RESUMEN
Mitochondrial aminoacyl-tRNA synthetases (mtARSs) are essential, ubiquitously expressed enzymes that covalently attach amino acids to their corresponding tRNA molecules during translation of mitochondrial genes. Deleterious variants in the mtARS genes cause a diverse array of phenotypes, many of which involve the nervous system. Moreover, distinct mutations in mtARSs often cause different clinical manifestations. Recently, the gene encoding mitochondrial tryptophanyl tRNA synthetase (WARS2) was reported to cause 2 different neurological phenotypes, a form of autosomal recessive intellectual disability and a syndrome of severe infantile-onset leukoencephalopathy. Here, we report the case of a 17-year-old boy with compound heterozygous mutations in WARS2 (p.Trp13Gly, p.Ser228Trp) who presented with infantile-onset, Levodopa-responsive Parkinsonism at the age of 2 years. Analysis of patient-derived dermal fibroblasts revealed decreased steady-state WARS2 protein and normal OXPHOS content. Muscle mitochondrial studies suggested mitochondrial proliferation without obvious respiratory chain deficiencies at the age of 9 years. This case expands the phenotypic spectrum of WARS2 deficiency and emphasizes the importance of mitochondrial protein synthesis in the pathogenesis of Parkinsonism.
Asunto(s)
Alelos , Mutación , Trastornos Parkinsonianos/diagnóstico , Trastornos Parkinsonianos/genética , Triptófano-ARNt Ligasa/genética , Adolescente , Edad de Inicio , Biopsia , Análisis Mutacional de ADN , Fibroblastos/metabolismo , Estudios de Asociación Genética , Genotipo , Humanos , Levodopa/uso terapéutico , Imagen por Resonancia Magnética , Masculino , Trastornos Parkinsonianos/tratamiento farmacológico , Fenotipo , Polimorfismo de Nucleótido Simple , Medicina de PrecisiónRESUMEN
Deposition of beta-amyloid protein (A beta) in senile plaques and in the walls of cerebral vessels is a pathologic hallmark of Alzheimer's disease (AD). The current diagnostic criteria for AD requires the presence of neurofibrillary tangles and a minimum number of senile plaques in cortex. Senile plaques are readily visualized by silver staining or immunocytochemistry using antibodies raised to A beta. Available histochemical and immunocytochemical methods are sensitive but the results may occasionally be variable and sampling from many brain regions is difficult and impractical. This study describes a simple biochemical method for quantifying the A beta load in unfixed brain homogenates. The immunoassay recognizes all forms of A beta deposits (neuritic and diffuse plaques, and cerebrovascular amyloid) and has a sensitivity and specificity comparable to immunocytochemistry. In direct comparisons, results from the dot blot method correspond well with both Western blot analysis of partially purified A beta and plaque counting by immunocytochemistry. In a retrospective series of 39 postmortem AD and control cases, the amount of A beta in brain by dot blot immunoreactivity effectively separated the two groups. Therefore, this method provides a rapid, sensitive, and accurate quantitation of A beta in postmortem brain tissue and represents an alternative approach for studying A beta deposition in aging and AD.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/análisis , Química Encefálica , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Western Blotting , Encéfalo/patología , Humanos , Immunoblotting , Inmunohistoquímica , Persona de Mediana Edad , Ovillos Neurofibrilares/patología , Tinción con Nitrato de PlataRESUMEN
Levetiracetam was recently approved as adjunctive therapy for partial onset seizures. The authors conducted an open-label trial of levetiracetam in eight patients with chronic myoclonus. Patients were assessed by using the Unified Myoclonus Rating Scale. Levetiracetam was well tolerated. Three of five patients with cortical myoclonus experienced reductions in their myoclonus scores, providing support for a larger, placebo-controlled trial in cortical myoclonus.
Asunto(s)
Anticonvulsivantes/administración & dosificación , Epilepsias Mioclónicas/tratamiento farmacológico , Piracetam/administración & dosificación , Adulto , Anciano , Anticonvulsivantes/efectos adversos , Enfermedad Crónica , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Quimioterapia Combinada , Epilepsias Mioclónicas/diagnóstico , Femenino , Humanos , Levetiracetam , Masculino , Persona de Mediana Edad , Proyectos Piloto , Piracetam/efectos adversos , Piracetam/análogos & derivados , Resultado del TratamientoAsunto(s)
Mianserina/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Temblor/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Masculino , Mianserina/análogos & derivados , Persona de Mediana Edad , Mirtazapina , Enfermedad de Parkinson/fisiopatología , Estudios Prospectivos , Estadísticas no Paramétricas , Temblor/fisiopatologíaRESUMEN
Posthypoxic myoclonus is a rare and devastating complication of near-fatal cardiopulmonary arrest. Despite treatment with available anti-myoclonic agents, some patients may recover cognitively but remain completely disabled by severe myoclonus. We report a 16-year-old patient with severe treatment-refractory posthypoxic myoclonus, which improved markedly with administration of the drug sodium oxybate.
Asunto(s)
Paro Cardíaco/complicaciones , Hipoxia Encefálica/complicaciones , Mioclonía/tratamiento farmacológico , Oxibato de Sodio/uso terapéutico , Adolescente , Electroencefalografía , Humanos , Masculino , Mioclonía/etiología , Mioclonía/fisiopatología , SíndromeRESUMEN
The authors performed an open-label, rater-blinded, add-on study of sodium oxybate in 20 patients with ethanol-responsive myoclonus or essential tremor. Blinded ratings of videotaped examinations showed improvements in myoclonus at rest, stimulus-sensitive myoclonus, action myoclonus, functional performance, and postural and kinetic tremor. Tolerability was acceptable, and more than half of the patients chose to continue treatment after the trial. Double-blind placebo-controlled studies in these disorders are warranted.
Asunto(s)
Temblor Esencial/tratamiento farmacológico , Mioclonía/tratamiento farmacológico , Oxibato de Sodio/administración & dosificación , Adyuvantes Anestésicos/administración & dosificación , Adyuvantes Anestésicos/efectos adversos , Adulto , Síntomas Afectivos/inducido químicamente , Anciano , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Mareo/inducido químicamente , Relación Dosis-Respuesta a Droga , Etanol/farmacología , Etanol/uso terapéutico , Femenino , Cefalea/inducido químicamente , Humanos , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Cooperación del Paciente , Pacientes Desistentes del Tratamiento/estadística & datos numéricos , Oxibato de Sodio/efectos adversos , Resultado del TratamientoRESUMEN
Neuroleptic malignant syndrome is a serious complication of levodopa withdrawal in patients with Parkinson's disease. We report a patient with advanced parkinsonism who developed neuroleptic malignant syndrome in the setting of inadequate levodopa intake. His symptoms improved with levodopa replacement, but dramatically worsened when enteral feeding was begun due to interference with intestinal absorption of levodopa.
Asunto(s)
Antiparkinsonianos/efectos adversos , Levodopa/efectos adversos , Síndrome Neuroléptico Maligno/etiología , Enfermedad de Parkinson/tratamiento farmacológico , Síndrome de Abstinencia a Sustancias , Adulto , Antiparkinsonianos/farmacocinética , Humanos , Levodopa/farmacocinética , Masculino , Prevención Secundaria , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: To evaluate the natural history and response to treatment in hemidystonia. METHODS: 190 Cases of hemidystonia were identified; 33 patients in this series and 157 from the world literature. Data was collected on aetiology, age of onset, latency, lesion location, and response to treatment. RESULTS: The most common aetiologies of hemidystonia were stroke, trauma, and perinatal injury. Mean age of onset was 20 years in this series and 25.7 years in the literature. The average latency from insult to dystonia was 4.1 years in this series and 2.8 years in the literature, with the longest latencies occurring after perinatal injury. Basal ganglia lesions were identified in 48% of cases in this series and 60% of the cases in the literature, most commonly involving the putamen. Patients experienced benefit from medical therapy in only 26% of medication trials in this series and in only 35% of trials in the literature. In the patients reported here, the benzodiazepines clonazepam and diazepam were the most effective medications with 50% of trials resulting in at least some benefit. In the literature, anticholinergic drugs were most effective with 41% of trials resulting in benefit. Surgery was successful in five of six cases in this series and in 22 of 23 cases in the literature. However, in 12 cases, results were transient. CONCLUSIONS: The most common cause of hemidystonia is stroke, with the lesion most commonly involving the basal ganglia. Hemidystonia responds poorly to most medical therapies, but some patients may benefit from treatment with benzodiazepines or anticholinergic drugs. Surgical therapy may be successful but benefit is often transient.
Asunto(s)
Enfermedades de los Ganglios Basales/complicaciones , Dominancia Cerebral/fisiología , Distonía/etiología , Enfermedades Talámicas/complicaciones , Adolescente , Adulto , Anciano , Ansiolíticos/uso terapéutico , Enfermedades de los Ganglios Basales/diagnóstico , Enfermedades de los Ganglios Basales/tratamiento farmacológico , Benzodiazepinas , Niño , Preescolar , Antagonistas Colinérgicos/uso terapéutico , Ensayos Clínicos como Asunto , Distonía/diagnóstico , Distonía/tratamiento farmacológico , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Examen Neurológico , Pronóstico , Enfermedades Talámicas/diagnóstico , Enfermedades Talámicas/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Focal task-specific dystonias are unusual disorders of motor control, often affecting individuals who perform complex repetitive movements. Musicians are especially prone to develop these disorders because of their training regimens and intense practice schedules. Task-specific dystonia occurring in keyboard or string instrumentalists usually affects the hand. In contrast, there have been few descriptions of musicians with task-specific dystonia affecting the muscles of the face and jaw. We report detailed clinical observations of 26 professional brass and woodwind players afflicted with focal task-specific dystonia of the embouchure (the pattern of lip, jaw, and tongue muscles used to control the flow of air into a mouthpiece). This is the largest and most comprehensively studied series of such patients. Patients developed embouchure dystonia in the fourth decade, and initial symptoms were usually limited to one range of notes or style of playing. Once present, dystonia progressed without remission and responded poorly to oral medications and botulinum toxin injection. Patients with embouchure dystonia could be separated by the pattern of their abnormal movements into several groups, including embouchure tremor, involuntary lip movements, and jaw closure. Dystonia not infrequently spread to other oral tasks, often producing significant disability. Effective treatments are needed for this challenging and unusual disorder.
Asunto(s)
Trastornos Distónicos/etiología , Trastornos Distónicos/fisiopatología , Músculos Faciales/fisiopatología , Música , Enfermedades Profesionales/etiología , Enfermedades Profesionales/fisiopatología , Adolescente , Adulto , Anciano , Diagnóstico Diferencial , Evaluación de la Discapacidad , Progresión de la Enfermedad , Trastornos Distónicos/diagnóstico , Femenino , Humanos , Masculino , Síndrome de Meige/etiología , Síndrome de Meige/fisiopatología , Persona de Mediana Edad , Enfermedades Profesionales/diagnóstico , Pronóstico , Grabación de Cinta de VideoRESUMEN
OBJECTIVE: To measure the effect of deep brain stimulation (DBS) of the subthalamic nucleus in patients with advanced Parkinson's disease. DESIGN: Open label follow up using blinded ratings of videotaped neurological examinations. PATIENTS: 30 patients with advanced Parkinson's disease (19 male, 11 female; mean age 58.8 years; mean disease duration 12.8 years), complicated by intractable wearing off motor fluctuations and dopaminergic dyskinesias. MAIN OUTCOME MEASURES: Unified Parkinson's disease rating scale (UPDRS), part III (motor), score at one year, from blinded reviews of videotaped neurological examinations. Secondary outcomes included the other UPDRS subscales, Hoehn and Yahr scale, activities of daily living (ADL) scale, mini-mental state examination (MMSE), estimates of motor fluctuations and dyskinesia severity, drug intake, and patient satisfaction questionnaire. RESULTS: Subthalamic nucleus stimulation was associated with a 29.5% reduction in motor scores at one year (p<0.0001). The only important predictors of improvement in UPDRS part III motor scores were the baseline response to dopaminergic drugs (p = 0.015) and the presence of tremor (p = 0.027). Hoehn and Yahr scores and ADL scores in the "on" and "off" states did not change, nor did the mean MMSE score. Weight gain occurred in the year after surgery, from (mean) 75.8 kg to 78.5 kg (p = 0.028). Duration of daily wearing off episodes was reduced by 69%. Dyskinesia severity was reduced by 60%. Drug requirements (in levodopa equivalents) declined by 30%. CONCLUSIONS: The 30% improvement in UPDRS motor scores was a more modest result than previously reported. DBS did not improve functional capacity independent of drug use. Its chief benefits were reduction in wearing off duration and dyskinesia severity.