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1.
Brain ; 147(8): 2652-2667, 2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-39087914

RESUMEN

Estimates of the spectrum and frequency of pathogenic variants in Parkinson's disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson's disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD.


Asunto(s)
Pruebas Genéticas , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/genética , Masculino , Femenino , Persona de Mediana Edad , Anciano , Pruebas Genéticas/métodos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Glucosilceramidasa/genética , alfa-Sinucleína/genética , Predisposición Genética a la Enfermedad , Ubiquitina-Proteína Ligasas/genética , Estudios de Cohortes , Proteínas Quinasas/genética , Mutación , Adulto
2.
Mov Disord ; 38(12): 2155-2162, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37916476

RESUMEN

Genetic subtyping of patients with Parkinson's disease (PD) may assist in predicting the cognitive and motor outcomes of subthalamic deep brain stimulation (STN-DBS). Practical questions were recently raised with the emergence of new data regarding suboptimal cognitive outcomes after STN-DBS in individuals with PD associated with pathogenic variants in glucocerebrosidase gene (GBA1-PD). However, a variety of gaps and controversies remain. (1) Does STN-DBS truly accelerate cognitive deterioration in GBA1-PD? If so, what is the clinical significance of this acceleration? (2) How should the overall risk-to-benefit ratio of STN-DBS in GBA1-PD be established? (3) If STN-DBS has a negative effect on cognition in GBA1-PD, how can this effect be minimized? (4) Should PD patients be genetically tested before STN-DBS? (5) How should GBA1-PD patients considering STN-DBS be counseled? We aim to summarize the currently available relevant data and detail the gaps and controversies that exist pertaining to these questions. In the absence of evidence-based data, all authors strongly agree that clinicians should not categorically deny DBS to PD patients based solely on genotype (GBA1 status). We suggest that PD patients considering DBS may be offered genetic testing for GBA1, where available and feasible, so the potential risks and benefits of STN-DBS can be properly weighed by both the patient and clinician. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Asunto(s)
Trastornos del Conocimiento , Estimulación Encefálica Profunda , Enfermedad de Parkinson , Núcleo Subtalámico , Humanos , Cognición , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/complicaciones , Núcleo Subtalámico/fisiología
3.
Mov Disord ; 38(3): 484-489, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36621944

RESUMEN

BACKGROUND: It is unknown whether Parkinson's disease (PD) genetic heterogeneity, leading to phenotypic and pathological variability, is also associated with variability in the unique PD electrophysiological signature. Such variability might have practical implications for adaptive deep brain stimulation (DBS). OBJECTIVE: The aim of our work was to study the electrophysiological activity in the subthalamic nucleus (STN) of patients with PD with pathogenic variants in different disease-causing genes. METHODS: Electrophysiological data from participants with negative genetic tests were compared with those from GBA, LRRK2, and PRKN-PD. RESULTS: We analyzed data from 93 STN trajectories (GBA-PD: 28, LRRK2-PD: 22, PARK-PD: 10, idiopathic PD: 33) of 52 individuals who underwent DBS surgery. Characteristics of ß oscillatory activity in the dorsolateral motor part of the STN were similar for patients with negative genetic tests and for patients with different forms of monogenic PD. CONCLUSIONS: The genetic heterogeneity in PD is not associated with electrophysiological differences. Therefore, similar adaptive DBS algorithms would be applicable to genetically heterogeneous patient populations. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Asunto(s)
Estimulación Encefálica Profunda , Enfermedad de Parkinson , Núcleo Subtalámico , Humanos , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/terapia , Núcleo Subtalámico/fisiología , Pruebas Genéticas
4.
J Clin Psychopharmacol ; 42(5): 454-460, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36018237

RESUMEN

PURPOSE/BACKGROUND: Tardive dyskinesia (TD) is a hyperkinetic movement disorder caused by exposure to dopamine-receptor blockers. Data on TD burden in Israel are scarce. This analysis assesses the clinical and economic burden of TD in Israeli patients. METHODS/PROCEDURES: This retrospective analysis used a national health plan database (Maccabi Healthcare Services), representing 25% of the Israeli population. The study included adults alive at index date with an International Classification of Diseases, Ninth Revision, Clinical Modification TD diagnosis before 2018 and more than or equal to 1-year enrollment before diagnosis. Tardive dyskinesia patients were matched to non-TD patients (1:3) by underlying psychiatric condition, birth year, and sex. Treatment patterns and 2018 annual health care resource utilization and costs were assessed. FINDINGS/RESULTS: Of 454 TD patients alive between 2013 and 2018, 333 alive on January 1, 2018, were matched to 999 non-TD patients. At baseline, TD patients had lower socioeconomic status and higher proportion of chronic kidney disease and antipsychotic medication use; all analyses were adjusted accordingly. Tardive dyskinesia patients had significantly more visits to general physicians, neurologists, psychiatrists, physiotherapists, and emergency departments versus non-TD patients (all P < 0.05). Tardive dyskinesia patients also had significantly longer hospital stays than non-TD patients ( P = 0.003). Total healthcare and medication costs per patient were significantly higher in the TD versus non-TD population (US $11,079 vs US $7145, P = 0.018). IMPLICATIONS/CONCLUSIONS: Israeli TD patients have higher clinical and economic burden than non-TD patients. Understanding real-world health care resource utilization and costs allows clinicians and decision makers to quantify TD burden and prioritize resources for TD patients' treatment.


Asunto(s)
Antipsicóticos , Discinesia Tardía , Adulto , Antipsicóticos/efectos adversos , Análisis de Datos , Antagonistas de Dopamina , Estrés Financiero , Humanos , Israel/epidemiología , Estudios Retrospectivos , Discinesia Tardía/inducido químicamente , Discinesia Tardía/tratamiento farmacológico , Discinesia Tardía/epidemiología
5.
Int J Mol Sci ; 23(20)2022 Oct 13.
Artículo en Inglés | MEDLINE | ID: mdl-36293067

RESUMEN

Carriers of GBA1 gene variants have a significant risk of developing Parkinson's disease (PD). A cohort study of GBA carriers between 40−75 years of age was initiated to study the presence of prodromal PD features. Participants underwent non-invasive tests to assess different domains of PD. Ninety-eight unrelated GBA carriers were enrolled (43 males) at a median age (range) of 51 (40−74) years; 71 carried the N370S variant (c.1226A > G) and 25 had a positive family history of PD. The Montreal Cognitive Assessment (MoCA) was the most frequently abnormal (23.7%, 95% CI 15.7−33.4%), followed by the ultrasound hyperechogenicity (22%, 95% CI 14−32%), Unified Parkinson's Disease Rating Scale part III (UPDRS-III) (17.2%, 95% CI 10.2−26.4%), smell assessment (12.4%, 95% CI 6.6−20.6%) and abnormalities in sleep questionnaires (11%, 95% CI 5.7−19.4%). Significant correlations were found between tests from different domains. To define the risk for PD, we assessed the bottom 10th percentile of each prodromal test, defining this level as "abnormal". Then we calculated the percentage of "abnormal" tests for each subject; the median (range) was 4.55 (0−43.5%). Twenty-two subjects had more than 15% "abnormal" tests. The limitations of the study included ascertainment bias of individuals with GBA-related PD in relatives, some incomplete data due to technical issues, and a lack of well-characterized normal value ranges in some tests. We plan to enroll additional participants and conduct longitudinal follow-up assessments to build a model for identifying individuals at risk for PD and investigate interventions aiming to delay the onset or perhaps to prevent full-blown PD.


Asunto(s)
Enfermedad de Gaucher , Enfermedad de Parkinson , Masculino , Humanos , Persona de Mediana Edad , Enfermedad de Gaucher/complicaciones , Enfermedad de Gaucher/diagnóstico , Enfermedad de Gaucher/genética , Glucosilceramidasa/genética , Estudios de Cohortes , Mutación , Heterocigoto , Síntomas Prodrómicos , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/psicología
7.
Mov Disord ; 36(11): 2687-2692, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34496081

RESUMEN

BACKGROUND: Continuous, subcutaneous (SC) levodopa/carbidopa infusion with ND0612 is under development as a treatment for patients with Parkinson's disease (PD) and motor fluctuations. OBJECTIVE: Evaluate 1-year safety data. METHODS: BeyoND is an open-label study evaluating the long-term safety of two ND0612 dosing regimens. RESULTS: Of the 214 enrolled patients (24-hour SC infusion: n = 90; 16-hour SC infusion: n = 124), 120 (56%) completed 12 months of treatment. Leading causes for study discontinuation were consent withdrawal (19.6%) and adverse events (17.3%). Rates of discontinuation were reduced from 49% to 29% after a protocol revision and retraining. Systemic safety was typical for PD patients treated with levodopa/carbidopa. Most patients experienced infusion site reactions, particularly nodules (30.8%) and hematoma (25.2%), which were judged mostly mild to moderate and led to discontinuation in only 10.3% of the participants. CONCLUSIONS: Subcutaneous levodopa/carbidopa continuous infusion with ND0612 is generally safe, with typical infusion site reactions for SC delivery as the main adverse event. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Asunto(s)
Levodopa , Enfermedad de Parkinson , Antiparkinsonianos/efectos adversos , Carbidopa/efectos adversos , Combinación de Medicamentos , Geles , Humanos , Levodopa/efectos adversos , Enfermedad de Parkinson/tratamiento farmacológico
8.
Neurol Sci ; 42(5): 1933-1940, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-32974798

RESUMEN

BACKGROUND: Lymphoma of the nervous system is rare and usually involves the brain, spinal cord, or peripheral nerves. Hence, it has varied clinical presentations, and correct diagnosis is often challenging. Incorrect diagnosis delays the appropriate treatment and affects prognosis. We report 5 patients with delayed diagnosis of lymphoma involving the central and/or peripheral nervous system, initially evaluated for other neurological diagnoses. We also discuss the challenge of diagnosis and appropriate testing. METHODS: Retrospective review of 2011-2019 records of patients with confirmed nervous system lymphoma diagnosed in a tertiary care medical center. RESULTS: We present 5 adult patients initially evaluated for inflammatory myelopathy, inflammatory lumbosacral plexopathy, atypical parkinsonism, and demyelinating disease of the CNS. Final diagnosis of the nervous system lymphoma was delayed by 4 to 18 months and was based on tissue biopsy in 4, and on CSF and bone marrow examination in 1 patient. CONCLUSIONS: Lymphoma may imitate various central and peripheral nervous system disorders. We suggest several red flags that indicate the need to consider lymphoma, including subacute but progressive symptomatic evolution, painful neurological deficit, unclear clinical diagnosis, and transient steroid responsiveness. Correct diagnosis often requires a combination of diagnostic tests, while pathology testing is crucial for early diagnosis and is strongly recommended in the appropriate clinical setting.


Asunto(s)
Linfoma , Adulto , Encéfalo , Errores Diagnósticos , Humanos , Linfoma/diagnóstico , Estudios Retrospectivos , Médula Espinal
9.
Neurobiol Dis ; 136: 104716, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31846735

RESUMEN

The subthalamic nucleus (STN), a preferred target for treating movement disorders, has a crucial role in inhibition and execution of movement. To better understand the mechanism of movement regulation in the STN of Parkinson's disease patients, we compared the same movement with different context, facilitation vs. inhibition context. We recorded subthalamic multiunit activity intra-operatively while parkinsonian patients (off medications, n = 43 patients, 173 recording sites) performed increasingly complex oddball paradigms with frequent and deviant tones: first, passive listening to tone series with no movement ('None-Go' task, n = 7, 28 recording sites); second, pressing a button after every tone ('All-Go' task, n = 7, 26 recording sites); and third, pressing a button only for frequent tones, thus adding inhibition of movement following deviant tones ('Go-NoGo' task, n = 29, 119 recording sites). The STN responded mainly to movement-involving tasks. In the limbic-associative STN, evoked response to the deviant tone (inhibitory cue) was not significantly different between the Go-NoGo and the All-Go task. However, the evoked response to the frequent tone (go cue) in the Go-NoGo task was significantly reduced. The reduction was mainly prominent in the negative component of the evoked response amplitude aligned to the press. Successful movement inhibition was correlated with higher baseline activity. We suggest that the STN in Parkinson's disease patients adapts to movement inhibition context by selectively decreasing the amplitude of neuronal activity. Thus, the STN enables movement inhibition not by increasing responses to the inhibitory cue but by reducing responses to the release cue. The negative component of the evoked response probably facilitates movement and a higher baseline activity enables successful inhibition of movement. These discharge modulations were found in the ventromedial, non-motor domain of the STN and therefore suggest a significant role of the limbic- associative STN domains in movement planning and in global movement regulation.


Asunto(s)
Lóbulo Límbico/fisiología , Corteza Motora/fisiología , Movimiento/fisiología , Enfermedad de Parkinson/fisiopatología , Desempeño Psicomotor/fisiología , Núcleo Subtalámico/fisiología , Estimulación Acústica/métodos , Anciano , Estimulación Encefálica Profunda/instrumentación , Estimulación Encefálica Profunda/métodos , Electrodos Implantados , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neuronas/fisiología , Enfermedad de Parkinson/terapia
10.
Mov Disord ; 35(2): 337-343, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31758821

RESUMEN

BACKGROUND: Therapeutic outcomes of STN-DBS for movement and psychiatric disorders depend on electrode location within the STN. Electrophysiological and functional mapping of the STN has progressed considerably in the past years, identifying beta-band oscillatory activity in the dorsal STN as a motor biomarker. It also has been suggested that STN theta-alpha oscillations, involved in impulse control and action inhibition, have a ventral source. However, STN local field potential mapping of motor, associative, and limbic areas is often limited by poor spatial resolution. OBJECTIVES: Providing a high-resolution electrophysiological map of the motor, associative and limbic anatomical sub-areas of the subthalamic nucleus. METHODS: We have analyzed high-spatial-resolution STN microelectrode electrophysiology recordings of PD patients (n = 303) that underwent DBS surgery. The patients' STN intraoperative recordings of spiking activity (933 electrode trajectories) were combined with their imaging data (n = 83 patients, 151 trajectories). RESULTS: We found a high theta-alpha (7-10 Hz) oscillatory area, located near the STN ventromedial border in 29% of the PD patients. Theta-alpha activity in this area has higher power and lower central frequency in comparison to theta-alpha activity in more dorsal subthalamic areas. When projected on the DISTAL functional atlas, the theta-alpha oscillatory area overlaps with the STN limbic subarea. CONCLUSIONS: We suggest that theta-alpha oscillations can serve as an electrophysiological marker for the ventral subthalamic nucleus limbic subarea. Therefore, theta-alpha oscillations can guide optimal electrode placement in neuropsychiatric STN-DBS procedures and provide a reliable biomarker input for future closed-loop DBS device. © 2019 International Parkinson and Movement Disorder Society.


Asunto(s)
Estimulación Encefálica Profunda , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/terapia , Núcleo Subtalámico/fisiopatología , Adulto , Anciano , Estimulación Encefálica Profunda/métodos , Fenómenos Electrofisiológicos/fisiología , Femenino , Humanos , Masculino , Microelectrodos , Persona de Mediana Edad , Movimiento/fisiología , Núcleo Subtalámico/fisiología
11.
J Inherit Metab Dis ; 43(5): 1056-1059, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32242941

RESUMEN

Neuronopathic Gaucher disease (nGD) has a very wide clinical and genotypic spectrum. However, there is no consensus definition of nGD, including no description of how best to diagnostically separate the acute form-Gaucher type 2-from the subacute or chronic form-Gaucher type 3. In this article, we define the various forms of Gaucher disease with particular emphasis on the presence of gaze palsy in all patients with nGD. This consensus definition will help in both clinical diagnosis and appropriate patient recruitment to upcoming clinical trials.


Asunto(s)
Enfermedad de Gaucher/diagnóstico , Enfermedad de Gaucher/genética , Enfermedad de Gaucher/fisiopatología , Genotipo , Glucosilceramidasa/deficiencia , Humanos , Oftalmoplejía/etiología , Terminología como Asunto
12.
Int J Mol Sci ; 21(19)2020 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-32987733

RESUMEN

Type-1 Gaucher disease (GD1) is considered to be non- neuronopathic however recent evidence of neurological involvement continues to accumulate. There is limited evidence of retinal abnormalities in GD1. The purpose of this study was to evaluate the retinal findings of patients with GD1. Thirty GD1 individuals and 30 healthy volunteers between the ages 40-75 years were prospectively enrolled. Macular and optic nerve optical coherence tomography (OCT) scans of both eyes of each patient were performed and thickness maps were compared between groups. Patients with a known neurodegenerative disease, glaucoma, high myopia and previous intraocular surgeries were excluded. It was shown that patients with GD1 presented with higher incidence of abnormal pRNFL OCT scan and showed significantly thinner areas of pRNFL and macular ganglion cell complex (GCC) when compared to a healthy control population. Changes in retinal thickness were not associated with GD1 genotype, treatment status, disease monitoring biomarker (lyso-Gb1) and severity score index (Zimran SSI). Further investigations are needed to determine whether these findings possess functional visual implications and if retinal thinning may serve as biomarker for the development of future neurodegenerative disease in this population.


Asunto(s)
Enfermedad de Gaucher/patología , Fibras Nerviosas/patología , Nervio Óptico/patología , Células Ganglionares de la Retina/patología , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Agudeza Visual
13.
Curr Neurol Neurosci Rep ; 19(10): 70, 2019 08 23.
Artículo en Inglés | MEDLINE | ID: mdl-31440850

RESUMEN

PURPOSE OF REVIEW: Until recently, the gene associated with the recessive form of familial brain calcification (PFBC, Fahr disease) was unknown. MYORG, a gene that causes recessive PFBC was only recently discovered and is currently the only gene associated with a recessive form of this disease. Here, we review the radiological and clinical findings in adult MYORG mutation homozygous and heterozygous individuals. RECENT FINDINGS: MYORG was shown to be the cause of a large fraction of recessive cases of PFBC in patients of different ethnic populations. Pathogenic mutations include inframe insertions and deletions in addition to nonsense and missense mutations that are distributed throughout the entire MYORG coding region. Homozygotes have extensive brain calcification in all known cases, whereas in some carriers of heterozygous mutation, punctuated calcification of the globus pallidus is demonstrated. The clinical spectrum in homozygotes ranges from the lack of neurological symptoms to severe progressive neurological syndrome with bulbar and cerebellar signs, parkinsonism and other movement disorders, and cognitive impairments. Heterozygotes are clinically asymptomatic. MYORG is a transmembrane protein localized to the endoplasmic reticulum and is mainly expressed in astrocytes. While the biochemical pathways of the protein are still unknown, information from its evolution profile across hundreds of species (phylogenetic profiling) suggests a role for MYORG in regulating ion homeostasis via its glycosidase domain. MYORG mutations are a major cause for recessive PFBC in different world populations. Future studies are required in order to reveal the cellular role of the MYORG protein.


Asunto(s)
Encefalopatías/genética , Encéfalo/patología , Adulto , Enfermedades de los Ganglios Basales , Calcinosis , Glicósido Hidrolasas , Heterocigoto , Humanos , Masculino , Mutación , Enfermedades Neurodegenerativas , Linaje , Filogenia
14.
Harefuah ; 158(7): 418-422, 2019 Jul.
Artículo en Hebreo | MEDLINE | ID: mdl-31339238

RESUMEN

INTRODUCTION: Treatment-resistant obsessive-compulsive disorder (OCD) is considered a severe psychiatric disorder that causes severe functional decline. In the past, these patients were treated by selective ablation of neuronal pathways related to the pathophysiology of OCD. Deep brain stimulation is an effective and safe treatment alternative that enables reversible changes in neural circuits and reduces OCD symptoms. In this paper we present the outcome of a treatment-resistant OCD patient who underwent deep brain stimulation procedure for the first time in Israel. The patient has achieved a significant decline in OCD symptoms as well as improvement in personal and social functioning. The discussion focuses on methods to implement deep brain stimulation for OCD patients in Israel.


Asunto(s)
Estimulación Encefálica Profunda , Trastorno Obsesivo Compulsivo/terapia , Humanos , Israel , Resultado del Tratamiento
15.
Blood Cells Mol Dis ; 68: 117-120, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-27866808

RESUMEN

Both patients with non-neuronopathic Gaucher disease (GD) and heterozygous GBA mutation carrier are at increased risk for Parkinson disease (PD). The risk for PD in these groups does not linearly increase with glucosylceramide (GC) accumulation or with acid ß-glucocerebrosidase (GCase) activity. This observation, together with other clinical systemic observations raises the possibility that extra-cellular GC actually has beneficial, anti-inflammatory, properties. Based on this hypothesis, we suggest here that the administration of supplementary oral GC to GBA carriers at risk for PD may slow inflammatory-driven secondary neuronal death. Such a treatment may act synergistically in GBA carriers once given in combination with an agent that prevent the primary pathologic process that leads to cell death. Ambroxol hydrochloride, a pharmacological chaperone, which reduces endoplasmic reticulum (ER) stress induced by accumulation of mutant misfolded GCase could serve as such an agent. The efficacy of this combined therapy, derived from clinical observations, in vivo and in vitro studies, should be evaluated in clinical trials.


Asunto(s)
Ambroxol/uso terapéutico , Antiinflamatorios/uso terapéutico , Expectorantes/uso terapéutico , Enfermedad de Gaucher/complicaciones , Enfermedad de Gaucher/tratamiento farmacológico , Glucosilceramidas/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/etiología , Animales , Descubrimiento de Drogas , Enfermedad de Gaucher/genética , Enfermedad de Gaucher/patología , Glucosilceramidasa/genética , Humanos , Mutación , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología
16.
Blood Cells Mol Dis ; 68: 115-116, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-27864021

RESUMEN

Heterozygote GBA (glucosylceramidase beta) mutations increase the risk of Parkinson's disease (PD). Data based on the measured frequencies of GBA mutated alleles in the healthy population suggest that severe GBA mutations are associated with even higher risk for PD. These data, however, are prone to methodological biases resulting from the rarity of severe mutations and from ethnic-dependent differences in allele frequencies. To overcome these biases, we traced 13 Gaucher disease (GD) patients who were compound heterozygotes for one mild (N370S) and one severe GBA mutation and who reported a parent with PD. We determined the GBA mutation status of all parents and examined them whenever possible. While 50% of the parents carried a mild GBA mutation, we hypothesized that PD cases would be more likely to carry a severe mutation. We found that 10/13 PD parents had a severe mutation and only 3/10 carried a mild mutation (binomial test P<0.05). Using an unbiased methodology, we show that carriers of severe GBA mutations are at higher risk for PD relative to carriers of the mild mutations.


Asunto(s)
Glucosilceramidasa/genética , Mutación , Enfermedad de Parkinson/genética , Anciano , Alelos , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Linaje , Mutación Puntual
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