Genetic aspects of Parkinson's disease

Movemcnt Disorders Vol. 13, No. 2, lYYS, pp. 203-211 0 1998 Movement Disorder Society

Review

Genetic Aspects of Parkinson’s Disease

Oliver Bandmann, MD, C. David Marsden, FRS, Nicholas W. Wood, MD

University Department of Clinical Neurology, Institute of Neurology, Queen Square, London, UK

la senile maladies the facts, that can be ascertuined regarding heredity probably fall short of the truth to a greater extent than in the maladies of earlier life, because, as life goes on, the death of older relations lessens the opportunities of ascertaining the facts. It is often astonishing how much disease inquiry sometimes reveals in the families of those who imagine, before the inquiry is made, that they are absolutely free from all morbid heredity . . .

W. R. Gowers (A manual of diseases of the nervous system.

London 1888, p. 5890

The relevance of genetic factors in the pathogenesis of neurologic diseases is being recognized increasingly, and enormous progress has been made in the understanding of the most common single-gene disorder of the basal ganglia, Huntington’s disease.’ It is less clear, however, to what extent genetic factors contribute to the pathogenesis of the most common of all basal ganglia disorders, Parkinson’s disease (PD). This article reviews the literature on epidemiological and family studies, and summa- rizes the results of molecular genetic research in this disease. Some of our own experimental work is included in this review.

EPIDEMIOLOGICAL STUDIES Gowers found evidence of heredity in “not more than

15%” of his personal series of patients with Parkinson’s disease (PD).2 Similar figures were reported by other contemporary authors (as quoted in references 2 and 3). The first systematic genetic study of PD was carried out by Mjiines who identified a positive family history in 79

Received June 11, 1997. Accepted June 12, 1997. Address correspondence and reprint requests to Dr. N. W. Wood at

the University Department of Clinical Neurology, Institute of Neurol- ogy, Queen Square, London, WClN 3BG, UK.

of his 194 patients (41%): However, Mjones included cases of isolated tremor, and even intention or vocal tremor, as well as patients with dementia or ataxic gait and bilateral Babinski signs as secondary cases of PD. If these unusual cases are omitted, however, then the prevalence of secondary cases among first-degree relatives falls to approximately 3%.5

In a disorder as common as PD, it is important to ascertain whether the rates of PD in families are the result of chance. More recent epidemiological studies have used a case-control design to address this An overview of recent case-control studies, including the calculated odds ratio or relative risk values, is given in Table 1. All of them find a higher prevalence of PD among relatives of index cases with PD, compared with the prevalence among relatives of unaffected controls. They thus support the hypothesis of a genetic etiologic component in this disorder. However, the conclusions of these studies have usually been based on data ascertained by questionnaires or interviews. It is likely that the awareness of the disease is considerably higher in the families of the affected index cases than the control subjects and this may lead to a recall bias. Some researchers have attempted to validate the reported diagnosis of PD in the questionnaire by personal examination of the relative, reviewing their case records, and so on, but others relied solely on the informant (see Table 1). Further- more, the prevalence of PD among first-degree relatives has not always been reported separately from the prevalence of PD among all relatives (see Table I ) .

The recent case-control studies can be divided into hospital-based and communitylpopulation-based studies (see Table 1). Hospital-based studies are open to a number of biases. Depending on the health care system, referral biases may be present, which may result in, for example, a younger age group (if geriatric services are provided elsewhere) or a lower social class (if there are

203

204 0. BANDMANN ET AL.

TABLE 1. Comparison of case-control studies in Parkinson’s disease

Patients with Controls with Mean Verification affected affected

relativeltotal relativekotal Odds ratio/ Hospital/ age of of diagnosis no. of no. of relative risk population patients in relatives

Study patients control subjects ( O m R ) based (yrs) attempted Commcnts

Payami et al.’ 19/114 (16.7%) 5/114 (4.4%) OR = 3.5 I hospital 68.6 + FR only 46/343 (1 3.4%) 5/365 (1.4%) I OR = 12.6 9 hospitals 56.2 - No differentiation Seidler et a1.’

between FR and AR; high proportion of missing values

Considerably higher

positive FH and OR than in other studies

Semchuk et al.’ 29/128 (22.7%) 16/256 (6.3%) OR = 5.8 (AR) population 68.5 Differenlialion between OR for FR and AR

9/359 (2.5%) 11 OR = 5.0

+ De Michele 38/116 (32.7%) 2/116(1.7%)III OR = 14.6 2 hospitals 62.5 et al? 611 16 (5.2%) IV figures for

OR = 2.4 (FR)

Marder et al.“’ 233 index pat., I172 index control RR = 2.3 population 73.6 FR only subjects

19/1458 FR affect. 38/7834 FR affected

FR: first-degree relatives only; AR, all relatives included: FH, family history; I, neighborhood controls; 11, regional controls; 111, spouses; IV, neurologic controls.

both private and state systems). Case registers have the advantage in that they aim to include all cases of a particular disease within a certain geographical area. How- ever, they may still be influenced by other local factors such as environmental toxins. The use of regional control groups addresses this problem.

Finally, it should not be forgotten that carefully calculated odds ratios or relative risks are sometimes more impressive than the absolute figures. For example, Marder and colleagues obtained a diagnosis of PD in only 19 of 1458 first-degree relatives (1.37%) of 233 index patients. lo The proportion of affected relatives among the controls was even lower (38 of 7834 [.48%]) and this led to a relative risk value of 2.3. However, the high proportion of unaffected first-degree relatives of the index patients indicates that factors other than a genetic predisposition play a major role in the pathogenesis of PD. It should also be considered that a higher incidence of PD within certain families could, at least in some cases, be the result of shared environment and thus shared exposure to hazardous toxins or infectious agents rather than a shared genetic susceptibility.11212

A positive family history is considerably more common in juvenile parkinsonism (JP), arbitrarily defined as parkinsonism with onset before age 21 years.13 JP is inherited in an autosomal-recessive fashion and is likely to form a separate entity distinct from adult-onset Lewy- body disease. l 4

TWIN STUDIES Twin studies are a tool used by geneticists to dissect

the relative contributions of genetic and environmental

factors in the etiology of a disease. If genetic predisposition predominates, concordance rates in monozygotic twins (MZ) are substantially higher than those in dizy- gotic twins (DZ), although DZ twins have a concordance rate substantially higher than the risk in the general population. However, if the disease is mainly the result of environmental or other exogenous factors, then concordance rates in MZ and DZ twins will be similar and these rates are higher than the risk among unrelated individuals; this is because twins share a similar environment as children and tend to have similar diets, lifestyle, and occupational exposure as a d ~ 1 t s . l ~

Accordingly, if there were a significant genetic component in PD, one would expect to find a high concordance rate of PD among MZ twins, and a lower concordance rate among DZ twins. Unfortunately, the twin studies in PD remain difficult to interpret. Initially, several studies found a similar concordance rate in both MZ and DZ and it was concluded that “major factors in the etiology of PD are nongenetic.”” How- ever, in two of these studies neither the proband twin nor the co-twin were examined by the researchers. A reanalysis of the study by Ward and colleagues, the only study where both probands and co-twins were personally examined, suggested that because of the small number of affected twins, the available data were not substantial enough to prove or disprove the hypothesis of a substantial genetic component to the etiology in PD.I9 Incon- clusive results were also obtained by a later clinical study. 2o

Twin studies in PD are hampered by several problems. First, preclinical PD has been estimated to be 10 to 15

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GENETIC ASPECTS OF PD 205

times more common than clinically overt PD?’ and it has been postulated that “for each affected co-twin there must be at least 10 and possibly 15 other co-twins with preclinical PD.’ 7 5 Twin studies concentrating on clinically overt PD may therefore result in false-negative conclusions. One imaging study using “F-dopa and positron emission tomography (PET) has shown a higher concordance rate for nigral dysfunction in clinically unaffected MZ than DZ twins.22 However, in this study, the mean age of the DZ co-twin group was 20 years younger than the MZ group. This difference is likely to be relevant because there is decline of normal nigrostriatal function with age. If both MZ and DZ twin groups had a similar mean age, then the concordance levels for nigral dysfunction might have been closer. Another PET study Fhowed reduced 18F-dopa uptake not only in the two MZ co-twins, but also in all of the five DZ co-twins studied.23 Even in classic autosomal-dominantly inherited diseases such as Huntington’s disease, a concordance rate of only 50% among DZ twins would be expected. These data could actually be interpreted as evidence agaimt a significant genetic component, at least as far as nuclear-encoded genes are concerned; the damage to the nigrostriatal system in all patients examined could more readily be explained by shared environmental exposure. The only compatible genetic model would be that of mitochondria1 inheritance (see below). However, one needs to be careful about drawing far-reaching conclusions from a single study with a comparatively small number of patients.

Whereas some MZ co-twins develop the disease at a similar age as the index case, there is a wide range of age of onset which further complicates the analysis of twin studies in PD. This is exemplified by a follow-up study of the original twin study by Ward and colleagues which revealed that one of the previously unaffected MZ co- twins developed PD 26 years after the index case.5 Simi- lar to many other areas of research in PD, twin studies are hampered by the fact that the clinical diagnosis of PD is only correct in approximately 80% of all cases,24 and clinically identified ‘‘PD twins” may actually suffer from a different disease which merely mimics PD. The only postmortem examination carried out in a proband with a clinical diagnosis of typical PD from the series by Ward and colleagues demonstrated pallidoluysian atrophy rather than Lewy-body PD.5

FAMILY STUDIES Bell and Clark reported a sibship with at least five

affected family members in 1926 and included a literature review on this topic in their article.2s Ten other Tibships with familial PD had already been described at

that time. Several large families with PD inherited in an autosomal-dominant fashion have now been reported in the recent literature. They provide the most convincing piece of evidence that PD can indeed be caused by a single gene defect.

Possibly the best known family is the large Contursi family.26727 There are 60 known affected members in five generations. Of particular importance is that nigral cell loss with Lewy bodies has been demonstrated in one deceased member of the family, although another member only showed Lewy bodies and cell loss in the locus ceruleus. The somewhat unusual clinical features in this family include early onset (mean age of 45.6 years) and a rapid course to death averaging 9.2 years, Recently, molecular genetic studies in this family have established linkage to chromosome 4q21-q23.26 This is the most exciting news as yet in the field of neurogenetic research on PD, and discovery of the actual gene in this particular family will provide new insight into the pathogenesis of this disorder. However, several other PD families have now been tested for linkage to 4q and none of them has linked to this locus.29 Thus, there is now clear evidence for genetic heterogeneity in PD. The same holds true for other neurodegenerative disorders such as Alzheimer’s disease or amyotrophic lateral

The clinical features of affected members in a western Nebraska family (“family D”) probably resemble the features seen in sporadic patients more closely than other reported large families.32 The average age of onset is 63 years and the survival of affected members is 12 years. PET studies with 18F-dopa have shown reduced putam- inal uptake in one affected member and there was nigral cell loss with Lewy bodies on postmortem examination of another affected member. Other identified families have had a considerably younger age of onset in some cases33 or have lacked pathologic confirmation.34x35

A recent PET study in several smaller families with PD has shown that there is subclinical damage to the nigrostriatal system in some clinically unaffected members.36 This has previously been demonstrated in a large Irish family37 and demonstrates that the dopaminergic system may be more frequently affected in such families than one would assume from clinicogenetic studies.

In an epidemiological study, various clinical charac- teristics such as age of onset, mode of onset, and predominant clinical features in sporadic PD compared with affected members of mostly small PD sibships were analyzed. No statistically significant differences were detected, although an early age of onset may be more common in familial PD.8 De Michele and colleagues found unilateral distribution of ancestral secondary cases on either the maternal or paternal side,* and Lazzarini and

Movement Disorders. Vol. 13. N o 2, 1998


colleagues described a significantly higher risk to siblings of index cases with affected parents than in those in whom the parents were unaffected. These important findings give further evidence for autosomal-dominant inheritance of PD even in families with a small number of affected members.

ANTICIPATION AND FAMILIAL PD Anticipation is the phenomenon of progressively ear-

lier appearance and increased seventy of a disease in successive generations. It is observed in a number of inherited autosomal-dominant neurodegenerative disorders such as Huntington’s disease, dentatorubral- pallidoluysian atrophy, and spinocerebellar ataxias. All of these disorders share an expansion of unstable trinucleotide repeats as the underlying pathogenic rnechan i~m.~~

Anticipation has also been considered to be present in PD. Payami and colleagues studied a series of 137 PD patients, 21 of whom had an affected parent, aunt, or uncle of known age at onset.39 On average, the age at onset in the proband’s generation was 17 years earlier than in the parents’ generation. There are, however, several problems with this study: cases were incompletely ascertained from a specialist referral center, neither alleged secondary cases of PD nor alleged unaffected per- sons were personally examined, and the age-at-onset data were often obtained indirectly. Most importantly, probands were not excluded from the analysis. As Mara- ganore and colleagues point out, there are reasons to believe that probands may be biased toward younger- onset PD.40 Patients with younger age of onset intrinsi- cally may be more likely to be referred to specialist tertiary referral centers and also seem to appear more likely to reply to recruitment for studies through adver- tisements. In addition, in younger generations, at-risk subjects and their families are likely to notice the disease earlier because of heightened awareness. Furthermore, in studies that only include personally examined cases, the proband will invariably have earlier age of onset if the other affected relative is his or her parent (otherwise the parent would no longer be alive).

Maraganore and colleagues reanalyzed 13 personally examined families to investigate anticipation and related biases.40 No statistically significant evidence for anticipation was found when probands were excluded. These authors also reviewed the evidence for anticipation in previously reported large families. Anticipation had been reported in two of them. However, in one of these families there were unusual features such as early onset, pro- longed course, muscle fatigability, visual disturbance, and poor response to L-dopa treatment as well as severe Purkinje cell loss in the cerebellar vermis on autopsy.26

No pathology was available in a further sibship with presumed an t i~ ipa t ion .~~ The interpretation and analysis of this family is also complicated by the fact that the age of onset varies by up to 20 years within one generation and that the precise age of onset of symptoms is not reported in all members of the family. The claim of defi- nite anticipation in this particular family would be supported if further members of the most recent generation in addition to the single affected case in generation V were to develop parkinsonism at a young age. The sug- gestion of anticipation disappeared in the large Contursi family after adjustment for age-related ascertainment bias.27 An analysis of other large by Ma- raganore and colleagues provided further evidence against anticipation.

The clinical observation of absent anticipation in PD is supported by a DNA study investigating familial cases of PD for a CAG trinucleotide repeat expansion. No abnormal expansions were detected in any of the analyzed cases.42

CANDIDATE GENE STUDIES Candidate gene research is based on the knowledge of

pathogenetic mechanisms and is therefore entirely different from the genome-wide searching methods using anonymous markers. Candidate gene studies are complicated by a number of different problems: First, the two recognized biochemical abnormalities in PD-oxidative stress and mitochondrial dysfunction-may only be secondary to other, as yet unidentified, disturbances. Thus, genetic studies concentrating on enzymes involved in the production of free radicals or protection against them, as well as studies of mitochondrial genes, may be unre- warding. Second, there is genetic heterogeneity in PD (see above). Thus, the result of any genetic study, whether it is linkage or direct gene analysis, does not neces- sarily apply to any family other than the particular family studied. Finally, for obvious reasons, only genes with an identified chromosomal location or DNA sequence are amenable to analysis. However, many interesting proteins, for example, the detoxification enzyme CYPl A2, are only characterized biochemically, with nothing being known about the structure and localization of the respec- tive gene. Thus, only a small proportion of potential- ly interesting proteins can currently be investigated genetically.

The different approaches used in candidate gene research include linkage studies in big families, direct DNA sequence analysis in either familial or sporadic cases, and allelic association studies in a series of sporadic cases.

Most of the linkage work on candidate genes has been

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carried out by Gasser and coworkers.43344 Initially, negative lod scores were obtained for glutathione peroxidase, tyrosine hydroxylase, brain-derived neurotrophic factor, catalase, amyloid precursor protein, superoxide dismutase 1 (SODl), and CYP2D6. Additional studies excluded the genes for basic fibroblast growth factor, pre- and postsynaptic dopamine transporter, aromatic hydro- carbon receptor and its nuclear translocating factor, as well as superoxide dismutase 2 (SOD2) and CYPlAl. Plante-Bordeneuve and colleagues also obtained negative lod scores for tyrosine hydroxylase and CYP2D6 in their linkage

However, most families with familial PD are too small for linkage analysis. In such cases, analysis of a particular gene by DNA sequencing is the most direct method. Oxidative stress resulting from increased free-radical production or defects in antioxidant defenses seems to play an important role in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and PD. Among other enzymes, superoxide dismutase 1 (SOD1) normally prevents tissue damage from oxidation-derived free radicals. Rosen and colleagues had shown that some families with amyotrophic lateral sclerosis (ALS) have mutations of the SODl gene.47 There is evidence of nigrostriatal damage in ALS and shared genetic susceptibility for both ALS and PD has been s ~ g g e s t e d . ~ * - ~ ~ Because transgenic mice with increased SODl activity show resistance to the neurotoxin MPTP, abnormal SODl activity in PD could result in increased susceptibility of dopaminergic neurons to neu- rotoxins such as MPTP.” We sequenced the entire cod- ing region of SODl in 23 familial index cases. No changes were detected in the sequence of the SODl gene in any of these 23 cases.” This makes involvement of SODl in PD unlikely. Using the screening method of single-stranded confirmation analysis, rather than direct sequencing, Parboosingh and colleagues analyzed SOD 1 as well as SOD2 and catalase in sporadic patients with PD; they also failed to find any pathogenic mutation^.'^

Patients with Machado-Joseph disease may only present with parkinsonism and a mild peripheral neuropathy in late life.’4 To evaluate a possible overlap between this disorder and autosomal-dominantly inherited parkinsonism, we analyzed the Machado-Joseph gene (SCA3) in 23 index cases of familial parkinsonism. The number of trinucleotide repeats was normal in all cases examined (unpublished observations). This makes overlap between Machado-Joseph disease and familial PD unlikely.

Allelic association studies compare the frequency of a certain polymorphism in patients with PD with that in control subjects. They are also complicated by the fact that the clinical diagnosis of PD is confirmed at autopsy

in only approximately 80% of all cases.24 The remainder have different pathology such as that of multiple system atrophy, Alzheimer’s disease, progressive supranuclear palsy, and other disorders. Moreover, whereas the frequency of various polymorphisms varies considerably between different regions, genders, and possibly also age groups, control subjects are often not age- or sex- matched. Incidental Lewy-body disease with subclinical dopaminergic cell loss shares some biochemical abnormalities with PD” and may be considerably more common than clinically manifested PD.21 Inclusion of such cases as control subjects may result in false high figures for a polymorphism in the control group. It is important to assess all association studies keeping these problems in mind.

Allelic association studies can be divided into studies that analyze functionally relevant genetic polymorphisms (that is, the “A” and “B” allele of CYP2D6, which lead to decreased enzymatic function) and others, which compare only sequence variants without any known functional relevance (that is, the polymorphism studied in the tyrosine hydroxylase gene).

Debrisoquine 4-hydroxylase (CYP2D6) has attracted more attention than any other detoxification enzyme. Earlier metabolic investigations led to inconclusive results,56-’9 but interest in this enzyme was fueled again by two reports published in 1992. One study identified an increased frequency of the mutant allele CYP2D6B in 53 patients compared with 72 non-age-matched, non-sex- matched controls, but failed to find an increased number of poor metabolizers (poor metabolizers carry two mutant alleles).h0 The second study described an increased frequency of poor metabolizers among 229 patients compared with 720 unmatched controls, but did not detect an increased frequency of the CYP2D6B allele.6’ An increased frequency of both poor metabolizers and the CYP2D6B allele were observed in another study; but this study from Arizona, USA, used European controls.62 A further study only found an increased frequency of the CYP2D6B allele among a subset of 33 PD patients with young onset.63 However, recent, more carefully designed studies have not found similar results. Gasser and colleagues found a similar frequency of the CYP2D6B allele among patients with PD and their spouses as well as in patients with Alzheimer’s disease.64 A further study analyzed both CYP2D6A and CYP2D6B6’; neither the frequency of poor metabolizers or the frequency of CYP2D6B differed between patients and the control group consisting of personally examined spouses and healthy blood donors. Sandy and colleagues examined a large group of PD patients with young onset and were unable to confirm the previous report of an increased

Movement Disorders, Vol. 13, No. 2, 1998


frequency of CYP2D6B in this subgroup of PD.66 Thus, with time, there now appears to be diminishing evidence for the involvement of CYP2D6 in the pathogenesis of PD.

The type 4 allele of apolipoprotein E is a genetic risk factor influencing the development and age of onset of Alzheimer's disease.30 However, it does not appear to influence the age of onset in PD and both demented as well as nondemented patients with PD have a normal frequency of this

The genes for both monoamineoxidase A and B (MAO-A and MAO-B) are encoded on the X chromosome. Activity of these enzymes can lead to the production of free radicals and hydrogen per~xide.~' Further- more, MAO-B produces the active neurotoxin l-methyl- 4-phenyl pyridinium (MPP+) from 1 -methyl-4-phenyl- I ,2,3,6-tetrahydropyridine (MPTP).71 Kurth and colleagues reported an increased frequency of a polymorphism in the noncoding region of MAO-B in PD." However, only a comparatively small number of patients was studied (n = 46) and the controls came from a different geographical area. Ho and colleagues analyzed the same polymorphism in 112 sporadic patients and failed to find any d i f f e r e n ~ e . ~ ~ Another study found some differences in the overall distribution of different alleles of both MAO-A and MAO-B, but no association was found between any single allele and PD.74

Further allelic association studies have found evidence against the involvement of tyrosine hydroxylase, the dopamine transport protein, and the dopamine receptors D2, D3, and D4.4637s

PD AND MUTANT MICE STRAINS Mutant mice strains have been helpful in the identifi-

cation and understanding of the pathogenetic basis of inherited neurologic disorders such as Charcot-Marie- Tooth disease and the cerebellar ataxias. In some mutant mice strains, the number of dopaminergic neurons in the SN is genetically controlled, and it has thus been suggested that these mice may give some clues to a better understanding of the nigral cell loss in PD.76

Weaver mice and patients with PD share promi- nent postnatal dopaminergic cell loss in the lateral parts of the substantia nigra as well as relative sparing of calbindin,,,, positive A putative inward rec- tifier K+ channel, mGIRK2, has been identified as the causative gene in the weaver mouse and a homozygous mutation has been described in the HS pore region of this channel." To evaluate the possibility of a shared genetic defect in weaver mice and PD, we analyzed the HS pore region of hiGIRK2, the human homologue of mGIRK2, in 50 familial and sporadic cases of PD. The sequence

was normal in all cases examined, suggesting a differing etiology of nigral cell loss in PD and weaver mice.82

Bcl-2 and pS3 are important genes in the regulation of cell growth and apoptotic cell death. Apoptosis may occur in PD,83 and neurons from bcl-2-deficient mice are more susceptible to dopamine-induced oxidative stress and apoptotic cell death than normal controls.84 We performed linkage analysis of Bcl-2 in 23 families with PD but found no evidence for an involvement of this gene in the pathogenesis of PD (unpublished observations). Re- sistance of dopaminergic neurons against MPTP toxicity has been reported in transgenic mice with a knock out of the p53 gene." If these data were to be confirmed in other studies, a study of p53 and other growth control genes may be an area worthy of further research in PD.

PD AND MITOCHONDRIAL DNA Several groups have reported inhibition of mitochon-

drial respiratory chain function in patients with PD. There is, however, controversy as to whether there is specific inhibition of complex I alone or whether other complexes are also affected.86-*8 The disturbed respiratory function could be the result of alterations of the mitochondria1 DNA (mtDNA) and a cell-hybrid study supports this hypothe~is.'~ Swerdlow and colleagues first depleted human neuroblastoma cells of their own mtDNA and then repopulated these cells with mitochondria derived from the platelets of PD or control subjects, In the cell hybrids containing the mtDNA of PD patients, a 20% decrement in complex I activity, increased oxygen radical production, and increased susceptibility to MPP+ were found.

Whereas these data suggest involvement of the mtDNA in the development of complex I deficiency and increased radical production, at least in some patients, direct genetic studies of the mtDNA in PD have so far been unsuccessful. Several groups have failed to find evidence of large-scale rearrangements of the mitochondrial DNA in PD.90-92 However, five single base-pair polymorphisms of the mitochondria1 DNA have been reported in white patients with PD either exclusively or with increased f r e q ~ e n c y . ~ ~ - ~ ~ To evaluate the posbible relevance of these data, we screened 100 white patients with PD for all five polymorphisms. Only DNA samples extracted from brain tissue with a pathologic diagnosis of PD were used for our study. When we found a polymorphism present among our patients, we also screened 100 white controls. We were either unable to detect the previously described polymorphisms in our series or found them to be present with the same frequency among control subjects.96 The difference between our results and previously published data may be the result of differ-

Movement Disorder.>, Vol. 13, No. 2, 1998

GENETIC ASPECTS

ences in both the homogeneity and the number of patients analyzed (for a detailed discussion, see reference 96).

MtDNA is exclusively inherited through the maternal line, and one would therefore expect to find exclusive or at least predominant maternal inheritance of familial PD if mtDNA were the predominant genetic factor. How- ever, several studies have now shown an excess of paternal rather than maternal i n h e r i t a n ~ e . ~ - ~ ~ , ~ ~ One recent study apparently contradicts these findings,99 but claims of evidence for maternal inheritance in this publication are based on a small number of identified families (n = 5) and fail to take into account previous reports describ- ing multiple affected siblings with an affected father.97

These apparently contradictory findings on a possible involvement of the mtDNA could be unified by assum- ing genetic heterogeneity: some patients may develop their PD because of some as yet unidentified alteration of the mtDNA, whereas others develop the disorder because of a disturbance of nuclear genes. The as yet unidentified pathogenic alteration of the mtDNA may consist of several different changes in DNA rather than a single point mutation, and it may only be the unusual combination of these sequence variants rather than a single sequence variant that results in the observed mitochondria1 dysfunction.

CONCLUSION AND OUTLOOK Recent epidemiological studies have established a

positive family history as a risk factor for PD. The identification of the first chromosomal locus for familial PD is exciting and genome-wide linkage studies are currently being performed in several other large families. Results of allelic association studies in sporadic cases have either been inconclusive or have only excluded the involvement of various candidate genes.

However, large pedigrees with autosomal-dominantly inherited PD are extremely rare. Perhaps the greatest challenge facing research into the genetic basis of PD is to find the putative susceptibility genes. The most robust way of achieving this end is to use the affected sib-pair method. This, however, requires large-scale collabora- tion to ascertain sufficiently large numbers of affected sib pairs to identify linkage.

Note: Since the submission of this article, a mutation in the a-synuclein gene has been described in one large Italian- American family and three Greek pedigrees. Further work will be needed to establish the relevance of this mutation to other families and its potential role in sporadic PD.””

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Genetic aspects of Parkinson's disease