become ambulatory by age 4. Ullrich CMD is a specific merosin-positive CMD characterized by proximal contractures, distal laxity, and rigidity of the spine associated with a deficiency of collagen VI [56]. Conversely, CMD
Congenital dystrophies with clinical cerebral involvement
The more frequent autosomal recessive CMD syndromes associated with clinical cerebral involvement are Fukuyama CMD, Walker-Warburg CMD, and muscle-eye-brain CMD. The Fukuyama type is most prevalent in Japan. The genetic abnormality responsible for Fukuyama CMD has been localized to a gene on chromosome 9 that encodes a protein called fukutin [57], [58]. Fukutin is expressed in glial cells and neurons [59]. The cerebral involvement is characterized by polymicrogyria, lissencephaly, and neuronal
Clinical evaluation of congenital myopathies/dystrophies
Patients with congenital myopathies/dystrophies often present as a floppy infant. Such infants frequently display decreased tone, weakness, decreased spontaneous movements, and delayed acquisition of motor skills. The vast majority of floppy infants, however, do not have a congenital neuromuscular disorder, and even the majority of floppy infants with neuromuscular disease do not have one of the congenital myopathies/dystrophies. Flabby muscles, absent deep tendon reflexes, and somatic
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