Mutations in Leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of sporadic and familial late onset Parkinson’s disease (PD). The G2019S common mutation has been identified about 1% of sporadic cases and 4–7% of familial cases. Over 50 variants have since been identified in LRRK2, and at least 7 of these are confirmed to be pathogenic. In addition to pathogenic mutations, several common polymorphisms in the LRRK2 gene (G2385R and R1628P) have been identified that may explain up to 10% of sporadic PD in Asian populations. LRRK2 is a large complex multidomain protein with 2,527-amino-acid and the molecular weight is 286 kDa. LRRK2 multidomain protein consists of a catalytic core domain, kinase domain and a number of putative protein-protein interaction domains. LRRK2 mutations found in PD families, including the G2019S and I2020T mutations show increased intrinsic kinase activity, when assessed with myelin basic protein as substrate. The modification of LRRK2 GTPase and kinase activity affecting residues in the ROC, COR and mitogen-activated protein kinase kinase kinases domains is believed to lead to neuronal cell death, but the pathways involved remain unclear. A number of in vivo models in C. elegans, D. melanogaster and mice have been developed to study the patho/physiological function of LRRK2. Based on current literature, a toxic gain of function in LRRK2 kinase activity is a possible pathophysiologic mechanism and thus inhibition of kinase activity in experimental models offers a potential therapeutic strategy for LRRK2-linked PD.

Citations

Citations to this article as recorded by  

• Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade
  Gunjan Thakur, Vikas Kumar, Keun Woo Lee, Chungkil Won
  Genes.2022; 13(8): 1426.     CrossRef
• Sequential screening nominates the Parkinson's disease associated kinase LRRK2 as a regulator of Clathrin-mediated endocytosis
  George R. Heaton, Natalie Landeck, Adamantios Mamais, Mike A. Nalls, Jonathon Nixon-Abell, Ravindran Kumaran, Alexandra Beilina, Laura Pellegrini, Yan Li, Kirsten Harvey, Mark R. Cookson
  Neurobiology of Disease.2020; 141: 104948.     CrossRef
• Target Engagement in Lead Generation
  Timothy B. Durham, Maria-Jesus Blanco
  Bioorganic & Medicinal Chemistry Letters.2015;[Epub]     CrossRef

The clinical phenotype of X-Linked Dystonia Parkinsonism (XDP) is typically one that involves a Filipino adult male whose ancestry is mostly traced in the Philippine island of Panay. Dystonia usually starts focally in the lower limbs or oromandibular regions, then spreads to become generalized eventually. Parkinsonism sets in later into the disease and usually in combination with dystonia. /DYT3/ and /TAF1/ are the two genes associated with XDP. An SVA retrotransposon insertion in an intron of /TAF1/ may reduce neuron-specific expression of the /TAF1/ isoform in the caudate nucleus, and subsequently interfere with the transcription of many neuronal genes. Polypharmacy with oral benzodiazepines, anticholinergic agents and muscle relaxants leaves much to be desired in terms of efficacy. The medications to date that may appear beneficial, especially in disabling dystonias, are zolpidem, muscle afferent block with lidocaine-ethanol and botulinum toxin type A. Despite the few cases undergoing deep brain stimulation, this functional surgery has shown the greatest promise in XDP. An illustrative case of XDP in a family depicts the variable course of illness, including a bout of “status dystonicus,” challenges in therapy, reckoning with the social impact of the disease, and eventual patient demise. Indeed, there remains some gaps in understanding some phenomenological, genetic and treatment aspects of XDP, the areas upon which future research directions may be worthwhile.

Citations

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• A scoping review on the diagnosis and treatment of X-linked dystonia-parkinsonism
  Anisah Hayaminnah D. Alonto, Roland Dominic G. Jamora
  Parkinsonism & Related Disorders.2024; 119: 105949.     CrossRef
• Progressive Decline in Voice and Voice-Related Quality of Life in X-Linked Dystonia Parkinsonism
  Sungjin A. Song, Criscely L. Go, Patrick B. Acuna, Jan Kristopher Palentinos De Guzman, Nutan Sharma, Phillip C. Song
  Journal of Voice.2023; 37(1): 134.     CrossRef
• X-linked dystonia parkinsonism: epidemiology, genetics, clinical features, diagnosis, and treatment
  Hok Leong Chin, Chia-Yi Lin, Oscar Hou-In Chou
  Acta Neurologica Belgica.2023; 123(1): 45.     CrossRef
• Basal Ganglia Atrophy as a Marker for Prodromal X‐Linked Dystonia‐Parkinsonism
  Henrike Hanssen, Cid C. E. Diesta, Marcus Heldmann, Jackson Dy, Jeffrey Tantianpact, Julia Steinhardt, Rosanna Sauza, Hans T. S. Manalo, Andreas Sprenger, Charles Jourdan Reyes, Raphael Tuazon, Björn‐Hergen Laabs, Aloysius Domingo, Raymond L. Rosales, Chr
  Annals of Neurology.2023; 93(5): 999.     CrossRef
• Oculomotor abnormalities indicate early executive dysfunction in prodromal X-linked dystonia-parkinsonism (XDP)
  Renana Mertin, Cid Diesta, Norbert Brüggemann, Raymond L. Rosales, Henrike Hanssen, Ana Westenberger, Julia Steinhardt, Marcus Heldmann, Hans T. S. Manalo, Jean Q. Oropilla, Christine Klein, Christoph Helmchen, Andreas Sprenger
  Journal of Neurology.2023; 270(9): 4262.     CrossRef
• Endemic parkinsonism: clusters, biology and clinical features
  Katerina Menšíková, John C. Steele, Raymond Rosales, Carlo Colosimo, Peter Spencer, Annie Lannuzel, Yoshikazu Ugawa, Ryogen Sasaki, Santiago Giménez-Roldán, Radoslav Matej, Lucie Tuckova, Dominik Hrabos, Kristyna Kolarikova, Radek Vodicka, Radek Vrtel, Mi
  Nature Reviews Neurology.2023; 19(10): 599.     CrossRef
• Elucidating Hexanucleotide Repeat Number and Methylation within the X-Linked Dystonia-Parkinsonism (XDP)-Related SVA Retrotransposon in TAF1 with Nanopore Sequencing
  Theresa Lüth, Joshua Laβ, Susen Schaake, Inken Wohlers, Jelena Pozojevic, Roland Dominic G. Jamora, Raymond L. Rosales, Norbert Brüggemann, Gerard Saranza, Cid Czarina E. Diesta, Kathleen Schlüter, Ronnie Tse, Charles Jourdan Reyes, Max Brand, Hauke Busch
  Genes.2022; 13(1): 126.     CrossRef
• Prodromal X‐Linked Dystonia‐Parkinsonism is Characterized by a Subclinical Motor Phenotype
  Julia Steinhardt, Henrike Hanssen, Marcus Heldmann, Andreas Sprenger, Björn‐Hergen Laabs, Aloysius Domingo, Charles Jourdan Reyes, Jannik Prasuhn, Max Brand, Raymond Rosales, Thomas F. Münte, Christine Klein, Ana Westenberger, Jean Q. Oropilla, Cid Diesta
  Movement Disorders.2022; 37(7): 1474.     CrossRef
• A Community-based study on the prevalence and predisposing factors of Parkinson’s disease in Barangay Mangilag Sur, Quezon Province, Philippines
  Raymond L. Rosales, Mary Camille E. Rosales, Danica Jane S.J. Robles, Ron Christian Neil T. Rodriguez, Nadia Beatrice S. Romana, Joseph Mariuz B. Rosales, Gerardo B. Salazar, Richelle Ann S. Santiano
  Clinical Parkinsonism & Related Disorders.2022; 7: 100169.     CrossRef
• Retroelement-derived RNA and its role in the brain
  Taylor A. Evans, Jennifer Ann Erwin
  Seminars in Cell & Developmental Biology.2021; 114: 68.     CrossRef
• Behandlungsstrategien bei oromandibulärer Dystonie
  Kazuya Yoshida
  Fortschritte der Neurologie · Psychiatrie.2021; 89(11): 562.     CrossRef
• X-linked dystonia Parkinsonism: crossing a new threshold
  Arlene R. Ng, Roland Dominic G. Jamora, Raymond L. Rosales
  Journal of Neural Transmission.2021; 128(4): 567.     CrossRef
• A Cross-Cultural Validation of the Filipino and Hiligaynon Versions of the Parts IIIB (Non-Motor Features) and IV (Activities of Daily Living) of the X-Linked Dystonia-Parkinsonism– MDSP Rating Scale
  Richelle Ann S. Santiano, Raymond L. Rosales
  Clinical Parkinsonism & Related Disorders.2021; 5: 100100.     CrossRef
• Speech and swallowing deficits in X-Linked Dystonia-Parkinsonism
  Ana Luiza Zaninotto, Jan K. de Guzman, Kaila L. Stipancic, Bridget J. Perry, Melanie L. Supnet, Criscely Go, Nutan Sharma, Jordan R. Green
  Parkinsonism & Related Disorders.2021; 89: 105.     CrossRef
• Tremor in Primary Monogenic Dystonia
  Sanjay Pandey, Sonali Bhattad, Shreya Dinesh
  Current Neurology and Neuroscience Reports.2021;[Epub]     CrossRef
• Oromandibular Dystonia: A Clinical Examination of 2,020 Cases
  Laura M. Scorr, Stewart A. Factor, Sahyli Perez Parra, Rachel Kaye, Randal C. Paniello, Scott A. Norris, Joel S. Perlmutter, Tobias Bäumer, Tatiana Usnich, Brian D. Berman, Marie Mailly, Emmanuel Roze, Marie Vidailhet, Joseph Jankovic, Mark S. LeDoux, Ric
  Frontiers in Neurology.2021;[Epub]     CrossRef
• Voice and swallowing dysfunction in X‐linked dystonia parkinsonism
  Phillip C. Song, Hoai Le, Patrick Acuna, Jan Kristopher Palentinos De Guzman, Nutan Sharma, Taylor N. Francouer, Marisela E. Dy, Criscely L. Go
  The Laryngoscope.2020; 130(1): 171.     CrossRef
• Increased insula-putamen connectivity in X-linked dystonia-parkinsonism
  Anne J. Blood, Jeff L. Waugh, Thomas F. Münte, Marcus Heldmann, Aloysius Domingo, Christine Klein, Hans C. Breiter, Lillian V. Lee, Raymond L. Rosales, Norbert Brüggemann
  NeuroImage: Clinical.2018; 17: 835.     CrossRef
• Altered glutamate response and calcium dynamics in iPSC-derived striatal neurons from XDP patients
  P. Capetian, N. Stanslowsky, E. Bernhardi, K. Grütz, A. Domingo, N. Brüggemann, M. Naujock, P. Seibler, C. Klein, F. Wegner
  Experimental Neurology.2018; 308: 47.     CrossRef
• Eye movement deficits in X-linked dystonia-parkinsonism are related to striatal degeneration
  Andreas Sprenger, Henrike Hanssen, Imke Hagedorn, Jannik Prasuhn, Raymond L. Rosales, Roland Dominic G. Jamora, Cid C. Diesta, Aloysius Domingo, Christine Klein, Norbert Brüggemann, Christoph Helmchen
  Parkinsonism & Related Disorders.2018;[Epub]     CrossRef
• Validation of a screening questionnaire for X‐linked dystonia parkinsonism: The first phase of the population‐based prevalence study of X‐linked dystonia parkinsonism in Panay
  Jose Danilo B Diestro, Paul Matthew D Pasco, Lillian V Lee
  Neurology and Clinical Neuroscience.2017; 5(3): 79.     CrossRef
• Validation of the XDP–MDSP rating scale for the evaluation of patients with X-linked dystonia-parkinsonism
  Paul Matthew D. Pasco, Roland Dominic G. Jamora, Raymond L. Rosales, Cid Czarina E. Diesta, Arlene R. Ng, Rosalia A. Teleg, Criscely L. Go, Lillian Lee, Hubert H. Fernandez
  npj Parkinson's Disease.2017;[Epub]     CrossRef
• Clinicopathological Phenotype and Genetics of X-Linked Dystonia–Parkinsonism (XDP; DYT3; Lubag)
  Toshitaka Kawarai, Ryoma Morigaki, Ryuji Kaji, Satoshi Goto
  Brain Sciences.2017; 7(12): 72.     CrossRef
• Prevalence and Predisposing Factors of Parkinson Disease: A Community-Based Study In Barangay Mangilag Sur, Candelaria, Quezon: A Research Protocol
  Danica Jane S.J Robles, Ron Christian Neil T Rodriguez, Nadia Beatrice S Romana, Joseph Mariuz B Rosales, Mary Camille E Rosales, Gerardo B Salazar, Raymond L Rosales
  Journal of Medicine, University of Santo Tomas.2017; 1(1): 109.     CrossRef
• Evidence of TAF1 dysfunction in peripheral models of X-linked dystonia-parkinsonism
  Aloysius Domingo, David Amar, Karen Grütz, Lillian V. Lee, Raymond Rosales, Norbert Brüggemann, Roland Dominic Jamora, Eva Cutiongco-dela Paz, Arndt Rolfs, Dirk Dressler, Uwe Walter, Dimitri Krainc, Katja Lohmann, Ron Shamir, Christine Klein, Ana Westenbe
  Cellular and Molecular Life Sciences.2016; 73(16): 3205.     CrossRef
• Can a Positive Allosteric Modulation of GABAergic Receptors Improve Motor Symptoms in Patients with Parkinson’s Disease? The Potential Role of Zolpidem in the Treatment of Parkinson’s Disease
  Antonio Daniele, Francesco Panza, Antonio Greco, Giancarlo Logroscino, Davide Seripa
  Parkinson's Disease.2016; 2016: 1.     CrossRef
• Introduction
  Erle C.H. Lim, Roongroj Bhidayasiri, Raymond L. Rosales, Ryuji Kaji
  Parkinsonism & Related Disorders.2011; 17: S1.     CrossRef

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• Early onset of propriospinal-like myoclonus in a child following a vertebral fracture
  Carlotta Facini, Marina Barsacchi, Benedetta Piccolo, Emanuela Claudia Turco, Francesco Pisani
  Neurology.2016; 87(9): 956.     CrossRef
• Propriospinal myoclonus: The spectrum of clinical and neurophysiological phenotypes
  E. Antelmi, F. Provini
  Sleep Medicine Reviews.2014;[Epub]     CrossRef

A decreased cardiac ¹²³I-metaiodobenzylguanidine (¹²³I-MIBG) uptake has been used as a powerful tool to identify Lewy body disease, such as idiopathic parkinson’s disease (IPD). We performed cardiac ¹²³I-MIBG scintigraphy in patient with autosomal recessive juvenile parkinsonism (ARJP) with parkin gene mutation (PARK2). The findings showed normal cardiac ¹²³I-MIBG uptake. Therefore, although the clinical features of ARJP are sometimes quite similar to those of late-onset IPD, cardiac ¹²³I-MIBG scintigraphy may be used as a valuable tool to identify patients with IPD and to distinguish them from patients with other parkinsonian syndromes.

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• Parkinsonism in spinocerebellar ataxia with axonal neuropathy caused by adult-onset COA7 variants: a case report
  Shogo Ouchi, Kazuhiro Ishii, Kenjiro Kosaki, Hisato Suzuki, Mamiko Yamada, Toshiki Takenouchi, Akira Tamaoka
  BMC Neurology.2023;[Epub]     CrossRef
• α‐Synuclein Deposition in Sympathetic Nerve Fibers in Genetic Forms of Parkinson's Disease
  Risa Isonaka, David S. Goldstein, William Zhu, Esther Yoon, Debra Ehrlich, Alice B. Schindler, Angela D. Kokkinis, Marya S. Sabir, Sonja W. Scholz, Sara Bandres‐Ciga, Cornelis Blauwendraat, Pedro Gonzalez‐Alegre, Grisel Lopez, Ellen Sidransky, Derek P. Na
  Movement Disorders.2021; 36(10): 2346.     CrossRef
• Cardiac sympathetic burden reflects Parkinson disease burden, regardless of high or low orthostatic blood pressure changes
  Sang-Won Yoo, Joong-Seok Kim, Yoon-Sang Oh, Dong-Woo Ryu, Seunggyun Ha, Ji-Yeon Yoo, Kwang-Soo Lee
  npj Parkinson's Disease.2021;[Epub]     CrossRef
• Normal ‘heart’ in Parkinson's disease: is this a distinct clinical phenotype?
  J.‐S. Kim, H.‐E. Park, I.‐S. Park, Y.‐S. Oh, D.‐W. Ryu, I.‐U. Song, Y.‐A. Jung, I. R. Yoo, H.‐S. Choi, P. H. Lee, K.‐S. Lee
  European Journal of Neurology.2017; 24(2): 349.     CrossRef

Huntington disease is a neurodegenerative disorder distinguished by the triad of dominant inheritance, choreoathetosis and dementia, usually with onset in the fourth and fifth decades. It is caused by an unstable cytosine-adenine-guanine (CAG) trinucleotide repeat expansion in the gene IT15 in locus 4p16.3. Juvenile HD that constitutes about 3% to 10% of all patients is clinically different from adult-onset form and characterized by a larger number of CAG repeats typically exceeding 60. We report a case of a 6-year-old boy with myoclonic seizure and 140 CAG repeats confirmed by molecular genetic analysis.

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• Drug-Resistant Epilepsy in Children with Juvenile Huntington's Disease: A Challenging Case and Brief Review
  Abdulhafeez M. Khair MD, Jessica Kabrt DO, Stephen Falchek MD
  Qatar Medical Journal .2020;[Epub]     CrossRef
• Introducing an expanded CAG tract into the huntingtin gene causes a wide spectrum of ultrastructural defects in cultured human cells
  Ksenia N. Morozova, Lyubov A. Suldina, Tuyana B. Malankhanova, Elena V. Grigor’eva, Suren M. Zakian, Elena Kiseleva, Anastasia A. Malakhova, Hiroyoshi Ariga
  PLOS ONE.2018; 13(10): e0204735.     CrossRef
• Tics as an initial manifestation of juvenile Huntington’s disease: case report and literature review
  Shi-Shuang Cui, Ru-Jing Ren, Ying Wang, Gang Wang, Sheng-Di Chen
  BMC Neurology.2017;[Epub]     CrossRef
• Neuropathological Comparison of Adult Onset and Juvenile Huntington’s Disease with Cerebellar Atrophy: A Report of a Father and Son
  Caitlin S. Latimer, Margaret E. Flanagan, Patrick J. Cimino, Suman Jayadev, Marie Davis, Zachary S. Hoffer, Thomas J. Montine, Luis F. Gonzalez-Cuyar, Thomas D. Bird, C. Dirk Keene
  Journal of Huntington's Disease.2017; 6(4): 337.     CrossRef

Clonus is the rhythmic muscle contraction which usually occurs in patients with lesions involving descending motor pathways. Sometimes, rhythmic oscillation of action induced clonus could be confused to action tremor. We report a case of action induced clonus associated with cervical schwannoma which was misdiagnosed as essential tremor. The patient had spasticity in all limbs with exaggerated tendon reflexes, and passive stretch-induced clonus. Imaging and histological examinations revealed a schwannoma extending from C2 to C7. The lesion was partially removed by surgery. Even though essential tremor is a common disease, clinician have to do sufficient neurologic examination considering differential diagnosis.

The cerebellar glucose metabolism of multiple system atrophy with predominant cerebellar ataxia (MSA-C) is known to be decreased but is not defined among areas of cerebellum. We encountered a 54-year-old man who developed dizziness and progressive ataxia followed by urinary incontinence and orthostatic hypotension, all of those symptoms progressed relentlessly and the symptoms responded poorly to levodopa therapy. Visual analysis and statistical parametric mapping analysis of F-18 fluorodeoxyglucose positron emission tomography showed hypometabolism of both cerebellar hemisphere, severe at cortical area, and pons. There was clear sparing of deep cerebellar nuclei. Our report, as we know, shows the first case of preserved glucose metabolism of deep cerebellar nuclei relative to cerebellar cortex in an MSA-C patient.

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) can be caused by a variety of drugs. Dopaminergic drugs might enhance the secretion of the antidiuretic hormone arginine vasopressin by reducing γ-amino butyric acid release through the dopaminergic receptor in supraoptic nucleus. A 75-year-old woman with Parkinson’s disease developed asthenia, delirium, aggravated parkinsonian symptoms, and hypotonic hyponatremia along with the diagnostic criteria for SIADH during dose escalation of pramipexole. After pramipexole withdrawal, these symptoms disappeared, and sodium levels returned to normal values. The serum sodium levels of patients receiving pramipexole should be monitored, especially during dose escalation.

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• Syndrome of Inappropriate Antidiuretic Hormone Secretion as a Presentation of Untreated Parkinson’s Disease
  Karim Ali, Yaseen Najjar, Swati Mehta , Geovani Faddoul
  Cureus.2023;[Epub]     CrossRef
• Is Restless Legs Syndrome De Facto Thyroid Disease?
  Szymon Suwała, Jakub Rzeszuto, Rafał Glonek, Magdalena Krintus, Roman Junik
  Biomedicines.2022; 10(10): 2502.     CrossRef
• Levodopa-carbidopa intestinal gel is an option in Parkinson’s disease with hyponatremia induced by dopamine agonists
  Marina Picillo, Vincenzo Canoro, Giulio Cicarelli, Roberto Erro, Paolo Barone
  Neurological Sciences.2020; 41(11): 3361.     CrossRef
• Liquid Levodopa/Carbidopa: Old Solution, Forgotten Complication
  Nirosen Vijiaratnam, Shuli Cheng, Kelly Lucinda Bertram, David Richard Williams
  Journal of Movement Disorders.2017; 10(3): 164.     CrossRef