The disease progresses very slowly, and some patients survive to old age without serious disability. In general, the earlier the onset, the less favorable the prognosis; however, even the most severely affected patients retain the ability to walk for at least 10 years after the onset. Admittedly, it is difficult to make a sharp distinction between these cases of Wohlfart-Kugelberg-Welander disease and certain milder instances of Werdnig-Hoffmann disease with onset in late infancy and early childhood and prolonged survival (Byers and Banker).
A form that is intermediate between the severe
Werdnig-Hoffman type and the milder Wohlfart-
Kugelberg-Welander is termed Dubowitz syndrome and designated SMA 2. It is in this disorder that the intrathecal administration of nusinersen, the antisense oligonucleotide referenced above, has been shown to be effective (Mercuri et al).
Kennedy Disease (X-Linked Bulbospinal Muscular Atrophy, AR Mutation)
An unusual pattern of distal muscular atrophy with prominent bulbar signs and, less often, ocular palsies was described by Kennedy and coworkers. The onset has varied from childhood to adult age, but symptoms typically begin in the third decade. The condition has an X-linked pattern of inheritance; female carriers may occasionally be mildly symptomatic. The proximal shoulder and hip musculature are involved first by weakness and atrophy, followed in about half of patients by dysarthria and dysphagia. Muscle cramps or twitching often precedes weakness. Facial fasciculations and mild weakness are characteristic and may be striking. The tendon reflexes become depressed and may be absent; a mild sensory neuropathy is almost universal. In the family described by Kaeser, which is representative of the disease as described by others, 12 members in 5 generations were affected, the pattern of weakness was shoulder-shank, that is scapuloperoneal; it may therefore be mistaken for muscular dystrophy. Two-thirds of patients have gynecomastia, a feature that may first identify affected men in a kindred; oligospermia and diabetes are additional associations; therefore, the presence of genuine progeny virtually excludes the disease in a male. The CK level is elevated, sometimes tenfold, and physiologic studies reveal denervation and reinnervation as well as indications of a mild sensory neuropathy.
As in Huntington disease and certain of the spinocerebellar atrophies, the genetic defect is a CAG expansion, in this case in the gene (AR) that codes for the androgen receptor on the short arm of the X-chromosome (La Spada et al; see Table 38-7). Indeed, the first reported polyglutamine disease was Kennedy syndrome. Lengthened sequences correlate with an earlier age of onset (anticipation, as in Huntington disease) but have no relation to the severity of disease. Androgen receptors have been found on motor neurons of the spinal cord; the subpopulation of motor neurons that is susceptible to both Kennedy syndrome and ALS express abundant surface androgen receptors, but it is not clear whether this finding has direct pathogenic significance. Neuronal inclusions have been described, composed of aggregations of the abnormally long polyglutamine protein sequences that correspond to the CAG expansion. The diagnosis can be confirmed by genetic testing for the lengthened trinucleotide sequence. Prenatal diagnosis and identification of female carriers are also possible by this method.
Progressive Bulbar Palsy of Childhood (Fazio-Londe Disease)