Nonmotor and Extracerebellar Features in Machado-Joseph Disease: A Review Jos e Luiz Pedroso, MD, PhD, 1† * Marcondes C. Franc ¸a, Jr., MD, PhD, 2† Pedro Braga-Neto, MD, PhD, 1 Anelyssa D’Abreu, MD, PhD, 2 Maria Luiza Saraiva-Pereira, PhD, 3,4 Jonas A. Saute, MD, PhD, 4,5 H elio A. Teive, MD, PhD, 6 Paulo Caramelli, MD, PhD, 7 Laura Bannach Jardim, MD, PhD, 3,4,5,8 Iscia Lopes-Cendes, MD, PhD, 9 Orlando Graziani P. Barsottini, MD, PhD 1 1 Department of Neurology, General Neurology and Ataxia Unit, Universidade Federal de S~ ao Paulo, S~ ao Paulo, Brazil 2 Department of Neurology, University of Campinas (Unicamp), Campinas, S~ ao Paulo, Brazil 3 Department of Biochemistry Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil 4 Medical Genetics Service, Hospital de Cl  ınicas de Porto Alegre, Porto Alegre, Brazil 5 Postgraduate Program in Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil 6 Movement Disorders Unit, Neurology Service, Internal Medicine Department, Hospital de Cl  ınicas, Universidade Federal do Paran a (UFPR), Curitiba, Paran a, Brazil 7 Cognitive and Behavioral Neurology Unit, Department of Internal Medicine, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil 8 Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil 9 Department of Medical Genetics, School of Medical Sciences, University of Campinas (UNICAMP), Campinas S~ ao Paulo, Brazil ABSTRACT: Spinocerebellar ataxia type 3 or Machado-Joseph disease is the most common spinocerebellar ataxia worldwide, and the high fre- quency of nonmotor manifestations in Machado-Jo- seph disease demonstrates how variable is the clinical expression of this single genetic entity. Ana- tomical, physiological, clinical, and functional neuroi- maging data reinforce the idea of a degenerative process involving extracerebellar regions of the nerv- ous system in Machado-Joseph disease. Brain imag- ing and neuropathologic studies have revealed atrophy of the pons, basal ganglia, midbrain, me- dulla oblongata, multiple cranial nerve nuclei, and thalamus and of the frontal, parietal, temporal, occi- pital, and limbic lobes. This review provides relevant information about nonmotor manifestations and extracerebellar symptoms in Machado-Joseph dis- ease. The main nonmotor manifestations of Machado-Joseph disease described in previous data and discussed in this article are: sleep disorders, cognitive and affective disturbances, psychiatric symptoms, olfactory dysfunction, peripheral neuropa- thy, pain, cramps, fatigue, nutritional problems, and dysautonomia. In addition, we conducted a brief dis- cussion of noncerebellar motor manifestations, high- lighting movement disorders. V C 2013 Movement Disorder Society Key Words: spinocerebellar ataxia type 3; Machado-Joseph disease; nonmotor symptoms; extrac- erebellar signs Spinocerebellar ataxias (SCAs) are defined as a group of autosomal dominant ataxic disorders caused by degeneration of the cerebellum and its afferent and efferent connections. SCAs have a wide range of neurological symptoms, including axial and appendicular ataxia, dysarthria, oculomo- tor disturbances, extra-pyramidal signs, and several nonmotor clinical manifestations, such as retinopa- thy, optic atrophy, peripheral neuropathy (PN), sphincter disturbances, cognitive impairment, and epilepsy. 1,2 SCA type 3 (SCA3), also known as Machado-Joseph disease (MJD), was first described in 1972 in Azorean ancestry families. 3 In the ensuing years, apparently the same disease was repeatedly described in other coun- tries among non-Azorean ancestry patients. In the late 1980s, the eponym “Machado-Joseph Disease” (MJD) ------------------------------------------------------------ *Corresponence to: Dr. Jos e Luiz Pedroso, Department of Neurology, Ataxia Unit, Universidade Federal de S~ ao Paulo, S~ ao Paulo, Brazil; jlpedroso.neuro@gmail.com Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online ver- sion of this article. † These authors contributed equally to this work. Received: 15 January 2013; Revised: 27 March 2013; Accepted: 16 April 2013 Published online 17 June 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25513 REVIEW 1200 Movement Disorders, Vol. 28, No. 9, 2013