Institute National Of Neurologie

Tunis, Tunisia

Institute National Of Neurologie

Tunis, Tunisia

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Fendri-Kriaa N.,University of Sfax | Rouissi A.,Institute National Of Neurologie | Ghorbel R.,University of Sfax | Mkaouar-Rebai E.,University of Sfax | And 3 more authors.
Gene | Year: 2012

Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting almost exclusively girls. Rett patients present an apparently normal psychomotor development during the first 6-18. months of life. Thereafter, they show a short period of developmental stagnation followed by a rapid regression in language and motor development. RTT is currently considered as monogenic X-linked dominant disorder due to mutations in the . MECP2 gene, encoding the methyl-CpG binding protein 2. The aim of this study was to perform a mutational analysis of the . MECP2 gene in a classical Rett patient.The results showed the presence of a novel point mutation c.C1142T (p.P381L) and two deletions at the heterozygous state: a novel deletion c.1075delTTC (p.S359) and a known one c.1157del44 (p.L386Q fs . X2) in the C-terminal region of MeCP2. © 2012 Elsevier B.V.


Kefi M.,Institute National Of Neurologie | Jasinska-Myga B.,Medical University of Silesia, Katowice | Heckman M.G.,Biostatistics Unit | Middleton L.T.,Imperial College London | And 8 more authors.
Journal of Neurology, Neurosurgery and Psychiatry | Year: 2010

Genetic classification of Parkinson's disease (PD) subtypes may become the preferred diagnostic tool for neurologists. Herein we compare clinical features from a large cohort of patients with familial PD of unknown aetiology or attributable to distinct genetic forms. Comprehensive neurological examinations were performed in 231 familial PD patients from Tunisia. Analysis was previously performed to screen for mutations in leucine rich repeat kinase 2 (LRRK2), PTEN induced kinase 1 (PINK1) and parkin (PRKN). Clinical features were compared between patients with genetically undefined PD (n107) and those with LRRK2 (n=73) and PINK1 (n42) mutations using regression analyses adjusted for gender, age of onset and disease duration. PRKN cases (n9) were too few for meaningful statistical analysis. In comparison with genetically undefined patients, LRRK2 mutation carriers had more severe motor symptoms (median Unified Parkinson's Disease Rating Scale scores w1.6 times higher, p<0.001), a higher rate of dyskinesia (OR 4.21, p0.002) and use of dopamine agonists (OR 3.64, p<0.001), and less postural tremor (OR 0.21, p<0.001). PINK1 mutation carriers presented an increased rate of drug induced dyskinesia (OR 3.81, p=0.007) and a lower rate of postural tremor (OR 0.16, p<0.001) than genetically undefined patients. As expected, PINK1 patients had younger ages and ages at disease onset, and a longer disease duration compared with LRRK2 mutation carriers and genetically undefined patients. Clinical differences between LRRK2, PINK1 and genetically undefined familial PD appear more pronounced than previously appreciated, and may prove useful in clinical practice. As future therapies are targeted to specific protein abnormalities, identifying the genetic causes and associated clinical and pathological features will determine diagnosis, preventative medicine and drug intervention strategies.


Jasinska-Myga B.,Medical University of Silesia, Katowice | Kefi M.,Institute National Of Neurologie | Middleton L.T.,Imperial College London | Ishihara-Paul L.,Glaxosmithkline | And 7 more authors.
Movement Disorders | Year: 2010

The LRRK2 gene is a key player in Parkinson's disease (PD), however prevalence and pathogenicity of LRRK2 variants remain to be investigated in ethnically diverse populations. Herein, we performed comprehensive sequencing of the LRRK2 gene in 92 Tunisian probands with familial PD. We then performed an association study using all identified variants in a series of 167 Lrrk2 p.G2019S-negative patients with sporadic PD and 365 Lrrk2 p.G2019Snegative healthy control subjects, all from the same Arab-Berber ethnicity. We identified one novel coding substitution (p.M2408I) and 24 known coding changes. Only the Lrrk2 p.G2019S mutation segregated with disease within families and was found in 39% of familial probands. None of the variants displayed significant association with risk for sporadic PD, however a trend was observed for Lrrk2 p.Y2189C. The present study underscores the importance of the LRRK2 gene in the Tunisian PD population. © 2010 Movement Disorder Society.


Vilarino-Guell C.,University of British Columbia | Wider C.,University of Lausanne | Puschmann A.,Lund University | Evans D.M.,University of British Columbia | And 19 more authors.
American Journal of Human Genetics | Year: 2011

The identification of genetic causes for Mendelian disorders has been based on the collection of multi-incident families, linkage analysis, and sequencing of genes in candidate intervals. This study describes the application of next-generation sequencing technologies to a Swiss kindred presenting with autosomal-dominant, late-onset Parkinson disease (PD). The family has tremor-predominant doparesponsive parkinsonism with a mean onset of 50.6 ± 7.3 years. Exome analysis suggests that an aspartic-acid-to-asparagine mutation within vacuolar protein sorting 35 (VPS35 c.1858G>A; p.Asp620Asn) is the genetic determinant of disease. VPS35 is a central component of the retromer cargo-recognition complex, is critical for endosome-trans-golgi trafficking and membrane-protein recycling, and is evolutionarily highly conserved. VPS35 c.1858G>A was found in all affected members of the Swiss kindred and in three more families and one patient with sporadic PD, but it was not observed in 3,309 controls. Further sequencing of familial affected probands revealed only one other missense variant, VPS35 c.946C>T; (p.Pro316Ser), in a pedigree with one unaffected and two affected carriers, and thus the pathogenicity of this mutation remains uncertain. Retromer-mediated sorting and transport is best characterized for acid hydrolase receptors. However, the complex has many types of cargo and is involved in a diverse array of biologic pathways from developmental Wnt signaling to lysosome biogenesis. Our study implicates disruption of VPS35 and retromer-mediated trans-membrane protein sorting, rescue, and recycling in the neurodegenerative process leading to PD. © 2011 by The American Society of Human Genetics. All rights reserved.


Dachsel J.C.,Mayo Medical School | Nishioka K.,Mayo Medical School | Vilarino-Guell C.,Mayo Medical School | Lincoln S.J.,Mayo Medical School | And 10 more authors.
Mechanisms of Ageing and Development | Year: 2010

LRRK2 mutations are recognized as the most frequent genetic cause of both familial and sporadic parkinsonism identified to date. A remarkable feature of this form of parkinsonism is the variable penetrance of symptom manifestation resulting in a wide range of age-at-onset in patients. Herein we use a functional approach to identify the Lrrk1 protein as a potential disease modifier demonstrating an interaction and heterodimer formation with Lrrk2. In addition, evaluation of LRRK1 variants in our large Lrrk2 p.G2019S-parkinsonism series from a Tunisian (n=145) identified a missense mutation (p.L416M) resulting in an average 6.2 years younger age at disease onset. In conclusion we show that the interaction of Lrrk1-Lrrk2 can form protein dimers and this interaction may influence the age of symptomatic manifestation in Lrrk2-parkinsonism patients. © 2010 Elsevier Ireland Ltd.


Chartier-Harlin M.-C.,University of Lille Nord de France | Chartier-Harlin M.-C.,French Institute of Health and Medical Research | Vilarino-Guell C.,University of British Columbia | Lepretre F.,University of Lille Nord de France | And 42 more authors.
American Journal of Human Genetics | Year: 2011

Genome-wide analysis of a multi-incident family with autosomal-dominant parkinsonism has implicated a locus on chromosomal region 3q26-q28. Linkage and disease segregation is explained by a missense mutation c.3614G>A (p.Arg1205His) in eukaryotic translation initiation factor 4-gamma (EIF4G1). Subsequent sequence and genotype analysis identified EIF4G1 c.1505C>T (p.Ala502Val), c.2056G>T (p.Gly686Cys), c.3490A>C (p.Ser1164Arg), c.3589C>T (p.Arg1197Trp) and c.3614G>A (p.Arg1205His) substitutions in affected subjects with familial parkinsonism and idiopathic Lewy body disease but not in control subjects. Despite different countries of origin, persons with EIF4G1 c.1505C>T (p.Ala502Val) or c.3614G>A (p.Arg1205His) mutations appear to share haplotypes consistent with ancestral founders. eIF4G1 p.Ala502Val and p.Arg1205His disrupt eIF4E or eIF3e binding, although the wild-type protein does not, and render mutant cells more vulnerable to reactive oxidative species. EIF4G1 mutations implicate mRNA translation initiation in familial parkinsonism and highlight a convergent pathway for monogenic, toxin and perhaps virally-induced Parkinson disease. © 2011 The American Society of Human Genetics.


Chaouch N.,Service de pneumologie | Mejid M.,Service de pneumologie | Zarrouk M.,Service de pneumologie | Racil H.,Service de pneumologie | And 3 more authors.
Revue de Pneumologie Clinique | Year: 2011

Drug-induced muscle disorders are now well known and vary from a simple isolated increase in muscle enzymes to severe drug-induced myopathy. The list of drugs inducing myopathy is very long and continues to grow. The onset of muscle disorders under isoniazid often falls within a drug-induced neuropathy or a drug-induced lupus. However, the occurrence of isolated isoniazid-induced drug myopathy without neuropathy is an extremely rare condition especially with non-toxic doses. The authors report the case of a 28-year-old man, without a previous medical history, hospitalized for pulmonary tuberculosis. After initiating tuberculosis treatment for five days, he presented muscle pain, fasciculation and weakness initially involving the lower left limb that quickly propagated to all four limbs. The physical examination noted a left ankle flush, a swollen left calf and fasciculation of both calves while the neurological examination was normal. The CPK was normal. Electromyography confirmed the myopathy without neuropathic findings. Isoniazid withdrawal was marked by the rapid disappearance of the symptoms. The reintroduction of a half-dose of isoniazid only induced a few transitional muscular fasciculations. The onset of the symptoms under tuberculosis treatment, the absence of later muscle disorders, the absence of any other cause of myopathy and the total disappearance of the symptoms after isoniazid withdrawal confirmed the diagnosis of isoniazid-induced myopathy. © 2010 Elsevier Masson SAS.


Drissi C.,St Vincent Of Paul Hospital | Drissi C.,Institute National Of Neurologie | Mitrofanoff M.,St Vincent Of Paul Hospital | Talandier C.,St Vincent Of Paul Hospital | And 5 more authors.
European Radiology | Year: 2011

Objective: To demonstrate the feasibility of dynamic MRI with near-real-time temporal resolution for analysing velopharyngeal closure. Methods: Eleven children and young adults (seven girls, four boys, mean age: 8.4 years) with suspected velopharyngeal insufficiency (VPI), and one healthy volunteer underwent MRI (1.5 Tesla) using T2 fast imaging sequences. Imaging was done without any sedation at rest and during various phonations in the axial and sagittal planes. Images were analysed by two radiologists, a plastic surgeon and a speech therapist. Results: The MRI examinations were well tolerated by even the youngest patient. A qualitative analysis found that the sagittal dynamic sequences during phonation were in relation to the clinical data in all patients. A quantitative analysis enabled calculation of the elevation angle of the soft palate in relation to the hard palate, the velar eminence angle and the percentage of reduction of the antero-posterior diameter of the pharyngeal lumen. Conclusion: Dynamic MRI is a non-invasive, rapid and repeatable method. It can be considered a complementary tool to endoscopy and fluoroscopy, particularly in children, for assessing VPI without any sedation or radiation exposure. © 2011 European Society of Radiology.


Dzamko N.,University of Dundee | Deak M.,University of Dundee | Hentati F.,Institute National Of Neurologie | Reith A.D.,Glaxosmithkline | And 4 more authors.
Biochemical Journal | Year: 2010

LRRK2 (leucine-rich repeat protein kinase 2) is mutated in a significant number of Parkinson's disease patients. Since a common mutation that replaces Gly2019 with a serine residue enhances kinase catalytic activity, small-molecule LRRK2 inhibitors might have utility in treating Parkinson's disease. However, the effectiveness of inhibitors is difficult to assess, as no physiological substrates or downstream effectors have been identified that could be exploited to develop a robust cell-based assay. We recently established that LRRK2 bound 14-3-3 protein isoforms via its phosphorylation of Ser 910 and Ser935. In the present study we showthat treatment of Swiss 3T3 cells or lymphoblastoid cells derived from control or a Parkinson's disease patient harbouring a homozygous LRRK2(G2019S) mutation with two structurally unrelated inhibitors of LRRK2 (H-1152 or sunitinib) induced dephosphorylation of endogenous LRRK2 at Ser910 and Ser 935, thereby disrupting 14-3-3 interaction. Our results suggest that H-1152 and sunitinib induce dephosphorylation of Ser910 and Ser 935 by inhibiting LRRK2 kinase activity, as these compounds failed to induce significant dephosphorylation of a drug-resistant LRRK2(A2016T) mutant. Moreover, consistent with the finding that non-14-3-3-binding mutants of LRRK2 accumulated within discrete cytoplasmic pools resembling inclusion bodies, we observed that H-1152 causes LRRK2 to accumulate within inclusion bodies. These findings indicate that dephosphorylation of Ser910/Ser935, disruption of 14-3-3 binding and/or monitoring LRRK2 cytoplasmic localization can be used as an assay to assess the relative activity of LRRK2 inhibitors in vivo. These results will aid the elaboration and evaluation of LRRK2 inhibitors. They will also stimulate further research to understand howphosphorylation of Ser910 and Ser935 is controlled by LRRK2, and establish any relationship to development of Parkinson's disease. © The Authors.


Nishioka K.,Mayo Clinic Jacksonville | Vilarino-Guell C.,Mayo Clinic Jacksonville | Cobb S.A.,Mayo Clinic Jacksonville | Kachergus J.M.,Mayo Clinic Jacksonville | And 4 more authors.
Parkinsonism and Related Disorders | Year: 2010

NADH dehydrogenase ubiquinone flavoprotein 2 (NDUFV2), encoding a subunit of mitochondrial complex I, is a candidate gene for several neuronal diseases; schizophrenia, bipolar disorder and Parkinson disease (PD). We screened the entire coding region of NDUFV2 in 33 familial PD patients of North African Arab-Berber ethnicity in which all known genetic forms of PD had been excluded. We detected one novel substitution p.K209R (c.626A > G) in one PD proband. Segregation analysis within the family is inconclusive due to small sample size, but consistent with an autosomal dominant mode of inheritance. Subsequent screening of this mutation in ethnically matched sporadic PD patients (n =238) and controls (n =371) identified p.K209R in one additional patient. The clinical features of the mutation carriers revealed a mild form of parkinsonism with a prognosis similar to idiopathic PD. Our findings suggest further studies addressing the role of NDUFV2 variation in PD may be warranted. © 2010 Elsevier Ltd.

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