Hypotonia and weakness are the major clinical features. Other characteristic features such as scoliosis, ptosis, and ophthalmoplegia may not be apparent at birth, and diagnosis may be delayed until gross-motor developmental delay and associated weakness develop in late infancy or early childhood. The creatine phosphokinase (CPK) level is usually normal or slightly elevated, and diagnosis is heavily dependent on the muscle biopsy.
The term nemaline (Greek nema, thread) characterizes the presence of rods or threadlike structures seen in the muscle biopsies of patients with this type of congenital myopathy. The neonatal type is the most severe, presenting with hypotonia, diminished spontaneous activity, history of poor fetal movements, and early respiratory distress. More commonly, presentation is delayed until after the newborn period when gross-motor delay with proximal weakness develops.
The nemaline bodies on muscle biopsy originate from the Z disks and tend to cluster under the sarcolemma. To date, six genes have been involved in the pathogenesis of nemaline myopathy (gene products α-tropomyosin-3, nebulin, α-actin, β-tropomyosin, troponin T type I, and cofilin-2). It is transmitted by autosomal dominant or recessive inheritance.
CENTRAL CORE DISEASE
Most patients with central core disease (CCD) present with hypotonia in early infancy and childhood and a subsequent delay in motor milestones. Rarely, severe hypotonia and marked contractures are present at birth. Skeletal abnormalities are present, also. The clinical course varies from nonprogressive to slowly progressive. An association between CCD and malignant hyperthermia has been observed. On muscle biopsy, central cores appear to be packed with myofiber material and depleted of organelles.
CCD is an autosomal dominant condition. Mutations of the ryanodine receptor-1 have been detected in families with susceptibility to malignant hyperthermia and patients with CCD.
The mode of inheritance of centronuclear/myotubular myopathy can be X-linked recessive, autosomal dominant, or recessive. Early-onset cases are the most common form and present with severe hypotonia, weakness, and respiratory distress. Affected infants are very weak and have major feeding difficulties, facial diplegia, bilateral ptosis, and limitation of eye movements (external ophthalmoplegia). Despite intensive respiratory support, infants rarely survive or improve their motor function. The muscle biopsy shows central nuclei present in many muscle fibers and type I fiber predominance. The gene product in the X-linked recessive variety (MTM1) was designated myotubularin. Dynamin-2, amphiphysin (B1N1), and also RYR1 mutations have also been described in patients with centronuclear myopathy.
CONGENITAL FIBER-TYPE DISPROPORTION
Congenital fiber-type disproportion (CFTD) typically presents with hypotonia and weakness at birth or in the neonatal period. There is delay in acquisition of motor milestones. CPK is normal, and electromyography (EMG) may be normal or myopathic. The muscle biopsy shows type I fiber predominance but also nonspecific type I fiber atrophy seen in other, clinically diverse conditions. Therefore the existence of CFTD as an entity has been debated. α-Actin (ACTA1), RYR1, α-tropomyosin, and selenoprotein N (SEPN1) mutations have been described in patients with CFTD.
OTHER CONGENITAL MYOPATHIES
In addition to the four most common congenital myopathies described above, there are uncommon types with similar clinical characteristics but less well-defined patterns of inheritance. Their names reflect their myopathologic features and include (1) actin myopathy (non-nemaline), (2) fingerprint body myopathy, (3) sarcotubular myopathy, (4) hyaline body myopathy, (5) reducing body myopathy, (6) cytoplasmic body myopathy, (7) myopathy with myotubular aggregates, (8) zebra body myopathy, and (9) trilaminar myopathy. The mutated genes are known in some of them, but diagnosis is made by muscle biopsy.