ARTICLE IN PRESS Parkinsonism and Related Disorders xxx (2008) 1–5

Contents lists available at ScienceDirect

Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis

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 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 ´ de de Porto Alegre, and Hospital Santa Casa de Miserico ´ rdia, Brazil Morphological Sciences Department, Universidade Federal de Cieˆncias da Sau b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 22 July 2008 Received in revised form 17 September 2008 Accepted 18 September 2008

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.

Keywords: Parkinson’s disease Dominant inheritance SCA2 SCA3 Spinocerebellar ataxia

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

* 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: [email protected] (L.B. Jardim).

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, levodoparesponsive 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 parkinsonism has been associated with small CAG repeat expansions ranging from 33 to 43, interrupted by codons CAA [4,11–13]. These

1353-8020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2008.09.005

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

ARTICLE IN PRESS 2

M.P. Socal et al. / Parkinsonism and Related Disorders xxx (2008) 1–5

findings raised the hypothesis that the structure of the expanded repeat is also an important factor accounting for phenotypic differences [13]. Several studies have analyzed the frequency of SCA gene mutations among PD patients, detecting positive SCA expansions in 0.35–1.47% [12,14] of the cases. These low rates may have discouraged clinicians to look for etiologies. These frequencies can be partly explained by the inclusion of large unselected series of patients in most of studies. When testing only patients with familial autosomal dominant PD, the positive diagnostic rate increases by up to 10% [15]. The aim of the present study was to screen SCA expansions among selected high-risk PD patients in order to increase the rate of diagnostic success, thus helping to identify positive families and offer genetic counseling for Mendelian forms of parkinsonism.

Table 1 Clinical characteristics of the present sample Families (total patients)

23 (27)

Male/female Age (years)* Age of onset (years)* Disease duration (years)* Time on L-dopa (months)* Daily L-dopa dose (in mg)* MMSE* HY* UPDRS* Mean ADL*

16/11 51.55  15.4 45.62  12 7.92  6.3 65.21  80.9 572.50  409.690 27.64  3.828 2.73  1 29.61  17.624 65.50  24.597

*Mean  SD.

family and one SCA3 brother also affected with PD were included in the total sample of PD patients, which totaled 27 PD patients.

2. Patients and methods Parkinsonian patients were recruited in the movement disorders outpatient clinics of the study hospitals. PD was diagnosed according to the clinical criteria proposed by Gelb [16] – in other words, if they presented an adequate combination of the following signs: resting tremor, rigidity, bradykinesia, asymmetric onset, and a positive levodopa response. Patients were included if they showed at least one of the following: an autosomal dominant family history, or atypical clinical findings besides their parkinsonian signs (pyramidal signs, early or disproportionally severe dysarthria and/or dysphagia, ataxic gait, early or disproportionally severe stance impairment, eyelid retraction, limb ataxia, sensory loss, amyotrophy, nystagmus, and impaired ocular movement). Full neurological examination was conducted by a single neurologist (MS); it included the Hoehn and Yahr modified scale (HY), the motor part of the unified Parkinson’s disease rating scale (UPDRS), the mini-mental state examination (MMSE), and the Schwab and England activities of daily living scale (ADL). The study was approved by the local ethics committees, and all patients signed an informed consent form. Peripheral blood was collected, and genomic DNA was isolated from peripheral blood leukocytes using the salting-out technique as previously described [17]. The fluorescence-based assay (Quant-iT – Invitrogen) was used to quantify DNA samples. ATXN1, ATXN2, ATXN3, CACNA1A, and ATXN7 screenings were performed by PCR amplification using fluorescent primers [11,18–20]. Following multiplex PCR amplification, an aliquot of PCR products were mixed with formamide (HiDye formamide, Applied Biosystems) and GeneScanÔ 500 LIZ (Applied Biosystems), and electrophoresis was performed in an ABI 3130xl Genetic Analyzer (Applied Biosystems). Amplicon lengths were calculated using GeneScanÔ 500 LIZ; molecular weight, using GeneMapper 3.2 software (Applied Biosystems). The repeat lengths examined by PCR amplification and fragment analysis were also sequenced. Means between groups were analyzed using Student’s t-test or Mann– Whitney’s U-test according to the distribution of variables and data acquisition. Chi-square with Fisher’s exact test was used to analyze categorical variables. All tests were two-tailed; p values less than 0.05 were considered statistically significant. Statistical analyses were performed using SPSS 14.0 for Windows.

3. Results Twenty-seven patients from 23 families were included (16 men), all Brazilians with the same geographical origin: Rio Grande do Sul, the Southernmost state of Brazil. Mixed ancestries were the majority, including Portuguese, Amerindian, African, German and Italian. Since color, as determined by physical evaluation, is a poor predictor of ancestries, in Brazil [21], we did not analysed these data. Patient’s main clinical characteristics are listed in Table 1. Of the 23 index cases, 13 (56%) had an autosomal dominant family history of PD, and 16 (69%) had atypical clinical manifestations (six patients had both). The subgroups with and without atypical manifestations showed similar ages, ages of onset, disease duration, time on L-dopa, MMSE, UDPRS and ADL scores, except mean HY score, which was lower in the seven cases without atypical manifestations (1.75  0.5 versus 2.96  1, p ¼ 0.011). Three cases were diagnosed as positive for an SCA gene expansion. Two index cases carried an ATXN3 mutant allele, and one, an ATXN2 expansion. In order to improve the clinical description, other three affected siblings belonging to an SCA2

3.1. The SCA2 pedigree The kindred of four affected sibs was detected through index case III.2 (Fig. 1). Molecular data will be described in detail elsewhere. Clinical and molecular findings are summarized in Table 2. All of them had a PD phenotype as their initial finding. The two sibs with the longest disease duration, i.e., 16 and 10 years, also had minor ataxic symptoms. All the expanded sequences were interrupted with one CAA repeat; all the normal alleles were unexpectedly large with 33 repeats and showed two CAA interruptions. Although SCA2 patients tended to be sick for a longer time when compared to the others (9.75 versus 7.59 years, ns), they used significantly lower doses of L-dopa than the remaining group (312 versus 624 mg, p ¼ 0.033). Other characteristics such as the presence of atypical manifestations, L-dopa-induced motor fluctuations and dyskinesia were similar to those found in the general sample. 3.2. The SCA3 pedigrees Two SCA3 pedigrees were detected. The first family (SCA3 ‘‘C’’ family) was detected through patient III.3 (Fig. 2a). This patient started with parkinsonian manifestations at the age of 39. After 10 years, his PD was well controlled by L-dopa treatment, but ataxia appeared and increased progressively. Patient III.4 showed a purely parkinsonian phenotype as of the age of 38, and after 5 years of the disease onset this was his only manifestation of the disease. The second family (SCA3 ‘‘O’’ family) was discovered through case IV.1 (Fig. 2b). At the age 35, this patient began with tremor. He showed limb rigidity and bradykinesia, and there was a significant improvement after the onset of levodopa treatment. His family history was positive for an autosomal dominant ataxia trait: His mother (III.1), grandmother (II.1), and great-grandfather (I.1)

I.

II.

III. 34/33

34/33

34/33

44/33

Fig. 1. The SCA2 pedigree.

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

ARTICLE IN PRESS M.P. Socal et al. / Parkinsonism and Related Disorders xxx (2008) 1–5

3

Table 2 Clinical and molecular characteristics of the SCA2 patients

Sex ATXN2 CAGn Age of onset (years) Disease duration (years) Parkinsonian phenotype Parkinsonian characteristics

First symptom Asymmetric onset Tremor Rigidity Bradykinesia Use of antiparkinsonian medication Levodopa response Dyskinesias Motor fluctuations

Gait ataxia Limb ataxia Pyramidal signs Nystagmus Dysarthria Dysphagia Sensory loss MMSE HY UPDRS (motor part) ADL on (%)

presented with ataxia. Table 3 summarizes the clinical and molecular findings of both pedigrees. SCA3 patients had earlier ages of onset of parkinsonian symptoms (37.3  2 versus 46.7  12 years; p ¼ 0.003). All SCA3 patients had more sleep benefit in their parkinsonian manifestations (p ¼ 0.047, Fisher’s exact test), more disturbances of ocular motility and more ataxic manifestations (p ¼ 0.003 and 0.049, respectively; Fisher’s exact test), than the remaining 24 individuals.

4. Discussion The importance of SCA gene mutations among PD patients has been repeatedly shown in populations with diverse ethnic backgrounds. In contrast to previous studies, the rate of positive diagnoses in the present sample was high (13%), showing that the strategy of selecting a high-risk group for SCAs among PD patients increases the rate of diagnostic success. Our results were only similar to those found by Lu et al. (2004); among patients with autosomal dominant PD, the ATXN2 mutation was present in four of 40 families, or 10% [15]. Our diagnoses comprised two SCA3 and one SCA2 cases, the two most common SCAs worldwide. In the present population, the prevalence of SCA3 and the remaining SCAs are respectively

I. I. II.

II.

III. III.

69/30 70/21

IV.

71/21 70/23

“C” family

“O” family Fig. 2. The SCA3 pedigrees.

III.1

III.2

III.4

III.7

Male 34/33 41 16 þþþ Tremor þ þ þ þ þ þ   þ þ þ þ þ þ  30 2,5 34 90

Female 34/33 46 7 þþþ Rigidity   þþ þ þ þþ    þ þ     30 3 16 100

Female 34/33 35 10 þþþ Rigidity  þþ þ þ þ þþ þþþ þ þ þ þ     30 3 2 90

Male 44/33 40 1 þþþ Postural imbalance  þ þ  þ þ   þ  þ  Stammering   25 2,5 9 100

3/100,000 and 0.2/100,000 [22,23]. SCA3 and SCA2 account for 84% and 4.4% of our molecularly confirmed cases of ataxia [24]. Moreover, SCA3 and SCA2 compose the most frequent SCAs associated to the PD phenotype. Thus, the finding of ATXN2 and ATXN3 mutations among our series of patients is in accordance with expectation. The usual SCA2 phenotype is characterized by slowly progressive ataxia and dysarthria associated with the ocular findings of nystagmus, slow saccadic eye movements, and in some individuals, ophthalmoparesis. Brisk tendon reflexes in the first years of life, and a high incidence of dystonia or chorea and dementia are other findings. In contrast, patients with the parkinsonian phenotype usually have no additional, neurological manifestations. These carriers of ATXN2 expansion have been reported either in familial and in sporadic forms of parkinsonism [3,25], and presented borderline expansions of 32–43 repeats, interrupted by CAA triplets like normal alleles [3,4,26–28]. The present molecular results were also in favor of the association between the parkinsonian phenotype and the presence of CAA interruptions inside the ATXN2 CAG expanded repeats. In contrast, the relation between SCA2-PD and expanded repeats in the lower range of expansion was doubtful, since one of our SCA2 patients had a larger allele than other SCA2PD patients (44 versus 34 repeats) with no obvious shifts in the phenotype, except for mild cognitive loss (mini-mental state examination ¼ 25; the patient had 16 school years). This finding also raises an important question about the effect of CAA interruption in the stabilization of the CAG tract. Intrafamilial, phenotypic homogeneity was observed in this SCA2 kindred, confirming what has already been described in several previous reports [3,5,12–14]. On the contrary, the two SCA3 families showed intrafamilial heterogeneity of phenotypes that did not seem to be related to the CAG length (Table 3). In previous literature, intrafamilial phenotypes were described either as homogeneous [29,30] or as heterogeneous [31]. It is already known that the SCA3 phenotype varies according to disease duration [32]. For instance, in the present SCA3 ‘‘C’’ family, the affected individual with longer disease duration added a typical SCA phenotype to his initial parkinsonian symptoms. In contrast, his brother had a pure PD phenotype, that could be attributable to a shorter disease duration. In the SCA3 ‘‘O’’ family, the heterogeneity was even more striking, since the pure PD

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

ARTICLE IN PRESS 4

M.P. Socal et al. / Parkinsonism and Related Disorders xxx (2008) 1–5

Table 3 Clinical and molecular description of the SCA 3 patients SCA 3 ‘‘C’’ pedigree

Sex Age of onset (years) ATXN3 CAGn Disease duration (years) Main phenotype First symptom Asymmetric onset Parkinsonian signs Tremor Rigidity Postural instability Response to levodopa Dyskinesias Motor fluctuations Gait ataxia Limb ataxia Pyramidal signs Ataxic eye movements Eyelid retraction Dysarthria Dysphagia Sensory loss MMSE HY UPDRS (motor part) ADL on (%)

SCA3 ‘‘O’’ pedigree

Case III.3

Case III.4

Case IV.1

Case III.1

Male 39 70/21 10 Parkinson plus ataxia Dysesthesia in lower extremities  þ þ þþ þþ   þþ þ þ þþ  þ  þ 30 4 56 60

Male 38 71/27 5 Parkinson Pain in lower extremities; tremor  þ þ þþ þþ      þ  þ þ þ 30 3 20 100

Male 35 70/23 5 Parkinson plus ataxia Postural instability  þ þ þþ þþ þ þ þ þ þ þ  þ/2   30 2 28 90

Female 50 69/30 12 Ataxia Postural instability    þ Not applicable Not applicable Not applicable þ þ þ þ        

index case was born from a pure SCA mother. So, the observation of two different phenotypes, that is, the Parkinson syndrome or the SCA syndrome, into the same kindred could be a matter of chance. Our results suggest that in SCA2, PD phenotype was probably determined by intragenic familial characteristics (CAA interruptions perhaps?). On the other hand, PD phenotype of SCA3 may be either related disease duration or to extragenic, unknown modifying factors, because in the same families strict parkinsonian and strict ataxic phenotypes do coexist with little variation in the CAG length of the affected individuals. In conclusion, a screening for SCA expansions in a high-risk sample of PD seems to be a good approach to identify positive cases. An autosomal dominant family history or the presence of atypical manifestations were suggested as clues to increase the diagnostic suspicion of SCA mutations. Acknowledgements We are grateful to the patients and their relatives who agreed to participate in this project. This study was supported by CNPq, FAPERGS, and FIPE-HCPA. V. Emmel and Profs. L.B. Jardim and M.L. Saraiva-Pereira were supported by CNPq. References [1] Rosenberg RN. Dominant ataxias. In: Kety SS, Rowland LP, Sidman RL, Matthysse SW, editors. Genetics of neurological and psychiatric disorders. New York: Raven Press; 1983. p. 195–213. [2] Tuite PJ, Rogaeva EA, St George-Hyslop PH, Lang AE. Dopa-responsive parkinsonism phenotype of Machado–Joseph disease: confirmation of 14q CAG expansion. Ann Neurol 1995;38(4):684–7. [3] Gwinn-Hardy K, Chen JY, Liu HC, Liu TY, Boss M, Seltzer W, et al. Spinocerebellar ataxia type 2 with parkinsonism in ethnic Chinese. Neurology 2000 Sep 26;55(6):800–5. [4] Furtado S, Farrer M, Tsuboi Y, Klimek ML, de la Fuente-Ferna´ndez R, Hussey J, et al. SCA-2 presenting as parkinsonism in an Alberta family. Clinical, genetic, and PET findings. Neurology 2002;59:1625–7. [5] Modoni A, Contarino MF, Bentivoglio AR, Tabollaci E, Santoro M, Calcagni ML, et al. Prevalence of spinocerebellar ataxia type 2 mutation among Italian Parkinsonian patients. Mov Disord 2007;22(3):324–7.

[6] Lee WY, Jin DK, Oh MR, Lee JE, Song SM, Lee EA, et al. Frequency analysis and clinical characterization of spinocerebellar ataxia types 1, 2, 3, 6, and 7 in Korean patients. Arch Neurol 2003;60(6):858–63. [7] Scho¨ls L, Kruger R, Amoiridis G, Przuntek H, Epplen JT, Riess O. Spinocerebellar ataxia type 6: genotype and phenotype in German kindreds. J Neurol Neurosurg Psychiatry 1998;64(1):67–73. [8] Wu YR, Lin HY, Chen CM, Gwinn-Hardy K, Ro LS, Wang YC, et al. Genetic testing in spinocerebellar ataxia in Taiwan: expansions of trinucleotide repeats in SCA8 and SCA17 are associated with typical Parkinson’s disease. Clin Genet 2004;65(3):209–14. [9] Kish SJ, Guttman M, Robitaille Y, El-Awar M, Chang LJ, Levey AI. Striatal dopamine nerve terminal markers but not nigral cellularity are reduced in spinocerebellar ataxia type 1. Neurology 1997;48(4):1109–11. [10] Scho¨ls L, Bauer P, Schmidt T, Schulte T, Riess O. Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. Lancet Neurol 2004;3(5):291–304. [11] Pulst SM, Nechiporuk A, Nechiporuk T, Gispert S, Chen XN, Lopes-Cendes I, et al. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet 1996;14:269–76. [12] Payami H, Nutt J, Gancher S, Bird T, McNeal MG, Seltzer WK, et al. SCA2 may present as levodopa-responsive parkinsonism. Mov Disord 2003;18(4): 425–9. [13] Charles P, Camuzat A, Benammar N, Sellal F, Deste´e A, Bonnet AM, et al. Are interrupted SCA2 CAG repeat expansions responsible for parkinsonism? Neurology 2007 Nov 20;69(21):1970–5. [14] Simon-Sanchez J, Hanson M, Singleton A, Hernandez D, McInerney A, Nussbaum R, et al. Analysis of SCA-2 and SCA-3 repeats in Parkinsonism: evidence of SCA-2 expansion in a family with autosomal dominant Parkinson’s disease. Neurosci Lett 2005;382(1-2):191–4. [15] Lu CS, Wu Chou YH, Kuo PC, Chang HC, Weng YH. The parkinsonian phenotype of spinocerebellar ataxia type 2. Arch Neurol 2004;61(1):35–8. [16] Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson disease. Arch Neurol 1999;56(1):33–9. [17] Miller SA, Dykes DD, Polesky HF. A simple salting-out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988;16:1215. [18] Del-Favero J, Krols L, Michalik A, Theuns J, Lo¨fgren A, Goossens D, et al. Molecular genetic analysis of autosomal dominant cerebellar ataxia with retinal degeneration (ADCA Type II) caused by CAG triplet repeat expansion. Hum Mol Genet 1998;7:177–86. [19] Kawaguchi Y, Okamoto T, Taniwaki M, Aizawa M, Inoue M, Katayama S, et al. CAG expansions in a novel gene for Machado–Joseph disease at chromosome 14q32.1. Nat Genet 1994;8:221–7. [20] Orr H, Chung MY, Banfi S, Kwiatkowski Jr TJ, Servadio A, Beaudet AL, et al. Expansion of an unstable trinucleotide (CAG) repeat in spinocerebellar ataxia type 1. Nat Genet 1993;4:221–6. [21] Parra FC, Amado RC, Lambertucci JR, Rocha J, Antunes CM, Pena SD. Color and genomic ancestry in Brazilians. Proc Natl Acad Sci U S A 2003 Jan 7;100(1):177–82. Epub 2002 Dec 30.

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

ARTICLE IN PRESS M.P. Socal et al. / Parkinsonism and Related Disorders xxx (2008) 1–5 [22] Jardim LB, Silveira I, Pereira ML, Ferro A, Alonso I, Moreira MC, et al. A survey on spinocerebellar ataxia in South Brazil– 66 new patients with Machado– Joseph disease, SCA7, SCA8, or unidentified disease causing mutations. J Neurol 2001;248:870–6. [23] Prestes PR, Saraiva-Pereira ML, Silveira I, Sequeiros J, Jardim LB. Machado– Joseph disease enhances genetic fitness: a comparison between affected and unaffected women and between MJD and the general population. Ann Hum Genet. 2008 Jan;72(Pt 1):57–64. Epub 2007 Aug 7. [24] Trott A, Jardim LB, Ludwig HT, Saute JAM, Artigala´s O, Kieling C, et al. Spinocerebellar ataxias in 114 Brazilian families: clinical and molecular findings. Clin Genet 2006;70(2):173–6. [25] Shan DE, Liu RS, Sun CM, Lee SJ, Liao KK, Soong BW. Presence of spinocerebellar ataxia type 2 gene mutation in a patient with apparently sporadic Parkinson’s disease: clinical implications. Mov Disord 2004 Nov;19(11): 1357–60. [26] Costanzi-Porrini S, Tessarolo D, Abbruzzese C, Liguori M, Ashizawa T, Giacanelli M. An interrupted 34-CAG repeat SCA-2 allele in patients with sporadic spinocerebellar ataxia. Neurology 2000 Jan 25;54(2):491–3.

5

[27] Shan DE, Soong BW, Sun CM, Lee SJ, Liao KK, Liu RS. Spinocerebellar ataxia type 2 presenting as familial levodopa-responsive parkinsonism. Ann Neurol 2001 Dec;50(6):812–5. [28] Lu CS, Wu Chou YH, Yen TC, Tsai CH, Chen RS, Chang HC. Dopa-responsive parkinsonism phenotype of spinocerebellar ataxia type 2. Mov Disord 2002 Sep;17(5):1046–51. [29] Giunti P, Sweeney MG, Harding AE. Detection of the Machado–Joseph disease/ spinocerebellar ataxia three trinucleotide repeat expansion in families with autosomal dominant motor disorders, including the Drew family of Walworth. Brain 1995 Oct;118(Pt 5):1077–85. [30] Gwinn-Hardy K, Singleton A, O’Suilleabhain P, Boss M, Nicholl D, Adam A, et al. Spinocerebellar ataxia type 3 phenotypically resembling Parkinson disease in a black family. Arch Neurol 2001 Feb;58(2):296–9. [31] Yoritaka A, Nakagawa-Hattori Y, Hattori N, Kitahara A, Mizuno Y. A large Japanese family with Machado–Joseph disease: clinical and genetic analysis. Acta Neurol Scand 1999 Apr;99(4):241–4. [32] Jardim LB, Pereira ML, Silveira I, Ferro A, Sequeiros J, Giugliani R. Neurologic findings in Machado–Joseph disease. Arch Neurol 2001;58:899–904.

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