The genetics of Parkinson disease: implications for neurological care

Article classé dans la catégorie "Parkinson et Gaucher".

Si les patients atteints de maladie de Gaucher sont suceptibles d'être atteints par la maladie de Parkinson, il a été constaté que certaines personnes hétérozygotes avec la mutation S370 sont retrouvés parmi les patients atteints de Parkinson.

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Review

Nature Clinical Practice Neurology (2006) 2, 136-146
doi:10.1038/ncpneuro0126 
Received 26 July 2005 | Accepted 21 December 2005

The genetics of Parkinson disease: implications for neurological care

Christine Klein* and Michael G Schlossmacher  About the authors

Correspondence *Department of Neurology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany

Email christine.klein@neuro.uni-luebeck.de

Summary

The identification of single genes linked to heritable forms of Parkinson disease (PD) has challenged the previously held view of a nongenetic etiology for this progressive movement disorder. Detailed analyses of individuals with mutations in SNCA, Parkin, PINK1, DJ1 or LRRK2 have greatly advanced our knowledge of preclinical and clinical, morphological, and pathological changes in PD. These genetic breakthroughs have had profound implications for scientists, neurologists and patients alike. Such advances have provided unique opportunities to pursue the mechanisms of neuronal degeneration in models of PD pathogenesis, thereby reinforcing the significance of oxidative stress and mitochondrial dysfunction. With emerging clues from familial variants, researchers have begun to explore factors that lead to the expression of the more common, sporadic disease phenotype (idiopathic PD), including interactions between various genes, modifying effects of susceptibility alleles and epigenetic factors, and the influence of environmental agents and aging on the expression of PD-linked genes. These genetic leads have added to the urgency of developing translational drug treatments, and neurologists and their patients are confronting considerations relating to DNA testing. In this article, we summarize recent progress in establishing a neurogenetic component of PD, emphasize the need for developing PD biomarkers to improve diagnostic accuracy (in both clinical practice and therapeutic trials), and discuss scenarios in which specific DNA tests might be considered for diagnostic purposes. In the absence of consensus guidelines for DNA testing in PD and of any neuroprotective treatment for this nonfatal disorder, we remind ourselves of the omnipresent mandate, 'Primum nil nocere!' ('First, do no harm!').

Review criteria

PubMed was searched, using Entrez, for articles published up to July 2005, including electronic early-release publications. Search terms included "Parkinson disease" or "parkinsonism", as well as "genetics" and the individual "PARK" loci. The abstracts of retrieved citations were reviewed and prioritized by relative content. Full articles were obtained and references checked for additional material when appropriate. The results of some experiments conveyed to the authors by personal communication were also included.

Keywords:

-synuclein, biomarker, mutational screening, neurogenetics, Parkinson disease

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Introduction

During the past decade, Parkinson disease (PD) has evolved from a textbook example of a mostly nonhereditary disease to a complex disorder with a well-established genetic component in a considerable subset of patients (Figure 1). In the clinical setting, this evolution is reflected in an increasing demand for mutational analysis of PD-associated genes by doctors and well-informed patients. Recent advances in the molecular genetics of PD have markedly improved our conception of its etiology and pathophysiology; however, the identification of different forms of monogenic PD has revealed an unexpectedly large amount of clinical and genetic heterogeneity. Additional complexity is added by the existence of as yet unidentified PD genes, and by the still-incomplete picture of the scope of mutations in already identified genes.

Figure 1 Frequency of heritable Parkinson disease.

Estimated frequency of monogenic Parkinson disease variants in different groups separated by age at onset of disease. LRRK2, leucine-rich repeat kinase 2; PD, Parkinson disease; PINK1, phosphatase and tensin homolog (PTEN)-induced putative kinase 1; SNCA, -synuclein.

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Terminology and genetic categories of parkinsonian syndromes

Consensus statements for terminology and diagnostic criteria have been developed for several parkinsonian disorders,¹ and the umbrella term 'parkinsonism' was coined to broadly categorize this set of disorders. PD accounts for 75% of cases of parkinsonism² and is clinically characterized by the cardinal features of bradykinesia, tremor, rigidity, postural instability, and responsiveness to dopaminergic therapy.^{3, 4} The diagnosis of 'IDIOPATHIC' PD usually refers to clinically typical, late-onset, nonheritable parkinsonism, which at autopsy reveals one of six stages of neuronal loss, astrocytic gliosis, and formation of hallmark inclusions in the brainstem and elsewhere (LEWY BODIES and dystrophic neurites); this type of PD is considered distinct from other parkinsonian syndromes.^{2, 5}

The differential diagnosis of parkinsonian disorders often poses clinical challenges, owing to phenotypic variance, associated comorbidities, and the general lack of validated and ubiquitously available biomarkers for individual subtypes. Parkinsonian disorders other than PD are often associated with atypical features and, together with idiopathic PD, are believed to be genetically distinct from monogenic forms of parkinsonism. The rare monogenic variants, however, which can be sporadic or familial and usually, but not always, present at an earlier age of onset (<20 years of age for the juvenile form and <40 years of age for the early form), are often clinically indistinguishable from idiopathic PD;^{6, 7, 8, 9} these monogenic variants can also appear pathologically indistinguishable.^{10, 11, 12, 13} For clarity and practical purposes, this review will focus on forms of parkinsonism that can mimic idiopathic PD clinically, and, therefore, the term PD is used. We consider this practical approach to be justified for two reasons: first, the general lack of molecular tools for gaining more accurate insight into the individual pathogenesis of each patient with PD seen in the clinic; and second, the persistent uncertainty surrounding the actual role of neural inclusions. These inclusions have served as diagnostic tools in post-mortem analysis for decades, but they might not represent an accurate surrogate marker for the actual mechanism that promotes the death of vulnerable neurons.

The identification of several PD-associated genes has resulted in a 'classification' of monogenic PD variants that represent an assortment of clinically and genetically heterogeneous parkinsonian conditions. In Table 1, these conditions are listed in order of their first description. This growing list cannot, however, be recommended as a widely applicable categorization of parkinsonian syndromes, for several reasons.¹⁴ First, the clinical phenotype of some variants differs markedly from that of idiopathic PD, as is the case with mutations in the PARK9 gene (KUFOR–RAKEB SYNDROME). Second, the true contributory role in PD pathogenesis of the described mutations in some genes (e.g. Ile93Met in the UCHL1 gene product, previously known as PARK5) needs to be further established or the gene simply remains unknown (as in the case of the PARK3 locus). Third, in addition to the above-mentioned syndromes, mutations in various other genes have been linked to PD in individual cases or small numbers of families but have not yet been assigned a PARK locus number. Moreover, other movement disorder syndromes can occasionally present as a phenocopy of PD (Table 2). Last, even seemingly 'objective' genetic data should be interpreted with caution, because errors in locus assignment or in the distinction of POLYMORPHISMS from genuine mutations might occasionally occur.

Table 1 Known monogenic forms of Parkinson disease.

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Table 2 Selected genetically caused movement disorders that can present with clinical features of Parkinson disease.

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Monogenic variants of parkinson disease

Disease phenotypes associated with the PARK1–9 chromosomal loci follow a typical MENDELIAN pattern of inheritance (Table 1), whereas PARK10 and PARK11 represent susceptibility loci with as yet undefined modes of transmission. In Mendelian genetics, the relationship between genotype and phenotype is not always readily apparent; for example, as illustrated in Figure 2, single heterozygous mutations in 'recessive' genes can act as susceptibility factors, thereby appearing pseudodominant. Similarly, dominant forms can present in a pseudorecessive fashion, and heritability should be suspected even in early-onset patients with a negative family history (Figure 2). An apparent lack of heritability might be explained by small family size, nonpaternity, adoption, variable clinical characteristics, reduced PENETRANCE, or de-novo mutations. Conversely, because sporadic PD is a relatively common condition, familial PD might be phenocopied by an occurrence of sporadic PD in a pedigree with a well-established genetic background of the disease.^{9, 12}

Figure 2 Examples of pedigrees, to illustrate mode of inheritance in monogenic Parkinson disease (PD).

Mendelian modes of inheritance for known monogenic forms of PD are represented schematically. Definitely affected family members are shaded in black, probably affected members in gray. A dot in the pedigree symbol represents an unaffected mutation carrier. The two bars next to the pedigree symbols represent the two alleles of the gene of interest. A mutation is indicated by the star symbol. PD associated with -synuclein (SNCA) and leucine-rich repeat kinase 2 (LRRK2) is transmitted in an autosomal dominant fashion (A). In cases of reduced penetrance, the mode of inheritance may appear pseudorecessive (B) or even sporadic. In several families with recessively inherited PD associated with mutations in Parkin, phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), or DJ1 genes (C), a number of heterozygous mutation carriers have been reported to be probably or definitely affected. The inheritance might, therefore, appear pseudodominant (D), mimicking the scenario outlined in (A).

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When evaluating a patient for a possible monogenic form of PD, more information than simply the family history needs to be considered, including the age at onset, distribution of symptoms, disease course, therapeutic response, geographic history, consanguinity, and careful accounting for and, if possible, neurological examination of first-degree and second-degree relatives. For example, when compared with patients without mutations in the Parkin gene (also known as PARK2), Parkin-mutation carriers tend to have an earlier age of onset, a slower disease progression, a more symmetrical onset, dystonia as a more frequently encountered initial sign (in addition to hyperreflexia), and the tendency to respond to low doses of levodopa.^{7, 15} To the informed neurologist, these features might represent important clues to heritable PD (Table 3). Clear-cut predictions cannot, however, be made in the individual patient solely on clinical grounds, as considerable overlap with idiopathic PD has been described clinically. Furthermore, the natural evolution of each phenotype in mutation carriers (identified in cross-sectional studies) remains to be delineated.

Table 3 Parkinson disease-associated genes listed in order of their estimated mutation frequency in different patient subgroups.

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Recessively inherited parkinson disease: Probable loss-of-function mechanism

Parkin-associated Parkinson disease

Mutations in the Parkin gene¹⁶ represent the commonest known factor responsible for early-onset PD (10–20%; Figure 1) and have been shown in numerous families of different ethnic backgrounds.¹⁷ The large number and wide spectrum of Parkin mutations include alterations in each of its 12 exons. Importantly, about 50% of carriers of this mutation have exon rearrangements that, in the heterozygous state, are not detectable by conventional screening methods, such as sequencing alone.¹⁸

The Parkin gene is expressed in presynaptic and postsynaptic processes and cell bodies of many neurons.¹⁹ The Parkin protein is presumed to function as an E3-type, E2-enzyme-dependent ubiquitin ligase that is involved in the proteasomal degradation of target proteins.²⁰ The available E3 activity is disrupted by mutations associated with PD, thereby supporting the predominant loss-of-function theory.²¹ A growing number of putative ('to-be-ubiquitinated') Parkin substrates have been identified, and accumulation of these proteins is proposed to cause the selective death of neurons in the substantia nigra and locus coeruleus in humans.²² Although these putative substrates await convincing validation in animal models with disrupted parkin alleles, Drosophila melanogaster and mice that are deficient of wild-type parkin revealed unequivocal, systemic signs of increased oxidative stress and mitochondrial dysfunction.^{23, 24, 25} It is currently unclear if these biochemical changes can be attributed solely to the E3-ligase activity of the protein (or lack thereof) or to an—as yet unknown—function of the parkin homologs. An equally contentious issue is whether Parkin expression is essential for formation of neuronal inclusions in vivo, and if so, whether its ubiquitin ligase activity is responsible for the formation of Lewy bodies, as suggested (but not proven) by the abundance of ubiquitinated proteins in Lewy inclusions isolated from human brain.¹⁹ Disappointingly, the pathognomonic loss of human substantia nigra neurons has not been replicated in any of the published mouse models of three monogenic PD variants (-synuclein [SNCA]-transgenic mice, parkin-null mice and dj1-null mice). By contrast, the fruit fly (D. melanogaster) appears more susceptible to PD-type pathology.²⁶

Recently, two biochemical modifications of Parkin (S-nitrosylation and dopamine quinone-adduct formation) were identified in cellular studies and human brain specimens.²⁷ These data indicated that reduced E3-ligase activity of the wild-type Parkin protein (rather than an autosomal recessive mutation in the two Parkin alleles) could also occur as a result of the principal pathogenetic process that is responsible for the development of sporadic PD.

PINK1-associated Parkinson disease

Two homozygous mutations in the phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1; also known as PARK6) gene were initially detected in three consanguineous families with early-onset PD.²⁸ The frequency of PINK1 mutations is in the range of 1–9%,^{29, 30, 31, 32, 33, 34} with considerable variation across different ethnic groups. Most of the currently described mutations are localized near or within the functional SERINE/THREONINE PROTEIN KINASE domain of PINK1³³ and are expected to result in loss of function in vivo. Wild-type PINK1 is thought to function as a protein kinase with possible activity inside the mitochondria, thereby strengthening the hypothesized link between mitochondrial dysfunction and oxidative stress in PD pathogenesis.^{22, 35, 36}

DJ1-associated Parkinson disease

The DJ1 gene (also known as PARK7)³⁷ is associated with early-onset PD in about 1–2% of cases.³⁸ It is presumed that the described mutations have a loss-of-function effect. The DJ1 gene is ubiquitously expressed and was initially described in association with oncogenesis and infertility in male rats. The protein has also been shown to confer CHAPERONE-like activity, however, and to function as an intracellular sensor of oxidative stress.³⁹ Of probable relevance, the pH-change-induced ELECTROPHORETIC SHIFT of human DJ1, and the sulfoxidation of Cys106-mediated translocation of the protein to the mitochondria in response to oxidative stress, imply a role for the protein in the cellular response to oxidative stress, as recently supported by a mouse model of Dj1 inactivation.^{39, 40} In addition, Dj1 was found to be involved in in-vivo signaling of the dopamine D2-receptor subtype in mice.⁴¹

The neurological, brain-imaging and pharmacodynamic patterns of PINK1-linked and DJ1-linked PD are widely interchangeable with those of Parkin-associated cases, but the precise roles of these three proteins in promoting the survival of neurons that are affected in PD remain unknown. Moreover, the findings of brain autopsies in patients with mutations in PINK1 or DJ1 have not yet been published. Nevertheless, it is possible to speculate that Parkin, DJ1 and PINK1 are critically involved in the sensing of a dysregulated redox equilibrium or mitochondrial dysfunction (or both) and, accordingly, in the activation of an integrated cellular-response program.^{23, 24, 25, 36, 37, 39, 40} The primary purpose of this integrated response could be the maintenance of both redox homeostasis and mitochondrial integrity, thereby facilitating the sustained survival of at-risk neurons during 10 decades of human aging (Figure 3).

Figure 3 Parkinson disease (PD) as a complex disorder.

A model of known pathogenetic events in PD shows a principal imbalance between factors that promote PD (e.g. increased total metal content in the substantia nigra, altered steady-state levels of -synuclein proteins, including its phosphorylation, rise in dopamine-metabolism-related stress, and exposure to neurotoxins) and factors that prevent PD (e.g. cigarette smoking, caffeine consumption, expression of wild-type Parkin, DJ1, and PINK1, and normal levels of glutathione). LRRK2, leucine-rich repeat kinase 2; mt, mutant; phosphor., phosphorylation of -synuclein at residue Ser129; PINK1, phosphatase and tensin homolog (PTEN)-induced putative kinase 1; Ser18, serine at residue 18; Tyr, tyrosine at residue 18; UCHL1, ubiquitin carboxyl-terminal esterase L1; wt, wild-type.

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Dominantly inherited parkinson disease: Probable gain-of-function mechanism

SNCA-associated Parkinson disease

The SNCA gene (also known as PARK1) was the first gene to be unequivocally associated with familial PD.⁴² In addition to three point mutations, several PD families were recently identified as carrying single-allele triplication (initially assigned a separate locus, PARK4,⁴³ but later corrected) or duplication events in the wild-type SNCA gene.⁴⁴ Interestingly, the severity of the phenotype appears to depend on gene dosage, and patients with SNCA duplications bear a closer clinical resemblance to idiopathic PD patients than do patients with triplications. Nevertheless, both MIS-SENSE and multiplication events are extremely rare.⁴⁵

The SNCA protein is abundantly expressed as a 140-residue cytosolic and lipid-binding phosphoprotein in the vertebrate nervous system, where it is believed to participate in the maturation of presynaptic vesicles and to function as a negative co-regulator of neurotransmitter release.⁴⁶ Intriguingly, fibril-forming, phosphorylated species of SNCA were found to be abundant in insoluble inclusions (Lewy bodies and Lewy neurites), prompting neuropathologists to group several SNCA-inclusion-rich diseases together. These 'synucleinopathy disorders' (a term coined by Trojanowski and Lee⁴⁷) primarily encompass sporadic PD, SNCA-linked PD, dementia with Lewy bodies, and multiple-system atrophy,⁴⁸ but can also be variably found in other neurodegenerative syndromes.¹³ Nevertheless, the elucidation of the relevant neurotoxic SNCA species in vivo and the critical steps required for the gain-of-function mechanism remain areas of intense research activity.

LRRK2-associated Parkinson disease

Recently, the leucine-rich repeat kinase 2 (LRRK2; also known as PARK8) gene has been identified by two independent groups.^{49, 50}LRRK2 is a large gene that consists of 51 exons, and which encodes a 2,527-amino-acid protein named LRRK2 or Dardarin, with various conserved domains recognized in its primary amino-acid sequence. To date, more than 40 variants have been reported in this gene. Owing to reduced penetrance and phenocopies, the role of some of these variants currently remains elusive, although at least 16 variants appear to be pathogenic. These variants, which include eight recurrent mutations, occur in only 10 of the 51 exons of LRRK2,^{49, 50, 51, 52, 53, 54, 55, 56, 57} indicating that it might be justifiable to limit genetic testing to these exons. For the most frequent and well-investigated mutation (c.6055GA), a common FOUNDER has been suggested.^{56, 57} This single mutation has been reported in 1.5% of tested index cases (100 out of 6,500 cases) and in only 2 out of 12,000 healthy individuals. More recently, LRRK2 mutations have been detected in 1% of early-onset PD cases (Hedrich K et al., unpublished data). Post-mortem analysis of four patients from a family with one of the recurrent mutations surprisingly revealed a broad spectrum of abnormalities: Lewy bodies restricted to brainstem nuclei in the first patient; diffuse Lewy bodies in the second patient; NEUROFIBRILLARY TANGLES, but no Lewy bodies, in the third patient; and isolated cell loss without neurofibrillary tangles or Lewy bodies in the fourth patient.¹¹

Numerous working models have been proposed to integrate the complexities of environmental, biochemical, genetic and neuropathological evidence, but a more simplistic model of PD pathogenesis depicts a progressive imbalance between the forces that promote the degeneration of at-risk neurons by increasing mitochondrial dysfunction, oxidative stress, iron accumulation and lipid dysregulation during the aging process, and those that encompass individual or integrated cellular-defense mechanisms (Figure 3).

Genetic susceptibility factors in parkinson disease

Monogenic PD accounts for only a minority of cases; most other cases are probably caused by complex interactions between several genes encoded by nuclear or mitochondrial DNA (or both), modifying effects of susceptibility alleles and epigenetic factors, and effects on PD-linked-gene expression that are attributable to environmental agents and aging. There are several challenges, however, for PD geneticists: there is no readily available test of high specificity and sensitivity that immediately distinguishes PD from other parkinsonian conditions; PD has a long preclinical phase; and PD is a late-life disorder. Several genetic variations probably act only as disease modifiers, influencing the disease's penetrance, age of onset,⁵⁸ or severity and progression.

Role of heterozygous mutations in 'recessive' genes

A considerable percentage of patients with PD was shown to carry a single heterozygous mutation in the Parkin, DJ1 or PINK1 genes,^{7, 9, 15, 17, 30, 32, 33} raising the intriguing question of whether the much more frequent heterozygous mutations in 'recessive' genes might act as susceptibility factors for PD. There are several ways to explore the potential role of these mutations.

First, the frequency of single heterozygous mutations in ethnically matched PD cases and controls could be compared. According to recent reports, heterozygosity for Parkin mutations was similar between patients and controls,⁵⁹ whereas heterozygous PINK1 mutations were rarer in controls.^{28, 30} Lincoln et al.⁵⁹ indicated that there was no elevation in PD risk for people who carry a single mutant Parkin allele. In most studies, however, healthy controls are not subjected to detailed neurological and neuroimaging examinations, leaving open the possibility that mild clinical (or preclinical) changes could have been present but were not screened for. As recently shown for Parkin¹² and PINK1⁹ families, subtle, but unequivocal, clinical signs of possible or probable PD can be found on careful motor examination, and verified by blinded video review, in a considerable number of the heterozygous mutation carriers who consider themselves asymptomatic (Figure 2). Furthermore, it could be argued that at least some of the controls had not yet reached the age of their disease onset.

Second, the heterozygous offspring of homozygous or COMPOUND HETEROZYGOUS mutation carriers could be examined in a prospective manner, an approach that is currently being used in several cohorts. The probability that a second mutation might have been overlooked in these carriers is much lower than the probability of a mutation being missed in sporadic cases of PD.

Last, further functional studies of the affected allele carriers would be highly valuable. HAPLOINSUFFICIENCY, leading to a functional loss of heterozygosity or a DOMINANT-NEGATIVE effect of some mutant alleles (Figure 2), could explain why a second mutation cannot (and need not) be found for some mutations in the above-mentioned recessive genes.

Although the role of heterozygous mutations in the development of clinical signs currently remains a matter for debate, there is growing evidence that they are associated with preclinical changes. PET studies have revealed reduced [¹⁸F]fluoro-dopa uptake by nerve terminals in the striatum of heterozygotes;^{60, 61} there are also structural neuroimaging changes that indicate an increased deposition of metals in the substantia nigra,⁶² and there is reorganization of striatocortical motor loops with detectable changes in connectivity patterns.⁶³

These collective data have important implications. Some carriers of heterozygous mutations might be in the preclinical period of PD, thereby affording unique opportunities to examine the relative risk associated with the affected allele and to study the natural history of the disease. This group also represents an ideal study population to be used not only to investigate compensatory mechanisms, facilitating the development of a sensitive surrogate marker, but also to detect the earliest PD-specific changes, allowing the development of urgently needed clinical biomarkers. Finally, these individuals could provide a small, but important, target population in which to evaluate the 'proof of principle' of a therapeutic intervention in future neuroprotection trials.

Identification of susceptibility genes

To identify susceptibility genes, genome-wide scans have been performed in large cohorts of sibling pairs, and linkage has been demonstrated to chromosomes 2, 10 and X.⁶⁴ By contrast, association studies do not depend on the availability of affected (or unaffected) family members, but instead compare frequencies of polymorphisms in PD candidate genes in matched patient and control groups. Proposed associations cannot always be replicated in follow-up studies, however, and few PD candidate genes were confirmed in meta-analyses.⁶⁵ Nevertheless, some polymorphisms—such as those in the N-acetyltransferase 2 (NAT2), monoamine oxidase B (MAOB), ferritin (light chain), and glutathione S-transferase theta 1 (GSTT1) genes,⁶⁵ the tau H1 haplotype,⁶⁶ and, most recently, the Gaucher-disease-linked glucocerebrosidase beta (GBA) gene⁶⁷—were consistently shown to be associated with an increased risk for PD. These data indicate that common genetic variants might alter the primary susceptibility to developing PD by interacting with environmental factors, contribute to the pathogenesis of PD, modify disease penetrance, or determine the age of onset of PD (or any combination thereof). In another extensively studied example, a promoter polymorphism in the SNCA gene that probably affects the rate of expression of the SCNA protein was found to be synergistic with a protective variant (Ser18Tyr polymorphism) in the UCHL1 (PARK5) gene (Figure 3). The latter variant in turn might alter the rate of SNCA degradation,⁶⁸ thereby affecting the relative risk of developing sporadic PD.⁶⁹

Genetic testing in parkinson disease

When discussing genetic testing in PD, several important points need to be considered, including the primary indication for testing, concerns regarding the implications of symptomatic, presymptomatic and susceptibility testing, the available technical expertise, the feasibility of specific-PD-gene testing and its coverage by a health insurance provider, the mutation frequency in the gene of interest, the general lack of neuroprotective treatment options in PD, and the prognosis of the condition diagnosed (nonfatal in the case of PD). Other important issues include general clinical management decisions, such as the pursuit of further diagnostic work-up, the empiric treatment of a given parkinsonian syndrome because of its clinical resemblance to a treatable condition (e.g. chelation therapy in Wilson disease) or more confident planning for deep-brain stimulation in the future, and important patient-confidentiality concerns.

Several PD-associated genes are quite large (e.g. Parkin) or contain a sizable number of exons (e.g. LRRK2), and gene-dosage alterations have been found in many of them. Therefore, mutational analysis is technically demanding, labor-intense, and expensive. Importantly, a negative result does not fully exclude a mutation, because introns and promoter regions are not usually sequenced, and the sensitivity and specificity of many testing methods are less than 100%.

Factors associated with mutation frequencies have been studied most extensively in Parkin-associated PD. In such cases, the frequency of mutations appears to be highly correlated to a lower age of onset and a positive family history.⁷⁰ The observed mutation rate in a given gene will be influenced by ethnic background, mode of patient ascertainment, the exclusion of mutations in known genes before testing of a novel gene, and the extent of the mutational analysis. It is important to note that for idiopathic, late-onset PD, data on the frequency and spectrum of mutations in the above-mentioned genes are currently scarce, limiting the extent to which genetic insights can be applied to clinical practice (Figure 1).

Symptomatic testing for PD is aimed at elucidating the origin of the present condition, whereas presymptomatic testing is usually performed on an individual with a clear-cut family history, who has no symptoms of PD at the time of testing. These approaches involve looking for genetic mutations that have a high penetrance, such as homozygous or compound heterozygous mutations in recessively inherited genes (e.g. Parkin, PINK1, and DJ1) or dominantly inherited SNCA or LRRK2 mutations. By contrast, susceptibility testing is employed to test for higher probability—rather than certainty—of developing signs of PD in the future. Susceptibility testing is more relevant to a much larger at-risk population, and obviously yields more-ambiguous information (e.g. when testing for heterozygous mutations in recessively inherited genes, such as Parkin, DJ1, PINK1 or GBA, or for polymorphisms in candidate genes). Because of this ambiguity, it is recommended that this approach should be confined to the research setting, rather than being applied to routine clinical practice.

Genetic testing for Parkin and PINK1 has become increasingly commercially available. In addition, testing of these two genes, as well as of SCNA, DJ1 and LRRK2, is performed at a number of research laboratories, some of which provide individual reports to the referring neurologist. In the absence of established guidelines for genetic testing in PD, however, genetic analysis should not be recommended lightly as a diagnostic test. Testing needs to be accompanied by proper pre-test and post-test education and counseling at an experienced center. This approach differs from that of genetic research studies, where test results are not communicated back to the patients, in accordance with most study designs and stipulations by ethics review boards. Moreover, in the management of essentially all monogenic PD cases, symptomatic treatment will not be affected. Furthermore, there is no widely accepted neuroprotective treatment regimen available in our standard-of-care options at the present time. In contrast to the usually highly informative results obtained in Huntington disease—historically the frontrunner in genetic testing for a neurodegenerative (but also fatal, in contrast to PD) disorder—the result of a genetic test in PD might be inconclusive.⁷¹

It is important to stress that no formal guidelines have been established by the Movement Disorder Society or any other international PD alliance group. In our experience, to minimize further work-up, clarify treatment approaches, and to assist with future family planning, genetic testing will most frequently be considered in the following clinical scenarios affecting symptomatic subjects: juvenile-onset PD (age of onset <20 years) irrespective of family history; early-onset PD (age of onset 21–40 years) with a positive family history and/or atypical features (e.g. dystonia in the lower extremities); or onset of PD after age 40 years with a strongly positive family history (especially of early-onset PD). In addition, presymptomatic testing in carefully selected individuals with an identified mutation in a first-degree family member might be considered (Figure 1). The unknown clinical significance of heterozygous mutations in recessively inherited genes should, however, be strongly emphasized in predicted carriers of heterozygous mutations (Figure 4), and genetic testing for diagnostic purposes in lieu of a readily available and inexpensive biomarker of the disease state (e.g. [¹⁸F]fluoro-dopa PET scanning) should be strongly discouraged. When considering genetic testing in routine neurological practice, we should remind ourselves of the timeless mandate, 'Primum nil nocere!' ('First, do no harm!'): the academic curiosity of a knowledgeable practitioner has to be weighed against the actual benefit (or lack thereof) of genetic testing to the patient. Therefore, we strongly recommend involving an expert in movement disorders and genetic counseling when considering a genetic test for PD-linked genes.

Figure 4 Genetic testing: a case example.

Inference of mutational status in a single pedigree with one identified carrier of homozygous mutations in a recessively inherited Parkinson disease gene (shaded in black). The two bars next to the pedigree symbols represent the two alleles of the respective genes. A mutation is indicated by the star symbol. With nonpaternity excluded, individuals I.1, I.2, and III.1 can be inferred to be carriers of heterozygous mutations on the basis of the pedigree structure, whereas the mutational status in individuals II.2, II.3, and II.4 is unknown. Confirmation of predicted heterozygous mutations should be discouraged because their clinical significance is still unresolved. The uncertainties associated with the (possible) finding of a heterozygous mutation in individuals II.2, II.3, and II.4 need to be carefully considered in pre-test and post-test counseling of these individuals.

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Conclusions and implications for translational research

More than 40 years ago, Hornykiewicz discovered the selective dopamine deficiency in PD and, together with Birkmayer, introduced the first form of neurotransmitter-replacement therapy,⁷² which remains the basis of symptomatic treatment in PD to this day. The discovery of a familial PD-associated gene in 1997 and the ensuing breakthroughs heralded the beginning of a new era. The PD field now enjoys an embarrassment of riches in genetic leads that also represent a mandate for translational research success. In the clinic, two immediate goals need to be met.

First, it is necessary to develop a widely available, inexpensive biomarker for PD⁷³ that improves diagnostic accuracy by all practitioners. Such a test (or combination of tests) should ideally capture individuals at risk during their presymptomatic period,⁶² distinguish patients with classical PD from those with other disorders in their symptomatic stage, and accurately reflect disease progression, or its arrest following successful intervention.

Second, recent pathogenetic insights need to be urgently translated into cause-directed therapy for neuropreventive treatment during the presymptomatic phase of PD and neuroprotection of residual at-risk cells in the symptomatic stages.

For pharmacological purposes, the plethora of research developments since 1997 has generated two intriguing leads. Lowering the SNCA steady-state level in vivo (in particular in individuals with elevated levels of SNCA) and increasing the expression of Parkin (and possibly the DJ1 and PINK1 proteins) in the aging human brain could help to slow PD progression in our already diagnosed patients and, ideally, delay disease onset in high-risk individuals.

Note added in proof The c.6055GA mutation has been found to be a frequent cause of PD in certain ethnic populations, accounting for as many as 18% of cases in Ashkenazi Jews⁷⁴ and 37% of cases in North African Arabs.⁷⁵

Key points

• Over the past decade, Parkinson disease (PD) has evolved from a textbook example of a mostly nonhereditary disease to a complex disorder with a well-established genetic component in a considerable subset of patients

• PD is clinically characterized by the cardinal features of bradykinesia, tremor, rigidity, postural instability, and responsiveness to dopaminergic therapy

• Disease phenotypes associated with the PARK1–9 chromosomal loci follow a typical Mendelian pattern of inheritance, but PARK10 and PARK11 represent susceptibility loci with an as yet undefined mode of transmission

• Monogenic PD accounts for a minority of cases; most of the other cases are probably caused by complex interactions between several genes, modifying effects of susceptibility alleles and epigenetic factors, and effects on PD-linked-gene expression that are attributable to environmental agents and aging

• When considering genetic testing in routine PD practice, the academic curiosity of a knowledgeable practitioner has to be weighed against the actual benefit of genetic testing to the subject

• The PD field now enjoys an embarrassment of riches in genetic leads that also represent a mandate for translational research success

Acknowledgments

We thank our patients and their families for encouragement and support. The authors wish to express their gratitude to their colleagues M Farrer, A Lang and L Sudarsky for critical comments on earlier versions of the manuscript. CK received support through a Lichtenberg Grant from the Volkswagen Foundation, the Deutsche Forschungsgemeinschaft, and a Research Grant from the University of Lübeck; MGS received support from the National Institute of Neurological Disorders and Stroke/National Institutes of Health, Michael J Fox Foundation, and Multiple System Atrophy Fund at Brigham and Women's Hospital.

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Ghislaine SURREL

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