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1.
Brain ; 146(7): 2730-2738, 2023 07 03.
Artículo en Inglés | MEDLINE | ID: mdl-36860166

RESUMEN

ATP5F1B is a subunit of the mitochondrial ATP synthase or complex V of the mitochondrial respiratory chain. Pathogenic variants in nuclear genes encoding assembly factors or structural subunits are associated with complex V deficiency, typically characterized by autosomal recessive inheritance and multisystem phenotypes. Movement disorders have been described in a subset of cases carrying autosomal dominant variants in structural subunits genes ATP5F1A and ATP5MC3. Here, we report the identification of two different ATP5F1B missense variants (c.1000A>C; p.Thr334Pro and c.1445T>C; p.Val482Ala) segregating with early-onset isolated dystonia in two families, both with autosomal dominant mode of inheritance and incomplete penetrance. Functional studies in mutant fibroblasts revealed no decrease of ATP5F1B protein amount but severe reduction of complex V activity and impaired mitochondrial membrane potential, suggesting a dominant-negative effect. In conclusion, our study describes a new candidate gene associated with isolated dystonia and confirms that heterozygous variants in genes encoding subunits of the mitochondrial ATP synthase may cause autosomal dominant isolated dystonia with incomplete penetrance, likely through a dominant-negative mechanism.


Asunto(s)
Distonía , Trastornos Distónicos , Humanos , Distonía/genética , Trastornos Distónicos/genética , ATPasas de Translocación de Protón Mitocondriales/genética , Mutación Missense , Linaje , Proteínas/genética
2.
Neurol Sci ; 42(11): 4447-4457, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34471947

RESUMEN

BACKGROUND: Huntington's disease (HD) is a neurodegenerative disorder characterized by involuntary movements, cognitive decline, and behavioral changes. The complex constellation of clinical symptoms still makes the therapeutic management challenging. In the new era of functional neurosurgery, deep brain stimulation (DBS) may represent a promising therapeutic approach in selected HD patients. METHODS: Articles describing the effect of DBS in patients affected by HD were selected from Medline and PubMed by the association of text words with MeSH terms as follows: "Deep brain stimulation," "DBS," and "HD," "Huntington's disease," and "Huntington." Details on repeat expansion, age at operation, target of operation, duration of follow-up, stimulation parameters, adverse events, and outcome measures were collected. RESULTS: Twenty eligible studies, assessing 42 patients with HD, were identified. The effect of globus pallidus internus (GPi) DBS on Unified Huntington's Disease Rating Scale (UHDRS) total score revealed in 10 studies an improvement of total score from 5.4 to 34.5%, and in 4 studies, an increase of motor score from 3.8 to 97.8%. Bilateral GPi-DBS was reported to be effective in reducing Chorea subscore in all studies, with a mean percentage reduction from 21.4 to 73.6%. CONCLUSIONS: HD patients with predominant choreic symptoms may be the best candidates for surgery, but the role of other clinical features and of disease progression should be elucidated. For this reason, there is a need for more reliable criteria that may guide the selection of HD patients suitable for DBS. Accordingly, further studies including functional outcomes as primary endpoints are needed.


Asunto(s)
Corea , Estimulación Encefálica Profunda , Enfermedad de Huntington , Globo Pálido , Humanos , Enfermedad de Huntington/terapia , Resultado del Tratamiento
3.
Mov Disord ; 35(8): 1287-1292, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32449528

RESUMEN

The impact of coronavirus disease 2019 (COVID-19) on clinical features of Parkinson's disease (PD) has been poorly characterized so far. Of 141 PD patients resident in Lombardy, we found 12 COVID-19 cases (8.5%), whose mean age and disease duration (65.5 and 6.3 years, respectively) were similar to controls. Changes in clinical features in the period January 2020 to April 2020 were compared with those of 36 PD controls matched for sex, age, and disease duration using the clinical impression of severity index for PD, the Movement Disorders Society Unified PD Rating Scale Parts II and IV, and the nonmotor symptoms scale. Motor and nonmotor symptoms significantly worsened in the COVID-19 group, requiring therapy adjustment in one third of cases. Clinical deterioration was explained by both infection-related mechanisms and impaired pharmacokinetics of dopaminergic therapy. Urinary issues and fatigue were the most prominent nonmotor issues. Cognitive functions were marginally involved, whereas none experienced autonomic failure. © 2020 International Parkinson and Movement Disorder Society.


Asunto(s)
Betacoronavirus/patogenicidad , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/virología , Enfermedad de Parkinson/fisiopatología , Neumonía Viral/complicaciones , Neumonía Viral/virología , COVID-19 , Estudios de Casos y Controles , Cognición/fisiología , Trastornos del Conocimiento/virología , Depresión/psicología , Depresión/virología , Humanos , Pandemias , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/virología , SARS-CoV-2
6.
Mov Disord ; 31(11): 1720-1728, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27383763

RESUMEN

INTRODUCTION: Parkin disease (PARK2, OMIM 602544) is an autosomal-recessive early-onset parkinsonism characterized by an early occurrence of lower limb dystonia. The aim of this study was to analyze spatiotemporal, kinematic, and kinetic gait parameters in patients with parkin disease in the OFF and ON conditions compared to healthy age-matched controls. METHODS: Fifteen patients with parkin disease and 15 healthy age-matched controls were studied in a gait analysis laboratory with an integrated optoelectronic system. Spatiotemporal, kinematic, and kinetic gait parameters at a self-selected speed were recorded in the OFF and ON conditions. A jerk index was computed to quantify the possible reduction of smoothness of joint movements. RESULTS: Compared to controls, parkin patients had, either in the OFF or in the ON conditions, significant reduction of walking velocity, increased step width, and decreased percentage of double support. Kinematic analysis in both conditions showed: increased ankle dorsiflexion and knee flexion at the initial contact; maximal flexion and increased range of motion in mid stance; increased hip flexion and max extension in stance at pelvis; and increased mean tilt antiversion. Kinetics showed increased hip and knee power generation in stance in either condition. The jerk index was increased at all joints both in OFF and ON. There were no correlations between individual gait parameters and clinical ratings. CONCLUSION: Parkin patients have an abnormal gait pattern that does not vary between the OFF and the ON conditions. Variations recorded with instrumented analysis are more evident for kinematic than kinetic parameters at lower limbs. Severity of dystonia does not correlate with any individual kinematic parameter. © 2016 International Parkinson and Movement Disorder Society.


Asunto(s)
Distonía/fisiopatología , Trastornos Neurológicos de la Marcha/fisiopatología , Enfermedad de Parkinson/fisiopatología , Ubiquitina-Proteína Ligasas , Adulto , Fenómenos Biomecánicos , Distonía/etiología , Femenino , Trastornos Neurológicos de la Marcha/etiología , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/genética
7.
Mov Disord ; 30(11): 1547-56, 2015 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-26301801

RESUMEN

Knowledge on dystonia has greatly improved recently, because of a renewed effort in understanding its cause, pathophysiology, and clinical characterization. Different drug classes traditionally have been used for the symptomatic treatment of dystonia, more recently surpassed by the introduction of botulinum neurotoxins and deep brain stimulation. No curative or disease-modifying treatments are available. Recent knowledge regarding the pathophysiology of inherited dystonias is highlighting new potential treatment strategies. We review therapeutic advances in dystonia that have been published over the last 3 years, particularly regarding oral medications, local injections of botulinum neurotoxins, deep brain stimulation, and transcranial or epidural brain stimulations. We discuss evidence of efficacy, highlight recent advances, and focus on key areas under development.


Asunto(s)
Toxinas Botulínicas/uso terapéutico , Estimulación Encefálica Profunda , Distonía/terapia , Neurotoxinas/uso terapéutico , Estimulación Magnética Transcraneal , Humanos
8.
Artículo en Inglés | MEDLINE | ID: mdl-38617829

RESUMEN

Background: Spinocerebellar ataxia 21 (SCA21) is a rare neurological disorder caused by heterozygous variants in TMEM240. A growing, yet still limited number of reports suggested that hyperkinetic movements should be considered a defining component of the disease. Case Series: We describe two newly identified families harboring the recurrent pathogenic TMEM240 p.Pro170Leu variant. Both index patients and the mother of the first proband developed movement disorders, manifesting as myoclonic dystonia and action-induced dystonia without co-occurring ataxia in one case, and pancerebellar syndrome complicated by action-induced dystonia in the other. We reviewed the literature on TMEM240 variants linked to hyperkinetic disorders, comparing our cases to described phenotypes. Discussion: Adding to prior preliminary observations, our series highlights the relevance of hyperkinetic movements as clinically meaningful features of SCA21. TMEM240 mutation should be included in the differential diagnosis of myoclonic dystonia and ataxia-dystonia syndromes.


Asunto(s)
Distonía , Trastornos Distónicos , Mioclonía , Degeneraciones Espinocerebelosas , Humanos , Distonía/diagnóstico , Distonía/genética , Mioclonía/diagnóstico , Mioclonía/genética , Hipercinesia , Ataxia , Enfermedades Raras , Síndrome , Proteínas de la Membrana
9.
Nat Neurosci ; 27(3): 573-586, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38388734

RESUMEN

Frontal circuits play a critical role in motor, cognitive and affective processing, and their dysfunction may result in a variety of brain disorders. However, exactly which frontal domains mediate which (dys)functions remains largely elusive. We studied 534 deep brain stimulation electrodes implanted to treat four different brain disorders. By analyzing which connections were modulated for optimal therapeutic response across these disorders, we segregated the frontal cortex into circuits that had become dysfunctional in each of them. Dysfunctional circuits were topographically arranged from occipital to frontal, ranging from interconnections with sensorimotor cortices in dystonia, the primary motor cortex in Tourette's syndrome, the supplementary motor area in Parkinson's disease, to ventromedial prefrontal and anterior cingulate cortices in obsessive-compulsive disorder. Our findings highlight the integration of deep brain stimulation with brain connectomics as a powerful tool to explore couplings between brain structure and functional impairments in the human brain.


Asunto(s)
Estimulación Encefálica Profunda , Corteza Motora , Enfermedad de Parkinson , Humanos , Encéfalo , Corteza Motora/fisiología , Enfermedad de Parkinson/terapia , Mapeo Encefálico
10.
medRxiv ; 2023 Aug 25.
Artículo en Inglés | MEDLINE | ID: mdl-36945497

RESUMEN

Frontal circuits play a critical role in motor, cognitive, and affective processing - and their dysfunction may result in a variety of brain disorders. However, exactly which frontal domains mediate which (dys)function remains largely elusive. Here, we study 534 deep brain stimulation electrodes implanted to treat four different brain disorders. By analyzing which connections were modulated for optimal therapeutic response across these disorders, we segregate the frontal cortex into circuits that became dysfunctional in each of them. Dysfunctional circuits were topographically arranged from occipital to rostral, ranging from interconnections with sensorimotor cortices in dystonia, with the primary motor cortex in Tourette's syndrome, the supplementary motor area in Parkinson's disease, to ventromedial prefrontal and anterior cingulate cortices in obsessive-compulsive disorder. Our findings highlight the integration of deep brain stimulation with brain connectomics as a powerful tool to explore couplings between brain structure and functional impairment in the human brain.

11.
Parkinsonism Relat Disord ; 97: 52-56, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35306330

RESUMEN

INTRODUCTION: The genetic basis of autosomal-recessive dystonia remains poorly understood. Our objective was to report identification of additional individuals with variants in AOPEP, a recently described gene for recessively inherited dystonic disorders (OMIM:619565). METHODS: Ongoing analysis on a high-throughput genetic platform and international case-recruitment efforts were undertaken. RESULTS: Novel biallelic, likely pathogenic loss-of-function alleles were identified in two pedigrees of different ethnic background. Two members of a consanguineous Iranian family shared a homozygous c.1917-1G>A essential splice-site variant and featured presentations of adolescence-onset generalized dystonia. An individual of Chinese descent, homozygous for the nonsense variant c.1909G>T (p.Glu637*), displayed childhood-onset generalized dystonia combined with later-manifesting parkinsonism. One additional Iranian patient with adolescence-onset generalized dystonia carried an ultrarare, likely protein-damaging homozygous missense variant (c.1201C>T [p.Arg401Trp]). CONCLUSIONS: These findings support the implication of AOPEP in recessive forms of generalized dystonia and dystonia-parkinsonism. Biallelic AOPEP variants represent a worldwide cause of dystonic movement-disorder phenotypes and should be considered in dystonia molecular testing approaches.


Asunto(s)
Aminopeptidasas/genética , Distonía , Trastornos Distónicos , Trastornos Parkinsonianos , Niño , Distonía/genética , Trastornos Distónicos/genética , Humanos , Irán , Mutación , Linaje
12.
Mov Disord ; 26(5): 852-7, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21370265

RESUMEN

BACKGROUND: Preclinical and clinical evidence suggests that impaired gamma-aminobutyric (GABA) control, leading to disinhibition within the sensorimotor system, might play a role in dystonia. Aim of this study is the in vivo assessment of the GABAergic system in dystonia using positron emission tomography (PET) and (11) C-flumazenil, a selective GABA(A) receptor ligand. METHODS: Fourteen subjects with primary dystonia (9 carriers of the DYT1 mutation and 5 sporadic cases) were compared to 11 controls, using a simplified reference tissue model to measure binding potential. RESULTS: Voxel-based analyses showed a reduction in GABA(A) receptor expression/affinity both in DYT1 carriers and sporadic patients in primary motor and premotor cortex, primary and secondary somatosensory cortex, and in the motor component of the cingulate gyrus. CONCLUSIONS: Dysfunction of GABA(A) receptors in sensorimotor systems in primary (genetic and sporadic) dystonia supports the view that lack of GABAergic control may be associated with the generation of dystonic movements.


Asunto(s)
Corteza Cerebral/metabolismo , Trastornos Distónicos/patología , Receptores de GABA-A/metabolismo , Adulto , Análisis de Varianza , Mapeo Encefálico , Corteza Cerebral/diagnóstico por imagen , Trastornos Distónicos/diagnóstico , Trastornos Distónicos/diagnóstico por imagen , Trastornos Distónicos/genética , Femenino , Flumazenil/farmacocinética , Moduladores del GABA/farmacocinética , Humanos , Masculino , Persona de Mediana Edad , Chaperonas Moleculares/genética , Cintigrafía , Eliminación de Secuencia/genética , Repeticiones de Trinucleótidos/genética
13.
Brain ; 133(9): 2664-76, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20802207

RESUMEN

Deep brain stimulation of the subthalamic nucleus represents the most important innovation for treatment of advanced Parkinson's disease. Prospective studies have shown that although the beneficial effects of this procedure are maintained at 5 years, axial motor features and cognitive decline may occur in the long term after the implants. In order to address some unsolved questions raised by previous studies, we evaluated a series of 20 consecutive patients who received continuous stimulation for 8 years. The overall motor improvement reported at 5 years (55.5% at Unified Parkinson's Disease Rating Scale-motor part, P < 0.001 compared with baseline) was only partly retained 3 years later (39%, P < 0.001, compared with baseline; -16.5%, P < 0.01, compared with 5 years), with differential effects on motor features: speech did not improve and postural stability worsened (P < 0.05). The preoperative levodopa equivalent daily dose was reduced by 58.2% at 5 years and by 60.3% at 8 years. In spite of subtle worsening of motor features, a dramatic impairment in functional state (-56.6% at Unified Parkinson's Disease Rating Scale-Activities of Daily Living, P < 0.01) emerged after the fifth year of stimulation. The present study did not reveal a predictive value of preoperative levodopa response, whereas few single features at baseline (such as gait and postural stability motor scores and the preoperative levodopa equivalent daily dose) could predict long-term motor outcome. A decline in verbal fluency (slightly more pronounced than after 5 years) was detected after 8 years. A significant but slight decline in tasks of abstract reasoning, episodic memory and executive function was also found. One patient had developed dementia at 5 years with further progression at 8 years. Executive dysfunction correlated significantly with postural stability, suggesting interplay between axial motor deterioration and cognition. Eight years after surgery, no significant change was observed on scales assessing depression or anxiety when compared with baseline. At 8 years, there was no significant increase of side-effects when compared with 5-year follow-up. In conclusion, deep brain stimulation of the subthalamic nucleus is a safe procedure with regard to cognitive and behavioural morbidity over long-term follow-up. However, the global benefit partly decreases later in the course of the disease, due to progression of Parkinson's disease and the appearance of medication- and stimulation-resistant symptoms.


Asunto(s)
Trastornos del Conocimiento/terapia , Estimulación Encefálica Profunda/métodos , Actividad Motora/fisiología , Enfermedad de Parkinson/terapia , Núcleo Subtalámico/fisiología , Anciano , Trastornos del Conocimiento/etiología , Femenino , Trastornos Neurológicos de la Marcha/etiología , Trastornos Neurológicos de la Marcha/terapia , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Examen Neurológico , Pruebas Neuropsicológicas , Enfermedad de Parkinson/complicaciones , Estudios Retrospectivos , Estadísticas no Paramétricas , Síncope/etiología , Síncope/terapia , Factores de Tiempo , Resultado del Tratamiento
14.
Mov Disord Clin Pract ; 7(8): 920-929, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-33163563

RESUMEN

BACKGROUND: Functional motor disorders (FMDs) are abnormal movements that are significantly altered by distractive maneuvers and are incongruent with movement disorders seen in typical neurological diseases. OBJECTIVE: The objectives of this article are to (1) describe the clinical manifestations of FMDs, including nonmotor symptoms and occurrence of other functional neurological disorders (FND); and (2) to report the frequency of isolated and combined FMDs and their relationship with demographic and clinical variables. METHODS: For this multicenter, observational study, we enrolled consecutive outpatients with a definite diagnosis of FMDs attending 25 tertiary movement disorders centers in Italy. Each patient underwent a detailed clinical evaluation with a definition of the phenotype and number of FMDs (isolated, combined) and an assessment of associated neurological and psychiatric symptoms. RESULTS: Of 410 FMDs (71% females; mean age, 47 ± 16.1 years) the most common phenotypes were weakness and tremor. People with FMDs had higher educational levels than the general population and frequent nonmotor symptoms, especially anxiety, fatigue, and pain. Almost half of the patients with FMDs had other FNDs, such as sensory symptoms, nonepileptic seizures, and visual symptoms. Patients with combined FMDs showed a higher burden of nonmotor symptoms and more frequent FNDs. Multivariate regression analysis showed that a diagnosis of combined FMDs was more likely to be delivered by a movement disorders neurologist. Also, FMD duration, pain, insomnia, diagnosis of somatoform disease, and treatment with antipsychotics were all significantly associated with combined FMDs. CONCLUSIONS: Our findings highlight the need for multidimensional assessments in patients with FMDs given the high frequency of nonmotor symptoms and other FNDs, especially in patients with combined FMDs.

16.
Mov Disord ; 24(4): 557-63, 2009 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-19097175

RESUMEN

Stimulation of the subthalamic nucleus (STN) is an effective treatment for advanced Parkinson's disease (PD), but the medication requirements after implant are poorly known. We performed a long-term prospective evaluation of 20 patients maintained at stable dopaminergic therapy for 5 years after bilateral STN implants, who were evaluated 6 months, 1 year, 3 years, and 5 years after surgery. We measured, during the entire observation period, the effect of deep brain stimulation on motor and functional outcome measures, the levodopa equivalent daily dose and the total electrical energy delivered. At 5 years, the UPDRS motor score had improved by 54.2% and levodopa equivalent dose was reduced by 61.9%, compared with preimplant. Dopaminergic medication remained stable during the observation period, but energy was progressively increased over time. Rest tremor, rigidity, gait, lower and upper limb akinesia, and total axial score were improved in decreasing order. Postural stability and speech improved transiently, whereas on-period freezing of gait, motor fluctuations and dyskinesias recovered durably. Functional measures did not show improvement in autonomy and daily living activities after STN implant. Chronic STN stimulation allows to replace for dopaminergic medications in the long-term at the expense of an increase of the total energy delivered. This is associated with marked improvement of motor features without a matching benefit in functional measures.


Asunto(s)
Estimulación Encefálica Profunda/métodos , Enfermedad de Parkinson/terapia , Núcleo Subtalámico/fisiología , Evaluación de la Discapacidad , Dopaminérgicos/uso terapéutico , Electrodos Implantados , Femenino , Humanos , Levodopa/uso terapéutico , Estudios Longitudinales , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Enfermedad de Parkinson/fisiopatología , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del Tratamiento
17.
J Neural Eng ; 16(6): 066011, 2019 10 23.
Artículo en Inglés | MEDLINE | ID: mdl-31370042

RESUMEN

OBJECTIVE: Deep brain stimulation (DBS) of basal ganglia effectively tackles motor symptoms of movement disorders such as Tourette syndrome (TS). The precise location of target stimulation site determines the range of clinical outcome in DBS patients, and the occurrence of side-effects of DBS. DBS implant procedures currently localize stimulation target relying on a combination of pre-surgical imaging, standardized brain atlases and on-the-spot clinical tests. Here we show that temporal structure of single unit activity in subthalamic nucleus (STN) of patients affected by pure TS can contribute to identify the optimal target location of DBS. APPROACH: Neural activity was recorded at different depths within STN with microelectrodes during DBS implant surgery. Depth specific neural features were extracted and correlated with the optimal depth for tic control. MAIN RESULTS: We describe for the first time temporal spike patterns of single neurons from sensorimotor STN of anesthetized TS patients. A large fraction of units (31.2%) displayed intense bursting in the delta band (<4 Hz). The highest firing irregularity and hence the higher density of bursting units (42%) were found at the optimal spot for tic control. Discharge patterns irregularity and dominant oscillations frequency (but not firing rate) carried significant information on optimal target. SIGNIFICANCE: We found single unit activity features in the STN of TS patients reliably associated to optimal DBS target site for tic control. In future works measures of firing irregularity could be integrated with current target localization methods leading to a more effective and safer DBS for TS patients.


Asunto(s)
Anestesia/métodos , Estimulación Encefálica Profunda/métodos , Electrodos Implantados , Imagenología Tridimensional/métodos , Neuronas/fisiología , Núcleo Subtalámico/fisiología , Síndrome de Tourette/terapia , Adulto , Estimulación Encefálica Profunda/instrumentación , Femenino , Humanos , Masculino , Microelectrodos , Persona de Mediana Edad , Núcleo Subtalámico/diagnóstico por imagen , Síndrome de Tourette/diagnóstico por imagen
19.
Eur J Paediatr Neurol ; 22(2): 308-315, 2018 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-29396170

RESUMEN

Cerebral palsy (CP) is a heterogeneous group of syndromes that cause a non-progressive disorder of early onset, with abnormal control of movement and posture. Various aetiologies can cause the CP clinical spectrum, but all have a disruption of motor control in common. CP can be divided into four major types based on the motor disability: predominant spastic, dyskinetic, ataxic and mixed form. Dyskinetic CP (DCP) is the most common cause of acquired dystonia in children. The treatment of DCP is challenging because most individuals have mixed degrees of chorea, athetosis and dystonia. Pharmacological treatment is often unsatisfactory. Functional neurosurgery, in particular deep brain stimulation targeting the basal ganglia or the cerebellum, is emerging as a promising therapeutic approach in selected patients with DCP. We evaluated herein the effects of DBS on patients with DCP in a review of published patient data in the largest available studies.


Asunto(s)
Parálisis Cerebral/complicaciones , Parálisis Cerebral/terapia , Estimulación Encefálica Profunda/métodos , Distonía/etiología , Distonía/terapia , Niño , Femenino , Humanos , Masculino
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