RESUMEN
In behavioral learning, reward-related events are encoded into phasic dopamine (DA) signals in the brain. In particular, unexpected reward omission leads to a phasic decrease in DA (DA dip) in the striatum, which triggers long-term potentiation (LTP) in DA D2 receptor (D2R)-expressing spiny-projection neurons (D2 SPNs). While this LTP is required for reward discrimination, it is unclear how such a short DA-dip signal (0.5-2 s) is transferred through intracellular signaling to the coincidence detector, adenylate cyclase (AC). In the present study, we built a computational model of D2 signaling to determine conditions for the DA-dip detection. The DA dip can be detected only if the basal DA signal sufficiently inhibits AC, and the DA-dip signal sufficiently disinhibits AC. We found that those two requirements were simultaneously satisfied only if two key molecules, D2R and regulators of G protein signaling (RGS) were balanced within a certain range; this balance has indeed been observed in experimental studies. We also found that high level of RGS was required for the detection of a 0.5-s short DA dip, and the analytical solutions for these requirements confirmed their universality. The imbalance between D2R and RGS is associated with schizophrenia and DYT1 dystonia, both of which are accompanied by abnormal striatal LTP. Our simulations suggest that D2 SPNs in patients with schizophrenia and DYT1 dystonia cannot detect short DA dips. We finally discussed that such psychiatric and movement disorders can be understood in terms of the imbalance between D2R and RGS.
Asunto(s)
Dopamina/fisiología , Modelos Neurológicos , Receptores de Dopamina D2/fisiología , Adenilil Ciclasas/fisiología , Animales , Biología Computacional , Cuerpo Estriado/fisiología , Distonía Muscular Deformante/fisiopatología , Proteínas de Unión al GTP/fisiología , Humanos , Aprendizaje/fisiología , Potenciación a Largo Plazo/fisiología , Trastornos Mentales/fisiopatología , Trastornos del Movimiento/fisiopatología , Neuronas/fisiología , Recompensa , Esquizofrenia/fisiopatología , Transducción de Señal/fisiologíaRESUMEN
DYT1 dystonia is a movement disorder mainly caused by a trinucleotide deletion (ΔGAG) in DYT1 (TOR1A), coding for torsinA. DYT1 dystonia patients show trends of decreased striatal ligand-binding activities to dopamine receptors 1 (D1R) and 2 (D2R). Dyt1 ΔGAG knock-in (KI) mice, which have the corresponding ΔGAG deletion, similarly exhibit reduced striatal D1R and D2R-binding activities and their expression levels. While the consequences of D2R reduction have been well characterized, relatively little is known about the effect of D1R reduction. Here, locomotor responses to D1R and D2R antagonists were examined in Dyt1 KI mice. Dyt1 KI mice showed significantly less responsiveness to both D1R antagonist SCH 23390 and D2R antagonist raclopride. The electrophysiological recording indicated that Dyt1 KI mice showed a significantly increased paired-pulse ratio of the striatal D1R-expressing medium spiny neurons and altered miniature excitatory postsynaptic currents. To analyze the in vivo torsinA function in the D1R-expressing neurons further, Dyt1 conditional knockout (Dyt1 d1KO) mice in these neurons were generated. Dyt1 d1KO mice had decreased spontaneous locomotor activity and reduced numbers of slips in the beam-walking test. Dyt1 d1KO male mice showed abnormal gait. Dyt1 d1KO mice showed defective striatal D1R maturation. Moreover, the mutant striatal D1R-expressing medium spiny neurons had increased capacitance, decreased sEPSC frequency, and reduced intrinsic excitability. The results suggest that torsinA in the D1R-expressing cells plays an important role in the electrophysiological function and motor performance. Medical interventions to the direct pathway may affect the onset and symptoms of this disorder.
Asunto(s)
Distonía Muscular Deformante/genética , Chaperonas Moleculares/genética , Receptores de Dopamina D1/metabolismo , Animales , Encéfalo/fisiología , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Distonía/genética , Distonía/metabolismo , Distonía Muscular Deformante/metabolismo , Distonía Muscular Deformante/fisiopatología , Potenciales Postsinápticos Excitadores/fisiología , Femenino , Técnicas de Sustitución del Gen , Masculino , Ratones , Ratones Noqueados , Chaperonas Moleculares/metabolismo , Trastornos del Movimiento/metabolismo , Neuronas/metabolismo , Receptores Dopaminérgicos/metabolismo , Receptores de Dopamina D1/genéticaRESUMEN
In inherited neurodevelopmental diseases, pathogenic processes unique to critical periods during early brain development may preclude the effectiveness of gene modification therapies applied later in life. We explored this question in a mouse model of DYT1 dystonia, a neurodevelopmental disease caused by a loss-of-function mutation in the TOR1A gene encoding torsinA. To define the temporal requirements for torsinA in normal motor function and gene replacement therapy, we developed a mouse line enabling spatiotemporal control of the endogenous torsinA allele. Suppressing torsinA during embryogenesis caused dystonia-mimicking behavioral and neuropathological phenotypes. Suppressing torsinA during adulthood, however, elicited no discernible abnormalities, establishing an essential requirement for torsinA during a developmental critical period. The developing CNS exhibited a parallel "therapeutic critical period" for torsinA repletion. Although restoring torsinA in juvenile DYT1 mice rescued motor phenotypes, there was no benefit from adult torsinA repletion. These data establish a unique requirement for torsinA in the developing nervous system and demonstrate that the critical period genetic insult provokes permanent pathophysiology mechanistically delinked from torsinA function. These findings imply that to be effective, torsinA-based therapeutic strategies must be employed early in the course of DYT1 dystonia.
Asunto(s)
Distonía Muscular Deformante/terapia , Terapia Genética/métodos , Chaperonas Moleculares/genética , Factores de Edad , Animales , Sistema Nervioso Central/crecimiento & desarrollo , Sistema Nervioso Central/patología , Sistema Nervioso Central/fisiopatología , Modelos Animales de Enfermedad , Distonía Muscular Deformante/genética , Distonía Muscular Deformante/fisiopatología , Regulación de la Expresión Génica , Humanos , Ratones , Ratones Mutantes , Chaperonas Moleculares/fisiología , Mutación , Fenotipo , Análisis Espacio-Temporal , Factores de TiempoRESUMEN
DYT1 or DYT-TOR1A dystonia is early-onset, generalized dystonia. Most DYT1 dystonia patients have a heterozygous trinucleotide GAG deletion in DYT1 or TOR1A gene, with a loss of a glutamic acid residue of the protein torsinA. DYT1 dystonia patients show reduced striatal dopamine D2 receptor (D2R) binding activity. We previously reported reduced striatal D2R proteins and impaired corticostriatal plasticity in Dyt1 ΔGAG heterozygous knock-in (Dyt1 KI) mice. It remains unclear how the D2R reduction contributes to the pathogenesis of DYT1 dystonia. Recent knockout studies indicate that D2R on cholinergic interneurons (Chls) has a significant role in corticostriatal plasticity, while D2R on medium spiny neurons (MSNs) plays a minor role. To determine how reduced D2Rs on ChIs and MSNs affect motor performance, we generated ChI- or MSN-specific D2R conditional knockout mice (Drd2 ChKO or Drd2 sKO). The striatal ChIs in the Drd2 ChKO mice showed an increased firing frequency and impaired quinpirole-induced inhibition, suggesting a reduced D2R function on the ChIs. Drd2 ChKO mice had an age-dependent deficient performance on the beam-walking test similar to the Dyt1 KI mice. The Drd2 sKO mice, conversely, had a deficit on the rotarod but not the beam-walking test. Our findings suggest that D2Rs on Chls and MSNs have critical roles in motor control and balance. The similarity of the beam-walking deficit between the Drd2 ChKO and Dyt1 KI mice supports our earlier notion that D2R reduction on striatal ChIs contributes to the pathophysiology and the motor symptoms of DYT1 dystonia.
Asunto(s)
Neuronas Colinérgicas/metabolismo , Cuerpo Estriado/metabolismo , Distonía Muscular Deformante/metabolismo , Distonía Muscular Deformante/fisiopatología , Interneuronas/metabolismo , Actividad Motora/fisiología , Equilibrio Postural/fisiología , Receptores de Dopamina D2/metabolismo , Animales , Conducta Animal/fisiología , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Ratones Noqueados , Ratones TransgénicosRESUMEN
DYT1 gene mutations lead to early-onset dystonia that begins with focal limb onset and spreads to other body regions within 5 years, with typical sparing of the oromandibular muscles. In the present study, we describe two patients with an unusual presentation of the disease.
Asunto(s)
Distonía Muscular Deformante/fisiopatología , Tortícolis/fisiopatología , Adulto , Niño , Distonía Muscular Deformante/complicaciones , Distonía Muscular Deformante/genética , Distonía Muscular Deformante/terapia , Femenino , Humanos , Masculino , Tortícolis/etiología , Tortícolis/genética , Tortícolis/terapiaRESUMEN
DYT1 dystonia is an inherited movement disorder without obvious neurodegeneration. Multiple mutant mouse models exhibit motor deficits without overt "dystonic" symptoms and neurodegeneration. However, some mouse models do. Among the later models, the N-CKO mouse model, which has a heterozygous Tor1a/Dyt1 knockout (KO) in one allele and Nestin-cre-mediated conditional KO in the other, exhibits a severe lack of weight gain, neurodegeneration, overt "dystonic" symptoms, such as overt leg extension, weak walking, twisted hindpaw and stiff hindlimb, and complete infantile lethality. However, it is not clear if the overt dystonic symptoms were caused by the neurodegeneration in the dying N-CKO mice. Here, the effects of improved maternal care and nutrition during early life on the symptoms in N-CKO mice were analyzed by culling the litter and providing wet food to examine whether the overt dystonic symptoms and severe lack of weight gain are caused by malnutrition-related neurodegeneration. Although the N-CKO mice in this study replicated the severe lack of weight gain and overt "dystonic" symptoms during the lactation period regardless of culling at postnatal day zero or later, there was no significant difference in the brain astrocytes and apoptosis between the N-CKO and control mice. Moreover, more than half of the N-CKO mice with culling survived past the lactation period. The surviving adult N-CKO mice did not display overt "dystonic" symptoms, and in addition they still exhibited small body weight. The results suggest that the overt "dystonic" symptoms in the N-CKO mice were independent of prominent neurodegeneration, which negates the role of neurodegeneration in the pathogenesis of DYT1 dystonia.
Asunto(s)
Sacrificio de Animales , Distonía Muscular Deformante/fisiopatología , Distonía/fisiopatología , Chaperonas Moleculares/genética , Animales , Caspasa 3/metabolismo , Modelos Animales de Enfermedad , Distonía/genética , Distonía Muscular Deformante/genética , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Lactancia , Masculino , Ratones , Ratones Noqueados , Tasa de Supervivencia , DesteteRESUMEN
A recent report of autosomal-recessive primary isolated dystonia (DYT2 dystonia) identified mutations in HPCA, a gene encoding a neuronal calcium sensor protein, hippocalcin (HPCA), as the cause of this disease. However, how mutant HPCA leads to neuronal dysfunction remains unknown. Using a multidisciplinary approach, we demonstrated the failure of dystonic N75K HPCA mutant to decode short bursts of action potentials and theta rhythms in hippocampal neurons by its Ca2+-dependent translocation to the plasma membrane. This translocation suppresses neuronal activity via slow afterhyperpolarization (sAHP) and we found that the N75K mutant could not control sAHP during physiologically relevant neuronal activation. Simulations based on the obtained experimental results directly demonstrated an increased excitability in neurons expressing N75K mutant instead of wild type (WT) HPCA. In conclusion, our study identifies sAHP as a downstream cellular target perturbed by N75K mutation in DYT2 dystonia, demonstrates its impact on neuronal excitability, and suggests a potential therapeutic strategy to efficiently treat DYT2.
Asunto(s)
Potenciales de Acción/fisiología , Señalización del Calcio/fisiología , Distonía Muscular Deformante/genética , Distonía Muscular Deformante/fisiopatología , Hipocalcina/genética , Mutación/fisiología , Animales , Animales Recién Nacidos , Células Cultivadas , Distonía Muscular Deformante/metabolismo , Femenino , Células HEK293 , Hipocalcina/metabolismo , Hipocampo/citología , Hipocampo/fisiología , Humanos , Masculino , Ratas , Ratas WistarRESUMEN
Clinical movement disorders are classified by an algorithm implemented by a practising movement disorder specialist based on information extracted during the history and clinical examination of a patient. Most simply, dystonia, is a classifier which is reached when a predominant abnormality of posture is noted. In this chapter we summarize studies that have used a variety of techniques to probe beyond the clinical examination and study kinematic features experimentally. We also outline our experimental work in DYT1 dystonia, a group of patients that share a genetically homogenous etiology and can be considered a prototypical dystonic disorder. Our results build on previous studies, confirming that motor variability on a trial-by-trial basis is selectively increased and provide evidence that increases in variability are negatively related to forms of motor learning essential for healthy motor control. Potential neural correlates of increased motor variability are discussed and the implications such work has for the rehabilitation of patients with dystonia are also highlighted.
Asunto(s)
Adaptación Fisiológica/fisiología , Trastornos Distónicos/fisiopatología , Aprendizaje/fisiología , Actividad Motora/fisiología , Desempeño Psicomotor/fisiología , Fenómenos Biomecánicos , Distonía Muscular Deformante/fisiopatología , Distonía Muscular Deformante/rehabilitación , Trastornos Distónicos/rehabilitación , HumanosRESUMEN
Trihexyphenidyl, a nonselective muscarinic receptor antagonist, is the small molecule drug of choice for the treatment of DYT1 dystonia, but it is poorly tolerated due to significant side effects. A better understanding of the mechanism of action of trihexyphenidyl is needed for the development of improved treatments. Because DTY1 dystonia is associated with both abnormal cholinergic neurotransmission and abnormal dopamine regulation, we tested the hypothesis that trihexyphenidyl normalizes striatal dopamine release in a mouse model of DYT1 dystonia using ex vivo fast scan cyclic voltammetry and in vivo microdialysis. Trihexyphenidyl increased striatal dopamine release and efflux as assessed by ex vivo voltammetry and in vivo microdialysis respectively. In contrast, Ê-DOPA, which is not usually effective for the treatment of DYT1 dystonia, did not increase dopamine release in either Dyt1 or control mice. Trihexyphenidyl was less effective at enhancing dopamine release in Dyt1 mice relative to controls ex vivo (mean increase WT: 65% vs Dyt1: 35%). Trihexyphenidyl required nicotinic receptors but not glutamate receptors to increase dopamine release. Dyt1 mice were more sensitive to the dopamine release decreasing effects of nicotinic acetylcholine receptor antagonism (IC50: WTâ¯=â¯29.46â¯nM, Dyt1â¯=â¯12.26â¯nM) and less sensitive to acetylcholinesterase inhibitors suggesting that nicotinic acetylcholine receptor neurotransmission is altered in Dyt1 mice, that nicotinic receptors indirectly mediate the differential effects of trihexyphenidyl in Dyt1 mice, and that nicotinic receptors may be suitable therapeutic targets for DYT1 dystonia.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Dopamina/biosíntesis , Distonía Muscular Deformante , Transmisión Sináptica/efectos de los fármacos , Trihexifenidilo/farmacología , Animales , Modelos Animales de Enfermedad , Distonía Muscular Deformante/metabolismo , Distonía Muscular Deformante/fisiopatología , Técnicas de Sustitución del Gen , Ratones , Chaperonas Moleculares/genética , Antagonistas Muscarínicos/farmacología , Receptores Nicotínicos/metabolismoRESUMEN
Dystonia is a movement disorder characterized by involuntary and repetitive co-contractions of agonist and antagonist muscles. Dystonia 6 (DYT6) is an autosomal dominant dystonia caused by loss-of-function mutations in the zinc finger transcription factor THAP1. We have generated Thap1 knock-out mice with a view to understanding its transcriptional role. While germ-line deletion of Thap1 is embryonic lethal, mice lacking one Thap1 allele-which in principle should recapitulate the haploinsufficiency of the human syndrome-do not show a discernable phenotype. This is because mice show autoregulation of Thap1 mRNA levels with upregulation at the non-affected locus. We then deleted Thap1 in glial and neuronal precursors using a nestin-conditional approach. Although these mice do not exhibit dystonia, they show pronounced locomotor deficits reflecting derangements in the cerebellar and basal ganglia circuitry. These behavioral features are associated with alterations in the expression of genes involved in nervous system development, synaptic transmission, cytoskeleton, gliosis and dopamine signaling that link DYT6 to other primary and secondary dystonic syndromes.
Asunto(s)
Proteínas de Unión al ADN/genética , Distonía Muscular Deformante/genética , Trastornos Distónicos/genética , Animales , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/fisiología , Proteínas de Unión al ADN/fisiología , Modelos Animales de Enfermedad , Distonía/genética , Distonía Muscular Deformante/fisiopatología , Trastornos Distónicos/fisiopatología , Regulación de la Expresión Génica/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación , Proteínas Nucleares/genética , Proteínas Nucleares/fisiología , Síndrome , Dedos de ZincRESUMEN
Dopamine D2 receptor signaling is central for striatal function and movement, while abnormal activity is associated with neurological disorders including the severe early-onset DYT1 dystonia. Nevertheless, the mechanisms that regulate D2 receptor signaling in health and disease remain poorly understood. Here, we identify a reduced D2 receptor binding, paralleled by an abrupt reduction in receptor protein level, in the striatum of juvenile Dyt1 mice. This occurs through increased lysosomal degradation, controlled by competition between ß-arrestin 2 and D2 receptor binding proteins. Accordingly, we found lower levels of striatal RGS9-2 and spinophilin. Further, we show that genetic depletion of RGS9-2 mimics the D2 receptor loss of DYT1 dystonia striatum, whereas RGS9-2 overexpression rescues both receptor levels and electrophysiological responses in Dyt1 striatal neurons. This work uncovers the molecular mechanism underlying D2 receptor downregulation in Dyt1 mice and in turn explains why dopaminergic drugs lack efficacy in DYT1 patients despite significant evidence for striatal D2 receptor dysfunction. Our data also open up novel avenues for disease-modifying therapeutics to this incurable neurological disorder.
Asunto(s)
Cuerpo Estriado/patología , Distonía Muscular Deformante/patología , Distonía Muscular Deformante/fisiopatología , Chaperonas Moleculares/genética , Proteínas RGS/análisis , Receptores de Dopamina D2/análisis , Transducción de Señal , Animales , Modelos Animales de Enfermedad , Expresión Génica , Técnicas de Silenciamiento del Gen , Ratones Endogámicos C57BL , Proteínas de Microfilamentos/análisis , Proteínas del Tejido Nervioso/análisis , Proteínas RGS/genéticaRESUMEN
For the healthy motor control system, an essential regulatory role is maintaining the equilibrium between keeping unwanted motor variability in check whilst allowing informative elements of motor variability. Kinematic studies in children with generalised dystonia (due to mixed aetiologies) show that movements are characterised by increased motor variability. In this study, the mechanisms by which high motor variability may influence movement generation in dystonia were investigated. Reaching movements in the symptomatic arm of 10 patients with DYT1 dystonia and 12 age-matched controls were captured using a robotic manipulandum and features of motor variability were extracted. Given that task-relevant variability and sensorimotor adaptation are related in health, markers of variability were then examined for any co-variance with performance indicators during an error-based learning visuomotor adaptation task. First, we confirmed that motor variability on a trial-by-trial basis was selectively increased in the homogenous and prototypical dystonic disorder DYT1 dystonia. Second, high baseline variability predicted poor performance in the subsequent visuomotor adaptation task offering insight into the rules which appear to govern dystonic motor control. The potential mechanisms behind increased motor variability and its corresponding implications for the rehabilitation of patients with DYT1 dystonia are highlighted.
Asunto(s)
Distonía Muscular Deformante/fisiopatología , Adaptación Fisiológica/fisiología , Estudios de Casos y Controles , Humanos , Desempeño Psicomotor/fisiologíaRESUMEN
BACKGROUND: DYT1 mutation is characterized by focal to generalized dystonia and incomplete penetrance. To explore the complex perturbations in the different neural networks and the mutual interactions among them, we studied symptomatic and asymptomatic DTY1 mutation carriers by resting-state functional MRI. METHODS: A total of 7 symptomatic DYT1, 10 asymptomatic DYT1, and 26 healthy controls were considered. Resting-state functional MRI (Oxford Centre for Functional MRI of the Brain) [FMRIB] Software Library) (FSL) MELODIC, dual regression, (as a toolbox of FSL, with Nets is referred to "networks") (FSLNets) (http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/FSLNets) was performed on 9 resting-state neural networks. RESULTS: DYT1 mutation signature (symptomatic DYT1 and asymptomatic DYT1) was characterized by increased connectivity in the dorsal attention network and in the left fronto-parietal network. Functional correlates of symptomatic DYT1 patients (symptomatic DYT1 vs healthy controls) showed increased connectivity in the sensorimotor network. DISCUSSION: This study argues that DYT1 dystonia is a network disorder, with crucial nodes in sensory-motor integration of posterior parietal structures. A better characterization of cortical networks involved in dystonia is crucial for possible neurophysiological therapeutic interventions. © 2016 International Parkinson and Movement Disorder Society.
Asunto(s)
Corteza Cerebral/fisiopatología , Conectoma/métodos , Distonía Muscular Deformante/fisiopatología , Chaperonas Moleculares/genética , Adulto , Corteza Cerebral/diagnóstico por imagen , Distonía Muscular Deformante/diagnóstico por imagen , Femenino , Heterocigoto , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana EdadRESUMEN
Although primary dystonia is defined by its characteristic motor manifestations, non-motor signs and symptoms have increasingly been recognized in this disorder. Recent neuroimaging studies have related the motor features of primary dystonia to connectivity changes in cerebello-thalamo-cortical pathways. It is not known, however, whether the non-motor manifestations of the disorder are associated with similar circuit abnormalities. To explore this possibility, we used functional magnetic resonance imaging to study primary dystonia and healthy volunteer subjects while they performed a motion perception task in which elliptical target trajectories were visually tracked on a computer screen. Prior functional magnetic resonance imaging studies of healthy subjects performing this task have revealed selective activation of motor regions during the perception of 'natural' versus 'unnatural' motion (defined respectively as trajectories with kinematic properties that either comply with or violate the two-thirds power law of motion). Several regions with significant connectivity changes in primary dystonia were situated in proximity to normal motion perception pathways, suggesting that abnormalities of these circuits may also be present in this disorder. To determine whether activation responses to natural versus unnatural motion in primary dystonia differ from normal, we used functional magnetic resonance imaging to study 10 DYT1 dystonia and 10 healthy control subjects at rest and during the perception of 'natural' and 'unnatural' motion. Both groups exhibited significant activation changes across perceptual conditions in the cerebellum, pons, and subthalamic nucleus. The two groups differed, however, in their responses to 'natural' versus 'unnatural' motion in these regions. In healthy subjects, regional activation was greater during the perception of natural (versus unnatural) motion (P < 0.05). By contrast, in DYT1 dystonia subjects, activation was relatively greater during the perception of unnatural (versus natural) motion (P < 0.01). To explore the microstructural basis for these functional changes, the regions with significant interaction effects (i.e. those with group differences in activation across perceptual conditions) were used as seeds for tractographic analysis of diffusion tensor imaging scans acquired in the same subjects. Fibre pathways specifically connecting each of the significant functional magnetic resonance imaging clusters to the cerebellum were reconstructed. Of the various reconstructed pathways that were analysed, the ponto-cerebellar projection alone differed between groups, with reduced fibre integrity in dystonia (P < 0.001). In aggregate, the findings suggest that the normal pattern of brain activation in response to motion perception is disrupted in DYT1 dystonia. Thus, it is unlikely that the circuit changes that underlie this disorder are limited to primary sensorimotor pathways.
Asunto(s)
Encéfalo/patología , Encéfalo/fisiopatología , Distonía Muscular Deformante/patología , Distonía Muscular Deformante/fisiopatología , Percepción de Movimiento , Adulto , Mapeo Encefálico , Estudios de Casos y Controles , Cerebelo/fisiopatología , Imagen de Difusión Tensora , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Vías Nerviosas/fisiopatología , Puente/fisiopatología , Núcleo Subtalámico/fisiopatologíaRESUMEN
Recently, mutations in the TUBB4A gene have been found to underlie hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) syndrome, a rare neurodegenerative disorder of infancy and childhood. TUBB4A mutations also have been described as causative of DYT4 ("hereditary whispering dysphonia"). However, in DYT4, brain imaging has been reported to be normal and, therefore, H-ABC syndrome and DYT4 have been construed to be different disorders, despite some phenotypic overlap. Hence, the question of whether these disorders reflect variable expressivity or pleiotropy of TUBB4A mutations has been raised. We report four unrelated patients with imaging findings either partially or totally consistent with H-ABC syndrome, who were found to have TUBB4A mutations. All four subjects had a relatively homogenous phenotype characterized by severe generalized dystonia with superimposed pyramidal and cerebellar signs, and also bulbar involvement leading to complete aphonia and swallowing difficulties, even though one of the cases had an intermediate phenotype between H-ABC syndrome and DYT4. Genetic analysis of the TUBB4A gene showed one previously described and two novel mutations (c.941C>T; p.Ala314Val and c.900G>T; p.Met300Ile) in the exon 4 of the gene. While expanding the genetic spectrum of H-ABC syndrome, we confirm its radiological heterogeneity and demonstrate that phenotypic overlap with DYT4. Moreover, reappraisal of previously reported cases would also argue against pleiotropy of TUBB4A mutations. We therefore suggest that H-ABC and DYT4 belong to a continuous phenotypic spectrum associated with TUBB4A mutations.
Asunto(s)
Ganglios Basales/patología , Cerebelo/patología , Distonía Muscular Deformante/genética , Pleiotropía Genética , Leucoencefalopatías/genética , Tubulina (Proteína)/genética , Trastornos de la Voz/congénito , Adulto , Distonía Muscular Deformante/patología , Distonía Muscular Deformante/fisiopatología , Exones , Femenino , Heterocigoto , Humanos , Leucoencefalopatías/patología , Leucoencefalopatías/fisiopatología , Masculino , Mutación , Fenotipo , Trastornos de la Voz/genética , Trastornos de la Voz/patología , Trastornos de la Voz/fisiopatologíaRESUMEN
BACKGROUND AND PURPOSE: Traditionally dystonia has been considered a disorder of basal ganglia dysfunction. However, recent research has advocated a more complex neuroanatomical network. In particular, there is increasing interest in the pathophysiological role of the cerebellum. Patients with cervical and focal hand dystonia have impaired cerebellar associative learning using the paradigm eyeblink conditioning. This is perhaps the most direct evidence to date that the cerebellum is implicated in patients. METHODS: Eleven patients with DYT1 dystonia and five patients with DYT6 dystonia were examined and rates of eyeblink conditioning were compared with age-matched controls. A marker of brainstem excitability, the blink reflex recovery, was also studied in the same groups. RESULTS: Patients with DYT1 and DYT6 dystonia have a normal ability to acquire conditioned responses. Blink reflex recovery was enhanced in DYT1 but this effect was not seen in DYT6. CONCLUSIONS: If the cerebellum is an important driver in DYT1 and DYT6 dystonia our data suggest that there is specific cerebellar dysfunction such that the circuits essential for conditioning function normally. Our data are contrary to observations in focal dystonia and suggest that the cerebellum may have a distinct role in different subsets of dystonia. Evidence of enhanced blink reflex recovery in all patients with dystonia was not found and recent studies calling for the blink recovery reflex to be used as a diagnostic test for dystonic tremor may require further corroboration.
Asunto(s)
Parpadeo/fisiología , Enfermedades Cerebelosas/fisiopatología , Condicionamiento Psicológico/fisiología , Distonía Muscular Deformante/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Tronco Encefálico/fisiopatología , Estimulación Eléctrica , Electromiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
A common form of the hyperkinetic movement disorder dystonia is caused by mutations in the gene TOR1A (located within the DYT1 locus), which encodes the ATPase torsinA. The underlying neurobiological mechanisms that result in dystonia are poorly understood, and progress in the field has been hampered by the absence of a dystonia-like phenotype in animal models with genetic modification of Tor1a. In this issue of the JCI, Liang et al. establish the first animal model with a dystonic motor phenotype and link torsinA hypofunction to the development of early neuropathological changes in distinct sensorimotor regions. The findings of this study will likely play an important role in elucidating the neural substrate for dystonia and should stimulate systematic neuropathological and imaging studies in carriers of TOR1A mutations.
Asunto(s)
Distonía Muscular Deformante/fisiopatología , Chaperonas Moleculares/fisiología , Animales , Humanos , MasculinoRESUMEN
Lack of a preclinical model of primary dystonia that exhibits dystonic-like twisting movements has stymied identification of the cellular and molecular underpinnings of the disease. The classical familial form of primary dystonia is caused by the DYT1 (ΔE) mutation in TOR1A, which encodes torsinA, AAA⺠ATPase resident in the lumen of the endoplasmic reticular/nuclear envelope. Here, we found that conditional deletion of Tor1a in the CNS (nestin-Cre Tor1a(flox/-)) or isolated CNS expression of DYT1 mutant torsinA (nestin-Cre Tor1a(flox/ΔE)) causes striking abnormal twisting movements. These animals developed perinuclear accumulation of ubiquitin and the E3 ubiquitin ligase HRD1 in discrete sensorimotor regions, followed by neurodegeneration that was substantially milder in nestin-Cre Tor1a(flox/ΔE) compared with nestin-Cre Tor1a(flox/-) animals. Similar to the neurodevelopmental onset of DYT1 dystonia in humans, the behavioral and histopathological abnormalities emerged and became fixed during CNS maturation in the murine models. Our results establish a genetic model of primary dystonia that is overtly symptomatic, and link torsinA hypofunction to neurodegeneration and abnormal twisting movements. These findings provide a cellular and molecular framework for how impaired torsinA function selectively disrupts neural circuits and raise the possibility that discrete foci of neurodegeneration may contribute to the pathogenesis of DYT1 dystonia.
Asunto(s)
Distonía Muscular Deformante/fisiopatología , Chaperonas Moleculares/fisiología , Animales , Encéfalo/patología , Encéfalo/fisiopatología , Modelos Animales de Enfermedad , Distonía Muscular Deformante/genética , Distonía Muscular Deformante/patología , Técnicas de Inactivación de Genes , Humanos , Masculino , Ratones , Ratones Noqueados , Ratones Mutantes , Ratones Transgénicos , Chaperonas Moleculares/genética , Neuronas Motoras/patología , Mutación , Degeneración Nerviosa/genética , Degeneración Nerviosa/patología , Degeneración Nerviosa/fisiopatología , Células Receptoras Sensoriales/patología , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
The authors compared the outcomes of 17 children aged 7 to 15 years with DYT1 dystonia or cerebral palsy following deep brain stimulation. While patients with cerebral palsy presented with significantly greater motor disability than the DYT1 cohort at baseline, both groups demonstrated improvement at 1 year (cerebral palsy = 24%; DYT1 = 6%). The group as a whole demonstrated significant improvement on the Barry-Albright Dystonia Scale across time. Gains in motor function were apparent in both axial and appendicular distributions involving both upper and lower extremities. Gains achieved by 6 months were sustained in the cerebral palsy group, whereas the DYT1 group demonstrated continued improvement with ongoing pallidal stimulation beyond 18 months. Young patients with dystonia due to cerebral palsy responded comparably to patients with DYT1 dystonia. The severity of motor impairment in patients with cerebral palsy at baseline and follow-up raises the issue of even earlier intervention with neuromodulation in this population to limit long-term motor impairments due to dystonia.