[A case suspected of dystonia with marked cerebellar atrophy with torsion dystonia of the neck and cerebellar ataxia that developed during pharmacologic schizophrenia treatment].

A 46 year-old man with schizophrenia had taken several anti-psychotic drugs since 25 years of age. From ~35 years of age, he noticed occasional neck torsion to the left, and later an ataxic gait; both symptoms gradually worsened. On admission, the patient was taking olanzapine (5 mg/day) and biperiden hydrochloride (1 mg/day) because his schizophrenia was well controlled. His parents were not consanguineous, and there was no family history of neuropsychiatric diseases. On neurological examination, he showed mild cognitive impairment, saccadic eye pursuit with horizontal gaze nystagmus, mild dysarthria, dystonic posture and movement of the neck, incoordination of both hands, and an ataxic gait. Deep tendon reflexes were normal except for the patellar tendon reflex, which was exaggerated bilaterally. Pathological reflexes were negative and there was no sign of rigidity, sensory disturbance or autonomic dysfunction. Ophthalmological examinations detected thinning of the outer macula lutea in both eyes, indicative of macular dystrophy. After admission, all anti-psychotic drugs were ceased, but his dystonia was unchanged. Levodopa and trihexyphenidyl hydrochloride were not effective. General blood, urine and cerebrospinal fluid examinations showed no abnormalities. Brain MRI showed cerebellar atrophy and bilateral symmetrical thalamic lesions without brainstem atrophy or abnormal signals in the basal ganglia. I123-IMP SPECT also revealed a decreased blood flow in the cerebellum. Genetic screening, including whole exome sequencing conducted by the Initiative on Rare and Undiagnosed Disease identified no possible disease-causing variants. The patient's dystonia worsened and choreic movements manifested on his right hand and foot. We suspected dystonia with marked cerebellar atrophy (DYTCA), but could not exclude drug-induced dystonia. Macular dystrophy and bilateral thalamic lesions on brain MRI have not been previously described in DYTCA. Whether these features might be primarily associated with dystonia or cerebellar ataxia now remains to be determined.

MR Imaging of the Brain in Neurologic Wilson Disease.

BACKGROUND AND PURPOSE: Neurologic Wilson disease is an inherited disease characterized by a copper metabolic disorder that causes damage to many organs, especially the brain. Few studies report the relationships between these neurologic symptoms and MR imaging of the brain. Therefore, we investigated the correlation of brain abnormalities in patients with neurologic Wilson disease with their clinical symptoms, age of onset, and lag time to diagnosis. MATERIALS AND METHODS: A cohort of 364 patients was recruited in China between January 2003 and December 2017. Age of onset, lag time until diagnosis, and neurologic symptoms were recorded, and cranial MR imaging was performed. Patients were divided into groups within each of these factors for correlation analysis with the MR imaging brain scans. RESULTS: Abnormal signals in the MR imaging brain scans were seen in all 364 cases. Affected regions included the putamen, pons, midbrain, and thalamus, while the medulla and occipital lobe were unaffected. The putamen was the most frequently damaged brain region in this study. With the age of onset younger than 10 years, cranial MR imaging scans showed only impairment in the putamen. Patients with a longer lag time before diagnosis were more likely to have impairment in the pons, midbrain, and cortex. Among neurologic symptoms of Wilson disease, torsion spasm is associated with the midbrain and cortex, and choreoathetosis is related to the caudate nucleus. CONCLUSIONS: Abnormalities in the putamen, pons, midbrain, and thalamus are part of the neuroimaging spectrum of Wilson disease. There is a significant correlation between the site of brain injury and diagnosis lag time.

Torsion of the urinary bladder after pelvic trauma and surgical fixation.

Urinary bladder torsion in a dog was successfully treated with reduction of the torsion and cystopexy. Urinary bladder torsion is a rare occurrence in dogs and has only been reported once previously. In the previous report, the bladder torsion was iatrogenic. This brief communication describes a case of bladder torsion and subtotal necrosis following reduction and stabilisation of pelvic fractures sustained during a road traffic accident. Proposed aetiology, diagnosis, treatment and postoperative management are discussed.

Genetics of primary torsion dystonia.

Advances in the genetics of dystonia have further elucidated the pathophysiology of this clinically and etiologically heterogeneous group of movement disorders. Currently, 20 monogenic forms of dystonia, designated by the acronym DYT, are grouped as 1) pure dystonias, 2) dystonia-plus syndromes, and 3) paroxysmal dystonias/dyskinesias. We summarize recently discovered genes and loci, including the 1) detection of two primary dystonia genes (DYT6, DYT16), 2) identification of the DYT17 locus, 3) association of a dystonia/dyskinesia phenotype with a gene previously linked to GLUT1 (glucose transporter of the blood-brain barrier) deficiency syndrome (DYT18), 4) designation of paroxysmal kinesigenic and nonkinesigenic dyskinesia as DYT19 and DYT20, and 5) redefinition of DYT14 as DYT5. Further, we review current knowledge regarding genetic modifiers and susceptibility factors. Because recognizing and diagnosing monogenic dystonias have important implications for patients and their families with regard to counseling, prognosis, and treatment, we highlight clinical "red flags" of individual subtypes and review guidelines for genetic testing.

Síndromes postencefalíticos en la literatura médica española / Post-encephalitic syndromes in the spanish medical literature

Objetivo. Un gran número de pacientes de encefalitis letárgica desarrollaba diferentes síndromes postencefalíticos (SPE), de importante impacto medicosocial. Hemos estudiado los aspectos clínicos e históricos de los SPE en España, mediante una revisión de la literatura médica publicada en este país en el período 1918-1936. Desarrollo. No existen datos estadísticos sobre los SPE en España, aunque médicos españoles llamaron la atención sobre su alta prevalencia y su repercusión sociosanitaria. La mayoría de los 140 pacientes revisados (74%) presentaron parkinsonismo predominante, pero en casi todos se apreciaba algún rasgo parkinsoniano. Se describieron otros trastornos del movimiento (distonías focales, corea, mioclonías, crisis oculógiras, anomalías del ritmo respiratorio), así como trastornos del sueño, endocrinos y vegetativos. A menudo se comunicaron alteraciones psiquiátricas: la más frecuente era la bradifrenia asociada a parkinsonismo, pero fue muy característico un cuadro hipomaníaco con conducta impulsiva en jóvenes. El diagnóstico del SPE se realizó una media de dos años después del episodio de encefalitis letárgica aguda, aunque con frecuencia apareció inmediatamente después. En muchos trabajos se discute sobre la contribución de los SPE al desarrollo del conocimiento de la fisiopatología de las enfermedades extrapiramidales y sobre la implicación de los ganglios basales en los trastornos psiquiátricos y de conducta. Conclusiones. En ausencia de datos estadísticos, los autores españoles reflejaron la importante repercusión sociosanitaria de los SPE, así como su papel en el conocimiento de la fisiopatología de los ganglios basales. Predominaron los parkinsonismos, aunque se describieron todo tipo de manifestaciones postencefalíticas

Aim. A large number of patients with encephalitis lethargica developed different post-encephalitic syndromes (PES), which have an important medical and social impact. We studied the clinical and historical aspects of PES in Spain by reviewing the medical literature published in this country between 1918 and 1936. Development. There are no statistical data concerning PES in Spain, although Spanish physicians drew attention to their high rate of prevalence and their repercussions on community health. Most of the 140 patients that were reviewed (74%) presented predominant Parkinsonism, but some features of Parkinsonism were observed in nearly all cases. Other movement disorders (focal dystonias, chorea, myoclonus, oculogyric crises, abnormalities affecting breathing rate) were described, as well as sleep, endocrine and vegetative disorders. Psychiatric disorders were often reported, the most frequent being bradyphrenia associated to Parkinsonism, but a hypomanic picture with impulsive behaviour was very characteristic among young people. PES was diagnosed on average two years after the episode of acute encephalitis lethargica, although it often appeared immediately afterwards. Many studies discuss the contribution made by PES to further our knowledge of the pathophysiology of extrapyramidal diseases and about the involvement of the basal ganglia in psychiatric and behavioural disorders. Conclusions. Despite the absence of statistical data, Spanish authors highlighted the important repercussions the PES had on community health, as well as the role they played in extending our knowledge of the pathophysiology of the basal ganglia. Cases of Parkinsonism were predominant, although all kinds of post-encephalitic manifestations were reported

Un caso de síndrome de Pisa (distonía tardía) inducido por risperidona / A case of Pisa syndrome (tardive distony) induced by risperidone

Introducción: Los antipsicóticos atípicos o de segunda generación producen efectos extrapiramidales con poca frecuencia. Risperidona a dosis bajas produce pocos efectos extrapiramidales. El síndrome de Pisa, una forma de distonía tadía, es un cuadro extremadamente raro. Con risperidona se ha comunicado recientemente algún caso. Caso Clínico: Paciente de 60 años de edad, diagnosticada de esquizofrenia desde los 16 años. Ha seguido tratamiento con diversos neurolépticos a los largo de 44 años. Con risperidona siguió tratamiento durante 1 año. Desarrolló un cuadro de distonía tadía grave, que remitió a lo largo de varios meses con clozapina, después de intentar otras estrategias. Discusión y conclusiones: la fisiopatología, la clínica y el tratamiento de este raro cuadro se discute a la luz de este caso. La resolución después de varios meses con clozapina es una de las posibles actuaciones aconsejadas

Introduction: The atypical antipsychotics of second generation produce not frequently extrapyramidal effects. Risperidone in low doses produces a few extrapyramidal effects. The Pisa syndrome, a form of tardive distony, is an extremely rare medical-board. With risperidone some cases have been reported recently. Clinical case: A sixty years old patient was diagnosticated of schizophrenia since she was sixtee. She has continued treatment with different neuroleptics during forty-four years. Se went on treatment with risperidone for a year. Se developed a grave tardive distony medical-board that remitted all along several months with clozapine, after have attempted another strategics. Discussion and conclusions: The physiopathology, the clinical and the treatment in this rare medica´l-board is discussed at the light of this case. The resolution after several months with clozapine is one of the possible adviced actuations

Effect of torsinA on membrane proteins reveals a loss of function and a dominant-negative phenotype of the dystonia-associated DeltaE-torsinA mutant.

Most cases of early-onset torsion dystonia (EOTD) are caused by a deletion of one glutamic acid in the carboxyl terminus of a protein named torsinA. The mutation causes the protein to aggregate in perinuclear inclusions as opposed to the endoplasmic reticulum localization of the wild-type protein. Although there is increasing evidence that dysfunction of the dopamine system is implicated in the development of EOTD, the biological function of torsinA and its relation to dopaminergic neurotransmission has remained unexplored. Here, we show that torsinA can regulate the cellular trafficking of the dopamine transporter, as well as other polytopic membrane-bound proteins, including G protein-coupled receptors, transporters, and ion channels. This effect was prevented by mutating the ATP-binding site in torsinA. The dystonia-associated torsinA deletion mutant (DeltaE-torsinA) did not have any effect on the cell surface distribution of polytopic membrane-associated proteins, suggesting that the mutation linked with EOTD results in a loss of function. However, a mutation in the ATP-binding site in DeltaE-torsinA reversed the aggregate phenotype associated with the mutant. Moreover, the deletion mutant acts as a dominant-negative of wild-type torsinA through a mechanism presumably involving association of wild-type and mutant torsinA. Taken together, our results provide evidence for a functional role for torsinA and a loss of function and a dominant-negative phenotype of the DeltaE-torsinA mutation. These properties may contribute to the autosomal dominant nature of the condition.

A Drosophila model of early onset torsion dystonia suggests impairment in TGF-beta signaling.

To investigate the cellular and molecular etiology of early onset torsion dystonia, we have established a Drosophila model of this disorder. Expression of mutant human torsinA deleted for a single glutamic acid residue (DeltaE HtorA), but not normal HtorA, elicits locomotor defects in Drosophila. As in mammalian systems, DeltaE HtorA in flies forms protein accumulations that localize to synaptic membranes, nuclei and endosomes. Various morphological defects at the neuromuscular junction in larvae expressing DeltaE HtorA were observed at the EM level, some of which resemble those recently reported for mutants with defects in TGF-beta signaling. These results together with the distribution patterns and localizations of DeltaE HtorA accumulations suggested that DeltaE HtorA could interfere with some aspect of TGF-beta signaling from synapses to endosomes or nuclei. Consistent with this possibility, neuronal overexpression of Drosophila or human Smad2, a downstream effector of the TGF-beta pathway, suppressed the behavioral and ultrastructural defects of DeltaE HtorA flies. These results raise the possibility that a defect in TGF-beta signaling might also underlie early onset torsion dystonia in humans.

Post-traumatic cervical dystonia: a distinct entity?

BACKGROUND/OBJECTIVE: The incidence of head/neck trauma preceding cervical dystonia (CD) has been reported to be 5-21%. There are few reports comparing the clinical characteristics of patients with and without a history of injury. Our aim was to compare the clinical characteristics of idiopathic CD (CD-I) to those with onset precipitated by trauma (CD-T). METHODS: We evaluated 114 consecutive patients with CD over a 9-month period. All patients were interviewed using a detailed questionnaire and had a neurological examination. Their clinical charts were also reviewed. RESULTS: Fourteen patients (12%) had mild head/neck injury within a year preceding the onset of CD. Between the two groups (CD-I and CD-T), the gender distribution (F:M of 3:2), family history of movement disorders (32% vs. 29%), the prevalence of gestes antagonistes (65% vs. 64%), and response to botulinum toxin were similar. There were non-specific trends, including an earlier age of onset (mean ages 43.3 vs. 37.6), higher prevalence of neck pain (86% vs. 100%), head tremor (67% vs. 79%), and dystonia in other body parts (23% vs. 36%) in CD-T. CONCLUSIONS: CD-I and CD-T are clinically similar. Trauma may be a triggering factor in CD but this was only supported by non-significant trends in its earlier age of onset.

Functional brain networks in DYT1 dystonia.

Early-onset idiopathic torsion dystonia (ITD) is an autosomal dominant hyperkinetic movement disorder with incomplete penetrance, associated with a 3 base-pair deletion in the DYT1 gene on chromosome 9q34. To determine the metabolic substrates of brain dysfunction in DYT1 dystonia, we scanned 7 nonmanifesting and 10 affected DYT1 carriers and 14 normal volunteers with [18F]fluorodeoxyglucose and positron emission tomography. We found that DYT1 dystonia is mediated by the expression of two independent regional metabolic covariance patterns. The first pattern, identified in an analysis of nonmanifesting gene carriers was designated movement free (MF). This abnormal pattern was characterized by increased metabolic activity in the lentiform nuclei, cerebellum, and supplementary motor areas. The MF pattern was present in DYT1 carriers with and without clinical manifestations and persisted in DYT1 dystonia patients in whom involuntary movements were suppressed by sleep. The second pattern, identified in an analysis of affected gene carriers with sustained contractions at rest, was designated movement related (MR). This pattern was characterized by increased metabolic activity in the midbrain, cerebellum, and thalamus. The expression of the MR pattern was increased in waking DYT1 patients with sustained dystonia, compared with DYT1 carriers who were unaffected or who had dystonia only on action, as well as normal controls. MR subject scores declined significantly with sleep in affected DYT1 patients but not in normal controls. These findings indicate the penetrance of the DYT1 gene is considerably greater than previously assumed. ITD is mediated through the interaction of functional brain networks relating separately to gene status and to abnormal movement.

Treatment of cervical dystonia: a comparison of measures for outcome assessment.

UNLABELLED: There is little agreement on which outcome measures to use to express the efficacy of treatments for cervical dystonia. We analyzed change scores on various scales of 64 new patients with cervical dystonia before and after repeated injections with botulinum toxin. METHOD: The association between change in impairment (Tsui), and change in pain (TWSTRS-Pain) and functional health (TWSTRS-D, MOS-20) was expressed in percentages of variance explained. Effect sizes of the outcome measures from patients who continued botulinum treatment and dropouts were compared. Performance of outcome measures to distinguish patients who continued treatment and dropouts was analyzed with ROC curves and areas under the curve (AUC). RESULTS: Impairments explained < or =7% of the score variance in functional health. There were no differences between the effect sizes of impairment and pain of patients who continued treatment and dropouts (p > 0.60). This suggests a poor reflection of the treatment efficacy by these outcome measures. Conversely, there were significant differences between the effect sizes of the functional status scales of the patients who continued treatment and the dropouts (p < or = 0.01). ROC curve analysis showed that the disability, handicap, and global disease burden scale accurately distinguished between the two groups (AUCs > 0.80). Impairments showed no discriminative accuracy (AUC = 0.46). CONCLUSION: Neurologic impairments have a small impact on the functional health of cervical dystonia patients. Disability, handicap, and a global measure of disease burden were the most suitable outcome parameters to express the clinical efficacy of botulinum therapy.

Pathogenesis of two axonopathies does not require axonal neurofilaments.

Neurofilaments are a major component of the axonal cytoskeleton and their abnormal accumulation is a prominent feature of the cytopathology encountered in several neurodegenerative diseases. Thus, an attractive and widely held model of pathogenesis involves the participation of disrupted neurofilaments as a common toxic intermediate. Here, in direct contrast to this hypothesis, we show that two neurodegenerative disease models in the mouse, dystonia musculorum (dt) and a superoxide dismutase 1 (SOD1)-mediated form of human motor neuron disease (amyotrophic lateral sclerosis, ALS), progress with little or no abatement on a transgenic background in which neurofilaments are withheld from the axonal compartment. By specifically excluding a necessary role for axonal neurofilaments, our observations redefine the components of the pathogenic pathway leading to axon disruption in these two degenerative diseases.

Idiopathic torsion dystonia linked to chromosome 8 in two Mennonite families.

The DYT1 locus on chromosome 9q34 is responsible for most childhood limb-onset idiopathic torsion dystonia (ITD). Linkage to DYT1 has been excluded in families with adult-onset, and predominantly cranial-cervical, ITD. We mapped a locus (DYT6) associated with prominent cranial-cervical ITD in two large Mennonite families to chromosome 8. An identical haplotype spanning 40-cM segregates with ITD in these families, suggesting a shared mutation from the recent past.