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1.  Genetic burden in multiple sclerosis families 
Genes and immunity  2013;14(7):434-440.
A previous study using cumulative genetic risk estimations in multiple sclerosis (MS) successfully tracked the aggregation of susceptibility variants in multi-case and single-case families. It used a limited description of susceptibility loci available at the time (17 loci). Even though the full roster of MS risk genes remains unavailable, we estimated the genetic burden in MS families and assess its disease predictive power using up to 64 single-nucleotide polymorphism (SNP) markers according to the most recent literature. A total of 708 controls, 3251 MS patients and their relatives, as well as 117 twin pairs were genotyped. We validated the increased aggregation of genetic burden in multi-case compared with single-case families (P = 4.14e – 03) and confirm that these data offer little opportunity to accurately predict MS, even within sibships (area under receiver operating characteristic (AUROC) = 0.59 (0.55, 0.53)). Our results also suggest that the primary progressive and relapsing-type forms of MS share a common genetic architecture (P = 0.368; difference being limited to that corresponding to ±2 typical MS-associated SNPs). We have confirmed the properties of individual genetic risk score in MS. Comparing with previous reference point for MS genetics (17 SNPs), we underlined the corrective consequences of the integration of the new findings from GWAS and meta-analysis.
doi:10.1038/gene.2013.37
PMCID: PMC4102601  PMID: 23903824
multiple sclerosis; family study; genetic risk
2.  The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment 
Brain  2009;133(1):9-22.
The non-dystrophic myotonias are an important group of skeletal muscle channelopathies electrophysiologically characterized by altered membrane excitability. Many distinct clinical phenotypes are now recognized and range in severity from severe neonatal myotonia with respiratory compromise through to milder late-onset myotonic muscle stiffness. Specific genetic mutations in the major skeletal muscle voltage gated chloride channel gene and in the voltage gated sodium channel gene are causative in most patients. Recent work has allowed more precise correlations between the genotype and the electrophysiological and clinical phenotype. The majority of patients with myotonia have either a primary or secondary loss of membrane chloride conductance predicted to result in reduction of the resting membrane potential. Causative mutations in the sodium channel gene result in an abnormal gain of sodium channel function that may show marked temperature dependence. Despite significant advances in the clinical, genetic and molecular pathophysiological understanding of these disorders, which we review here, there are important unresolved issues we address: (i) recent work suggests that specialized clinical neurophysiology can identify channel specific patterns and aid genetic diagnosis in many cases however, it is not yet clear if such techniques can be refined to predict the causative gene in all cases or even predict the precise genotype; (ii) although clinical experience indicates these patients can have significant progressive morbidity, the detailed natural history and determinants of morbidity have not been specifically studied in a prospective fashion; (iii) some patients develop myopathy, but its frequency, severity and possible response to treatment remains undetermined, furthermore, the pathophysiogical link between ion channel dysfunction and muscle degeneration is unknown; (iv) there is currently insufficient clinical trial evidence to recommend a standard treatment. Limited data suggest that sodium channel blocking agents have some efficacy. However, establishing the effectiveness of a therapy requires completion of multi-centre randomized controlled trials employing accurate outcome measures including reliable quantitation of myotonia. More specific pharmacological approaches are required and could include those which might preferentially reduce persistent muscle sodium currents or enhance the conductance of mutant chloride channels. Alternative strategies may be directed at preventing premature mutant channel degradation or correcting the mis-targeting of the mutant channels.
doi:10.1093/brain/awp294
PMCID: PMC2801326  PMID: 19917643
ion channels; neuromuscular; genetics; EMG
3.  NEONATAL HYPOTONIA CAN BE A SODIUM CHANNELOPATHY: RECOGNITION OF A NEW PHENOTYPE 
Neurology  2008;71(21):1740-1742.
doi:10.1212/01.wnl.0000335269.21550.0e
PMCID: PMC2676969  PMID: 19015492
4.  Spastin mutations are frequent in sporadic spastic paraparesis and their spectrum is different from that observed in familial cases 
Journal of Medical Genetics  2005;43(3):259-265.
Background
SPG4 encodes spastin, a member of the AAA protein family, and is the major gene responsible for autosomal dominant spastic paraplegia. It accounts for 10–40% of families with pure (or eventually complicated) hereditary spastic paraparesis (HSP).
Objective
To assess the frequency of SPG4 mutation in patients with spastic paraplegia but without family histories.
Methods
146 mostly European probands with progressive spastic paraplegia were studied (103 with pure spastic paraplegia and 43 with additional features). Major neurological causes of paraplegia were excluded. None had a family history of paraplegia. DNA was screened by DHPLC for mutations in the 17 coding exons of the SPG4 gene. Sequence variants were characterised by direct sequencing. A panel of 600 control chromosomes was used to rule out polymorphisms.
Results
The overall rate of mutations was 12%; 19 different mutations were identified in 18 patients, 13 of which were novel. In one family, where both parents were examined and found to be normal, the mutation was transmitted by the asymptomatic mother, indicating reduced penetrance. The parents of other patients were not available for analysis but were reported to be normal. There was no evidence for de novo mutations. The mutations found in these apparently isolated patients were mostly of the missense type and tended to be associated with a less severe phenotype than previously described in patients with inherited mutations.
Conclusions
: The unexpected presence of SPG4 gene mutations in patients with sporadic spastic paraplegia suggests that gene testing should be done in individuals with pure or complicated spastic paraplegia without family histories.
doi:10.1136/jmg.2005.035311
PMCID: PMC2563242  PMID: 16055926
SPG4; mutation; spastic paraplegia
6.  Occupational cancer in France: epidemiology, toxicology, prevention, and compensation. 
Environmental Health Perspectives  1999;107(Suppl 2):245-252.
This article is a description of the current situation in France with regard to occupational cancer: research, prevention, and occupation. Toxicologic experiments are carried out using (italic)in vitro(/italic) and (italic)in vivo(/italic) tests, particularly using transgenic mice. Several epidemiologic studies have been conducted over the last decades: population-based case-control studies; mortality studies and cancer incidence studies carried out in historical cohorts of workers employed in the industry; and case-control studies nested in occupational cohorts. French ethical aspects of toxicologic and epidemiologic studies are described. The results thus obtained are used to establish regulations for the prevention and the compensation of cancers attributable to occupational exposure. This French regulation for prevention of occupational cancer involves several partners: (italic)a(/italic)) the states authorities, including labor inspectors, responsible for preparing and implementing the labor legislation and for supervising its application, particularly in the fields of occupational health and safety and working conditions; (italic)b(/italic)) the Social Security Organisation for the analysis of present or potential occupational risks based on tests, visits in plants, complaints or requests from various sources, and statistics. These activities are performed within the framework of the general French policy for the prevention of occupational cancer. This organization includes the National Institute for Research and Safety, particularly involved in research in the various fields of occupational risks--animal toxicology, biologic monitoring, exposure measurements epidemiology, psychology, ergonomy, electronic systems and machineries, exposure to chemicals, noise, heat, vibration, and lighting; and (italic)c(/italic)) companies where the regulation defines the role of the plant manager, the occupational physician, and the Health, Safety and Working Conditions Committee (comprising the manager, employees' representatives, the occupational physician, and the safety department) in dealing with any problem regarding safety, occupational hygiene, and working conditions. These organizations along with medical practitioners are involved with the compensation of occupational cancers. The regulation for compensation includes the tables of occupational cancer, the possibility of recognition of a cancer case when the requirements of the tables are not met, and the postprofessional follow-up of workers exposed to a carcinogenic agent.
PMCID: PMC1566288  PMID: 10350507
7.  Alphabetical paragraphia in a limited middle cerebral artery stroke. 
A Yugoslavian perfectly bilingual for French and Serb had a limited left middle cerebral artery stroke. He developed a peculiar dysgraphia characterised by the use of Latin characters (French spelling) to transcribe Serb phonemes that would normally have been spelt in the Cyrillic alphabet. This dysgraphia was likely to be due to an impairment of the allographic procedure. It is concluded that allographs of the two alphabets are produced concomitantly in bialphabetical patients during the allographic procedure.
Images
PMCID: PMC1072941  PMID: 8201350
8.  Dementia in two histologically confirmed cases of multiple sclerosis: one case with isolated dementia and one case associated with psychiatric symptoms. 
During the past 10 years, considerable attention has been devoted to cognitive impairment in multiple sclerosis. Occasionally this impairment may be so severe that multiple sclerosis presents as a dementia associated with only minor neurological signs and symptoms. The cases of two women affected by multiple sclerosis who presented with a pure dementia are reported. In the first patient, a progressive apragmatic behavioural disturbance with reduced short term memory and learning abilities were the main clinical features. Neuropathological examination of the brain disclosed numerous plaques in the periventricular white matter, with severe atrophy of the corpus callosum. Plaques were also seen in the white matter of both hippocampus and in the columns of the fornix. The impairment of short term memory could be linked to these lesions. Behavioural changes were probably related to the bilateral lesions of the long associative bundles that disconnected the frontal lobes from other parts of the cerebral hemispheres. In the second patient, visual hallucinations were associated with cognitive dysfunction. MRI showed large plaques in the white matter of both left frontal and temporal lobes. Smaller plaques were also present in the periventricular white matter of the occipital lobes, the nature of which were confirmed by a stereotactic biopsy.
Images
PMCID: PMC1072828  PMID: 8158186

Results 1-8 (8)