History The classic form of spinal muscular atrophy was described by Werdnig in 1891 and 1894, by Hoffmann in 1893 and, at about the same time, by Thomsen and Bruce. The cases described by these authors were all in infants. Further clinical analyses, however, indicated the inadequacy of this narrow grouping for the large number of spinal muscular atrophies. Brandt, in his study of 112
Danish patients, found that in about one-third the weakness was present at birth, and in 97 the onset was in the first year of life; in 9 patients, the disease was not recognized until after the first year of life. In 1956,
Walton, and later Wohlfart and colleagues and Kugelberg and Welander (see below), identified milder forms of spinal muscular atrophy in which the onset was between 2 and 17 years and walking was still possible in adult life. Byers and Banker, in a study of 52 patients, subdivided them into 3 groups on the basis of age of onset; in 1 group the disease was recognized at birth or in the first month or two of life; in a second, between 6 and 12 months; and in a third, after the first year. In their last group, it was not unusual for the patient to survive into adolescence and adult life. In a few of the late-onset types, signs of corticospinal tract involvement are conjoined, and Bonduelle has also included some patients with areflexia, pes cavus, Babinski signs, choreiform movements, and developmental delay in this group. More recently, the designations SMA I, II, and III have been introduced, based on the age of onset and genetic variant (see Table 38-7).
Genetic aspects of spinal muscular atrophies Familial spinal muscular atrophy that begins in infancy and childhood is inherited mainly as an autosomal recessive trait. All the SMA phenotypes in children have been mapped to mutations affecting the “survival of motor neuron” (SMN1) gene. The SMN protein participates in forming protein-RNA complexes (small nuclear ribonucleoproteins and RNA) that are essential for gene splicing. Within the SMN locus there are 2 alleles: SMN1, which generates a full-length, fully functional form of SMN, and SMN2, which makes a truncated, partially functional SMN. The latter can partially compensate for the loss of SMN1. Making matters more complex, individuals vary in the number copies of SMN2. As a result, disease due to loss of both copies of SMN1 causes very severe SMA in individuals who carry only one copy of SMN2, while those with multiple copies of SMN2 have milder disease. Thus, the amount of SMN2 protein determines the severity and time of onset of disease.
Although affected siblings demonstrate very similar clinical patterns of disease, the same mutation may give rise to very different phenotypes in different families, so that additional modifying posttranscriptional or nongenetic attributes must be playing a role. Less often, autosomal dominant and X-linked patterns of inheritance have been found, resulting from mutations in UBA1, usually in adults. A rare autosomal dominant adult form is the result of mutations in VABP and a form that affects only the legs is associated with mutations in DYNC1H1.