This entity of MSA-C has been discussed with the degenerative disorders of the basal ganglia earlier in the chapter. Here it is pointed out that a number of cases of sporadic progressive ataxia in mid and late life are attributable to this process and have been termed MSA-C to signify the predominant cerebellar feature. The extrapyramidal, corticospinal, or autonomic aspects of the illness may or may not become evident with continued observation or by pathologic examination. Some guidance as to the frequency of MSA as the cause of otherwise undifferentiated sporadic ataxia is given in the study by Abele and colleagues who found that it accounts for almost one-third of cases, but the precise number is open to question as pathologic examinations were not made.
Machado-Joseph-Azorean Disease (SCA3, ATXN3)
A special form of hereditary ataxia with brainstem and extrapyramidal signs has been described in patients mainly, but not exclusively, of Portuguese-Azorean origin. The disorder is characterized by an autosomal dominant pattern of inheritance and by a slowly progressive ataxia beginning in adolescence or early adult life in association with one or more features of dysarthria, hyperreflexia, extrapyramidal rigidity, dystonia, and as the illness evolves, bulbar signs, distal motor weakness, polyneuropathy, or ophthalmoplegia. There is usually no impairment of intellect and in the examples the authors have seen, the extrapyramidal symptoms were mainly rigidity and slowness of movement. Early Machado-Joseph disease characteristically demonstrates the finding of dysmetric horizontal and vertical saccades, even before the ataxia is obvious (Hotson et al). This conjunction of a parkinsonian syndrome with cerebellar ataxia is suggestive of MSA-C except for an earlier age of onset and the prominence in some cases of dystonia, amyotrophy, and ophthalmoplegia in Machado-Joseph. Postmortem examination discloses a degeneration of the dentate nuclei and spinocerebellar tracts and a loss of anterior horn cells and neurons of the pons, substantia nigra, and oculomotor nuclei. Cancel and colleagues found an unstable number of CAG repeating sequences in ataxin-3, and named the disorder spinocerebellar ataxia type 3 (SCA3).
An affected Azorean family named Joseph was described in 1976 by Rosenberg and colleagues under the name of autosomal dominant striatonigral degeneration. Using the term Azorean disease of the nervous system (now better known as Machado-Joseph disease), Romanul and colleagues described yet another family of Portuguese-Azorean descent, many members of which were affected by a syndrome comprising a progressive ataxia of gait, parkinsonian features, limitation of conjugate gaze, fasciculations, areflexia, nystagmus, ataxic tremor, and extensor plantar responses; the pathologic changes closely resembled those described by Woods and Schaumburg. Romanul and coworkers compared the genetic, clinical, and pathologic features of their cases with those described in other Portuguese-Azorean families and concluded that all of them represent a single genetic entity with variable expression. This concept of the disease has been corroborated by the further observations of Rosenberg and of Fowler who studied 20 patients with the Machado-Joseph-Azorean disease over a 10-year period and more recently by genetic testing.
The disease is not limited to Azoreans. Cases conforming to the above descriptions have now been observed among African American, Indian, and Japanese families (Sakai et al; Yuasa et al; Bharucha et al). There are no signs of polyneuropathy, which is the main feature of another disease in Portuguese emigrants caused by amyloid deposition, described by Nakano and colleagues as “Machado disease,” this being the name of the progenitor of the afflicted family.