Nemaline myopathy appears to be genetically heterogeneous but about 20 percent are due to mutations in ACTA1. The pattern of inheritance is most often autosomal dominant with variable penetrance. In some families there has been an autosomal recessive or an X-linked pattern of inheritance. Studies of the various gene defects have begun to clarify the uncertainties about inheritance and explain the relationships between the different forms of the disease. The genes implicated in nemaline myopathy include those for alpha-tropomyosin, beta-tropomyosin, alpha-actin, nebulin, troponin, coflin-1, and the ryanodine receptor (the last of these is more commonly implicated in central core disease, as mentioned above).
The disease is so named for the rods or coils of threadlike structures in pathology material. Frozen muscle tissue stained with Gomori trichrome discloses the characteristic lesion, which can be seen under the light microscope. Myriads of bacillus-like rods, singly and in small packets, are seen beneath the plasma membrane of the muscle fiber. They are composed of material that resembles that of Z bands under the electron microscope, and often actin filaments are attached, just as they are to Z bands. The type 1 fibers, which usually predominate, are smaller than normal, as in central core disease. The size of the motor neurons has been reported to be reduced. Weakness is probably related to a smallness and reduction in the number of muscle fibers and possibly to focal interruption of their cross-striations, particularly of the Z bands.
In this familial disease, hypotonia and weakness become manifest soon after birth or in infancy or early childhood. In the mildest form, the diagnosis does not become evident until adult years. All the striated skeletal muscles are involved to some degree, but distinctive features are ptosis and ocular palsies combined with weakness of facial, masticatory, lingual, pharyngeal, laryngeal, and cervical muscles in most of the infants with this disease, but not in adults. In the limbs, distal weakness keeps pace with proximal weakness. The limbs remain thin and are flexic throughout life. Motor development is secondarily slowed, though some improvement with maturation can occur. Later, however, motor functions that had been acquired may be lost as the disease slowly advances. Several patients have shown signs of cerebral abnormality with seizures and an abnormal electroencephalogram (EEG), but it is not clear whether this is truly part of the disease. Needle EMG examination shows the usual myopathic pattern as well as both positive sharp waves and fibrillation potentials in some cases. Abundant spontaneous activity should suggest the diagnosis of centronuclear myopathy (Griggs et al).
Heckmatt and colleagues classified this disorder into three types, based on severity, mode of presentation, and genetic pattern: (1) a severe neonatal X-linked recessive type, now known to be associated mainly with mutations in myotubularin, MTM1; (2) a less severe early infantile, late-infantile, or childhood autosomal recessive type associated with BIN1, RYR1, or titin; and (3) a still milder late childhood–adult autosomal dominant type associated in some cases with mutations in DYN2 (dynamin) or MYF6, a helix-loop-helix protein that appears to function as a myogenic transcription factor.