Study of a Swiss dopa-responsive dystonia family with a deletion in GCH1: redefining DYT14 as DYT5.

OBJECTIVE: To report the study of a multigenerational Swiss family with dopa-responsive dystonia (DRD). METHODS: Clinical investigation was made of available family members, including historical and chart reviews. Subject examinations were video recorded. Genetic analysis included a genome-wide linkage study with microsatellite markers (STR), GTP cyclohydrolase I (GCH1) gene sequencing, and dosage analysis. RESULTS: We evaluated 32 individuals, of whom 6 were clinically diagnosed with DRD, with childhood-onset progressive foot dystonia, later generalizing, followed by parkinsonism in the two older patients. The response to levodopa was very good. Two additional patients had late onset dopa-responsive parkinsonism. Three other subjects had DRD symptoms on historical grounds. We found suggestive linkage to the previously reported DYT14 locus, which excluded GCH1. However, further study with more stringent criteria for disease status attribution showed linkage to a larger region, which included GCH1. No mutation was found in GCH1 by gene sequencing but dosage methods identified a novel heterozygous deletion of exons 3 to 6 of GCH1. The mutation was found in seven subjects. One of the patients with dystonia represented a phenocopy. CONCLUSIONS: This study rules out the previously reported DYT14 locus as a cause of disease, as a novel multiexonic deletion was identified in GCH1. This work highlights the necessity of an accurate clinical diagnosis in linkage studies as well as the need for appropriate allele frequencies, penetrance, and phenocopy estimates. Comprehensive sequencing and dosage analysis of known genes is recommended prior to genome-wide linkage analysis

Résistances thérapeutiques dans les mouvements anormaux [Resistance to treatment in movement disorders].

Therapeutic strategies for essential tremor (ET) and Parkinson's disease (PD) can be divided into two successive steps, one based on oral medications and the other, more invasive, using pumps or functional neurosurgery. When ET becomes refractory to propranolol, primidone and other, second-choice compounds, deep brain stimulation of the VIM nucleus of the thalamus can be considered. When PD becomes resistant to dopamine replacement therapy using various combinations of dopaminergic agents, then three options can be discussed: first, a subcutaneous apomorphine mini-pump, second, a jejunal levodopa-delivery system by means of percutaneous gastrostomy, and third, bilateral deep brain stimulation of the subthalamic nucleus. The above interventions are successful in about 80% of cases

Dégénérescence, régénérescence: un espoir thérapeutique pour la maladie de Parkinson [Neuronal death and growth factors: new therapeutic approaches in Parkinson's disease]

Neurodegenerative disorders represent a major and growing cause of morbidity and mortality in our populations, and a therapeutic challenge for the years to come. This paper reviews the mechanisms implicated in neuronal death, focusing on the model of Parkinson's disease. Available data are critically presented, and oriented in a therapeutic perspective. Neuroprotective strategies are mentioned, along with stem cell transplantation, growth factor production and gene therapy

Chronic parkinsonism associated with cirrhosis: a distinct subset of acquired hepatocerebral degeneration.

CONTEXT: The clinical, neuroradiological, and biological characteristics of the so-called acquired hepatocerebral degeneration have not yet been fully determined and its frequency remains largely uncertain. OBJECTIVES: To prospectively study the prevalence of extrapyramidal symptoms in patients with moderate to severe cirrhosis of various causes, to delineate the main neurological features of the condition, and to establish correlations with neuroradiological and biological findings. PATIENTS AND METHODS: During a 1-year period, all consecutive patients with cirrhosis who were potential candidates for liver transplantation were screened for extrapyramidal features. When extrapyramidal features were present, further workup included a detailed neurological examination, magnetic resonance imaging of the brain, a comprehensive battery of neuropsychological tests, extensive blood tests, and, in some cases, cerebrospinal fluid analysis. SETTING: A community-based hospital. RESULTS: From 51 patients screened, 11 (21.6%) exhibited moderate to severe parkinsonism sometimes associated with focal dystonia. Typical features included rapid progression over months, symmetric akinetic-rigid syndrome, postural but not resting tremor, and early postural and gait impairment. Neuropsychiatric manifestations were minimal. Some patients were responsive to levodopa therapy. In all patients, magnetic resonance imaging scans showed striking hyperintensities on T1-weighted images typically involving the substantia nigra and the globus pallidus bilaterally. Whole blood and cerebrospinal fluid manganese concentrations were severalfold above the reference range. CONCLUSIONS: Cirrhosis-related parkinsonism may represent a unique, consistent, and common subset of acquired hepatocerebral degeneration, whose features are permanent and entirely different from acute hepatic encephalopathy episodes. This form of parkinsonism can be clearly distinguished from other forms of parkinsonism of middle to advanced age, based on a suggestive association of clinical, neuroradiological, and biological abnormalities. Our findings support the concept of the toxic effects of manganese being the major determinant of basal ganglia dysfunction leading to the predominantly extrapyramidal central nervous system manifestations of cirrhosis observed in these patients

Autoanticorps en neurologie: implications cliniques [Autoantibodies in neurological diseases: clinical implications]

Autoantibodies are defined as antibodies directed against self antigens, i.e., against a normal antigenic endogenous tissue constituent. They can be the immediate cause of the neurological syndrome or be detected as an epiphenomenon of the pathogenic process. Autoantibodies are often considered useful biomarkers for the improvement of diagnostic accuracy, for the staging of disease progression or for the follow up of a biological response to a therapeutic intervention. The purpose of this article is to review the autoantibodies that are available to investigate immune-mediated neurological conditions. The detection of some of these autoantibodies may help the clinician to establish a definite diagnosis which may further facilitate the therapeutic decision

Long-term outcome of 50 consecutive Parkinson's disease patients treated with subthalamic deep brain stimulation.

OBJECTIVE: To describe the long-term outcome in 50 consecutive advanced Parkinson's disease (PD) patients treated with subthalamic nucleus deep brain stimulation (STN-DBS). METHOD: Assessments were carried out at baseline, 6 months, 2 years, and 5 years postoperatively. RESULTS: Compared to baseline scores without medication, we found a highly significant improvement of UPDRS III with stimulation, maintained at 5 years (p<0.001). This improvement, however, tended to diminish over time. Dyskinesia and off periods were also improved (p<0.0001 for both). Seventeen patients died during follow-up, who tended to be older at surgery (p<0.01). CONCLUSIONS: STN-DBS is an effective treatment for advanced PD patients, and the beneficial effect is maintained at 5 years. However, worsening occurs over time due to disease progression

A novel approach to reducing number of sensing units for wearable gait analysis systems.

Gait analysis methods to estimate spatiotemporal measures, based on two, three or four gyroscopes attached on lower limbs have been discussed in the literature. The most common approach to reduce the number of sensing units is to simplify the underlying biomechanical gait model. In this study, we propose a novel method based on prediction of movements of thighs from movements of shanks. Datasets from three previous studies were used. Data from the first study (ten healthy subjects and ten with Parkinson's disease) were used to develop and calibrate a system with only two gyroscopes attached on shanks. Data from two other studies (36 subjects with hip replacement, seven subjects with coxarthrosis, and eight control subjects) were used for comparison with the other methods and for assessment of error compared to a motion capture system. Results show that the error of estimation of stride length compared to motion capture with the system with four gyroscopes and our new method based on two gyroscopes was close ( -0.8 ±6.6 versus 3.8 ±6.6 cm). An alternative with three sensing units did not show better results (error: -0.2 ±8.4 cm). Finally, a fourth that also used two units but with a simpler gait model had the highest bias compared to the reference (error: -25.6 ±7.6 cm). We concluded that it is feasible to estimate movements of thighs from movements of shanks to reduce number of needed sensing units from 4 to 2 in context of ambulatory gait analysis