Levodopa-responsive Parkinsonism Research Articles

Genetic and clinical study of PARK7 in Japanese Parkinson's disease

BackgroundBiallelic variants in PARK7, which encodes protein-nucleic acid deglycase DJ-1, can cause early-onset Parkinson's disease (PD). Although many patients with PARK7 variants have been identified from European and Middle Eastern ethnic groups, there have been no reports in the Japanese population. ObjectivesTo determine the prevalence and clinical features of patients with PD harboring PARK7 variants in Japan. MethodsWe performed a molecular genetic analysis of PD patients with PARK7 variants identified using comprehensive panel sequencing, to explore the details of variants. Moreover, clinical neurological features were investigated, including neuroimaging analyses. This study followed STROBE guidelines. ResultsFour patients with biallelic rare variants of PARK7 were identified in the cohort. All four patients presented with levodopa-responsive parkinsonism, with an age at onset in the early 30s. Furthermore, two of the four patients had psychiatric complications. Dopamine transporter imaging revealed nigrostriatal pathway dysfunction. ConclusionsTo our knowledge, this is the first report of Japanese patients with PARK7 variants. We identified a relatively low frequency of PARK7 variants in patients in Japan. As opposed to typical patients with sporadic PD, the identified patients developed the disease in their 30s and presented with a variety of non-motor symptoms and complications. Further studies are needed to identify the clinical features related to PARK7 variants in Japanese patients with PD, and to analyze the pathophysiology of how the variants identified in the present study might affect DJ-1 function.

Levodopa-responsive dystonia, parkinsonism, and treatment-resistant schizoaffective disorder in Williams syndrome.

Williams syndrome (WS; chromosome 7q11.23 deletion) is a rare, multisystemic, neurodevelopmental disorder with variable penetrance and expressivity. Although movement and psychiatric disorders are known to occur in individuals with WS, parkinsonism, dystonia, and treatment-resistant schizoaffective disorder have not been formally described. We present two unrelated cases of adults with molecularly confirmed WS and typical histories of developmental delays, intellectual/learning disabilities, and treatment-responsive anxiety/mood disorder who developed similar noteworthy neuropsychiatric expressions. We reviewed detailed neuropsychiatric histories, laboratory investigations, neuroimaging, and treatment responses and compared data for the two cases. Both individuals developed treatment-resistant schizoaffective disorder in adulthood requiring multiple trials of antipsychotic treatments. While on clozapine, both patients developed parkinsonism and generalized dystonia with truncal involvement that responded to trials of low-dose levodopa without exacerbating underlying psychotic or affective symptoms. This report illustrates the novel occurrence of levodopa-responsive movement disorders and treatment-resistant schizoaffective disorder in individuals with WS, adding to the expanding neuropsychiatric phenotypes, and highlighting potential shared underlying mechanisms. The observed treatment response suggests that levodopa, in relatively low doses, may be safe and useful in ameliorating presumed antipsychotic-associated parkinsonism and tardive dystonia in WS.

Parkinson's Disease Associated with G2019S LRRK2 Mutations without Lewy Body Pathology.

The G2019S leucine-rich repeat kinase 2 (LRRK2) gene mutation is an important and commonly found genetic determinant of Parkinson's disease (PD). The neuropathological findings associated with this mutation have thus far been varied but are most often associated with Lewy body (LB) pathology. Describe a case of clinical Parkinson's disease with levodopa responsiveness found to have LRRK2 mutations and the absence of Lewy bodies. We present an 89-year-old man with a 10-year history of slowly progressive parkinsonism suspected to be secondary to Parkinson's disease. Neuropathological evaluation revealed nigral degeneration without Lewy bodies or Lewy neurites, but there were frequent tau-immunopositive neurites and astrocytes in the putamen and substantia nigra, neocortical glial tau positive astrocytes associated with aging-related tau astrogliopathy (ARTAG), as well as neurofibrillary tangles, beta amyloid plaques, and amyloid angiopathy typical of advanced Alzheimer's disease. G2019S LRRK2 homozygous mutations were found. This case illustrates that levodopa-responsive clinical PD caused by G2019S LRRK2 mutations can occur without Lewy bodies.

Expanding the phenotypic and genotypic spectrum of DYT-TUBB4A with seven patients from India

BackgroundVariants in the TUBB4A gene are associated with dystonia (DYT-TUBB4A), Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum (H-ABC) and spastic paraplegia. Phenotypes intermediate to these three broad phenotypes are also observed. These are rare disorders, and data from diverse populations remains limited. We report seven Indian cases with dystonia phenotype related to TUBB4A mutation. CasesAmong these seven patients, age at onset ranged from 5 to 48 years. Five patients had cranio-cervical onset of dystonia. One patient had prominent parkinsonism with dystonia. Patients responded well to botulinum toxin injected for laryngeal, cervical and jaw dystonia. The patient with parkinsonism responded well to levodopa, albeit with development of dyskinesias. Apart from the common p.Arg2Gly variant in three patients with DYT-TUBB4A, other variants included p.Arg262Pro, p.Arg39Cys and p.Asp245Asn. ConclusionsWe report the first collection of cases with TUBB4A mutation from India. We expand the phenotype to include levodopa-responsive parkinsonism. Indian patients, consistent with global literature, harbor prominent adductor dysphonia, cervical and jaw dystonia, which responds well to botulinum treatment.

Delayed levodopa-responsive parkinsonism following acute midbrain injury

Acute midbrain injury may cause both hyperkinetic movement disorders and parkinsonism. The temporal interval between the insult and the emergence of hyperkinetic disorders can last years. A delayed appearance of parkinsonism, on the other hand, was rarely described. We present three cases of male patients (50-, 58- and 28-year-old) who developed levodopa-responsive parkinsonism 20, 8 and two years, respectively, after acute brain insult involving the midbrain. Insults included subcortical intracerebral hemorrhage dissecting into the midbrain, embolic basilar occlusion and trauma. A fluorodopa scan, performed in two cases, revealed reduced striatal uptake. All individuals improved on low doses of levodopa and developed motor fluctuations shortly after levodopa was introduced. We conclude that delayed, levodopa-responsive parkinsonism following midbrain injury should be recognized in the relevant clinical setup. Possible mechanisms include age-related loss of dopaminergic neurons superimposed on acute injury and secondary neurodegeneration.

Joubert Syndrome Presenting With Levodopa-Responsive Parkinsonism.

Joubert Syndrome Presenting With Levodopa-Responsive Parkinsonism.

Multiple system atrophy: an update and emerging directions of biomarkers and clinical trials.

Multiple system atrophy is a rare, debilitating, adult-onset neurodegenerative disorder that manifests clinically as a diverse combination of parkinsonism, cerebellar ataxia, and autonomic dysfunction. It is pathologically characterized by oligodendroglial cytoplasmic inclusions containing abnormally aggregated α-synuclein. According to the updated Movement Disorder Society diagnostic criteria for multiple system atrophy, the diagnosis of clinically established multiple system atrophy requires the manifestation of autonomic dysfunction in combination with poorly levo-dopa responsive parkinsonism and/or cerebellar syndrome. Although symptomatic management of multiple system atrophy can substantially improve quality of life, therapeutic benefits are often limited, ephemeral, and they fail to modify the disease progression and eradicate underlying causes. Consequently, effective breakthrough treatments that target the causes of disease are needed. Numerous preclinical and clinical studies are currently focusing on a set of hallmarks of neurodegenerative diseases to slow or halt the progression of multiple system atrophy: pathological protein aggregation, synaptic dysfunction, aberrant proteostasis, neuronal inflammation, and neuronal cell death. Meanwhile, specific biomarkers and measurements with higher specificity and sensitivity are being developed for the diagnosis of multiple system atrophy, particularly for early detection of the disease. More intriguingly, a growing number of new disease-modifying candidates, which can be used to design multi-targeted, personalized treatment in patients, are being investigated, notwithstanding the failure of most previous attempts.

Phenotypic Spectrum of Progressive Supranuclear Palsy: Clinical Study and Apolipoprotein E Effect.

Progressive supranuclear palsy (PSP) is a rare neurodegenerative disorder encompassing several phenotypes with various motor and cognitive deficits. We aimed to study motor and cognitive characteristics across PSP phenotypes and to assess the influence of apolipoprotein E (APOE) gene variants on PSP phenotypic expression. In this 20-year cross-sectional study, we retrospectively reviewed the charts of all patients classified as PSP patients and recategorized them according to phenotype using the Movement Disorder Society criteria (2017). Phenotypes were divided into three subgroups, Richardson's syndrome (PSP-RS), PSP-cortical (PSP with predominant frontal presentation [PSP-F] + PSP with predominant speech/language disorder [PSP-SL] + PSP with predominant corticobasal syndrome [PSP-CBS]) and PSP-subcortical (PSP with predominant parkinsonism [PSP-P] + PSP with progressive gait freezing [PSP-PGF] + PSP with predominant postural instability [PSP-PI] + PSP with predominant ocular motor dysfunction [PSP-OM] + PSP with cerebellar ataxia [PSP-C] + PSP with primary lateral sclerosis [PSP-PLS]), based on clinical presentation during the first 3 years after symptom onset, which defines the early disease stage. Clinical and neuropsychological assessment data were collected. Genotyping of APOE was performed using restriction fragment length polymorphism polymerase chain reaction and verified by Sanger sequencing. We included 112 PSP patients comprising 10 phenotypes classified into 48 PSP-RS, 34 PSP-cortical (PSP-CBS, 17.6%; PSP-F, 9.4%; PSP-SL, 8.2%) and 30 PSP-subcortical (PSP-P, 11.6%; PSP-PI, 8%; PSP-OM, 2.7%; PSP-PGF, 1.8%; PSP-C, 1.8%; PSP-PLS, 0.9%) subgroups. PSP-RS patients were older at disease onset (p = 0.009) and had more akinetic-rigid and levodopa-resistant parkinsonism (p = 0.006), while PSP-cortical patients had more tremors and asymmetric and/or levodopa-responsive parkinsonism (p = 0.025). Cognitive domains were significantly less altered in the PSP-subcortical subgroup. Overall, PSP-APOEε4 carriers developed parkinsonism earlier (p = 0.038), had earlier oculomotor dysfunction (p = 0.052) and had more altered cognitive profiles. The APOEε4 allele was also associated with a younger age of parkinsonism onset in the PSP-RS phenotype group (p = 0.026). This study demonstrated the wide phenotypic spectrum of PSP among Tunisians. Disease onset and akinetic-rigid and levodopa-resistant parkinsonism were the hallmarks of the PSP-RS phenotype, while milder cognitive impairment was characteristic of the PSP-subcortical subgroup. The APOEε4 allele was associated with earlier parkinsonism and oculomotor dysfunction and seemed to play a role in defining a more altered cognitive profile in PSP patients.

Novel RAB39B variant associated intellectual disability and levodopa-responsive young-onset parkinsonism

We report a 37-year-old Caucasian male with history of developmental delay, childhood onset Intellectual Disability (ID) and attention deficit hyperactivity disorder (ADHD) who presented at the age of 34 with tremor-dominant parkinsonism. Next Generation Sequencing (NGS) revealed pathogenic hemizygous sequence variant, c.200G > T, in the RAB39B gene. This report expands the number of described individuals with young onset PD associated with RAB39B mutation.

Continuous Subcutaneous Foslevodopa/Foscarbidopa in Parkinson's Disease: Safety and Efficacy Results From a 12-Month, Single-Arm, Open-Label, Phase 3 Study.

Foslevodopa/foscarbidopa, a soluble formulation of levodopa/carbidopa (LD/CD) prodrugs for the treatment of Parkinson's disease (PD), is administered as a 24-hour/day continuous subcutaneous infusion (CSCI) with a single infusion site. The efficacy and safety of foslevodopa/foscarbidopa versus oral immediate-release LD/CD was previously demonstrated in patients with PD in a 12-week, randomized, double-blind, phase 3 trial (NCT04380142). We report the results of a separate 52-week, open-label, phase 3 registrational trial (NCT03781167) that evaluated the safety/tolerability and efficacy of 24-hour/day foslevodopa/foscarbidopa CSCI in patients with advanced PD. Male and female patients with levodopa-responsive PD and ≥ 2.5hours of "Off" time/day received 24-hour/day foslevodopa/foscarbidopa CSCI at individually optimized therapeutic doses (approximately 700-4250mg of LD per 24hours) for 52weeks. The primary endpoint was safety/tolerability. Secondary endpoints included changes from baseline in normalized "Off" and "On" time, percentage of patients reporting morning akinesia, Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Parkinson's Disease Sleep Scale-2 (PDSS-2), 39-item Parkinson's Disease Questionnaire (PDQ-39), and EuroQol 5-dimension questionnaire (EQ-5D-5L). Of 244 enrolled patients, 107 discontinued, and 137 completed treatment. Infusion site events were the most common adverse events (AEs). AEs were mostly nonserious (25.8% of patients reported serious AEs) and mild/moderate in severity. At week 52, "On" time without troublesome dyskinesia and "Off" time were improved from baseline (mean [standard deviation (SD)] change in normalized "On" time without troublesome dyskinesia, 3.8 [3.3] hours; normalized "Off" time, -3.5 [3.1] hours). The percentage of patients experiencing morning akinesia dropped from 77.7% at baseline to 27.8% at week 52. Sleep quality (PDSS-2) and quality of life (PDQ-39 and EQ-5D-5L) also improved. Foslevodopa/foscarbidopa has the potential to provide a safe and efficacious, individualized, 24-hour/day, nonsurgical alternative for patients with PD. ClinicalTrials.gov identifier NCT03781167.

A case of levodopa responsive parkinsonism due to methanol toxicity, an impact of COVID-19 crisis

A case of levodopa responsive parkinsonism due to methanol toxicity, an impact of COVID-19 crisis

Spastic Paraplegia Type 30 Associated with Levodopa-Responsive Parkinsonism.

Movement Disorders Clinical PracticeAccepted Articles LETTERS: GENOTYPE AND PHENOTYPE Spastic paraplegia type 30 associated with levodopa-responsive parkinsonism Amy Gallagher MB MRCPI, Corresponding Author Amy Gallagher MB MRCPI [email protected] orcid.org/0000-0003-2068-5628 Department of Neurology, Dublin Neurological Institute at the Mater Misericordiae University Hospital, Dublin, Ireland Correspondence to: Amy Gallagher, Dublin Neurological Institute, 57 Eccles Street, Dublin 7, Co. Dublin, Ireland, E-mail: [email protected]Search for more papers by this authorConor Fearon BE MB PhD, Conor Fearon BE MB PhD orcid.org/0000-0002-8172-6094 Department of Neurology, Dublin Neurological Institute at the Mater Misericordiae University Hospital, Dublin, Ireland Department of Neurology, St Vincent's University Hospital, Elm Park, Dublin Health Affairs, University College DublinSearch for more papers by this authorKathryn Smith, Kathryn Smith Department of Neurology, Dublin Neurological Institute at the Mater Misericordiae University Hospital, Dublin, IrelandSearch for more papers by this authorTimothy Lynch MB, FRCPI, FRCP, MD, Timothy Lynch MB, FRCPI, FRCP, MD Department of Neurology, Dublin Neurological Institute at the Mater Misericordiae University Hospital, Dublin, Ireland Health Affairs, University College DublinSearch for more papers by this author Amy Gallagher MB MRCPI, Corresponding Author Amy Gallagher MB MRCPI [email protected] orcid.org/0000-0003-2068-5628 Department of Neurology, Dublin Neurological Institute at the Mater Misericordiae University Hospital, Dublin, Ireland Correspondence to: Amy Gallagher, Dublin Neurological Institute, 57 Eccles Street, Dublin 7, Co. Dublin, Ireland, E-mail: [email protected]Search for more papers by this authorConor Fearon BE MB PhD, Conor Fearon BE MB PhD orcid.org/0000-0002-8172-6094 Department of Neurology, Dublin Neurological Institute at the Mater Misericordiae University Hospital, Dublin, Ireland Department of Neurology, St Vincent's University Hospital, Elm Park, Dublin Health Affairs, University College DublinSearch for more papers by this authorKathryn Smith, Kathryn Smith Department of Neurology, Dublin Neurological Institute at the Mater Misericordiae University Hospital, Dublin, IrelandSearch for more papers by this authorTimothy Lynch MB, FRCPI, FRCP, MD, Timothy Lynch MB, FRCPI, FRCP, MD Department of Neurology, Dublin Neurological Institute at the Mater Misericordiae University Hospital, Dublin, Ireland Health Affairs, University College DublinSearch for more papers by this author First published: 15 June 2023 https://doi.org/10.1002/mdc3.13815 This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/mdc3.13815. AboutPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Accepted ArticlesAccepted, unedited articles published online and citable. The final edited and typeset version of record will appear in the future. RelatedInformation

ID: 197424 Improvement in Quality-of-Life and Motor Function: Real-World, Prospective Study of Directional DBS Systems

Early Deep Brain Stimulation (DBS) systems used ring-shaped electrodes to achieve axial selectivity in stimulation of target tissue. However, directional current steering allows for rotational selectivity (in addition to axial) and has the potential to further improve patient outcomes by avoiding off-target stimulation due to the ability to create a well-defined field around the intended target. Several pilot studies have corroborated the use of directionality and its impact on therapeutic window and adverse effects.1-3 In this report, real-world outcomes using Directional DBS Systems with multiple independent current source control (MIC() for use in managing symptoms of levodopa responsive Parkinson's disease (PD) are reported.

Assessment of Virtual Reality Devices as a Means of Objectively Monitoring Parkinson’s Disease (P10-11.014)

<h3>Objective:</h3> To show that consumer virtual reality (VR) devices are capable of providing statistically reliable and replicable data on treatment response in Parkinson Disease (PD). <h3>Background:</h3> Parkinson’s disease results in motor dysfunction with varying response to exogenous levodopa. Response to treatment is monitored with ratings scale such as the Unified Parkinson Disease Rating Scale (UPDRS). However, this paradigm of care results in slow response times and limited reliability. The development of technologies to assist with clinical assessments is essential to improving care. Mass market VR devices with their ability to measure movement and generate testing environments may be able to increase objectivity, validity, and monitoring frequency. <h3>Design/Methods:</h3> Individuals with levodopa responsive PD without other complicating conditions were selected (n=20). Participants were first evaluated in their off-state using the UPDRS motor scale and participated in a virtual reality assessment which mirrored the clinical exam. Hand positioning was recorded. Afterwards, levodopa was administered and individuals were reassessed clinically and with the VR device. <h3>Results:</h3> Severity of tremor decreased after levodopa administration in all assessed states with statistical significance achieved reliably in two of three states (p&lt;0.05). Bradykinesia measures improved in all three states, though statistical significance was only achieved reliably in one state. For tremor, strong correlations between various device and physician measures of tremor severity were present (r = 0.5–0.8). For bradykinesia, moderate correlations existed between the state which had achieved statistical significance in the on-off state comparison (r ~ 0.5). Patient perception surveys noted most individuals were willing to incorporate similar devices into their care. <h3>Conclusions:</h3> VR devices are can detect patient responsiveness to levodopa and device generated metrics correlate with validated physician metrics. Device use is accepted and essentially side-effect free. This study argues for the further evaluation of PD by VR devices with future focus on complex tasks. <b>Disclosure:</b> An immediate family member of Dr. Hirczy has received personal compensation for serving as an employee of Meta. Dr. Hirczy has received personal compensation in the range of $500-$4,999 for serving as a Author with Slack Enterprises. The institution of Dr. Salinas has received research support from North Texas VA Health Care System New Investigator Award.

Two Different PRKN Compound Heterozygous Variants Combinations in the Same Family.

Two Different PRKN Compound Heterozygous Variants Combinations in the Same Family.

PNPLA6-Related Disorder with Levodopa-Responsive Parkinsonism.

PNPLA6-Related Disorder with Levodopa-Responsive Parkinsonism.

Safety and efficacy of continuous subcutaneous foslevodopa-foscarbidopa in patients with advanced Parkinson's disease: a randomised, double-blind, active-controlled, phase 3 trial

Levodopa is the most effective symptomatic therapy for Parkinson's disease, but patients with advanced Parkinson's disease develop motor fluctuations with chronic oral levodopa therapy. Foslevodopa-foscarbidopa is a soluble formulation of levodopa and carbidopa prodrugs that is delivered as a 24-h/day continuous subcutaneous infusion, and we aimed to assess the safety and efficacy of this formulation in patients with advanced Parkinson's disease. A 12-week randomised, double-blind, double-dummy, active-controlled study was done at 65 academic and community study centres in the USA and Australia. Patients with levodopa-responsive advanced Parkinson's disease inadequately controlled on current therapy, including at least 2·5 h of average daily off time, were randomly assigned (1:1) to continuous subcutaneous infusion of foslevodopa-foscarbidopa plus oral placebo or to oral immediate-release levodopa-carbidopa plus continuous subcutaneous infusion of placebo solution. Randomisation was stratified by site by means of a permutated-block schedule with a block size of two. The participants, treating investigators, study site personnel, and sponsor were masked to treatment group allocation. The primary and first key secondary endpoint in the hierarchical testing strategy were change from baseline to week 12 in on time without troublesome dyskinesia and off time, respectively; both endpoints were evaluated by an intention-to-treat analysis applying a mixed model for repeated measures analysis. Safety and tolerability were assessed throughout the study. The study is completed and is listed on ClinicalTrials.gov, NCT04380142. Between Oct 19, 2020, and Sept 29, 2021, of 270 participants screened and 174 enrolled, 141 were randomly assigned and received continuous subcutaneous infusion of foslevodopa-foscarbidopa plus oral placebo capsules (n=74) or oral encapsulated immediate-release levodopa-carbidopa plus continuous subcutaneous infusion of placebo solution (n=67). Compared with levodopa-carbidopa, foslevodopa-foscarbidopa showed a significantly greater increase in on time without troublesome dyskinesia (model-based mean [SE] 2·72 [0·52] vs 0·97 [0·50] h; difference 1·75 h, 95% CI 0·46 to 3·05; p=0·0083) and a significantly greater reduction in off time (-2·75 [0·50] vs -0·96 [0·49] h; difference -1·79 h, -3·03 to -0·54; p=0·0054). Hierarchical testing ended after the first secondary endpoint. Adverse events were reported in 63 (85%) of 74 patients in the foslevodopa-foscarbidopa group versus 42 (63%) of 67 in the levodopa-carbidopa group, and incidences of serious adverse events were similar between the groups (six [8%] of 74 vs four [6%] of 67, respectively). The most frequent adverse events in the foslevodopa-foscarbidopa group were infusion site adverse events (erythema 20 [27%]), pain 19 [26%]), cellulitis (14 [19%]), and oedema (nine [12%]), most of which were non-serious and mild-moderate in severity. The only system organ class that had more than one serious adverse event in the foslevodopa-foscarbidopa group was infections and infestations (catheter site cellulitis [one [1%]] and infusion site cellulitis [one [1%]). Adverse events led to premature discontinuation of study drug in 16 (22%) of 74 participants in the foslevodopa-foscarbidopa group versus one (1%) of 67 participants in the oral levodopa-carbidopa group. Foslevodopa-foscarbidopa improved motor fluctuations, with benefits in both on time without troublesome dyskinesia and off time. Foslevodopa-foscarbidopa has a favourable benefit-risk profile and represents a potential non-surgical alternative for patients with advanced Parkinson's disease. AbbVie.

Multiple System Atrophy with Syndrome of Inappropriate Antidiuretic Hormone

Multiple System Atrophy (MSA) is a rare neurodegenerative disease which mainly affects extrapyramidal system, cerebellum and autonomic nervous system as well as hypothalamus. Hypothalamic disturbances can lead to the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) and resultant hyponatremia. MSA with SIADH is rarely reported. We reported a 71-year-old woman was admitted to our hospital because of fever for two months. She was diagnosed with probable multiple system atrophy based on poorly L-Dopa responsive parkinsonism, urinary incontinence and orthostatic hypotension. Hyponatremia, and the urine sodium and osmolality increased indicating that she had SIADH at the same time. Hyponatremia was corrected after water restriction and sodium supplementation. In this report, we describe the clinical characteristics and treatment in regard to MSA with SIADH.

Pathophysiological evaluation of the LRRK2 G2385R risk variant for Parkinson’s disease

Missense variants in leucine-rich repeat kinase 2 (LRRK2) lead to familial and sporadic Parkinson’s disease (PD). The pathological features of PD patients with LRRK2 variants differ. Here, we report an autopsy case harboring the LRRK2 G2385R, a risk variant for PD occurring mainly in Asian populations. The patient exhibited levodopa-responsive parkinsonism at the early stage and visual hallucinations at the advanced stage. The pathological study revealed diffuse Lewy bodies with neurofibrillary tangles, amyloid plaques, and mild signs of neuroinflammation. Biochemically, detergent-insoluble phospho-α-synuclein was accumulated in the frontal, temporal, entorhinal cortexes, and putamen, consistent with the pathological observations. Elevated phosphorylation of Rab10, a substrate of LRRK2, was also prominent in various brain regions. In conclusion, G2385R appears to increase LRRK2 kinase activity in the human brain, inducing a deleterious brain environment that causes Lewy body pathology.

Teaching Video NeuroImage: Facial-Faucial-Finger Myoclonus in Kufor-Rakeb Syndrome.

Two Chinese Australian siblings from nonconsanguineous parents presented with adolescent-onset dystonia-parkinsonism with prominent anxiety. Examination revealed eyelid, lower facial, and distal upper extremity myoclonus (Video 1), which was recorded using surface EMG (Figure 1). Compound heterozygous pathogenic variants in ATP13A2 were identified, c.3176T>G (p.L1059R) and c.3253delC (p.L1088WfsX4), confirming the diagnosis of Kufor-Rakeb syndrome (KRS).1 KRS classically presents as juvenile-onset, levodopa-responsive parkinsonism combined with pyramidal signs, upgaze palsy, cognitive decline, and, uniquely, facial-faucial-finger minimyoclonus.2 This distinctive pattern of myoclonus is a useful clue to the diagnosis in affected individuals and distinguishes it from other forms of juvenile-onset parkinsonism.