Michael C Kruer,Peter T Skidmore,Brielle Edwards,Jennifer Heim,James Kelbert,Nathan Evans,Alex King,Patricia Cornejo,Francisco Ponce,Lisa Vanatta,Alex M Pagnozzi,Ningning Zhao
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Valentina Leta PhD, Pavlos Zinzalias MSc, Lucia Batzu MD, Gargi Mandal MSc, Juliet Staunton MSc, Frida Jernstedt MSc, Kristina Rosqvist PhD, Jonathan Timpka PhD, Trinette van Vliet PhD, Dhaval Trivedi MD, Aleksandra Podlewska MSc, Miriam Parry MSc, Daniel J. van Wamelen PhD, Alexandra Rizos MSc, Carolina Sportelli PhD, Ana Laura Bonder, Guy Chung-Faye PhD, Cristian Falup-Pecurariu PhD, Simon Gaisford PhD, Edoardo Moretto PhD, Gwenaelle Le Gall PhD, David Vauzour PhD, Ana Rodriguez-Mateos PhD, Anna Sauerbier PhD, Carmen Rodriguez Blazquez PhD, Jonas Ghyselinck PhD, Benoît Marsaux MSc, Carmine Maria Pariante PhD, Alessandra Borsini PhD, Per Odin PhD, Kallol Ray Chaudhuri MD
Marcus W Koch,Lorraine V Kalia,Justyna Sarna,Camila Aquino,Daryl Wile,Tiago A Mestre,Michael G Schlossmacher,Miguel D'Haeseleer,Jop Mostert,Eva M M Strijbis,Bernard Uitdehaag,Tarrant McPherson,Gary Cutter
Teresa Kleinz MD, Francesco Cavallieri MD, PhD, Max Borsche MD, Giulia Toschi PhD, Franco Valzania MD, Valentina Fioravanti MD, PhD, Enza Maria Valente MD, Pierfrancesco Mitrotti MD, Micol Avenali MD, Simone Zittel MD, Rommi Born MD, Michele Matarazzo MD, Alessio Di Fonzo MD, PhD, Edoardo Monfrini MD, Mandy Radefeldt MSc, Letizia Santinelli MSc, Norman Griebner MD, Cholpon Shambetova MD, Max Brand MSc, Carolin Gabbert PhD, Cornelis Blauwendraat PhD, Joanne Trinh PhD, Katja Lohmann PhD, Christian Beetz PhD, Peter Bauer MD, Norbert Brüggemann MD, Global Parkinson's Genetics Program (GP2), Christine Klein MD
Background
The RAB32 p.Ser71Arg variant is a novel cause of monogenic Parkinson's disease (PD), for which detailed phenotypic information is currently scarce.
Objectives
Our aim was to clinically and biologically characterize individuals with PARK-RAB32 to gain insights into genotype–phenotype relationships, disease severity, and underlying pathology.
Methods
We conducted a literature review following the MDSGene protocol, alongside detailed phenotyping of 11 PARK-RAB32 patients and one prodromal individual from the Rostock International PD (ROPAD) study. In addition to comprehensive scale-based assessments, including olfactory testing, we obtained neuroimaging data and various biomaterials, and performed α-synuclein seeding assays (SAA) in cerebrospinal fluid in a subset.
Results
83 patients (72 from the literature) were included in the analysis. The median age at onset was 54 (IQR: 46–61) years. Typical parkinsonism with a favorable dopaminergic response was observed in all patients.
In our cohort, after a median disease duration of 11 years (IQR: 7–19.5), the mean Movement Disorders Society Modified Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III score was 38.5 ± 21.8 points. Targeted testing revealed autonomic symptoms were present in all individuals, and 10 of 11 patients had hyposmia. Misfolded α-synuclein was identified in 2 of 2 patients, but not in the prodromal individual. 123I-FP-CIT imaging was available for eight patients, revealing neurodegeneration in all of them.
Christos Ganos MD, Roberto Erro MD, PhD, Mohammad Abdullah MBChB, Tanya S. Hauck MD, PhD, Daniel Ciccarone MD, Christy Sutherland MD, Parisa Saiyarsarai PhD, Connie Marras MD, PhD, Susan H. Fox MRCP, PhD, Alfonso Fasano MD, PhD, Anthony E. Lang MD, Jonathan Squires MD, Kailash P. Bhatia FRCP, MD
<p>Movement disorders resulting from illicit drug use can present with both hypokinetic and hyperkinetic features often leading to severe functional impairment. The seminal publication by Langston and colleagues,<span><sup>1</sup></span> for example, described four adults who became parkinsonian within a week of being exposed to heroin contaminated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These first cases marked the beginning of sporadic outbreaks of parkinsonism linked to synthetic opioid use.<span><sup>2</sup></span> The cause was attributed to MPP+, a MAO-B metabolite of MPTP, which results in mitochondrial dysfunction and neuronal death.<span><sup>2</sup></span> Importantly, although these cases affected relatively few individuals worldwide, they were pivotal in highlighting the vulnerability of dopamine-producing neurons to a variety of neurotoxins and established groundbreaking models for studying Parkinson's disease (PD).<span><sup>2</sup></span> Other examples of drug-induced movement disorders include dystonia-parkinsonism resulting from manganese toxicity due to ephedrine (methcathinone) use<span><sup>3</sup></span> and chorea and dystonia—also referred to as “crack-dancing”—or tics caused by cocaine use.<span><sup>4</sup></span></p><p>Over the past few years, a new and much larger-scale trend of people with movement disorders caused by illicit drug use has emerged. This phenomenon appears to be driven by synthetic opioids such as fentanyl and its analogues, often combined with the veterinary sedative xylazine, the combination colloquially known as “tranq,” as well as methamphetamines.<span><sup>5-7</sup></span> Although the epicenter is the United States and Canada, cases have been reported by prominent media outlets in various parts of the world.<span><sup>7-11</sup></span> Affected individuals commonly exhibit characteristic postural and other motor abnormalities, which from a phenomenological standpoint have important similarities with movement disorders such as camptocormia in parkinsonism or generalized dystonia. This hypothesis-driven connection has not been sufficiently considered, despite its potential to deepen our knowledge about the mechanisms modulating postural motor control. Given the alarming prevalence of this phenomenon, it further holds significant implications for public health.</p><p>Here, we draw from our own experience and use knowledge from neuroscience of motor control and movement disorders to speculate about the relationship between abnormal postural control and regular exposure to illicit fentanyl, xylazine, and methamphetamines, including combination use. We also highlight open questions that will need to be addressed in future research.</p><p>A characteristic phenotype linked to the current drug-use epidemic reported in the media is people with markedly bent spines, often flexed forward and while standing.<span><sup>7-11</sup></span> This distinctive posture that is primarily attributed to
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