There are other genetic variants where parkinsonism is part of the clinical spectrum but where detailed clinical evaluation may preclude PD as a diagnosis. Although it would be distracting to describe all diseases where parkinsonism may be a feature, we have chosen four to discuss briefly.
Spinocerebellar ataxias (SCAs) represent a family of genetically heterogeneous, dominant, neurodegenerative disorders that are mainly characterized by progressive ataxia resulting from the degeneration of cerebellar and spinal systems. In SCA-1, -2, -3, -6, -7, and -17, causal mutations have been characterized as expanded CAG repeats, which are translated into poly glutamine tracts within the protein product. L-dopa-responsive parkinsonism with minimal cerebellar deficits has been described in several of the SCAs, particularly SCA2 and SCA3 (also known as Machado-Joseph disease) (80-85).
In 2000, a Taiwanese family was described with SCA2 expansion ranging from 33 to 43 repeats (normal 17 to 31 repeats) segregating with disease (80). Two of the four affected family members fit clinical criteria for typical PD, one of the patients matched the criteria of probable progressive supranuclear palsy, and the fourth presented with ataxia. In an additional study, screening of 19 Taiwanesse families with a family history of PD revealed two individuals with 36 and 37 repeats in SCA2 (86) both presenting with levodopa-responsive parkinsonism. PET scanning in these patients revealed decreased 18F-dopa distribution in the bilateral striatum, indicating that the nigorstriatal dopaminergic system was involved. Parkinsonism is a presentation of SCA2 expansion not only in Asian patients but also in other populations. Screening of 136 unrelated patients with familial parkinsonism (most of them Caucasian) revealed two patients with expanded SCA2 repeats (33 and 35 repeats) with good response to L-dopa (83), and an Indian family with homozygous carriers of SCA2-expansion mutations presented early-onset dopa-responsive parkinsonism (87). It is as yet unclear what drives the clinical heterogeneity of SCA2 patients; however, it is of note that most parkinsonian SCA2 patients have relatively small pathogenic expansions at the SCA2 locus and, probably in the presence or absence of other genetic variabilities or environmental exposures, this may present with a markedly different phenotype, without cerebellar signs or symptoms, compared to larger pathogenic expansions that drive a clinically more typical SCA disease.
In 2002, SCA3 expansion from 67 to 75 repeats (normal 13 to 36 repeats) was reported in a family of Sub-Saharan African descent living in Antigua, the United States, and England. These individuals presented with clinical characteristics resembling PD, including good response to levodopa, bradykinesia, resting tremor, and no cerebellar signs (82). An analysis of eight different African American families with SCA3 disease revealed that the phenotype ranged from ataxia with parkin-sonian signs to a syndrome clinically almost indistinguishable from idiopathic, levodopa responsivene PD (88). The fact that parkinsonian symptoms appear less common in European families with SCA3 expansions, where ataxia is the predominant feature and parkinsonian signs are on the edge of the phenotype spectrum, suggested that differences in genetic background may alter the clinical phenotype of Machado-Joseph disease. A common founder for SCA3 mutation among the families of African descent was ruled out, suggesting that other trans-acting genetic variation or shared environmental exposures may drive the disease preferentially toward parkinsonism rather than pure ataxia.
X-linked recessive dystonia-parkinsonism (XDP) (also known as "Lubag") is a severe progressive disorder restricted to males predominantly from the Filipino Island of Panay. First described by Johnston and McKusick as a sex-linked recessively inherited spastic paraplegia and parkinsonism (89), and later renamed by Lee and collaborators in 1976 (90), it is characterized by a progressive dystonia often in conjunction with parkinsonism, which is predominantly a later element of the disease seen in approximately one-third of XDP patients. The range of onset ranges from 12 to 48 years (91). Because of overlapping features between dystonia and parkinsonism and the existence of patients with pure parkinsonism preceding, or even overshadowing, the dystonic symptoms (92,93), Lubag can be misdiagnosed as PD, PD-plus syndrome, or essential tremor. The genetic defect responsible for XDP has been localized to the long arm of chromosome X at Xql3.1, within a 350 kb interval (94). Sequencing of a substantial portion of this critical interval revealed a multiple-transcript system within the region and suggests a base change within exon 4 of this gene is causing disease (95). To date, this finding has not been replicated in any non-Filipino patients with a similar disorder, and although this variant segregates with disease, independent confirmation is required to prove pathogenicity.
Frontotemporal Dementia with Parkinsonism Linked To Chromosome 17
Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) is an autosomal dominant disease, characterized initially by behavioral and motor disturbances that, in the latter stage of the disease, are associated with cognitive impairment. This disorder was linked to chromosome 17q21 in several nonrelated families, and termed frontotemporal dementia with parkinsonism linked to chromosome 17 (96-98). In 1998, exonic and intronic mutations in the gene MAPT were reported to segregate with FTDP-17 (99,100). Subsequent to this discovery, in excess of 60 separate families carrying more than 25 different mutations in MAPT have been identified (101,102). The vast majority of MAPT mutations are missense, deletion, or silent mutations in the coding region (most of them within exon 10), or mutations located close to the splice-donor site of the intron that follows alternatively-spliced exon 10. Clinical presentation can differ not only between mutations, but also within a single mutation and even within individual families. This allelic and clinical heterogeneity suggests that the genotypic background of an individual might also affect the phenotype observed with a particular MAPT mutation.
Parkinsonism features seem to be more frequently present in families with mutations that alter tau splicing, whereas Pick's disease without motor dysfunctions has been diagnosed in individuals with different missense mutations in exon 9 and exon 13 (103-105). Beneficial response to levodopa therapy has also been observed in some families with FTDP-17; however, this response was shown to be temporary and occurred only in the initial stages of the disease (106-108).
IDENTIFYING COMMON RISK-FACTOR GENES FOR PARKINSON'S DISEASE
As described earlier, the hunt for genes causing parkinsonism in rare families has been particularly successful over the past eight years. Less successful, both in PD and in other complex genetic disorders, are attempts at understanding the role common variability in genes plays in the disease process. While it seems clear that genetic variability influences disease pathogenesis, course, and endpoint, it is also evident that these aspects of disease are also modulated by factors extrinsic to the genome.
The probable interplay between genetics and environment makes risk-gene identification difficult. In the past 15 years, more than 150 case-control candidate-gene association studies have been performed that aim to test genes for association with disease. These reports, which are often positive, are largely unsubstantiated or subsequently refuted. The problem of assessing a single gene from the compliment of ~30,000 and choosing the correct variant to genotype, mean that these approaches are largely explorative endeavors. Where this field has found some success is in the more focused assessment of genes involved in monogenic forms of disease as risk-factor loci. Most notably, common variation within the a-synuclein gene appears to be a risk factor for PD (109,110). A large amount of this research has focused on a polymorphic repeat within the promoter of SNCA, and risk variants of this polymorphism have been shown to increase a-synuclein expression in vitro (111-113). These data are consistent with the SNCA duplication and triplication mutations described earlier and suggest that increased a-synuclein levels are central to the etiology of PD. Likewise, similar analysis has been performed for the gene encoding tau, which contains mutations causing FTDP-17. While much of the published data suggest a role for MAPT polymorphism as a risk factor for neurodegenerative diseases, the data relating to PD are still relatively preliminary and should be interpreted with caution (114,115).
Case-control genetic-association analyses have received a hard press over the previous five years, many were performed with a poor study design that captured little genetic variability and tested hypotheses in underpowered sample series. Sample size remains an issue, but the development of more sophisticated methodologies, such as haplotype tagging and whole genome association, in combination with the availability of increasing numbers of sample series, including a publicly available cohort, suggests that this approach may be fruitful in the near future.
In summary, the previous decade has been an incredibly successful one for geneticists working on PD. Numerous genes and chromosomal loci have been identified, and it is hoped that these will provide a key into the pathogenesis and etiology of PD. Identifying risk factor loci for PD will likely present a considerable challenge, but technologic advances suggest that, provided the necessary resources are available, this is a tractable problem.
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