Publications by authors named "Alice Poisson"

33 Publications

Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior.

Genet Med 2021 Mar 3. Epub 2021 Mar 3.

Division of Medical Genetics, Nemours/A.I. DuPont Hospital for Children, Wilmington, DE, USA.

Purpose: We describe a novel neurobehavioral phenotype of autism spectrum disorder (ASD), intellectual disability, and/or attention-deficit/hyperactivity disorder (ADHD) associated with de novo or inherited deleterious variants in members of the RFX family of genes. RFX genes are evolutionarily conserved transcription factors that act as master regulators of central nervous system development and ciliogenesis.

Methods: We assembled a cohort of 38 individuals (from 33 unrelated families) with de novo variants in RFX3, RFX4, and RFX7. We describe their common clinical phenotypes and present bioinformatic analyses of expression patterns and downstream targets of these genes as they relate to other neurodevelopmental risk genes.

Results: These individuals share neurobehavioral features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes.

Conclusion: These results establish a likely role of deleterious variation in RFX3, RFX4, and RFX7 in cases of monogenic intellectual disability, ADHD and ASD, and position these genes as potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
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http://dx.doi.org/10.1038/s41436-021-01114-zDOI Listing
March 2021

Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome.

Epilepsia 2020 11 21;61(11):2461-2473. Epub 2020 Sep 21.

Reference Center for Rare Developmental Abnormalities CLAD-Ouest, Rennes University Hospital Center, Rennes, France.

Objective: We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy.

Methods: We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association "KCNB1 France." Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the long-term outcome in patients older than 12 years from our series and from literature.

Results: Our series included 36 patients (21 males, median age = 10 years, range = 1.6 months-34 years). Twenty patients (56%) had DEE with infantile onset seizures (seizure onset = 10 months, range = 10 days-3.5 years), whereas 16 (33%) had DE with late onset epilepsy in 10 (seizure onset = 5 years, range = 18 months-25 years) and without epilepsy in six. Cognitive impairment was more severe in individuals with DEE compared to those with DE. Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports) showed developmental delay in all with severe to profound intellectual disability in 67% (n = 41/61) and autistic features in 56% (n = 32/57). Long-term outcome in 22 individuals older than 12 years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome. Epilepsy course was variable. Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants.

Significance: Our study describes the phenotypic spectrum of KCNB1 encephalopathy, which varies from severe DEE to DE with or without epilepsy. Although cognitive impairment is worse in patients with DEE, long-term outcome is poor for most and missense variants are associated with more severe epilepsy outcome. Further understanding of disease mechanisms should facilitate the development of targeted therapies, much needed to improve the neurodevelopmental prognosis.
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http://dx.doi.org/10.1111/epi.16679DOI Listing
November 2020

Neural representations of transitive relations predict current and future math calculation skills in children.

Neuropsychologia 2020 04 22;141:107410. Epub 2020 Feb 22.

Lyon Neuroscience Research Center (CRNL), Experiential Neuroscience and Mental Training Team, INSERM U1028 - CNRS UMR5292, University of Lyon, France. Electronic address:

A large body of evidence suggests that math learning in children is built upon innate mechanisms for representing numerical quantities in the intraparietal sulcus (IPS). Learning math, however, is about more than processing quantitative information. It is also about understanding relations between quantities and making inferences based on these relations. Consistent with this idea, recent behavioral studies suggest that the ability to process transitive relations (A > B, B > C, therefore A > C) may contribute to math skills in children. Here we used fMRI coupled with a longitudinal design to determine whether the neural processing of transitive relations in children could predict their current and future math skills. At baseline (T), children (n = 31) processed transitive relations in an MRI scanner. Math skills were measured at T and again 1.5 years later (T). Using a machine learning approach with cross-validation, we found that activity associated with the representation of transitive relations in the IPS predicted math calculation skills at both T and T. Our study highlights the potential of neurobiological measures of transitive reasoning for forecasting math skills in children, providing additional evidence for a link between this type of reasoning and math learning.
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http://dx.doi.org/10.1016/j.neuropsychologia.2020.107410DOI Listing
April 2020

Chromatin remodeling dysfunction extends the etiological spectrum of schizophrenia: a case report.

BMC Med Genet 2020 01 8;21(1):10. Epub 2020 Jan 8.

Institut Neuromyogène, métabolisme énergétique et développement durable, CNRS UMR 5310, INSERM U1217, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France.

Background: The role of deleterious copy number variations in schizophrenia is well established while data regarding pathogenic variations remain scarce. We report for the first time a case of schizophrenia in a child with a pathogenic mutation of the chromodomain helicase DNA binding protein 2 (CHD2) gene.

Case Presentation: The proband was the second child of unrelated parents. Anxiety and sleep disorders appeared at the age of 10 months. He presented febrile seizures and, at the age of 8, two generalized tonic-clonic seizures. At the age of 10, emotional withdrawal emerged, along with a flat affect, disorganization and paranoid ideation, without seizures. He began to talk and giggle with self. Eventually, the patient presented daily auditory and visual hallucinations. The diagnosis of childhood onset schizophrenia (DSM V) was then evoked. Brain imaging was unremarkable. Wakefulness electroencephalography showed a normal background and some bilateral spike-wave discharges that did not explain the psychosis features. A comparative genomic hybridization array (180 K, Agilent, Santa Clara, CA, USA) revealed an 867-kb 16p13.3 duplication, interpreted as a variant of unknown significance confirmed by a quantitative PCR that also showed its maternal inheritance. Risperidone (1,5 mg per day), led to clinical improvement. At the age of 11, an explosive relapse of epilepsy occurred with daily seizures of various types. The sequencing of a panel for monogenic epileptic disorders and Sanger sequencing revealed a de novo pathogenic heterozygous transition in CHD2 (NM_001271.3: c.4003G > T).

Conclusions: This case underlines that schizophrenia may be, sometimes, underpinned by a Mendelian disease. It addresses the question of systematic genetic investigations in the presence of warning signs such as a childhood onset of the schizophrenia or a resistant epilepsy. It points that, in the absence of pathogenic copy number variation, the investigations should also include a search for pathogenic variations, which means that some of the patients with schizophrenia should benefit from Next Generation Sequencing tools. Last but not least, CHD2 encodes a member of the chromodomain helicase DNA-binding (CHD) family involved in chromatin remodeling. This observation adds schizophrenia to the phenotypic spectrum of chromodomain remodeling disorders, which may lead to innovative therapeutic approaches.
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http://dx.doi.org/10.1186/s12881-019-0946-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950831PMC
January 2020

Widening of the genetic and clinical spectrum of Lamb-Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency.

Genet Med 2020 03 3;22(3):524-537. Epub 2019 Oct 3.

CHU de Rennes, service de génétique clinique, Rennes, France.

Purpose: Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved.

Methods: Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types ofSOX5 alterations. Functional consequences of selected substitutions were investigated.

Results: Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated.

Conclusions: This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features.
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http://dx.doi.org/10.1038/s41436-019-0657-0DOI Listing
March 2020

Expanding the genetic and phenotypic relevance of KCNB1 variants in developmental and epileptic encephalopathies: 27 new patients and overview of the literature.

Hum Mutat 2020 01 4;41(1):69-80. Epub 2019 Oct 4.

Departments of Neurology and Paediatrics, Royal Children's Hospital, University of Melbourne, Melbourne, Victoria, Australia.

Developmental and epileptic encephalopathies (DEE) refer to a heterogeneous group of devastating neurodevelopmental disorders. Variants in KCNB1 have been recently reported in patients with early-onset DEE. KCNB1 encodes the α subunit of the delayed rectifier voltage-dependent potassium channel K 2.1. We review the 37 previously reported patients carrying 29 distinct KCNB1 variants and significantly expand the mutational spectrum describing 18 novel variants from 27 unreported patients. Most variants occur de novo and mainly consist of missense variants located on the voltage sensor and the pore domain of K 2.1. We also report the first inherited variant (p.Arg583*). KCNB1-related encephalopathies encompass a wide spectrum of neurodevelopmental disorders with predominant language difficulties and behavioral impairment. Eighty-five percent of patients developed epilepsies with variable syndromes and prognosis. Truncating variants in the C-terminal domain are associated with a less-severe epileptic phenotype. Overall, this report provides an up-to-date review of the mutational and clinical spectrum of KCNB1, strengthening its place as a causal gene in DEEs and emphasizing the need for further functional studies to unravel the underlying mechanisms.
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http://dx.doi.org/10.1002/humu.23915DOI Listing
January 2020

Smith-Magenis Syndrome: Molecular Basis of a Genetic-Driven Melatonin Circadian Secretion Disorder.

Int J Mol Sci 2019 Jul 19;20(14). Epub 2019 Jul 19.

GénoPsy, Reference Center for Diagnosis and Management of Genetic Psychiatric Disorders, Centre Hospitalier le Vinatier and EDR-Psy Q19 Team (Centre National de la Recherche Scientifique & Lyon 1 Claude Bernard University), 69678 Bron, France.

Smith-Magenis syndrome (SMS), linked to () haploinsufficiency, is a unique model of the inversion of circadian melatonin secretion. In this regard, this model is a formidable approach to better understand circadian melatonin secretion cycle disorders and the role of the gene in this cycle. Sleep-wake cycle disorders in SMS include sleep maintenance disorders with a phase advance and intense sleepiness around noon. These disorders have been linked to a general disturbance of sleep-wake rhythm and coexist with inverted secretion of melatonin. The exact mechanism underlying the inversion of circadian melatonin secretion in SMS has rarely been discussed. We suggest three hypotheses that could account for the inversion of circadian melatonin secretion and discuss them. First, inversion of the circadian melatonin secretion rhythm could be linked to alterations in light signal transduction. Second, this inversion could imply global misalignment of the circadian system. Third, the inversion is not linked to a global circadian clock shift but rather to a specific impairment in the melatonin secretion pathway between the suprachiasmatic nuclei (SCN) and pinealocytes. The development of diurnal SMS animal models that produce melatonin appears to be an indispensable step to further understand the molecular basis of the circadian melatonin secretion rhythm.
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http://dx.doi.org/10.3390/ijms20143533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679101PMC
July 2019

Corpus callosum metrics predict severity of visuospatial and neuromotor dysfunctions in ARID1B mutations with Coffin-Siris syndrome.

Psychiatr Genet 2019 12;29(6):237-242

Faculty of Medicine, University of Paris Descartes (SPC) INSERM UMR 1178/1018-CESP, University of Paris Sud-Paris Saclay, UVSQ Villejuif and Paris Descartes, SPC.

ARID1B mutations in Coffin-Siris syndrome are a cause of intellectual disability (0.5-1%), with various degrees of autism and agenesis of the corpus callosum (10%). Little is known regarding the cognitive and motor consequences of ARID1B mutations in humans and no link has been made between corpus callosum anomalies and visuospatial and neuromotor dysfunctions. We have investigated the visuospatial and neuromotor phenotype in eight patients with ARID1B mutations. A paramedian sagittal section of the brain MRI was selected, and corpus callosum was measured in anteroposterior length, genu and trunk width. Spearman's rank order coefficients were used to explore correlations between visuospatial and social cognitive variables and dimensions of the corpus callosum. A significant correlation between genu width size and visual cognition was observed. Retrocerebellar cysts were associated with corpus callosum anomalies. Here, we show that corpus callosum anomalies caused in ARID1B mutations may be predictive of the visuospatial and motor phenotype in Coffin-Siris syndrome.
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http://dx.doi.org/10.1097/YPG.0000000000000225DOI Listing
December 2019

12q13.12q13.13 microdeletion encompassing ACVRL1 and SCN8A genes: Clinical report of a new contiguous gene syndrome.

Eur J Med Genet 2019 Nov 30;62(11):103565. Epub 2018 Oct 30.

Hospices Civils de Lyon, Genetic Department and National HHT Reference Center, Femme-Mère-Enfants Hospital, Bron, F-69677, France.

Hereditary hemorrhagic telangiectasia is usually linked to the presence of a pathogenic mutation ACVRL1 or ENG. Thus, apparently there is no benefit to perform an array CGH in case of HHT. However, ENG has been involved in a contiguous gene syndrome due to a de novo 9q33.3q34.11 microdeletion. We describe here a new contiguous gene syndrome involving ACVRL1 gene. A 50-year-old female patient had a typical clinical presentation of hereditary hemorrhagic telangiectasia (HHT) with epistaxis, cutaneous-mucous telangiectases, arteriovenous malformation. She also presented a cognitive disability. Cognitive assessment showed a heterogeneous cognitive disorder predominating in the executive sphere without intellectual deficiency. She had no peculiar morphological feature. Neurological examination disclosed the presence of contralateral mirror movements during voluntary movement of each hand. A heterozygous deletion of the whole ACVRL1 gene (exons 1 to 10) was found to be responsible for the HHT features. To investigate further the dysexecutive syndrome and the mirror movements, we performed oligonucleotide array comparative genomic hybridization (array CGH) study (180K, Agilent, Santa-Clara, CA, USA). This study revealed a de novo 1.58 Mb deletion on chromosome 12q13.12q13.13 encompassing the ACVRL1 and SCN8A genes. To our knowledge, this deletion has not been previously reported and defines a new contiguous gene syndrome. The loss of one ACVRL1 allele is likely to be responsible for the HHT phenotype, while the deletion of the SCN8A gene is likely to be the cause of the mild cognitive disorder. SCN8A haploinsufficiency might also be involved in the occurrence of mirror movements. This report highlights the benefit of searching for large rearrangements in cases including unusual symptoms in association with HHT. On the other hand, an early diagnosis of 12q13.12q13.13 microdeletion based on the presence of a dysexecutive syndrome and/or mirror movement may allow to prevent HHT complications.
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http://dx.doi.org/10.1016/j.ejmg.2018.10.017DOI Listing
November 2019

Impaired neural processing of transitive relations in children with math learning difficulty.

Neuroimage Clin 2018 23;20:1255-1265. Epub 2018 Oct 23.

Institut des Sciences Cognitives Marc Jeannerod, UMR 5304, Centre National de la Recherche Scientifique (CNRS) & Université de Lyon, 67 Boulevard Pinel, 69675 Bron cedex, France. Electronic address:

Math learning difficulty (i.e., MLD) is common in children and can have far-reaching consequences in personal and professional life. Converging evidence suggests that MLD is associated with impairments in the intraparietal sulcus (IPS). However, the role that these impairments play in MLD remains unclear. Although it is often assumed that IPS deficits affect core numerical abilities, the IPS is also involved in several non-numerical processes that may contribute to math skills. For instance, the IPS supports transitive reasoning (i.e., the ability to integrate relations such as A > B and B > C to infer that A > C), a skill that is central to many aspects of math learning in children. Here we measured fMRI activity of 8- to 12-year-olds with MLD and typically developing (TD) peers while they listened to stories that included transitive relations. Children also answered questions evaluating whether transitive inferences were made during story comprehension. Compared to non-transitive relations (e.g., A > B and C > D), listening to transitive relations (e.g., A > B and B > C) was associated with enhanced activity in the IPS in TD children. In children with MLD, the difference in activity between transitive and non-transitive relations in the IPS was (i) non-reliable and (ii) smaller than in TD children. Finally, children with MLD were less accurate than TD peers when making transitive inferences based on transitive relations. Thus, a deficit in the online processing of transitive relations in the IPS might contribute to math difficulties in children with MLD.
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http://dx.doi.org/10.1016/j.nicl.2018.10.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308383PMC
February 2019

Regressive Autism Spectrum Disorder Expands the Phenotype of BSCL2/Seipin-Associated Neurodegeneration.

Biol Psychiatry 2019 02 24;85(4):e17-e19. Epub 2018 Aug 24.

GENDEV, Centre de Recherche en Neurosciences de Lyon, UMR 529, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale U1028, Université Claude Bernard Lyon 1, Lyon, France; HCL, Department of Genetics, Reference Center for Developmental Anomalies and Malformation Syndromes, Oullins, France.

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http://dx.doi.org/10.1016/j.biopsych.2018.05.010DOI Listing
February 2019

Computer-based cognitive remediation program for the treatment of behavioral problems in children with intellectual disability: the «COGNITUS & MOI» study protocol for a randomized controlled trial.

BMC Psychiatry 2018 07 20;18(1):235. Epub 2018 Jul 20.

GenoPsy, Reference center for rare diseases with psychiatric symptoms, Centre Hospitalier le Vinatier and EDR-Psy team (CNRS UMR 5229 & Lyon 1 University), 69678 BRON Cedex Lyon, Lyon, France.

Background: Comorbid psychiatric disorders are frequent in children with intellectual disability (ID). Given the limitations of drugs treatments, cognitive remediation could be a promising tool to reduce these challenging behaviors but evidence is still scarce. Our group recently developed the «COGNITUS & MOI» program that is designed to train the attentional and visuospatial skills in children with ID. This study investigates the efficiency of the «COGNITUS & MOI» program in this condition.

Methods: Children (age: 6.00-13.11) with mild to moderate ID and behavioral problems, will benefit from a therapy during a 16 week randomized controlled trial. One group will be randomly treated with the «COGNITUS & MOI» program and the other with a motor skill and video viewing intervention. All participants will undergo a behavioral, functional and neurocognitive assessment at baseline, post-intervention, and 6-month follow-up. Primary outcome will be the change from the baseline of the score on the "hyperactivity - noncompliance" subscale of the Aberrant Behavior Checklist.

Discussion: If the results are conclusive, the «COGNITUS & MOI» program could be added to the therapeutic arsenal against challenging behavior in children with ID.

Trial Registration: ClinicalTrials NCT02797418 . Date registered: 8th of June 2016.
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http://dx.doi.org/10.1186/s12888-018-1810-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053752PMC
July 2018

Additive Effect of Variably Penetrant 22q11.2 Duplication and Pathogenic Mutations in Autism Spectrum Disorder: To Which Extent Does the Tree Hide the Forest?

J Autism Dev Disord 2018 08;48(8):2886-2889

Département de génétique médicale, Institut Imagine, Hôpital Necker-Enfants Malades, INSERM UMR 1163, Université Paris Descartes-Sorbonne, Paris, France.

The 22q11.2 duplication is a variably penetrant copy number variant (CNV) associated with a broad spectrum of clinical manifestations including autism spectrum disorders (ASD), and epilepsy. Here, we report on pathogenic HUWE1 and KIF1A mutations in two severely affected ASD/ID participants carrying a 22q11.2 duplication. Based on previous studies, this CNV was originally considered as disease-causing. Yet, owing to their clinical severity, the participants were further investigated by next generation sequencing and eventually found to carry pathogenic mutations in HUWE1 and KIF1A respectively. We suggest giving consideration to additive effect of 22q11.2 duplication and pathogenic mutations when clinical presentation is either unusually severe or associated with atypical features. Caution should be exercised when delivering genetic counseling for variably penetrant CNVs, as uncertain penetrance of this CNV may lead to ignore additive pathogenic mutations. Systematic panel or exome sequencing of known ASD genes should be recommended when counseling families of patients carrying variably penetrant CNV.
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http://dx.doi.org/10.1007/s10803-018-3552-7DOI Listing
August 2018

Subthreshold social cognitive deficits may be a key to distinguish 22q11.2DS from schizophrenia.

Early Interv Psychiatry 2019 Apr 25;13(2):304-307. Epub 2018 Mar 25.

GénoPsy, Reference Center for Rare Diseases, Le Vinatier Hospital, Bron, France.

Aim: Social cognitive impairments are core features in 22q11.2 deletion syndrome (22q11.2DS) and schizophrenia (SCZ). Indeed, adults with 22q.11.2 DS often have poorer social competence as well as poorer performance on measures of social cognitive skills (emotion recognition and theory of mind, ToM) compared with typically developing people. However, studies comparing specific social cognitive components in 22q11.2DS and SCZ have not yet been widely conducted.

Methods: In this study we compared performances of 22q11.2DS and SCZ on both facial emotion recognition and ToM. Patients with 22q11.2DS (n = 18) and matched SCZ patients were recruited. After neuropsychological testing, the facial emotion recognition test assessed the patients' ability to recognize six basic, universal emotions (joy, anger, sadness, fear, disgust, and contempt). The Versailles-situational intentional reading evaluated ToM with six scenes from movies showing characters in complex interactions (involving hints, lies, and indirect speech).

Results: We show that 22q11.2DS exhibited significantly lower performance in emotion recognition than SCZ patients did, especially for disgust, contempt, and fear. This impairment seems to be a core cognitive phenotype in 22q11.2DS, regardless of the presence of SCZ symptoms. Concerning ToM, our results may highlight the same impairment level in 22q11.2DS and SCZ but require to be replicated in a larger cohort.

Conclusion: Our results document the existence of threshold social cognitive deficits distinguishing 22q11.2DS from SCZ.
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http://dx.doi.org/10.1111/eip.12557DOI Listing
April 2019

Weight loss induced by quetiapine in a 22q11.2DS patient.

Mol Genet Metab Rep 2017 Dec 17;13:95-96. Epub 2017 Oct 17.

Centre ressource de réhabilitation psychosociale et de remédiation cognitive, CH Le Vinatier et UMR 5229 (CNRS and Université Lyon 1), Bron, France.

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http://dx.doi.org/10.1016/j.ymgmr.2017.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5645303PMC
December 2017

Evidence for dopaminergic denervation in classical galactosemia.

Mov Disord 2017 06 3;32(6):940-942. Epub 2017 Apr 3.

Université de Lyon, Université Lyon 1, Faculté de Médecine et de maïeutique Lyon Sud Charles Mérieux, Lyon, France.

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http://dx.doi.org/10.1002/mds.26980DOI Listing
June 2017

Authors' reply - Clozapine for mitochondrial psychosis.

Mol Genet Metab Rep 2017 Mar 6;10:101. Epub 2017 Feb 6.

INSERM UMR 1163, Université Paris Descartes-Sorbonne, Service de génétique clinique, Institut Imagine, Hôpital Necker-Enfants Malades, Paris, France.

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http://dx.doi.org/10.1016/j.ymgmr.2017.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5295507PMC
March 2017

Autism spectrum disorder associated with 49,XYYYY: case report and review of the literature.

BMC Med Genet 2017 Jan 31;18(1). Epub 2017 Jan 31.

Centre de référence des anomalies du développement, Service de génétique, Hospices Civils de Lyon, & Centre de Recherche en Neurosciences de Lyon, Inserm U1028, UMR CNRS 5292, GENDEV Team, Lyon 1-Claude Bernard University, Bron, France.

Background: Sex chromosome aneuploidies occur in approximately one in 420 live births. The most frequent abnormalities are 45,X (Turner syndrome), 47,XXX (triple X), 47,XXY (Klinefelter syndrome), and 47,XYY. The prevalence of males with more than one extra sex chromosome (e.g. 48,XXYY or 48,XXXY) is less common. However, the literature provides little information about the cognitive and behavioural phenotype and the natural history of the disease. We report the clinical, neurocognitive, social cognitive and psychiatric characterization of a patient with 49,XYYYY syndrome.

Case Presentation: The patient presented with a complex phenotype including a particular cognitive profile with intellectual deficiency and autism spectrum disorder (ASD) with limited interests. Moreover, social anxiety disorder with selective mutism and separation anxiety disorder were observed (DSM-5 criteria, MINI Assessment).

Conclusion: It is now admitted that 49,XYYYY has unique medical, neurodevelopmental and behavioural characteristics. Interestingly, ASD is more common in groups with Y chromosome aneuploidy. This clinical report suggests that understanding the cognitive and social functioning of these patients may provide new insights into possible therapeutic strategies, as cognitive remediation or social cognitive training.
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http://dx.doi.org/10.1186/s12881-017-0371-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5282903PMC
January 2017

Low dose clozapine controls adult-onset psychosis associated with the neurogenic ataxia-retinitis pigmentosa (NARP) mutation.

Mol Genet Metab Rep 2017 Mar 13;10:20-22. Epub 2016 Dec 13.

INSERM UMR 1163, Université Paris Descartes-Sorbonne, Service de génétique clinique, Institut Imagine, Hôpital Necker-Enfants Malades, Paris, France.

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http://dx.doi.org/10.1016/j.ymgmr.2016.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5157794PMC
March 2017

Slowness in Movement Initiation is Associated with Proactive Inhibitory Network Dysfunction in Parkinson's Disease.

J Parkinsons Dis 2016 04;6(2):433-40

Université de Lyon,, Lyon, France.

Background: Impairment in initiating movements in PD might be related to executive dysfunction associated with abnormal proactive inhibitory control, a pivotal mechanism consisting in gating movement initiation in uncertain contexts.

Objective: Testing this hypothesis on the basis of direct neural-based evidence.

Methods: Twelve PD patients on antiparkinsonian medication and fifteen matched healthy controls performed a simple reaction time task during event-related functional MRI scanning.

Results: For all subjects, the level of activation of SMA was found to predict RT on a trial-by-trial basis. The increase in movement initiation latency observed in PD patients with regard to controls was associated with pre-stimulus BOLD increases within several nodes of the proactive inhibitory network (caudate nucleus, precuneus, thalamus).

Conclusions: These results provide physiological data consistent with impaired control of proactive inhibition over motor initiation in PD. Patients would be locked into a mode of control maintaining anticipated inhibition over willed movements even when the situation does not require action restraint. The functional and neurochemical bases of brain activity associated with executive settings need to be addressed thoroughly in future studies to better understand disabling symptoms that have few therapeutic options like akinesia.
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http://dx.doi.org/10.3233/JPD-150750DOI Listing
April 2016

Behavioral disturbance and treatment strategies in Smith-Magenis syndrome.

Orphanet J Rare Dis 2015 Sep 4;10:111. Epub 2015 Sep 4.

Center for Screening and Treatment of Psychiatric Disorders of Genetic Origin, Vinatier Hospital, 95 Bd Pinel, 69678, Lyon, France.

Background: Smith-Magenis syndrome is a complex neurodevelopmental disorder that includes intellectual deficiency, speech delay, behavioral disturbance and typical sleep disorders. Ninety percent of the cases are due to a 17p11.2 deletion encompassing the RAI1 gene; other cases are linked to mutations of the same gene. Behavioral disorders often include outbursts, attention deficit/hyperactivity disorders, self-injury with onychotillomania and polyembolokoilamania (insertion of objects into body orifices), etc. Interestingly, the stronger the speech delay and sleep disorders, the more severe the behavioral issues. Sleep disturbances associate excessive daytime sleepiness with nighttime agitation. They are underpinned by an inversion of the melatonin secretion cycle. However, the combined intake of beta-blockers in the morning and melatonin in the evening may radically alleviate the circadian rhythm problems.

Discussion: Once sleep disorders are treated, the next challenge is finding an effective treatment for the remaining behavioral problems. Unfortunately, there is a lack of objective guidelines. A comprehensive evaluation of such disorders should include sleep disorders, potential causes of pain, neurocognitive level and environment (i.e. family and school). In any case, efforts should focus on improving communication skills, identifying and treating attention deficit/hyperactivity, aggressiveness and anxiety. Treatment of Smith-Magenis syndrome is complex and requires a multidisciplinary team including, among others, geneticists, psychiatrists, neuropediatricians/neurologists, somnologists, developmental and behavioral pediatricians, and speech and language therapists.
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http://dx.doi.org/10.1186/s13023-015-0330-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559928PMC
September 2015

Complex phenotype with social communication disorder caused by mosaic supernumerary ring chromosome 19p.

BMC Med Genet 2014 Dec 11;15:132. Epub 2014 Dec 11.

Hospices Civils de Lyon, service de génétique et centre de référence des anomalies du développement, GHE, Lyon, France.

Background: Deletions or duplications of chromosome 19 are rare and there is no previous report in the literature of a ring chromosome derived from proximal 19p. Copy Number Variants (CNVs) responsible for complex phenotypes with Social Communication Disorder (SCD), may contribute to improve knowledge about the distinction between intellectual deficiency and autism spectrum disorders.

Case Presentation: We report the clinical and cytogenetic characterization of a patient (male, 33 years-old, first child of healthy Portuguese non-consanguineous parents) presenting with a complex phenotype including SCD without intellectual deficiency and carrying a mosaic supernumerary ring chromosome 19p. Microarray-Based Comparative Genomic Hybridization and Fluorescence in situ Hybridization were performed. Genetic analysis showed a large mosaic interstitial duplication 19p13.12p12 of the short arm of chromosome 19, spanning 8.35 Mb. Our data suggested a putative association between psychosocial dysfunction and mosaic pure trisomy 19p13.2p12.

Conclusion: This clinical report demonstrated the need to analyze more discreet trait-based subsets of complex phenotypes to improve the ability to detect genetic effects. To address this question and the broader issue of deciphering the yet unknown genetic contributors to complex phenotype with SCD, we suggest performing systematic psychological and psychiatric assessments in patients with chromosomal abnormalities.
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http://dx.doi.org/10.1186/s12881-014-0132-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4411819PMC
December 2014

A functional magnetic resonance imaging study of pathophysiological changes responsible for mirror movements in Parkinson's disease.

PLoS One 2013 25;8(6):e66910. Epub 2013 Jun 25.

Université de Lyon, Faculté de Médecine Lyon Sud Charles Mérieux, Lyon, France.

Mirror movements correspond to involuntary movements observed in the limb contralateral to the one performing voluntary movement. They can be observed in Parkinson's disease (PD) but their pathophysiology remains unclear. The present study aims at identifying their neural correlates in PD using functional magnetic resonance imaging. Ten control subjects and 14-off drug patients with asymmetrical right-sided PD were included (8 with left-sided mirror movements during right-hand movements, and 6 without mirror movements). Between-group comparisons of BOLD signal were performed during right-hand movements and at rest (p<0.005 uncorrected). The comparison between PD patients with and without mirror movements showed that mirror movements were associated with an overactivation of the insula, precuneus/posterior cingulate cortex bilaterally and of the left inferior frontal cortex and with a deactivation of the right dorsolateral prefrontal cortex, medial prefrontal cortex, and pre-supplementary motor area and occipital cortex. These data suggest that mirror movements in Parkinson's disease are promoted by: 1- a deactivation of the non-mirroring inhibitory network (dorsolateral prefrontal cortex, pre-supplementary motor area); 2- an overactivation of prokinetic areas (notably the insula). The concomitant overactivation of a proactive inhibitory network (including the posterior cingulate cortex and precuneus) could reflect a compensatory inhibition of mirror movements.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0066910PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3692538PMC
February 2014

FXTAS: new insights and the need for revised diagnostic criteria.

Neurology 2012 Oct 17;79(18):1898-907. Epub 2012 Oct 17.

AP-HP, Paris, France.

Objective: Fragile X-associated tremor ataxia syndrome (FXTAS) is defined by FMR1 premutation, cerebellar ataxia, intentional tremor, and middle cerebellar peduncle (MCP) hyperintensities. We delineate the clinical, neurophysiologic, and morphologic characteristics of FXTAS.

Methods: Clinical, morphologic (brain MRI, (123)I-ioflupane SPECT), and neurophysiologic (tremor recording, nerve conduction studies) study in 22 patients with FXTAS, including 4 women.

Results: A total of 43% of patients had no family history of fragile X syndrome (FXS), which contrasts with previous FXTAS series. A total of 86% of patients had tremor and 81% peripheral neuropathy. We identified 3 electroclinical tremor patterns: essential-like (35%), cerebellar (29%), and parkinsonian (12%). Two electrophysiologic patterns evocative of non-length-dependent (56%) and length-dependent sensory neuropathy (25%) were identified. Corpus callosum splenium (CCS) hyperintensity was as frequent (68%) as MCP hyperintensities (64%). Sixty percent of patients had parkinsonism and 47% abnormal (123)I-ioflupane SPECT. Unified Parkinson's Disease Rating Scale motor score was correlated to abnormal (123)I-ioflupane SPECT (p = 0.02) and to CGG repeat number (p = 0.0004). Scale for the assessment and rating of ataxia correlated with dentate nuclei hyperintensities (p = 0.03) and CCS hyperintensity was a marker of severe disease progression (p = 0.04).

Conclusions: We recommend to include in the FXTAS testing guidelines both CCS hyperintensity and peripheral neuropathy and to consider them as new major radiologic and minor clinical criterion, respectively, for the diagnosis of FXTAS. FXTAS should also be considered in women or when tremor, MCP hyperintensities, or family history of FXS are lacking. Our study broadens the spectrum of tremor, peripheral neuropathy, and MRI abnormalities in FXTAS, hence revealing the need for revised criteria.
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http://dx.doi.org/10.1212/WNL.0b013e318271f7ffDOI Listing
October 2012

Relationships between cognitive functions and driving behavior in Parkinson's disease.

Eur Neurol 2012 4;68(2):98-107. Epub 2012 Jul 4.

IFSTTAR, LESCOT, Fondation Partenariale, Bron, France. maud.ranchet @ ifsttar.fr

Alterations in cognitive functions in Parkinson's disease (PD) have been reported even in mild stages of the disease. These functions may play a role in complex daily activities, such as driving. This article provides an overview on the relationships between cognitive functions and driving behavior in PD in driving simulator and on-road studies. The role of attention, executive functions, visual memory, visuospatial construction and information processing speed is discussed. In driving simulator studies, driving performances were correlated with several neuropsychological measures, especially those of Trail Making Test (TMT), Brixton and Symbol Digit Modalities Test. In on-road studies, TMT, Useful Field Of View and Block Design tests appear as good predictors of driving performances. Most of these tests are also relevant to driving in Alzheimer's disease and traumatic brain injury.
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http://dx.doi.org/10.1159/000338264DOI Listing
January 2013

Functional imaging of non-motor signs in Parkinson's disease.

J Neurol Sci 2012 Apr 9;315(1-2):9-14. Epub 2011 Dec 9.

CNRS, UMR 5229, Centre de Neurosciences Cognitives, Bron, France.

Non-motor signs encountered in Parkinson's disease consist in a heterogeneous group of manifestations including hyposmia, pain, fatigue, sleep disorders, neuropsychic disorders. Functional imaging techniques provide an invaluable method to understand their pathophysiology, allowing us to study the abnormalities of brain metabolism or perfusion associated with these manifestations or the underlying dysfunction of different neurotransmission systems. The present paper covers the recent advances provided by functional imaging in this area.
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http://dx.doi.org/10.1016/j.jns.2011.11.008DOI Listing
April 2012

Surgery for tardive dyskinesia.

Int Rev Neurobiol 2011 ;98:289-96

Université Lyon I; Hospices Civils de Lyon, Hôpital Neurologique Pierre Wertheimer, service de Neurologie C, Lyon, France.

Tardive dyskinesia (TD) is an often bothersome side effect of antipsychotic treatment. Medical treatment options are usually disappointing. A few single case reports have suggested some efficacy of lesionning surgery (i.e. pallidotomy or thalamotomy). A much greater number of series (including one controlled-study) have assessed the effects of deep brain stimulation applied to the internal globus pallidus. All of them have shown a marked improvement of motor symptoms without any major psychiatric side effects.
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http://dx.doi.org/10.1016/B978-0-12-381328-2.00012-2DOI Listing
January 2012

The Almirall European Headache Awards 2009.

J Headache Pain 2010 Jun 6;11(3):207-14. Epub 2010 Apr 6.

Neurological Sciences Department, University of Bologna, Via U Foscolo 7, 40123 Bologna, Italy.

The Almirall European Headache Awards (AEHA) were organized in conjunction with the European Headache Federation. The awards were held in 2009, aiming to share clinical experience and best practice in headache-related disease management. 56 unusual and challenging cases of headache from 5 European countries (Belgium, France, Italy, Portugal and Spain) were judged by a Scientific Committee including expert representatives from participating countries, acting as reviewers. Three cases were selected from each country. The 15 resulting cases were presented to the Scientific Committee in Madrid, Spain in November 2009 and awards were given to the top 5 presentations. This article presents details of these cases, including the award winning entries. They have been categorized into four main groups: (a) headaches in rare syndromes; (b) secondary headaches to infectious/autoimmune causes or post-trauma/mass occupation; (c) headache in unresolved cases; and (d) other relevant cases. First prize was awarded to a case involving a 55-year-old male with familial thrombocytopenia and a unilateral neuralgiform headache secondary to trigeminal vascular contact, and which was successfully treated with carbamazepine. Conclusions from the meeting include: rare syndromes do occur and require appropriate treatment to improve outcomes; concomitant diseases may impair adequate diagnosis and should be investigated; physicians should be cautious and treat possible serious underlying disease, whilst accurately clarifying the correct diagnosis; neurological examination and complementary tests may be required; consideration should be given to possible rare medication events; and some cases may remain without a clear cause or diagnosis and symptoms should be treated whilst investigations continue.
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http://dx.doi.org/10.1007/s10194-010-0209-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3451906PMC
June 2010