Developmental delay with a flaccid rather than spastic weakness of the limbs is another major category of disease that must be distinguished. These include Down syndrome, cretinism, Prader-Willi syndrome, and achondrodysplasia. It should be commented that very sick children with celiac disease, cystic fibrosis, and other chronic diseases may be hypotonic to the point of simulating neuromuscular disease. Usually speech is not delayed and tendon reflexes are preserved in these purely medical states, and strength returns as the medical problem is corrected. Also, certain of the polioencephalopathies and leukodystrophies may weaken muscles and abolish tendon reflexes, but usually there is evidence of cerebral involvement.
There remains, after the assiduous study of the “floppy infant,” a group of cases of hypotonia and motor underdevelopment that cannot be classified. The term amyotonia congenita (Oppenheim) was once applied to this entire group but is now obsolete. Walton proposed the term benign congenital hypotonia to designate patients who manifest limp and flabby limbs in infancy and a delay in sitting up and walking but who improve gradually, some completely and others incompletely. It is likely that among this group there are examples of congenital myopathy that await differentiation by application of modern histochemical, ultrastructural, and genetic techniques.
Treatment Two novel treatments have been remarkable developments in this otherwise dismal field. One, nusinersen, is an antisense oligonucleotide that modifies splicing of SMN2 to result in increased production of SMN protein in motor neurons and compensate for the mutated SMN1 (Finkel et al). It is delivered by repeated intrathecal injection. It was shown to be effective in later onset SMA (types 2 and 3) as noted below. The second, is gene therapy with an adeno-associated viral vector containing SMN1, delivered as a single intravenous injection (Mendell et al). This has induced SMN expression. Both of these have been tested in small numbers of patients and in some cases, against historical controls.
Chronic childhood and juvenile proximal spinal muscular atrophy (Kugelberg-Welander syndrome, SMA 3 and Dubowitz syndrome SMA 2) This is a somewhat different form of heredofamilial spinal muscular atrophy, which, as the name indicates, involves the proximal muscles of the limbs predominantly and is only slowly progressive. It was first separated from other forms of motor system disease and from muscular dystrophy by Wohlfart et al and by Kugelberg and Welander in the mid-1950s. In about one-third of the cases the onset is before 2 years of age, and in half, between 3 and 18 years. Males predominate, especially among patients with juvenile and adult onset. The usual form of transmission is by an autosomal recessive pattern; most cases result from mutations in the SMN gene; as mentioned, multiple copies of the SMN2 gene partly rescue the loss of SMN1 and lead to this milder form of disease. Families with dominant and sex-linked inheritance have also been described.
The disease begins insidiously, with weakness and atrophy of the pelvic girdle and proximal leg muscles, followed by involvement of the shoulder girdle and upper arm muscles. Unlike the sporadic form of spinal muscular atrophy, the Wohlfart-Kugelberg-Welander variety (also listed in other books and monographs as Kugelberg-Welander disease) is bilaterally symmetrical from the beginning, and fasciculations are observed in only half the cases. Ultimately, the distal limb muscles are involved and tendon reflexes are lost. Bulbar musculature and corticospinal tracts are spared, although Babinski signs and an associated ophthalmoplegia (presumably neural) have been reported in rare instances.
The presence of fasciculations and the EMG and muscle biopsy findings—all of which show the characteristic abnormalities of neural atrophy—permit distinction from muscular dystrophy. Cases that have been examined postmortem have shown loss and degeneration of the anterior horn cells.