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Parkinsonian phenotype in Machado-Joseph disease (MJD/SCA3): a two-case report
© Bettencourt et al; licensee BioMed Central Ltd. 2011
Received: 5 May 2011
Accepted: 24 October 2011
Published: 24 October 2011
Machado-Joseph disease (MJD), or spinocerebellar ataxia type 3 (SCA3), is an autosomal dominant neurodegenerative disorder of late onset, which is caused by a CAG repeat expansion in the coding region of the ATXN3 gene. This disease presents clinical heterogeneity, which cannot be completely explained by the size of the repeat tract. MJD presents extrapyramidal motor signs, namely Parkinsonism, more frequently than the other subtypes of autosomal dominant cerebellar ataxias. Although Parkinsonism seems to segregate within MJD families, only a few MJD patients develop parkinsonian features and, therefore, the clinical and genetic aspects of these rare presentations remain poorly investigated. The main goal of this work was to describe two MJD patients displaying the parkinsonian triad (tremor, bradykinesia and rigidity), namely on what concerns genetic variation in Parkinson's disease (PD) associated loci (PARK2, LRRK2, PINK1, DJ-1, SNCA, MAPT, APOE, and mtDNA tRNA Gln T4336C).
Patient 1 is a 40 year-old female (onset at 30 years of age), initially with a pure parkinsonian phenotype (similar to the phenotype previously reported for her mother). Patient 2 is a 38 year-old male (onset at 33 years of age), presenting an ataxic phenotype with parkinsonian features (not seen either in other affected siblings or in his father). Both patients presented an expanded ATXN3 allele with 72 CAG repeats. No PD mutations were found in the analyzed loci. However, allelic variants previously associated with PD were observed in DJ-1 and APOE genes, for both patients.
The present report adds clinical and genetic information on this particular and rare MJD presentation, and raises the hypothesis that DJ-1 and APOE polymorphisms may confer susceptibility to the parkinsonian phenotype in MJD.
Autosomal dominant cerebellar ataxias (ADCA) constitute a heterogeneous group of neurodegenerative disorders, which involve, besides other systems, the extrapyramidal system in a highly variable manner. Within this group is Machado-Joseph disease (MJD; MIM #109150), also known as spinocerebellar ataxia type 3 (SCA3), that presents extrapyramidal motor signs (EPS) more frequently than the other subtypes of ADCA . Even within MJD, the EPS may vary, sometimes with marked dystonic postures, others with isolated parkinsonian features or even, though rarely, with the parkinsonian triad (resting tremor, bradykinesia and rigidity) . Although the causative mutation of MJD is known to be an expansion of a CAG repeat motif (consensually more than 52 repeats) in the coding region of the ATXN3 gene , the size of the of the repetitive tract does not completely explain the clinical heterogeneity observed in this disorder, namely concerning the presence of EPS.
There are only a few reports of a Parkinson's disease (PD)-like phenotype in molecularly confirmed MJD patients [4–6], and thus this particular MJD phenotype remains poorly documented, namely from the genetic point of view. The cases reported in the literature showed an initial phenotype indistinguishable from PD and a levodopa positive response. Only after several years of progression the characteristic features of MJD, namely cerebellar signs, were observed. The parkinsonian phenotype has been suggested to be more common in MJD patients of African descent, although rare in those of European origin .
MJD phenotypes with EPS, particularly those with a PD-like phenotype, may result from epistatic effects of variants in other loci. As primary candidates are PD associated loci, namely PARK2, LRRK2, PINK1, DJ-1, SNCA, MAPT, and APOE (e.g. [8–10]). Variation in mitochondrial DNA (mtDNA) has also been shown to have an impact on neurodegenerative diseases' phenotype, and the tRNA Gln T4336C mutation was previously associated with Alzheimer's disease (AD) and PD . The main goal of this work was to describe two unrelated MJD patients displaying the parkinsonian triad, for which the genetic variation (mutations and/or polymorphisms) in PD associated loci was investigated.
Out of a series of 70 molecularly confirmed MJD patients from the Azores Islands (Portugal), from whom DNA samples were available (extracted from blood samples, which were collected after obtaining written informed consent), two patients presenting the parkinsonian triad, and belonging to distinct MJD families (one from São Miguel Island and other from Graciosa Island), were identified.
Characteristics of Patient 1 and Patient 2
Age at Onset
Pure PD signs
PD plus cerebellar signs?
Family history for PD features
Mother and grandfather
ATXN3 (CAG)n tract length
PARK2 Gene Mutations
LRRK2 Gene Mutations
PINK1 Gene Mutations
The ATXN3 (CAG)n tract size was determined as previously described . All the exons and exon-introns boundaries of PARK2, LRRK2, PINK1 and DJ-1 genes were amplified by PCR. The resulting PCR products were purified by Exo-SAP treatment (GE Healthcare) and sequenced using the BigDye® Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems). Multiplex Ligation-Dependent Probe Amplification (MLPA) was used, according to Djarmati et al. , to search for large deletions or duplications in PARK2, PINK1 and DJ-1. The SNCA REP1 allele-length variants were genotyped as previously described . In MAPT locus, a SNP (rs242557) was genotyped by a custom Taqman assay according to the manufacturer's specifications, and its genotype was used to infer MAPT haplotypes. The APOE genotypes were determined according to Bettencourt et al. . The mtDNA haplogroup was established as previously described by Santos et al. , and the region encompassing the T4336C mutation was amplified by PCR, according to Ramos et al. . PCR products were purified using the JETQUICK PCR Purification Spin Kit (Genomed) and sequenced, using the BigDye® Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems), according to the manufacturer's specifications.
Both patients presented 72 CAG repeats in their expanded ATXN3 allele (Table 1), which corresponds to the mode for the expanded alleles in the Azorean MJD series . In PARK2, LRRK2, PINK1, DJ-1 and mtDNA tRNA Gln , no known pathogenic mutations were detected in the analyzed regions (Table 1). Several polymorphisms were found at the DJ-1 gene (Table 1). Results for the SNCA REP1, MAPT and APOE loci, as well as for the mtDNA haplogroup, are shown in Table 1.
Although MJD presents EPS more frequently than the other ADCAs, the manifestation of the parkinsonian triad is rare, being present in less than 3% of the analyzed MJD series. Even though the two studied cases are distinct, the grandfather-mother-daughter transmission in the family of Patient 1, and the heterogeneity presented by the family of Patient 2, suggests a supporting genetic background, e.g. modifier gene(s).
Mutations in the PARK2 gene have been described as the most frequent in the cases of early onset PD . However, none of the studied patients presented mutations in this gene. Similarly, no mutations were identified in LRRK2, PINK1 and DJ-1 genes, or in position 4336 of mtDNA.
Given the fact that both patients belong to a typically European mtDNA haplogroup , the hypothesis of an African background, in which the parkinsonian phenotype seems more common , was not supported, at least in terms of maternal origin.
Association studies have shown that certain alleles of the SNCA REP1 locus, as well as the presence of two copies of MAPT H1, increase the risk of PD (e.g. [9, 10]). In the patients analyzed, however, the homozygousity for the 261 allele (the commonest among Caucasians ), and the presence of at least one MAPT H2 was confirmed.
Although previous studies [19, 20] failed to find an association between DJ-1 g.168_185del polymorphism and PD, De Marco et al. , using a larger series of PD patients, have reported that several DJ-1 polymorphisms, including those observed in the present study and reported in Table 1, are significantly associated with PD.
In non-Parkinsonian patients (N = 55) from the Azorean MJD series (data not shown), the DJ-1 g.168_185del was found in 23% of the alleles, not differing from the frequency of this deletion in other non-Parkinsonian Caucasian populations studied previously (e.g. [19–21]). The APOE ε2 allele was present in only 4% of the alleles, which corresponds to a lower frequency than the one previously reported for this allele in the general Azorean population . Besides the two Parkinsonian MJD patients studied here, only 2 additional Azorean patients (non-Parkinsonian) carry both the DJ-1 g.168_185del and the APOE ε2 allele.
The present report, in these two MJD patients, adds information on this rare phenotype, by allowing a deeper knowledge of the clinical and genetic variation present in such particular cases. Analysis of both pedigrees supports a genetic background influence. Although we cannot conclude on the presence of associations by studying only two Parkinsonian patients, the present results are in agreement with previous studies on Parkinson's disease. The implication of these findings, on what concerns a possible epistatic effect of the DJ-1 g.168_185del and the APOE ε2 allele on the MJD phenotype deserves to be tested, using an appropriate study design, namely on what concerns adequate sized parkinsonian MJD series (presently unavailable, to our knowledge).
Written consent was obtained from both patients for the publication of this case report. A copy of written consent is available for review by the Editor-in-Chief of this journal.
This work was supported by "PRI-DMJ" (funded by Regional Government of the Azores), and "Transcriptional variation of the ATXN3 gene as modulator of the clinical heterogeneity in Machado-Joseph disease (MJD)" (PIC/IC/83074/2007, funded by "Fundação para a Ciência e a Tecnologia" - FCT). C.B. [SFRH/BPD/63121/2009] and T.C. [SFRH/BPD/38659/2007] are postdoctoral fellows from FCT.
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