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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. [ABSTRACT FROM AUTHOR]

Myopathy, lactic acidosis, and sideroblastic anemia 2 (MLASA2) is an autosomal recessive mitochondrial disorder caused by pathogenic variants in YARS2. YARS2 variants confer heterogeneous phenotypes ranging from the full MLASA syndrome to a clinically unaffected state. Symptom onset is most common in the first decade of life but can occur in adulthood and has been reported following intercurrent illness. Early death can result from respiratory muscle weakness and cardiomyopathy. We report a case of MLASA2 with compound heterozygous YARS2 pathogenic variants; a known pathogenic nonsense variant [NM_001040436.3:c.98C>A (p.Ser33Ter)] and a likely pathogenic missense variant not previously associated with disease [NM_001040436.3:c.948G>T (p.Arg316Ser)]. The proband initially presented with a relatively mild phenotype of myopathy and lactic acidosis. During pregnancy, anemia emerged as an additional feature and in the postpartum period she experienced severe decompensation of cardiorespiratory function. This is the first reported case of pregnancy‐related complications in a patient with YARS2‐related mitochondrial disease. This case highlights the need for caution and careful counseling when considering pregnancy in mitochondrial disease, due to the risk of disease exacerbation and pregnancy complications. [ABSTRACT FROM AUTHOR]

This document provides consensus‐based recommendations for general physicians and primary care physicians who diagnose and manage patients with mitochondrial diseases (MD). It builds on previous international guidelines, with particular emphasis on clinical management in the Australian setting. This statement was prepared by a working group of medical practitioners, nurses and allied health professionals with clinical expertise and experience in managing Australian patients with MD. As new treatments and management plans emerge, these consensus‐based recommendations will continue to evolve, but current standards of care are summarised in this document. [ABSTRACT FROM AUTHOR]

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 (ORPathogenic, 0.38; 95% CI, 0.21–0.67 and ORRiskVariant, 0.19; 95% CI, 0.04–0.99). Similar associations were observed for ibuprofen and aspirin separately (ORIbuprofen, 0.19; 95% CI, 0.07–0.50 and ORAspirin, 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 [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In Australia 1% of individuals aged over 50 years have Parkinson disease ( PD). Guidance for commencing device-assisted therapies ( DAT) for PD in Australia was developed based on a review of European recommendations and their relevance to the local clinical setting. An online survey and teleconference discussions were held by a group of eight local movement disorder experts to develop consensus. Referral to a movement disorder specialist and consideration of DAT is appropriate when motor fluctuations cause disability or reduced quality of life, response to treatment is inconsistent or motor fluctuations and dyskinesias require frequent treatment adjustment without apparent benefit and levodopa is required four or more times daily. Three types of DAT are available in Australia for patients with PD: continuous subcutaneous apomorphine; continuous levodopa-carbidopa intestinal gel infusion; and deep brain stimulation. All improve consistency of motor response. The most important aspects when considering which DAT to use are the preferences of the patient and their carers, patient comorbidities, age, cognitive function and neuropsychiatric status. Patients and their families need to be provided with treatment options that are suitable to them, with adequate explanations regarding the recommendations and comparison of potential device-related complications. DAT are best managed, where possible, in a specialist centre with experience in all three types of therapy. Proactive and early management of symptoms during disease progression is essential to maintain optimally motor responses and quality of life in patients with PD. [ABSTRACT FROM AUTHOR]

Hemiballism is a rare hyperkinetic movement disorder. The pathophysiology of hemiballism is poorly understood, and there have been few reports of neurophysiological recordings. The authors report three cases of hemiballism with associated radiological and neurophysiological findings. In patients 1 and 2, who were studied in the acute phase 4 and 14 days after presentation, irregularly timed and predominantly long-duration electromyographic ( EMG) bursts were observed typically ranging from 200 to 1500 milliseconds in duration and occurring asynchronously or alternating in antagonist muscles. In patient 3, who was studied 6 weeks after presentation when the involuntary movements had become choreiform, the EMG bursts were still from 200 to 1000 milliseconds in duration but were more synchronous or co-contracting. The flailing movements of hemiballism appear to occur as a result of prolonged bursts of EMG activity generated in individual muscles unopposed by EMG bursting in the antagonist. During the subacute phase when the movements become more choreiform, the results indicate that EMG activity becomes more synchronous or co-contracting. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Levodopa‐carbidopa intestinal gel offers superior treatment to standard oral therapy in selective patients with advanced Parkinson disease. The costs involved in instituting and maintaining this treatment are high but largely mitigated with the quality of life years the treatment offers. Key to this is ensuring a high retention rate once the treatment is instituted. We outline factors and considerations from our experience and viewpoints at each stage of the process to address in this ‘journey’ patients undertake that can help maximise retention rates and benefits. [ABSTRACT FROM AUTHOR]

Aims The hereditary spastic paraplegias ( HSPs) are a heterogeneous group of disorders characterized by spasticity in the lower limbs. We provide an overview of HSP with an emphasis on recent developments. Methods A PubMed search using the term 'hereditary spastic paraplegia' and 'hereditary spastic paraparesis' was conducted for a period from January 2012 to January 2015. We discuss and critique the major studies in the field over this 36-month period. Results A total of 346 publications were identified, of which 47 were selected for review. We provide an update of the common forms of HSP and include patient videos. We also discuss how next-generation sequencing (NGS) has led to the accelerated discovery of new HSP genes, including B4 GALNT1, DDHD1, C19orf12, GBA2, TECPR2, DDHD2, C12orf65, REEP2, and IBA57. Moreover, a single study alone identified 18 previously unknown putative HSP genes and created a model for the protein interactions of HSP, called the ' HSPome.' Many of the newly reported genes cause rare, complicated, autosomal recessive forms of HSP. NGS also has important clinical applications by facilitating the molecular diagnosis of HSP. Furthermore, common genetic forms of HSP have been studied using new disease models, such as neurons derived from induced pluripotent stem cells. These models have been used to elucidate important disease mechanisms and have served as platforms to screen for candidate drug compounds. Conclusion The field of HSP research has been progressing at a rapid pace. The challenge remains in translating these advances into new targeted disease therapies. [ABSTRACT FROM AUTHOR]

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 Zn2+ 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 [ABSTRACT FROM AUTHOR]

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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 [ABSTRACT FROM AUTHOR]

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. © 2012 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Introduction: [ABSTRACT FROM AUTHOR]

We investigated a 62-year-old man who had mild clinical features of myotonia congenita. He was found to have a novel heterozygous G-to-A nucleotide substitution at position 1652 in exon 15 of the CLCN1 gene. Clinicogenetic studies performed on his family revealed that his asymptomatic son also shared the mutation. We conclude that a novel chloride channel mutation (G1652A) has caused a mild form of autosomal-dominant myotonia congenita (Thomsen disease) in this family. Muscle Nerve, 2010 [ABSTRACT FROM AUTHOR]

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. © 2008 Movement Disorder Society [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The levodopa carbidopa intestinal gel is a device‐assisted therapy used for the management of fluctuating motor symptoms of Parkinson's disease that are refractory to oral therapy. The approach has demonstrable clinical value, but consideration of the associated need for expert care, access to services, and costs of the treatment impact the method of introduction to optimize uptake and minimize discontinuation across populations examined. Systematic approaches and modifications have been explored by different centers over the years to mitigate these considerations, with the aim of minimizing adverse events and maximizing the quality‐of‐life years gained with the treatment. In this presentation, we aim to outline an approach to managing this treatment while highlighting measures that can be utilized throughout the process to improve patients' experiences. View Supplementary Video 1 [ABSTRACT FROM AUTHOR]