Intrafamilial variability of Parkinson phenotype in SCAs: Novel cases due to SCA2 and SCA3 expansions M.P. Socal a , V.E. Emmel b , C.R.M. Rieder a, e , A. Hilbig i , M.L. Saraiva-Pereira a, b, c, f, g , L.B. Jardim a, b, d, f, h, * a Medical Sciences, Postgraduate Program, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil b Genetics and Molecular Biology Department, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil c Biochemistry Department, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil d Internal Medicine Department, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil e Neurology Service, Hospital de Clı ´nicas de Porto Alegre, Porto Alegre, Brazil f Medical Genetics Service, Hospital de Clı ´nicas de Porto Alegre, Porto Alegre, Brazil g Human Identification Laboratory, Hospital de Clı ´nicas de Porto Alegre, Porto Alegre, Brazil h Genomic Medicine Laboratory, Hospital de Clı ´nicas de Porto Alegre, Porto Alegre, Brazil i Morphological Sciences Department, Universidade Federal de Cieˆncias da Sau ´de de Porto Alegre, and Hospital Santa Casa de Miserico ´rdia, Brazil article info Article history: Received 22 July 2008 Received in revised form 17 September 2008 Accepted 18 September 2008 Keywords: Parkinson’s disease Dominant inheritance SCA2 SCA3 Spinocerebellar ataxia abstract Background: Parkinson’s disease (PD) has been related to mutations associated with spinocerebellar ataxias (SCA); the frequency of the diagnosis of these mutations is low in general late-onset PD cases. Our aim was to investigate a selected high-risk group of PD patients. Methods: PD patients with autosomal dominant inheritance or atypical neurological manifestations were enrolled, underwent a full neurological examination and had the CAG tracts of their SCA1, 2, 3, 6 and 7 genes analyzed. Results: Of the 23 studied families, two SCA3 and one SCA2 cases were identified. All had autosomal dominant inheritance. In the SCA2 pedigree, four affected sibs had a homogeneous PD phenotype. CAG repeats varied between 35 and 44 with CAA interruptions. Intrafamilial phenotypic heterogeneity was identified in the SCA3 pedigrees; parkinsonian and ataxic phenotypes coexisted in both kindreds. CAGn varied between 69 and 71 repeats. Age of onset was lower in the SCA3 patients than in the remaining 24 cases (38 versus 46.7  12 years of age, p ¼ 0.003). Conclusions: SCA2 and SCA3 mutations were detected in 13% of the present sample: the strategy of selecting a high-risk group increased the rate of making these diagnoses. The SCA2 cases confirmed an association between PD and interrupted expansions, as well as PD intrafamilial phenotypic homogeneity. Clinical heterogeneity of SCA3 pedigrees suggests that disease-modifying agents outside the MJD1 gene may play a role in determining PD symptoms in this disorder. Ó 2008 Elsevier Ltd. All rights reserved. 1. Introduction Among Mendelian mutations that have been causally related to Parkinson’s disease (PD), spinocerebellar ataxia (SCA) expansions are one of the most intriguing groups of diseases. Cerebellar ataxia is usually the predominant sign, in SCAs. However, the phenotype almost always includes a variable association of pyramidal and extrapyramidal signs, peripheral neuropathy, cognitive signs, and ophthalmologic features. These diseases are often caused by the expansion of (CAG)n repeats encoding polyglutamine (polyQ) tracts above a certain threshold, as in SCA1, 2, 3, 6, 7, and 17. In 1983, Rosenberg described a pure PD phenotype in a Machado–Joseph disease family (also known as SCA3) [1]. In 1995, SCA3 was molecularly confirmed in a patient with an atypical, levodopa- responsive PD phenotype, and since then this association has been eventually described in the literature [2]. Later, CAG expansions related to SCAs, such as SCA2 [3–5], SCA6 [6,7], SCA8, and SCA 17 [8], have been linked to levodopa-responsive PD. This was not exactly a surprise, since for these group of disorders there was pathological evidence of involvement of both basal ganglia and the substantia nigra with dopamine depletion in SCA1 [9], and marked cell loss and gliosis in SCA2 and SCA3 [10]. The expanded repeats associated with the cerebellar phenotype, in SCAs in general, are mostly pure. In contrast, in SCA2 parkin- sonism has been associated with small CAG repeat expansions ranging from 33 to 43, interrupted by codons CAA [4,11–13]. These * Corresponding author. Medical Genetics Service, Hospital de Clinicas de Porto Alegre, Rua Ramiro Barcelos 2350, 90.035-903 Porto Alegre, Brazil. Tel.: þ55 51 2101 8011; fax: þ55 51 2101 8010. E-mail address: ljardim@hcpca.ufrgs.br (L.B. Jardim). Contents lists available at ScienceDirect Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis ARTICLE IN PRESS 1353-8020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2008.09.005 Parkinsonism and Related Disorders xxx (2008) 1–5 Please cite this article in press as: Socal MP et al., Intrafamilial variability of Parkinson phenotype in SCAs: Novel cases due to SCA2 and SCA3 expansions, Parkinsonism and Related Disorders (2008), doi:10.1016/j.parkreldis.2008.09.005