Pathologic findings Muscle biopsy after 1 month of age reveals a typical picture of group atrophy; shortly after birth this change is difficult to discern. Aside from denervative atrophy, the essential abnormalities are in the anterior horn cells in the spinal cord and the motor nuclei in the lower brainstem. Nerve cells are greatly reduced in number, and many of the remaining ones are in varying stages of degeneration; a few are chromatolytic and contain cytoplasmic inclusions. It is not unusual to see figures of neuronophagia. There is replacement gliosis and secondary degeneration in roots and nerves. Other systems of neurons, including the corticospinal and corticobulbar systems, are entirely unaffected.
Differential diagnosis The major problem in diagnosis is to distinguish Werdnig-Hoffmann disease from an array of other diseases that cause hypotonia and delayed motor development in the neonate and infant. The list of disorders that imitates spinal muscular atrophy constitutes a large part of the differential diagnosis of the so-called floppy infant. The congenital myopathies (as described in Chap. 45), the glycogenoses, neonatal myasthenia gravis,
Prader-Willi syndrome, and disorders of fatty acid metabolism frequently present in this way. The preservation of tendon reflexes and relative lack of progression of muscle weakness distinguish the latter disorders. Because of the gravity of the diagnosis, genetic testing or muscle biopsy should be performed if there is any suspicion of spinal muscular atrophy. If studied properly, the biopsy usually yields the correct diagnosis.
Clinical disorders more or less similar to the spinal muscular atrophies may be identified occasionally in certain hereditary metabolic diseases. For example, Johnson and coworkers have described a patient who began experiencing weakness of the legs, cramping, and fasciculations during adolescence in what proved to be a variant of hexosaminidase A (GM2) deficiency, and biopsy of rectal mucosa showed nerve cells with the typical membranous cytoplasmic bodies of Tay-Sachs disease. Others have reported similar cases. A progressive motor neuron or motor nerve disorder has also been observed in glycogen storage disease affecting anterior horn cells. Motor nerve fibers also suffer damage in metachromatic and globoid body leukoencephalopathies.
Certain forms of muscular dystrophy, notably myotonic dystrophy, which is about twice as frequent as Werdnig-Hoffmann disease, may become manifest in the neonatal period and interfere with sucking and motor development (see Chap. 45). As a rule, the weakness is not as severe or diffuse as that in Werdnig-Hoffmann disease. The mother, but not the child, may display myotonia, either elicitable clinically or, if more subtle, with EMG recording. Also, a number of polyneuropathies may cause a serious degree of weakness in early childhood. Unfortunately, in respect to the latter, adequate sensory testing is not possible because of the patient’s age, but the CSF protein is often elevated. Again, diagnosis is greatly facilitated by nerve-muscle biopsy and measurement of nerve conduction velocities. These velocities are reduced but must be interpreted with caution because of incomplete development of axons and of myelination in the first months of life. The needle EMG examination shows subtle signs of denervation that cannot be easily distinguished from the finding in the spinal muscular atrophies. Examination of parents and siblings may disclose a clinically inapparent neuropathy. Polymyositis of childhood may also simulate both muscular dystrophy and motor neuron disease. Finally, nemaline and central core myopathy can manifest in infancy and early childhood and cause a floppy child syndrome.