Congenital muscle fiber-type disproportion is a condition that can be defined only in the muscle biopsy by 2 obligatory criteria of “disproportion”: (1) a massive type I myofiber predominance of 80% or more, and (2) myofibers of type I are uniformly smaller than normal for age by 2 standard deviations or more, but are not necessarily angular or rounded as in myofiber atrophy. Internal sarcolemmal nuclei are an inconstant additional feature in a minority of cases, but myofiber necrosis, inflammation, and fibrosis are not typical features. This condition may be isolated as a nonprogressive congenital myopathy inherited as an autosomal dominant or recessive trait; may be associated with other congenital myopathies, such as nemaline rod myopathy, minicore myopathy, and infantile myotonic dystrophy; and may present with a variety of genetic metabolic diseases, including Krabbe leukodystrophy in early stages and insulin-resistant diabetes mellitus. It also is associated with congenital malformations of the brain, particularly cerebellar hypoplasia. Clinically, patients often have dysmorphic facies with facial wasting similar to that of nemaline myopathy or myotonic dystrophy. Serum creatine kinase is normal, and EMG is nondiagnostic. Congenital muscle fiber-type disproportion, thus, is best regarded as a syndrome, and not a specific disease, except for isolated familial cases.
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• Pathological major criteria are: (1) uniform smallness of type I myofibers and (2) type I myofiber predominance. Pathological minor criteria are: (3) small myofibers remain polygonal, not angular, in transverse contour; (4) myofiber necrosis and degeneration is not a feature; (5) centronuclear fibers occur in a minority of cases.
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• Congenital muscle fiber-type disproportion associated with several congenital myopathies (neonatal myotonic dystrophy; nemaline myopathy) may occur as an isolated congenital myopathy, is associated with several systemic inborn metabolic diseases (multiple sulfatase deficiency; some mitochondrial cytopathies; Krabbe disease), and may be secondary to suprasegmental abnormal influences on the motor unit in midfetal life, particularly cerebellar hypoplasia and other posterior fossa malformations; this is not due to denervation or reinnervation of muscle (spinal muscular atrophy, congenital or genetic polyneuropathies).
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• Many diverse genes are now known to be associated, in addition to those that cause nemaline myopathy.
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• Serum CK is normal; EMG is nondiagnostic; NCV is normal.
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• Clinical phenotype is variable, depending on the associated disease (facial weakness and wasting in myotonic dystrophy and nemaline myopathy). Arthrogryposis is rare, but isolated contractures of proximal and distal joints may occur, and scoliosis is a frequent complication; cardiomyopathy is rare.
Historical note and terminology
The unique ratio of histochemical fiber types and sizes in the muscle biopsy of infants and children was described by Brooke and Engel (14), Farkas-Bargeton and colleagues (41), Karpati and colleagues (60), and Caille and colleagues (16), but was first recognized as a distinct entity and called "congenital fiber-type disproportion" by Brooke (12). He initially defined a difference in fiber size, type I smaller than II by 12% or more, but in later publications, he reconsidered and changed his criteria to 25% or more because the earlier difference was too little and, in most cases, even 25% was a conservative ratio. The 25% difference in fiber size is now accepted as the standard (28). By definition, it is a muscle biopsy diagnosis of selective uniform smallness of type I fibers relative to those of type II by 25% or more and also type I myofiber predominance of 80% or more. “Partial congenital muscle fiber-type disproportion” may be defined by uniform type I myofiber smallness but without the numerical predominance of classical congenital muscle fiber-type disproportion. This form is more usual in systemic metabolic diseases. An additional feature in some patients with congenital muscle fiber-type disproportion is the presence of large numbers of centronuclear fibers that are not regenerative fibers (125; 134; 17). In rare cases, type II fibers, rather than undergoing the usual compensatory hypertrophy, may become atrophic and angular (102).
Because the genetics are uncertain in most cases, despite the discovery of many new genetic mutations (see below), and because congenital muscle fiber-type disproportion is found in association with many other myopathies and diseases, Dubowitz characterized this unique histopathological pattern as “a pathology in search of a disease (38).
The ultrastructure of muscle in congenital muscle fiber-type disproportion shows only subtle changes without myofiber necrosis. The Z-band tends to be less regular than normal, and excessive Z-band streaming sometimes is seen (18). This finding is of interest because congenital muscle fiber-type disproportion is a constant feature in nemaline rod myopathy (see below), and nemaline rods are derived from Z-band material. Other findings by electron microscopy are abnormal exchanges of bundles of myofilaments between adjacent myofibrils and occasional peripheral sarcoplasmic masses containing bundles of disoriented myofilaments (18). In cases with demonstrated genetic mutations in the molecular structure of contractile proteins (see below), these specific myofilaments of actin or myosin are ultrastructurally altered and may predict the genetic defect.
Both the clinical features and the muscle biopsy findings were subsequently confirmed by many other authors. The diverse etiologies of the disorder as a syndrome rather than a disease and its association in some cases with specific metabolic diseases were first recognized by Martin and colleagues (79). The association with cerebellar hypoplasia was documented by Sarnat (116). A review of the known genetic mutations was provided by DeChene and colleagues (35).