Levodopa-responsive Parkinsonism Research Articles

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.

Bi-allelic PRKN variants are involved in 34% to 45% of familial recessive early-onset Parkinson's diseases,1, 2 also called PARK-Parkin (MIM #600116).3 PARK-Parkin differs from idiopathic Parkinson's disease (PD) in the age onset before 45 years, dystonia at presentation, less frequent dementia, slower progression, better levodopa-responsivity, and a limited dopaminergic neuron depletion.2-4 A vast mutational spectrum in PRKN has already been noticed, including all types of CNV (copy number variant) and SNV (single nucleotide variant).5 Here, we report four affected members of a family carrying two combinations of bi-allelic PRKN pathogenic variants. The proband (II.2) is the second child from non-consanguineous parents (Fig. 1A). At 40, he developed typical slowly progressive levodopa-responsive parkinsonism starting with right hand tremors. The disease have been stable for 20 years, and persists with asymmetric predominantly right-sided akineto-rigid syndrome (ARS) with tremors. At 69, he displayed body bradykinesia, moderate segmental akinesia and minimal impairment of postural stability without cognitive, psychobehavioral, or impulse control impairment. His sister (II.4) also displayed typical levodopa-responsive parkinsonism from age 42 with right foot akinesia and significant freezing of gait. His brother (II.1) displayed typical parkinsonism with chronic psychosis. Disease onset was difficult to precise because of previous neuroleptic-induced parkinsonism. Observation of asymmetrical parkinsonism around age 55 suggested instead degenerative parkinsonism, which was then confirmed by a severe dopaminergic depletion in the Datscan. At the age of 71, he displayed severe parkinsonism with tremors without postural instability. The proband's daughter (III.1) developed left foot akinesia and left arm tremors at 30 years old, approximately 10 years before other family members, and Datscan showed bilateral putaminal dopaminergic depletion (Fig. 1B). At 37, she displayed a persistent bilateral predominantly left-sided ARS with typical rest tremors and dystonic posture with clawed toes. Her disease progressed slowly without significant axial signs nor cognitive status or impulse control disorder. Screening of 127 genes involved in movement disorders6 revealed two heterozygous intragenic PRKN deletions in the proband II.2 (referred to PMD283 in6): NM_004562.2:c.(7+1_8–1)_(171+1_172–1)del in exon 2 and c.(534+1_535–1)_(734+1_735–1)del overlapping exons 5 and 6. These two deletions are out-of-frame5, 7 (Fig. 1C). Quantitative PCR (qPCR) confirmed both deletions in II.2, identified them in II.1 and II.4 (Fig. 1D) but retrieved only exon 2 deletion in III.1. Next-Generation Sequencing of III.1 DNA identified an additional heterozygous substitution in PRKN intron 8 (NM_004562.2:c.933+1G>T) inherited from her healthy mother (II.3). Localized on a canonic donor splicing site, this variant induced an out-of-frame exon 8 skipping as revealed by RT-PCR performed on blood cDNA (Fig. 1E). Finally, proband II.2 and siblings II.1 and II.4 carry two different PRKN deletions in trans, whereas III.1 is compound heterozygous for paternal exon 2 deletion and maternal splicing variant. We report four relatives displaying PARK-Parkin related to two combinations of PRKN pathogenic variants. To our knowledge, our report is the first to describe two sets of PRKN pathogenic variants CNV/CNV and CNV/SNV in the same family. This report highlights that different molecular mechanisms can induce one disease, even in the same family. It encourages geneticists to consider a recessive pathology even when dominant inheritance is suggested and supports the importance of combining CNV and SNV analysis. The hypothesis that heterozygous PRKN variants are risk factors of classical PD was definitively ruled out recently.8 Then our report strongly supports the re-assessment strategy of possible additional gene mutations in patients with single PRKN variant and familial PD. Bi-allelic PRKN variants are involved in PARK-Parkin and a vast mutational spectrum has already been described. However, no correlation between the severity and/or precocity of clinical involvement and the nature of the variants in PRKN has been established. Nevertheless, incomplete penetrance or variable expression has already been reported,9, 10 for example, in a family with five PRKN compound heterozygous relatives including one asymptomatic member.9 Phenotype could also be modulated by variants in other key genes belonging to the parkin pathway.9, 10 Such compensatory mechanism has already been suggested considering an additional PINK1 variant enhancing PRKN mutations.3 The daughter developed PARK-Parkin around 10 years before other relatives in the present family. Although PINK1 was included in the targeted genes panel with no anomaly detected, all genes among the parkin pathway have not been explored, and additional variant in a non-tested gene cannot be ruled out. This difference in age at onset could also be explained by the C-terminal position of the splice variant inducing abnormal protein production, compared to the absence of protein induced by the N-terminal deletions.4 For example, the most severe phenotype in Erer's cohort was reported with heterozygous exon 11 nonsense variant associated with a non-pathogenic variant in intron 4.1 Protein expression assays such as Western Blot could be interesting to support this hypothesis. In any case, other similar cases are requested to confirm this hypothesis. We thank M. Dolores Loriot and C. Feger for their technical support. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Clinical Management; (3) Manuscript: A. Writing of the first draft, B. Review and Critique. M.B.: 1C, 3A J.M.R.: 1C, 3A M.T.: 2 N.C.: 1A, 1B, 3B A.S.: 1A, 1B, 3B Ethical Compliance Statement: The authors confirm that ethical approval from an institutional review board was not required. Informed patient consent was obtained for this work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with these guidelines. Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report.

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.

Rare missense variants in the PPP2R5D gene associated with Parkinson’s disease in the Han Chinese population

BackgroundRecent studies have reported an association between PPP2R5D mutations and early-onset levodopa-responsive parkinsonism, but this gene has yet to be analyzed comprehensively in a large Parkinson’s disease (PD) cohort. ObjectiveThe aim of this study was to examine the frequency and spectrum of PPP2R5D mutations in a Han Chinese cohort with early- or late-onset PD. MethodsThe 5′- and 3′-untranslated regions as well as coding sequence of the PPP2R5D gene were sequenced in 668 patients with sporadic PD. Novel variants were detected and validated based on genomic databases, as well as verified using genetic data from unrelated controls. Sanger sequencing was used to confirm rare mutations found by next-generation sequencing. ResultsTwo of the 145 EOPD patients carried two novel, unique PPP2R5D exonic variants (p.R91S,p.R523L), while none was detected in late-onset Parkinson’s disease (LOPD). Two variants were predicted to be “disease-causing” by Mutation Taster, and both mutations were found to be highly conserved across species. ConclusionOur study identified two rare PPP2R5D variants among Han Chinese EOPD patients, which broadens the spectrum of PPP2R5D mutations potentially associated with the disease.

X-Linked Dystonia-Parkinsonism ("Lubag") May Present with Peripheral Synucleinopathy.

X-linked dystonia parkinsonism (XDP) or "Lubag" is a genetic dystonia syndrome observed among Filipinos that can present with levodopa-responsive parkinsonism and abnormal dopamine transporter (DAT) imaging. The aim of this study is to describe the results of skin biopsies for phosphorylated α-synuclein (P-SYN) in XDP. This study used the retrospective chart review. We report 6 patients who carried the XDP gene mutation with DAT imaging and skin biopsies to detect P-SYN. Five had segmental or multifocal dystonia and parkinsonism: 4 were levodopa-responsive and 1 non-levodopa-responsive. One patient was asymptomatic but had mild bradykinesia. Cutaneous P-SYN and abnormal DAT scans were noted in the 4 levodopa-responsive patients and 1 asymptomatic patient. We report for the first time the presence of cutaneous P-SYN in XDP. Our findings suggest that XDP may be a hitherto-undescribed synucleinopathy or that some XDP patients may have concurrent Parkinson's disease.

The neurological and neuropsychiatric spectrum of adults with late-treated phenylketonuria

IntroductionPhenylketonuria (PKU) is a rare, treatable inborn error of metabolism with frequent neurological and neuropsychiatric complications, especially in undiagnosed or insufficiently treated individuals. Given the wide range of clinical presentations and the importance of treatment implications, we here delineate the neurological and neuropsychiatric symptom spectrum in a large cohort of previously unreported adults with late-treated PKU. MethodsWe consecutively evaluated late-treated PKU cases and pooled clinical and paraclinical data, including video-material, from three centers with expertise in complex movement disorders, inborn errors of metabolism and pediatrics. Results26 individuals were included (10 females, median age 52 years). Developmental delay and intellectual disability were omnipresent with severe impairment of expressive communication noted in 50% of cases. Movement disorders were prevalent (77%), including tremor (38%, mostly postural), stereotypies (38%), and tics (19%). One case had neurodegenerative levodopa-responsive parkinsonism. Mild ataxia was noted in 54% of cases and 31% had a history of seizures. Neuropsychiatric characteristics included obsessive-compulsive (35%) and self-injurious behaviors (31%), anxiety (27%), depression (19%) and features compatible with those observed in individuals with autism spectrum disorder (19%). Neuroimaging revealed mild white matter changes. Adherence to dietary treatment was inconsistent in the majority of cases, particularly throughout adolescence. ConclusionA history of movement disorders, particularly tremor, stereotypies and tics, in the presence of developmental delay, intellectual disability and neuropsychiatric features, such as obsessive-compulsive and self-injurious behaviors in adults should prompt the diagnostic consideration of PKU. Initiation and adherence to (dietary) treatment can ameliorate the severity of these symptoms.

Midbrain atrophy related to parkinsonism in a non-coding repeat expansion disorder: five cases of spinocerebellar ataxia type 31 with nigrostriatal dopaminergic dysfunction

BackgroundSpinocerebellar ataxia type 31 (SCA31) is caused by non-coding pentanucleotide repeat expansions in the BEAN1 gene. Clinically, SCA31 is characterized by late adult-onset, pure cerebellar ataxia. To explore the association between parkinsonism and SCA31, five patients with SCA31 with concomitant nigrostriatal dopaminergic dysfunction (NSDD) development, including three cases of L-DOPA responsive parkinsonism, were analyzed.MethodsTo assess regional brain atrophy, cross-sectional and longitudinal imaging analyses were retrospectively performed using magnetic resonance imaging (MRI) planimetry. The midbrain-to-pons (M/P) area ratio and cerebellar area were measured on midsagittal T1-weighted MRI in five patients with SCA31 with concomitant NSDD (NSDD(+)), 14 patients with SCA31 without NSDD (NSDD(−)), 32 patients with Parkinson’s disease (PD), and 15 patients with progressive supranuclear palsy (PSP). Longitudinal changes in the M/P area ratio were assessed by serial MRI of NSDD(+) (n = 5) and NSDD(−) (n = 9).ResultsThe clinical characteristics assessed in the five patients with NSDD were as follows: the mean age at NSDD onset (72.0 ± 10.8 years), prominence of bradykinesia/akinesia (5/5), rigidity (4/5), tremor (2/5), dysautonomia (0/5), vertical gaze limitation (1/5), and abnormalities on 123I-ioflupane dopamine transporter scintigraphy (3/3) and 3-Tesla neuromelanin MRI (4/4). A clear reduction in the midbrain area and the M/P area ratio was observed in the NSDD(+) group (p < 0.05) while there was no significant difference in disease duration or in the pons area among the NSDD(+), NSDD(−), and PD groups. There was also a significant difference in the midbrain and pons area between NSDD(+) and PSP (p < 0.05). Thus, mild but significant midbrain atrophy was observed in NSDD(+). A faster rate of decline in the midbrain area and the M/P area ratio was evident in NSDD(+) (p < 0.05).ConclusionThe clinical characteristics of the five patients with SCA31 with concomitant NSDD, together with the topographical pattern of atrophy, were inconsistent with PD, PSP, and multiple system atrophy, suggesting that SCA31 may manifest NSDD in association with the pathomechanisms underlying SCA31.