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Genetic testing for persons with Parkinson's disease is becoming increasingly common. Significant gains have been made regarding genetic testing methods, and testing is becoming more readily available in clinical, research, and direct-to-consumer settings. Although the potential utility of clinical testing is expanding, there are currently no proven gene-targeted therapies, but clinical trials are underway. Furthermore, genetic testing practices vary widely, as do knowledge and attitudes of relevant stakeholders. The specter of testing mandates financial, ethical, and physician engagement, and there is a need for guidelines to help navigate the myriad of challenges. However, to develop guidelines, gaps and controversies need to be clearly identified and analyzed. To this end, we first reviewed recent literature and subsequently identified gaps and controversies, some of which were partially addressed in the literature, but many of which are not well delineated or researched. Key gaps and controversies include: (1) Is genetic testing appropriate in symptomatic and asymptomatic individuals without medical actionability? (2) How, if at all, should testing vary based on ethnicity? (3) What are the long-term outcomes of consumer- and research-based genetic testing in presymptomatic PD? (4) What resources are needed for clinical genetic testing, and how is this impacted by models of care and cost-benefit considerations? Addressing these issues will help facilitate the development of consensus and guidelines regarding the approach and access to genetic testing and counseling. This is also needed to guide a multidisciplinary approach that accounts for cultural, geographic, and socioeconomic factors in developing testing guidelines. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: There is growing clinical and research utilization of genetic testing in Parkinson's disease (PD), including direct-to-consumer testing., Objectives: The aim is to determine the international landscape of genetic testing in PD to inform future worldwide recommendations., Methods: A web-based survey assessing current practices, concerns, and barriers to genetic testing and counseling was administered to the International Parkinson and Movement Disorders Society membership., Results: Common hurdles across sites included cost and access to genetic testing, and counseling, as well as education on genetic counseling. Region-dependent differences in access to and availability of testing and counseling were most notable in Africa. High-income countries also demonstrated heterogeneity, with European nations more likely to have genetic testing covered through insurance than Pan-American and Asian countries., Conclusions: This survey highlights not only diversity of barriers in different regions but also the shared and highly actionable needs for improved education and access to genetic counseling and testing for PD worldwide. © 2023 International Parkinson and Movement Disorder Society., (© 2023 International Parkinson and Movement Disorder Society.)

Background: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited., Objective: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD., Methods: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed., Results: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published., Conclusions: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: The penetrance of leucine rich repeat kinase 2 (LRRK2) mutations is incomplete and may be influenced by environmental and/or other genetic factors. Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to reduce inflammation and may lower Parkinson's disease (PD) risk, but their role in LRRK2-associated PD is unknown., Objectives: The objective of this study is to evaluate the association of regular NSAID use and LRRK2-associated PD., Methods: Symptomatic ("LRRK2-PD") and asymptomatic ("LRRK2-non-PD") participants with LRRK2 G2019S, R1441X, or I2020T variants (definitely pathogenic variant carriers) or G2385R or R1628P variants (risk variant carriers) from 2 international cohorts provided information on regular ibuprofen and/or aspirin use (≥2 pills/week for ≥6 months) prior to the index date (diagnosis date for PD, interview date for non-PD). Multivariate logistic regression was used to evaluate the relationship between regular NSAID use and PD for any NSAID, separately for ibuprofen and aspirin in all carriers and separately in pathogenic and risk variant groups., Results: A total of 259 LRRK2-PD and 318 LRRK2-non-PD participants were enrolled. Regular NSAID use was associated with reduced odds of PD in the overall cohort (odds ratio [OR], 0.34; 95% confidence interval [CI], 0.21-0.57) and in both pathogenic and risk variant carriers (OR Pathogenic , 0.38; 95% CI, 0.21-0.67 and OR RiskVariant , 0.19; 95% CI, 0.04-0.99). Similar associations were observed for ibuprofen and aspirin separately (OR Ibuprofen , 0.19; 95% CI, 0.07-0.50 and OR Aspirin , 0.51; 95% CI, 0.28-0.91)., Conclusions: Regular NSAID use may be associated with reduced penetrance in LRRK2-associated PD. The LRRK2 protein is involved in inflammatory pathways and appears to be modulated by regular anti-inflammatory use. Longitudinal observational and interventional studies of NSAID exposure and LRRK2-PD are needed to confirm this association. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

The term "cerebral palsy mimic" is used to describe a number of neurogenetic disorders that may present with motor symptoms in early childhood, resulting in a misdiagnosis of cerebral palsy. Cerebral palsy describes a heterogeneous group of neurodevelopmental disorders characterized by onset in infancy or early childhood of motor symptoms (including hypotonia, spasticity, dystonia, and chorea), often accompanied by developmental delay. The primary etiology of a cerebral palsy syndrome should always be identified if possible. This is particularly important in the case of genetic or metabolic disorders that have specific disease-modifying treatment. In this article, we discuss clinical features that should alert the clinician to the possibility of a cerebral palsy mimic, provide a practical framework for selecting and interpreting neuroimaging, biochemical, and genetic investigations, and highlight selected conditions that may present with predominant spasticity, dystonia/chorea, and ataxia. Making a precise diagnosis of a genetic disorder has important implications for treatment, and for advising the family regarding prognosis and genetic counseling. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

The system of assigning locus symbols to specify chromosomal regions that are associated with a familial disorder has a number of problems when used as a reference list of genetically determined disorders,including (I) erroneously assigned loci, (II) duplicated loci, (III) missing symbols or loci, (IV) unconfirmed loci and genes, (V) a combination of causative genes and risk factor genes in the same list, and (VI) discordance between phenotype and list assignment. In this article, we report on the recommendations of the International Parkinson and Movement Disorder Society Task Force for Nomenclature of Genetic Movement Disorders and present a system for naming genetically determined movement disorders that addresses these problems. We demonstrate how the system would be applied to currently known genetically determined parkinsonism, dystonia, dominantly inherited ataxia, spastic paraparesis, chorea, paroxysmal movement disorders, neurodegeneration with brain iron accumulation, and primary familial brain calcifications. This system provides a resource for clinicians and researchers that, unlike the previous system, can be considered an accurate and criterion-based list of confirmed genetically determined movement disorders at the time it was last updated., (© 2016 International Parkinson and Movement Disorder Society.)

The importance of ATP13A2 (PARK9) in Parkinson's disease (PD) has emerged with the discovery that mutations in this gene cause Kufor-Rakeb syndrome, an autosomal recessive, juvenile-onset form of parkinsonism associated with the additional clinical triad of spasticity, supranuclear gaze palsy, and dementia. Eleven independent kindreds with homozygous or compound heterozygous ATP13A2 mutations have been identified. These reports make it clear that the condition exhibits considerable clinical heterogeneity, with a spectrum of disease even among family members carrying the same mutation. The relevance of the protein in sporadic PD is demonstrated by the presence of single heterozygous ATP13A2 mutations in this group of patients and altered expression of the gene in the substantia nigra from patients with the disease. The involvement of ATP13A2 in Zn(2+) homeostasis has recently been demonstrated, with the molecular consequences of this disturbance causing lysosomal impairment, α-synuclein accumulation, and mitochondrial dysfunction. These discoveries provide a new understanding of the role that ATP13A2 plays in the development of PD and identify a therapeutic target that may ameliorate α-synuclein accumulation and lysosomal and mitochondrial dysfunction in Parkinson's disease. © 2015 International Parkinson and Movement Disorder Society., (© 2015 International Parkinson and Movement Disorder Society.)

Background: Mutations in parkin have been associated with autosomal recessive early-onset Parkinson's disease (PD). Here, we report on unusual phenotypic variability within a family with mutations in parkin., Methods: The proband and her parents were clinically assessed. Mutation analysis was performed using genomic DNA and complementary DNA. The protein expression of Parkin and Mitofusin 2 was examined by western blotting., Results: The proband was a compound heterozygote with no detectable Parkin and presented with early-onset PD. The father, a single heterozygote with reduced expression of Parkin, had mild loss of arm swing. The mother, who had only very mild rigidity, was unexpectedly found to be a homozygote with no Parkin expression. The proband, but not the parents, met the Queen Square Brain Bank criteria for PD. Parkin-dependent ubiquitination of Mitofusin 2 was impaired in the mother and the proband., Conclusion: We report the first case of a homozygous mutation carrier in parkin who had no functional protein and only mild signs of parkinsonism in her seventh decade, whereas her daughter developed typical early-onset PD. This family demonstrates phenotypic variability in parkin-related parkinsonism. © 2012 Movement Disorder Society., (Copyright © 2012 Movement Disorder Society.)

Mohr-Tranebjaerg syndrome (MTS) is an X-linked recessive disorder characterized by deafness and dystonia. However the phenotypic expression of dystonia has not been systematically defined. We report clinical, neurophysiological, and ophthalmological data on 6 subjects from 3 Australian kindreds, including 2 with novel mutations, together with a systematic review of the literature, in order to define the phenotypic expression of dystonia. Profound hearing impairment in affected males develops by infancy and precedes the development of dystonia, which varies in time of onset from the first to the sixth decades, with a peak in the second and third decades. Dystonia in MTS tends to be focal, segmental, or multifocal in distribution at onset, with a predilection for the upper body, variably involving the head, neck, and upper limbs. The majority of patients have progression or generalization of their dystonia regardless of age of onset. Within our 3 kindreds, we observed relative intrafamilial homogeneity but interfamilial variation. The median time to the development of moderate-severely disabling dystonia in these subjects was 11 years. Associated features included progressive cognitive decline, pyramidal signs, and in 1 patient, gait freezing and postural instability. Optic atrophy and cortical visual impairment were both observed. We report for the first time a female patient who developed multiple disabling neurological complications of MTS. Our findings more clearly define and expand the phenotype of both the dystonia and other neurological features of MTS and have implications for the diagnosis and management of this condition., (Copyright © 2012 Movement Disorder Society.)

MtDNA haplogroups J and K have been associated with a decreased risk of developing Parkinson's disease (PD). To confirm this finding, we compared the distribution of mtDNA haplogroups J and K in a large sample of Australian patients with PD (n = 890) to population-based controls (n = 3,491). We assigned subjects to haplogroups J or K using standard PCR/RFLP techniques. Of the 890 subjects with PD, 10.6% were haplogroup J (95% CI 8.6-12.8, n = 94) and 7.1% were haplogroup K (95% CI 5.5-8.9, n = 63). In our controls, 10.2% belonged to haplogroup J (95% CI 9.2-11.2, n = 356), and 7.8% were in haplogroup K (95% CI 6.9-8.7, n = 272). There was no significant difference in the prevalence of mtDNA haplogroup J or K in PD patients compared to population-based controls. Our findings indicate that mtDNA haplogroups J and K are not associated with a lower risk of PD.

We determined the prevalence of two common leucine-rich repeat kinase 2 (LRRK2) gene mutations in Australian patients with Parkinson's disease (PD). Of 830 affected patients, eight were heterozygous for the G2019S mutation, and two were heterozygous for the R1441H (4,322 G > A) mutation. In addition, one familial patient had a novel A1442P (4,324 G > C) mutation. Haplotype analysis showed that all LRRK2 G2019S-positive individuals carried the common founder haplotype 1 and a putative founder haplotype for the R1441H mutation carriers. Clinically, patients with LRRK2 mutations had typical levodopa responsive Parkinsonism with tremor being the commonest presenting feature. Patients with the G2019S mutation in our series had a similar age of onset of symptoms when compared with patients with other LRRK2 mutations or sporadic PD, although they were more likely to have a family history of PD (2.4% of Australian patients with familial PD and 0.3% of Australian patients with sporadic PD). Our results demonstrate that the G2019S mutation carriers share the same ancestors who migrated to Australia originally from Europe and that other LRRK2 mutations (R1441H and A1442P) can be found in this population., ((c) 2007 Movement Disorder Society.)