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Molinari F.,Aix - Marseille University | Molinari F.,Institute Of Neurobiologie Of La Mediterranee Inmed
Journal of Bioenergetics and Biomembranes | Year: 2010

The mitochondrion is a key cellular structure involved in many metabolic functions such as ATP synthesis by oxidative phosphorylation, tricarboxylic acid cycle or fatty acid oxidation. These pathways are fundamental for biological processes such as cell proliferation or death. In the central nervous system, mitochondria dysfunctions have been involved in many neurological diseases and age-related neurodegenerative disorders, including epilepsy, Alzheimer's and Parkinson's diseases. Mitochondrial diseases are frequently caused by a disruption of the respiratory chain. Nevertheless, other mitochondrial functions, including organellar dynamics or metabolite transport, could also be involved in such pathologies. Here we described mitochondrial dysfunctions in a very severe, intractable and relatively rare neonatal epileptic encephalopathy, the Ohtahara syndrome. This condition is characterized by neonatal onset of seizures, interictal electroencephalogram with suppression burst pattern and a very poor outcome with very severe psychomotor retardation or death. The etiology of this disease remains elusive but seems to be very heterogeneous including brain malformations, metabolic errors, transcription factor and synaptic vesicle release defects. In this review, we discuss first the Ohtahara syndrome caused by mitochondrial respiratory chain damages, suggesting that these defects could be more common than previously thought. Then, we will adress the importance of the mitochondrial glutamate carrier SLC25A22 in these pathologies, since mutations of this gene were described in two distinct families. These findings suggest that glutamate metabolism should also be considered as an important cause of the Ohtahara syndrome. © 2010 Springer Science+Business Media, LLC.


Delcourt M.,Montpellier University Hospital Center | Riant F.,French Institute of Health and Medical Research | Mancini J.,Marseille University Hospital Center | Milh M.,Marseille University Hospital Center | And 21 more authors.
Journal of Neurology, Neurosurgery and Psychiatry | Year: 2014

Background Heterozygous dominant mutations of PRRT2 have been associated with various types of paroxysmal neurological manifestations, including benign familial infantile convulsions and paroxysmal kinesigenic dyskinesia. The phenotype associated with biallelic mutations is not well understood as few cases have been reported. Methods PRRT2 screening was performed by Sanger sequencing and quantitative multiplex PCR of short fluorescent fragments. A CGH array was used to characterise the size of the deletion at the 16p11.2 locus. Results Five patients with homozygous or compound heterozygous deleterious PRRT2 gene mutations are described. These patients differ from those with a single mutation by their overall increased severity: (1) the combination of at least three different forms of paroxysmal neurological disorders within the same patient and persistence of paroxysmal attacks; (2) the occurrence of uncommon prolonged episodes of ataxia; and (3) the association of permanent neurological disorders including learning difficulties in four patients and cerebellar atrophy in 2. Conclusions Our observations expand the phenotype related to PRRT2 insufficiency, and highlight the complexity of the phenotype associated with biallelic mutations, which represents a severe neurological disease with various paroxysmal disorders and frequent developmental disabilities. © 2015 by the BMJ Publishing Group Ltd.


Delcourt M.,Montpellier University Hospital Center | Riant F.,Laboratoire Of Genetique | Riant F.,French Institute of Health and Medical Research | Mancini J.,Marseille University Hospital Center | And 22 more authors.
Journal of Neurology, Neurosurgery and Psychiatry | Year: 2015

Background: Heterozygous dominant mutations of PRRT2 have been associated with various types of paroxysmal neurological manifestations, including benign familial infantile convulsions and paroxysmal kinesigenic dyskinesia. The phenotype associated with biallelic mutations is not well understood as few cases have been reported. Methods: PRRT2 screening was performed by Sanger sequencing and quantitative multiplex PCR of short fluorescent fragments. A CGH array was used to characterise the size of the deletion at the 16p11.2 locus. Results: Five patients with homozygous or compound heterozygous deleterious PRRT2 gene mutations are described. These patients differ from those with a single mutation by their overall increased severity: (1) the combination of at least three different forms of paroxysmal neurological disorders within the same patient and persistence of paroxysmal attacks; (2) the occurrence of uncommon prolonged episodes of ataxia; and (3) the association of permanent neurological disorders including learning difficulties in four patients and cerebellar atrophy in 2. Conclusions: Our observations expand the phenotype related to PRRT2 insufficiency, and highlight the complexity of the phenotype associated with biallelic mutations, which represents a severe neurological disease with various paroxysmal disorders and frequent developmental disabilities.


Cloarec R.,Institute Of Neurobiologie Of La Mediterranee Inmed | Cloarec R.,French Institute of Health and Medical Research | Cloarec R.,Aix - Marseille University | Bruneau N.,Institute Of Neurobiologie Of La Mediterranee Inmed | And 30 more authors.
Neurology | Year: 2012

Objective: Whole genome sequencing and the screening of 103 families recently led us to identify PRRT2 (proline-rich-transmembrane protein) as the gene causing infantile convulsions (IC) with paroxysmal kinesigenic dyskinesia (PKD) (PKD/IC syndrome, formerly ICCA). There is interfamilial and intrafamilial variability and the patients may have IC or PKD. Association of IC with hemiplegic migraine (HM) has also been reported. In order to explore the mutational and clinical spectra, we analyzed 34 additional families with either typical PKD/IC or PKD/IC with migraine. Methods: We performed Sanger sequencing of all PRRT2 coding exons and of exon-intron boundaries in the probands and in their relatives whenever appropriate. Results: Two known and 2 novel PRRT2 mutations were detected in 18 families. The p.R217Pfs*8 recurrent mutation was found in z50% of typical PKD/IC, and the unreported p.R145Gfs*31 in one more typical family. PRRT2 mutations were also found in PKD/IC with migraine: p.R217Pfs*8 cosegregated with PKD associated with HM in one family, and was also detected in one IC patient having migraine with aura, in related PKD/IC familial patients having migraine without aura, and in one sporadic migraineur with abnormal MRI. Previously reported p.R240X was found in one patient with PKD with migraine without aura. The novel frameshift p.S248Afs*65 was identified in a PKD/IC family member with IC and migraine with aura. Conclusions: We extend the spectrum of PRRT2 mutations and phenotypes to HM and to other types of migraine in the context of PKD/IC, and emphasize the phenotypic pleiotropy seen in patients with PRRT2 mutations. © 2012 American Academy of Neurology 2097.


Roll P.,French Institute of Health and Medical Research | Roll P.,Aix - Marseille University | Vernes S.C.,University of Oxford | Vernes S.C.,imp Inc | And 21 more authors.
Human Molecular Genetics | Year: 2010

It is a challenge to identify the molecular networks contributing to the neural basis of human speech. Mutations in transcription factor FOXP2 cause difficulties mastering fluent speech (developmental verbal dyspraxia, DVD), whereas mutations of sushi-repeat protein SRPX2 lead to epilepsy of the rolandic (sylvian) speech areas, with DVD or with bilateral perisylvian polymicrogyria. Pathophysiological mechanisms driven by SRPX2 involve modified interaction with the plasminogen activator receptor (uPAR). Independent chromatin-immunoprecipitation microarray screening has identified the uPAR gene promoter as a potential target site bound by FOXP2. Here, we directly tested for the existence of a transcriptional regulatory network between human FOXP2 and the SRPX2/uPAR complex. In silico searches followed by gel retardation assays identified specific efficient FOXP2-binding sites in each of the promoter regions of SRPX2 and uPAR. In FOXP2-transfected cells, significant decreases were observed in the amounts of both SRPX2 (43.6%) and uPAR (38.6%) native transcripts. Luciferase reporter assays demonstrated that FOXP2 expression yielded a marked inhibition of SRPX2 (80.2%) and uPAR (77.5%) promoter activity. A mutant FOXP2 that causes DVD (p.R553H) failed to bind to SRPX2 and uPAR target sites and showed impaired down-regulation of SRPX2 and uPAR promoter activity. In a patient with polymicrogyria of the left rolandic operculum, a novel FOXP2 mutation (p.M406T) was found in the leucine-zipper (dimerization) domain. p.M406T partially impaired the FOXP2 regulation of SRPX2 promoter activity, whereas that of the uPAR promoter remained unchanged. Together with recently described FOXP2-CNTNAP2 and SRPX2/uPAR links, the FOXP2-SRPX2/uPAR network provides exciting insights into molecular pathways underlying speech-related disorders. © The Author 2010. Published by Oxford University Press. All rights reserved.

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