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Multiple System Atrophy in a Patient with the Spinocerebellar Ataxia 3 Gene Mutation Melissa J. Nirenberg, MD, PhD, 1 * Jenny Libien, MD, PhD, 2 Jean-Paul Vonsattel, MD, 2 and Stanley Fahn, MD 3 1 Division of Movement Disorders, Department of Neurology, Weill Cornell Medical College, New York, New York, USA; 2 Department of Pathology, Columbia University Medical Center, New York, New York, USA; 3 Division of Movement Disorders, Department of Neurology, Columbia University Medical Center, New York, New York, USA Abstract: The cerebellar variant of multiple system atrophy (MSA-C) has overlapping clinical features with the hered- itary spinocerebellar ataxias (SCAs), but can usually be distinguished on a clinical basis. We describe a patient who developed a sporadic, late-onset, rapidly progressive neu- rodegenerative disorder consistent with MSA-C. Genetic testing, however, showed an abnormal expansion of one allele of the spinocerebellar ataxia 3 (SCA3) gene. The clinical impression of MSA-C was confirmed by identifica- tion of numerous -synuclein– containing glial cytoplasmic inclusions on autopsy. These findings suggest that abnormal expansion of the SCA3 gene may be a risk factor for the development of MSA-C. © 2006 Movement Disorder Society Key words: multiple system atrophy; spinocerebellar ataxia; glial cytoplasmic inclusion; Machado-Joseph; olivopontocer- ebellar atrophy Multiple system atrophy (MSA) is a sporadic, clini- cally heterogeneous, rapidly progressive neurodegenera- tive disorder that may include various combinations of cerebellar, extrapyramidal, autonomic, or pyramidal mo- tor symptoms. 1,2 There are two subtypes of MSA, de- fined by their most prominent motor features: cerebellar dysfunction (MSA-C, olivopontocerebellar degenera- tion) or Parkinsonism (MSA-P, striatonigral degenera- tion). Patients with MSA frequently have other promi- nent neurological findings, such as vocal cord paralysis or rapid eye movement (REM) sleep behavior disorder. 1 Although MSA is clinically heterogeneous, it is re- garded as a single disease because of its well-defined pathological features, the hallmark of which is the glial cytoplasmic inclusion (GCI), an -synuclein-, ubiquitin-, and tau-containing inclusion localized most prominently within oligodendrocytes. 1,3 The GCIs that occur in MSA are densely distributed in the pontocerebellar system, basal ganglia, supplementary and primary motor cortex, and reticular formation. Atypical GCIs have occasionally been observed in other neurodegenerative disorders, in- cluding 1 case of autosomal dominant spinocerebellar ataxia 1 (SCA1) and 1 of SCA2. 4–6 These atypical GCIs are few in number and may differ in composition from those seen in MSA; in the patient with SCA2, for exam- ple, the GCIs were positive for ubiquitin but negative for -synuclein. 5,6 Although it has been speculated that SCA1 or other SCA gene mutations with MSA-like features may cause MSA, one study of 80 MSA patients failed to detect SCA1 or SCA3 gene mutations. 4,7,8 The autosomal dominant SCAs are triplet repeat dis- orders that have overlapping clinical features with MSA-C, including prominent ataxia, dysmetria, and eye movement abnormalities. 9 SCA3 can also present with levodopa-responsive Parkinsonism, pyramidal tract in- volvement, and mild dysautonomia. 9,10 Nonetheless, SCA3 is usually easily distinguished from MSA on a clinical basis, given its typically younger age of onset, autosomal dominant inheritance pattern, and slower rate of progression. 11 The SCAs also have unique patholog- ical features that do not occur in MSA. In SCA3, for example, there are characteristic ubiquitinated neuronal This article includes Supplementary Video, available online at http:// www.interscience.wiley.com/jpages/0885-3185/suppmat *Correspondence to: Dr. Melissa J. Nirenberg, Weill Cornell Med- ical College, 428 East 72nd Street, New York, NY 10021. E-mail: mjnirenb@med.cornell.edu Received 12 May 2006; Revised 9 August 2006; Accepted 10 August 2006 Published online 28 November 2006 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/mds.21231 MSA WITH SCA3 MUTATION 251 Movement Disorders, Vol. 22, No. 2, 2007