Publications by authors named "Aurore Curie"

22 Publications

  • Page 1 of 1

Neuropsychological and neuroanatomical phenotype in 17 patients with cystinosis.

Orphanet J Rare Dis 2020 02 26;15(1):59. Epub 2020 Feb 26.

Centre de référence des maladies rénales rares - Néphrogones - Filière ORKiD, Bron, France.

Background: Cystinosis is a rare autosomal recessive disorder caused by intracellular cystine accumulation. Proximal tubulopathy (Fanconi syndrome) is one of the first signs, leading to end-stage renal disease between the age of 12 and 16. Other symptoms occur later and encompass endocrinopathies, distal myopathy and deterioration of the central nervous system. Treatment with cysteamine if started early can delay the progression of the disease. Little is known about the neurological impairment which occurs later. The goal of the present study was to find a possible neuroanatomical dysmorphic pattern that could help to explain the cognitive profile of cystinosis patients. We also performed a detailed review of the literature on neurocognitive complications associated with cystinosis.

Methods: 17 patients (mean age = 17.6 years, [5.4-33.3]) with cystinosis were included in the study. Neuropsychological assessment was performed including intelligence (Intelligence Quotient (IQ) with Wechsler's scale), memory (Children Memory Scale and Wechsler Memory Scale), visuo-spatial (Rey's figure test) and visuo-perceptual skills assessments. Structural brain MRI (3 T) was also performed in 16 out of 17 patients, with high resolution 3D T1-weighted, 3D FLAIR and spectroscopy sequences.

Results: Intellectual efficiency was normal in patients with cystinosis (mean Total IQ = 93). However the Perceptual Reasoning Index (mean = 87, [63-109]) was significantly lower than the Verbal Comprehension Index (mean = 100, [59-138], p = 0.003). Memory assessment showed no difference between visual and verbal memory. But the working memory was significantly impaired in comparison with the general memory skills (p = 0.003). Visuospatial skills assessment revealed copy and reproduction scores below the 50th percentile rank in more than 70% of the patients. Brain MRI showed cortical and sub-cortical cerebral atrophy, especially in the parieto-occipital region and FLAIR hypersignals in parietal, occipital and brain stem/cerebellum. Patients with atrophic brain had lower Total IQ scores compared to non-atrophic cystinosis patients.

Conclusions: Patients with cystinosis have a specific neuropsychological and neuroanatomical profile. We suggest performing a systematic neuropsychological assessment in such children aiming at considering adequate management.
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http://dx.doi.org/10.1186/s13023-019-1271-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7045592PMC
February 2020

Expanding the phenotypic spectrum of Allan-Herndon-Dudley syndrome in patients with SLC16A2 mutations.

Dev Med Child Neurol 2019 12 13;61(12):1439-1447. Epub 2019 Aug 13.

Centre de Compétence des Leucodystrophies et Leucoencéphalopathies de Cause Rare, Pôle Femme et Enfant, Hôpital Estaing, Centre Hospitalier Universitaire de Clermont-Ferrand, Clermont-Ferrand, France.

The aim of the study was to redefine the phenotype of Allan-Herndon-Dudley syndrome (AHDS), which is caused by mutations in the SLC16A2 gene that encodes the brain transporter of thyroid hormones. Clinical phenotypes, brain imaging, thyroid hormone profiles, and genetic data were compared to the existing literature. Twenty-four males aged 11 months to 29 years had a mutation in SLC16A2, including 12 novel mutations and five previously described mutations. Sixteen patients presented with profound developmental delay, three had severe intellectual disability with poor language and walking with an aid, four had moderate intellectual disability with language and walking abilities, and one had mild intellectual disability with hypotonia. Overall, eight had learned to walk, all had hypotonia, 17 had spasticity, 18 had dystonia, 12 had choreoathetosis, 19 had hypomyelination, and 10 had brain atrophy. Kyphoscoliosis (n=12), seizures (n=7), and pneumopathies (n=5) were the most severe complications. This study extends the phenotypic spectrum of AHDS to a mild intellectual disability with hypotonia. Developmental delay, hypotonia, hypomyelination, and thyroid hormone profile help to diagnose patients. Clinical course depends on initial severity, with stable acquisition after infancy; this may be adversely affected by neuro-orthopaedic, pulmonary, and epileptic complications. WHAT THIS PAPER ADDS: Mild intellectual disability is associated with SLC16A2 mutations. A thyroid hormone profile with a free T /T ratio higher than 0.75 can help diagnose patients. Patients with SLC16A2 mutations present a broad spectrum of neurological phenotypes that are also observed in other hypomyelinating disorders. Axial hypotonia is a consistent feature of Allan-Herndon-Dudley syndrome and leads to specific complications.
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http://dx.doi.org/10.1111/dmcn.14332DOI Listing
December 2019

Basal ganglia involvement in patients: The reason for patients very specific grasping?

Neuroimage Clin 2018 5;19:454-465. Epub 2018 Apr 5.

Psychiatric Neuroimaging Program, Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.

The () gene was identified in 2002 as responsible for XLAG syndrome, a lissencephaly characterized by an almost complete absence of cortical GABAergic interneurons, and for milder forms of X-linked Intellectual Disability (ID) without apparent brain abnormalities. The most frequent mutation found in the gene, a duplication of 24 base pairs (c.429_452dup24) in exon 2, results in a recognizable syndrome in which patients present ID without primary motor impairment, but with a very specific upper limb distal motor apraxia associated with a pathognomonic hand-grip, described as developmental Limb Kinetic Apraxia (LKA). In this study, we first present expression during human fetal brain development showing that it is strongly expressed in GABAergic neuronal progenitors during the second and third trimester of pregnancy. We show that although expression strongly decreases towards the end of gestation, it is still present after birth in some neurons of the basal ganglia, thalamus and cerebral cortex, suggesting that ARX also plays a role in more mature neuron functioning. Then, using morphometric brain MRI in 13 patients carrying c.429_452dup24 mutation and in 13 sex- and age-matched healthy controls, we show that patients have a significantly decreased volume of several brain structures including the striatum (and more specifically the caudate nucleus), hippocampus and thalamus as well as decreased precentral gyrus cortical thickness. We observe a significant correlation between caudate nucleus volume reduction and motor impairment severity quantified by kinematic parameter of precision grip. As basal ganglia are known to regulate sensorimotor processing and are involved in the control of precision gripping, the combined decrease in cortical thickness of primary motor cortex and basal ganglia volume in dup24 patients is very likely the anatomical substrate of this developmental form of LKA.
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http://dx.doi.org/10.1016/j.nicl.2018.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029499PMC
January 2019

A new mouse model of ARX dup24 recapitulates the patients' behavioral and fine motor alterations.

Hum Mol Genet 2018 06;27(12):2138-2153

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, 67404 Illkirch, France.

The aristaless-related homeobox (ARX) transcription factor is involved in the development of GABAergic and cholinergic neurons in the forebrain. ARX mutations have been associated with a wide spectrum of neurodevelopmental disorders in humans, among which the most frequent, a 24 bp duplication in the polyalanine tract 2 (c.428_451dup24), gives rise to intellectual disability, fine motor defects with or without epilepsy. To understand the functional consequences of this mutation, we generated a partially humanized mouse model carrying the c.428_451dup24 duplication (Arxdup24/0) that we characterized at the behavior, neurological and molecular level. Arxdup24/0 males presented with hyperactivity, enhanced stereotypies and altered contextual fear memory. In addition, Arxdup24/0 males had fine motor defects with alteration of reaching and grasping abilities. Transcriptome analysis of Arxdup24/0 forebrains at E15.5 showed a down-regulation of genes specific to interneurons and an up-regulation of genes normally not expressed in this cell type, suggesting abnormal interneuron development. Accordingly, interneuron migration was altered in the cortex and striatum between E15.5 and P0 with consequences in adults, illustrated by the defect in the inhibitory/excitatory balance in Arxdup24/0 basolateral amygdala. Altogether, we showed that the c.428_451dup24 mutation disrupts Arx function with a direct consequence on interneuron development, leading to hyperactivity and defects in precise motor movement control and associative memory. Interestingly, we highlighted striking similarities between the mouse phenotype and a cohort of 33 male patients with ARX c.428_451dup24, suggesting that this new mutant mouse line is a good model for understanding the pathophysiology and evaluation of treatment.
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http://dx.doi.org/10.1093/hmg/ddy122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985730PMC
June 2018

Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome.

Nat Rev Drug Discov 2018 04 8;17(4):280-299. Epub 2017 Dec 8.

Service de Génétique Médicale, Centre Hospitalier Universitaire Vaudois, Rue du Bugnon 46, 1011 Lausanne and University of Lausanne, Switzerland.

Neurodevelopmental disorders such as fragile X syndrome (FXS) result in lifelong cognitive and behavioural deficits and represent a major public health burden. FXS is the most frequent monogenic form of intellectual disability and autism, and the underlying pathophysiology linked to its causal gene, FMR1, has been the focus of intense research. Key alterations in synaptic function thought to underlie this neurodevelopmental disorder have been characterized and rescued in animal models of FXS using genetic and pharmacological approaches. These robust preclinical findings have led to the implementation of the most comprehensive drug development programme undertaken thus far for a genetically defined neurodevelopmental disorder, including phase IIb trials of metabotropic glutamate receptor 5 (mGluR5) antagonists and a phase III trial of a GABA receptor agonist. However, none of the trials has been able to unambiguously demonstrate efficacy, and they have also highlighted the extent of the knowledge gaps in drug development for FXS and other neurodevelopmental disorders. In this Review, we examine potential issues in the previous studies and future directions for preclinical and clinical trials. FXS is at the forefront of efforts to develop drugs for neurodevelopmental disorders, and lessons learned in the process will also be important for such disorders.
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http://dx.doi.org/10.1038/nrd.2017.221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904225PMC
April 2018

Outcome of isolated agenesis of the corpus callosum: A population-based prospective study.

Eur J Paediatr Neurol 2018 Jan 5;22(1):82-92. Epub 2017 Sep 5.

Université de Lyon, F-69008 Lyon, France; Radiologie pédiatrique et médecine fœtale, Hôpital Femme Mère Enfant, F-69677 Bron, France.

Objectives: Neurodevelopmental outcome of apparently isolated agenesis of the corpus callosum (ACC) remains a major concern with uncertain prognosis. Despite "normal" IQ reported in a majority of patients, the rates of learning disabilities and severe outcome (ranging from 0% to 20%) are not clearly established.

Methods: A large population-based series was investigated based on a longitudinal follow-up until school age, using Wechsler Intelligence scales at 3, 5, and 7 years.

Results: Fifty women were referred to a tertiary referral unit for an "apparently" isolated ACC confirmed by ultrasound, foetal MRI, and karyotyping or array CGH. Twelve pregnancies were terminated, one foetus died in utero, one pregnancy outcome was unknown, and 36 babies were born. Two were lost to follow-up. Thirty-four children could be classified into three groups. Group 1 comprised two children (6%) with severe intellectual disability (one Mowat-Wilson syndrome and one ASD). Group 2 comprised 10 children (29%) who had learning disabilities and borderline intellectual functioning (VIQ and/or PIQ scores >70 and <85); three patients had hypopituitarism with additional MRI anomalies revealed after birth. Group 3 comprised 22 children (65%) who had both VIQ and PIQ >85 (-1 SD) with a normal school level. Longitudinal follow-up revealed weaker PIQ in younger children which improved with age.

Conclusion: Our data indicate that intellectual ability is normal (IQ > 85) in approximately two thirds and borderline in just over a quarter of patients. However, a low risk of severe cognitive impairment exists, and this information should be shared with couples during prenatal counselling.
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http://dx.doi.org/10.1016/j.ejpn.2017.08.003DOI Listing
January 2018

Certainty of genuine treatment increases drug responses among intellectually disabled patients.

Neurology 2017 May 19;88(20):1912-1918. Epub 2017 Apr 19.

From the Department of Clinical Neuroscience (K.B.J., M.P., A.R.), Karolinska Institute, Sweden; Program in Placebo Studies (I.K., T.J.K.), BIDMC, Harvard Medical School; Department of Psychiatry (K.Y., R.L.G.), Massachusetts General Hospital, Boston; Institut des Sciences Cognitives (V.d.P., A.C.), Bron; Université Claude Bernard Lyon 1 (V.d.P., A.C.); Centre de Référence Déficiences Intellectuelles de Causes Rares (V.d.P., A.C.), Hôpital Femmes Mères Enfants, Hospices Civils de Lyon; and EPICIME-CIC1407/INSERM (A.C.), Bron, France.

Objective: To determine the placebo component of treatment responses in patients with intellectual disability (ID).

Methods: A statistical meta-analysis comparing bias-corrected effect sizes (Hedges ) of drug responses in open-label vs placebo-controlled clinical trials was performed, as these trial types represent different certainty of receiving genuine treatment (100% vs 50%). Studies in fragile X, Down, Prader-Willi, and Williams syndrome published before June 2015 were considered.

Results: Seventeen open-label trials (n = 261, 65% male; mean age 23.6 years; mean trial duration 38 weeks) and 22 placebo-controlled trials (n = 721, 62% male; mean age 17.1 years; mean trial duration 35 weeks) were included. The overall effect size from pre to post treatment in open-label studies was = 0.602 ( = 0.001). The effect of trial type was statistically significant ( = 0.001), and revealed higher effect sizes in studies with 100% likelihood of getting active drug, compared to both the drug and placebo arm of placebo-controlled trials. We thus provide evidence for genuine placebo effects, not explainable by natural history or regression toward the mean, among patients with ID.

Conclusions: Our data suggest that clinical trials in patients with severe cognitive deficits are influenced by the certainty of receiving genuine medication, and open-label design should thus not be used to evaluate the effect of pharmacologic treatments in ID, as the results will be biased by an enhanced placebo component.
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http://dx.doi.org/10.1212/WNL.0000000000003934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444309PMC
May 2017

Asperger syndrome and early-onset schizophrenia associated with a novel MECP2 deleterious missense variant.

Psychiatr Genet 2017 06;27(3):105-109

aClaude Bernard Lyon 1 University bInstitute of Cognitive Science, CNRS UMR 5304 cFrench National Reference Center for Rare Diseases with Intellectual Disability dReference Center on Learning Disabilities, Pediatric Functional Rehabilitation Department, Escale, Women Mothers and Children Hospital eDepartment of Child Psychiatry, Neurological Hospital fDepartment of Medical Genetics, Lyon University Hospital gCNRS UMR 5292, INSERM U1028, CNRL hDepartment of Child Psychiatry, Saint Jean de Dieu Hospital, Lyon, France.

Methyl-CpG-binding protein 2 (MECP2) deleterious variants, which are responsible for Rett syndrome in girls, are involved in a wide spectrum of developmental disabilities in males. A neuropsychiatric phenotype without intellectual disability is uncommon in patients with MECP2 deleterious variants. We report on two dizygotic twins with an MECP2-related psychiatric disorder without intellectual disability. Neuropsychological and psychiatric phenotype assessments were performed, and a genetic analysis was carried out. Both patients fulfilled the Pervasive Developmental Disorder criteria on Autism Diagnostic Observation Schedule and Asperger syndrome criteria on Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV). One patient developed early-onset schizophrenia (DSM-IV criteria) with two acute psychotic episodes, the latest one following corticosteroids and sodium valproate intake, with major hyperammonemia. A novel MECP2 gene transversion c.491 G>T [p.(Ser164Ile)] was found in both twins. Pathogenicity of this variant was considered on the basis of strong clinical and molecular data. The underlying molecular basis of neuropsychiatric disorders may have important consequences on genetic counseling and therapeutic strategies.
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http://dx.doi.org/10.1097/YPG.0000000000000165DOI Listing
June 2017

A new family with an SLC9A6 mutation expanding the phenotypic spectrum of Christianson syndrome.

Am J Med Genet A 2016 08 3;170(8):2103-10. Epub 2016 Jun 3.

Centre de Génétique et Centre de Référence Anomalies du développement et Syndromes malformatifs, Hôpital d'Enfants, CHU Dijon, Dijon, France.

Using targeted next generation sequencing, we have identified a splicing mutation (c.526-9_526-5del) in the SLC9A6 gene in a 9-year-old boy with mild intellectual disability (ID), microcephaly, and social interaction disabilities. This intronic microdeletion leads to the skipping of exon 3 and to an in-frame deletion of 26 amino acids in the TM4 domain. It segregates with cognitive impairment or learning difficulties in other members of the family. Mutations in SLC9A6 have been reported in X-linked Christianson syndrome associating severe to profound intellectual deficiency and an Angelman-like phenotype with microcephaly, absent speech, ataxia with progressive cerebellar atrophy, ophthalmoplegia, epilepsy, and neurological regression. The proband and his maternal uncle both have an attenuated phenotype with mild ID, attention deficit disorder, speech difficulties, and mild asymptomatic cerebellar atrophy. The proband also have microcephaly. The mutation cosegregated with learning disabilities and speech difficulties in the female carriers (mother and three sisters of the proband). Detailed neuropsychological, speech, and occupational therapy investigations in the female carriers revealed impaired oral and written language acquisition, with dissociation between verbal and performance IQ. An abnormal phenotype, ranging from learning disability with predominant speech difficulties to mild intellectual deficiency, has been described previously in a large proportion of female carriers. Besides broadening the clinical spectrum of SLC9A6 gene mutations, we present an example of a monogenic origin of mild learning disability. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.37765DOI Listing
August 2016

A Novel Analog Reasoning Paradigm: New Insights in Intellectually Disabled Patients.

PLoS One 2016 26;11(2):e0149717. Epub 2016 Feb 26.

Centre de Référence, Déficiences Intellectuelles de Causes Rares, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France.

Background: Intellectual Disability (ID) is characterized by deficits in intellectual functions such as reasoning, problem-solving, planning, abstract thinking, judgment, and learning. As new avenues are emerging for treatment of genetically determined ID (such as Down's syndrome or Fragile X syndrome), it is necessary to identify objective reliable and sensitive outcome measures for use in clinical trials.

Objective: We developed a novel visual analogical reasoning paradigm, inspired by the Progressive Raven's Matrices, but appropriate for Intellectually Disabled patients. This new paradigm assesses reasoning and inhibition abilities in ID patients.

Methods: We performed behavioural analyses for this task (with a reaction time and error rate analysis, Study 1) in 96 healthy controls (adults and typically developed children older than 4) and 41 genetically determined ID patients (Fragile X syndrome, Down syndrome and ARX mutated patients). In order to establish and quantify the cognitive strategies used to solve the task, we also performed an eye-tracking analysis (Study 2).

Results: Down syndrome, ARX and Fragile X patients were significantly slower and made significantly more errors than chronological age-matched healthy controls. The effect of inhibition on error rate was greater than the matrix complexity effect in ID patients, opposite to findings in adult healthy controls. Interestingly, ID patients were more impaired by inhibition than mental age-matched healthy controls, but not by the matrix complexity. Eye-tracking analysis made it possible to identify the strategy used by the participants to solve the task. Adult healthy controls used a matrix-based strategy, whereas ID patients used a response-based strategy. Furthermore, etiologic-specific reasoning differences were evidenced between ID patients groups.

Conclusion: We suggest that this paradigm, appropriate for ID patients and developmental populations as well as adult healthy controls, provides an objective and quantitative assessment of visual analogical reasoning and cognitive inhibition, enabling testing for the effect of pharmacological or behavioural intervention in these specific populations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0149717PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4771701PMC
July 2016

Placebo Responses in Genetically Determined Intellectual Disability: A Meta-Analysis.

PLoS One 2015 30;10(7):e0133316. Epub 2015 Jul 30.

Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Martinos Center for Biomedical Imaging, Boston, Massachusetts, United States of America; Program in Placebo Studies, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, Massachusetts, United States of America; Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.

Background: Genetically determined Intellectual Disability (ID) is an intractable condition that involves severe impairment of mental abilities such as learning, reasoning and predicting the future. As of today, little is known about the placebo response in patients with ID.

Objective: To determine if placebo response exists in patients with genetically determined ID.

Data Sources And Study Selection: We searched Medline/PubMed, EMBASE, CENTRAL and PsycINFO to find all placebo-controlled double-blind randomized clinical trials (RCTs) in patients with genetically determined ID, published up to April 2013, focusing on core ID symptoms.

Data Extraction And Synthesis: Two investigators extracted outcome data independently.

Main Outcomes And Measures: Bias-corrected standardized mean difference (Hedge's g) was computed for each outcome measure, using the Comprehensive Meta-Analysis software. A priori defined patient sub-groups were analyzed using a mixed-effect model. The relationship between pre-defined continuous variable moderators (age, IQ, year of publication and trial duration) and effect size was analyzed using meta-regression.

Results: Twenty-two placebo-controlled double-blind RCTs met the inclusion criteria (n = 721, mean age = 17.1 years, 62% men, mean trial duration = 35 weeks). There was a significant overall placebo response from pre- to post-treatment in patients with ID (g = 0.468, p = 0.002), both for "subjective outcomes" (a third-person's evaluation of the patient) (g = 0.563, p = 0.022) and "objective outcomes" (direct evaluation of the patient's abilities) (g = 0.434, p = 0.036). Individuals with higher IQ had higher response to placebo (p = 0.02) and no placebo response was observed in ID patients with comorbid dementia. A significant effect of age (p = 0.02) was found, indicating higher placebo responses in treatment of younger patients.

Conclusions And Relevance: Results suggest that patients with genetically determined ID improve in the placebo arm of RCTs. Several mechanisms may contribute to placebo effects in ID, including expectancy, implicit learning and "placebo-by-proxy" induced by clinicians/family members. As the condition is refractory, there is little risk that improvements are explained by spontaneous remission. While new avenues for treatment of genetically determined ID are emerging, our results demonstrate how contextual factors can affect clinical outcomes and emphasize the importance of being vigilant on the role of placebos when testing novel treatments in ID.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0133316PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520690PMC
May 2016

[Transient ischemic attack: as well a paediatric emergency].

Presse Med 2015 Feb 30;44(2):249-51. Epub 2014 Dec 30.

CHU de Saint-Étienne, hôpital Bellevue, Centre national de référence de l'AVC de l'enfant, 42055 Saint-Étienne, France. Electronic address:

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http://dx.doi.org/10.1016/j.lpm.2014.06.023DOI Listing
February 2015

The c.429_452 duplication of the ARX gene: a unique developmental-model of limb kinetic apraxia.

Orphanet J Rare Dis 2014 Feb 14;9:25. Epub 2014 Feb 14.

Centre de Référence « Déficiences Intellectuelles de Causes Rares », Hôpital Femme Mère Enfant, Hospices Civils de Lyon, F-69677 Bron, France.

Background: The c.429_452dup24 of the ARX gene is a rare genetic anomaly, leading to X-Linked Intellectual Disability without brain malformation. While in certain cases c.429_452dup24 has been associated with specific clinical patterns such as Partington syndrome, the consequence of this mutation has been also often classified as "non-specific Intellectual Disability". The present work aims at a more precise description of the clinical features linked to the c.429_452dup24 mutation.

Methods: We clinically reviewed all affected patients identified in France over a five-year period, i.e. 27 patients from 12 different families. Detailed cognitive, behavioural, and motor evaluation, as well as standardized videotaped assessments of oro-lingual and gestural praxis, were performed. In a sub-group of 13 ARX patients, kinematic and MRI studies were further accomplished to better characterize the motor impairment prevalent in the ARX patients group. To ensure that data were specific to the ARX gene mutation and did not result from low-cognitive functioning per se, a group of 27 age- and IQ-matched Down syndrome patients served as control.

Results: Neuropsychological and motor assessment indicated that the c.429_452dup24 mutation constitutes a recognizable clinical syndrome: ARX patients exhibiting Intellectual Disability, without primary motor impairment, but with a very specific upper limb distal motor apraxia associated with a pathognomonic hand-grip. Patients affected with the so-called Partington syndrome, which involves major hand dystonia and orolingual apraxia, exhibit the most severe symptoms of the disorder. The particular "reach and grip" impairment which was observed in all ARX patients, but not in Down syndrome patients, was further characterized by the kinematic data: (i) loss of preference for the index finger when gripping an object, (ii) major impairment of fourth finger deftness, and (iii) a lack of pronation movements. This lack of distal movement coordination exhibited by ARX patients is associated with the loss of independent digital dexterity and is similar to the distortion of individual finger movements and posture observed in Limb Kinetic Apraxia.

Conclusion: These findings suggest that the ARX c.429_452dup24 mutation may be a developmental model for Limb Kinetic Apraxia.
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http://dx.doi.org/10.1186/1750-1172-9-25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4016261PMC
February 2014

Neural correlates of non-verbal social interactions: a dual-EEG study.

Neuropsychologia 2014 Mar 21;55:85-97. Epub 2013 Oct 21.

Laboratoire sur le Langage, le Cerveau et la Cognition L2C2, Institut des Sciences Cognitives, CNRS/UCBL, 67 Bd Pinel, 69675 Bron Cedex, France.

Successful non-verbal social interaction between human beings requires dynamic and efficient encoding of others' gestures. Our study aimed at identifying neural markers of social interaction and goal variations in a non-verbal task. For this, we recorded simultaneously the electroencephalogram from two participants (dual-EEG), an actor and an observer, and their arm/hand kinematics in a real face-to-face paradigm. The observer watched "biological actions" performed by the human actor and "non-biological actions" performed by a robot. All actions occurred within an interactive or non-interactive context depending on whether the observer had to perform a complementary action or not (e.g., the actor presents a saucer and the observer either places the corresponding cup or does nothing). We analysed the EEG signals of both participants (i.e., beta (~20 Hz) oscillations as an index of cortical motor activity and motor related potentials (MRPs)). We identified markers of social interactions by synchronising EEG to the onset of the actor's movement. Movement kinematics did not differ in the two context conditions and the MRPs of the actor were similar in the two conditions. For the observer, however, an observation-related MRP was measured in all conditions but was more negative in the interactive context over fronto-central electrodes. Moreover, this feature was specific to biological actions. Concurrently, the suppression of beta oscillations was observed in the actor's EEG and the observer's EEG rapidly after the onset of the actor's movement. Critically, this suppression was stronger in the interactive than in the non-interactive context despite the fact that movement kinematics did not differ in the two context conditions. For the observer, this modulation was observed independently of whether the actor was a human or a robot. Our results suggest that acting in a social context induced analogous modulations of motor and sensorimotor regions in observer and actor. Sharing a common goal during an interaction seems thus to evoke a common representation of the global action that includes both actor and observer movements.
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http://dx.doi.org/10.1016/j.neuropsychologia.2013.10.001DOI Listing
March 2014

Motor resonance facilitates movement execution: an ERP and kinematic study.

Front Hum Neurosci 2013 15;7:646. Epub 2013 Oct 15.

Laboratoire sur le Langage, le Cerveau et la Cognition L2C2, Centre National de la Recherche Scientifique/UCBL, UMR 5304, Institut des Sciences Cognitives Lyon, France.

Action observation, simulation and execution share neural mechanisms that allow for a common motor representation. It is known that when these overlapping mechanisms are simultaneously activated by action observation and execution, motor performance is influenced by observation and vice versa. To understand the neural dynamics underlying this influence and to measure how variations in brain activity impact the precise kinematics of motor behavior, we coupled kinematics and electrophysiological recordings of participants while they performed and observed congruent or non-congruent actions or during action execution alone. We found that movement velocities and the trajectory deviations of the executed actions increased during the observation of congruent actions compared to the observation of non-congruent actions or action execution alone. This facilitation was also discernible in the motor-related potentials of the participants; the motor-related potentials were transiently more negative in the congruent condition around the onset of the executed movement, which occurred 300 ms after the onset of the observed movement. This facilitation seemed to depend not only on spatial congruency but also on the optimal temporal relationship of the observation and execution events.
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http://dx.doi.org/10.3389/fnhum.2013.00646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3796768PMC
October 2013

Stroke by carotid artery complete occlusion in Kawasaki disease: case report and review of literature.

Pediatr Neurol 2013 Dec 3;49(6):469-73. Epub 2013 Oct 3.

Hospices Civils de Lyon, HFME, Service de Neuropédiatrie, Bron, France; Université Claude Bernard Lyon 1, Lyon, France.

Background: Kawasaki disease is an acute and time-limited systemic vasculitis primarily affecting young children.

Patient: We describe an 18-month-old girl with Kawasaki disease who developed cerebral infarction following complete occlusion of her right internal carotid artery.

Results: The occlusion occurred 10 days after the onset of fever, while she was on high-dose aspirin, and the day after she received intravenous immunoglobulin treatment. We present the first literature review on this very rare complication.

Conclusion: Stroke is a rare neurological complication in Kawasaki disease. Optimal treatment should be begun as soon as possible after diagnosis. Intravenous immunoglobulins seem to reduce the cerebrovascular complications, but evaluation of hydration status is strongly recommended before performing such treatment.
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http://dx.doi.org/10.1016/j.pediatrneurol.2013.08.011DOI Listing
December 2013

Syntax at hand: common syntactic structures for actions and language.

PLoS One 2013 22;8(8):e72677. Epub 2013 Aug 22.

L2C2- Institut des Sciences Cognitives, CNRS UMR 5304, Bron, France.

Evidence that the motor and the linguistic systems share common syntactic representations would open new perspectives on language evolution. Here, crossing disciplinary boundaries, we explore potential parallels between the structure of simple actions and that of sentences. First, examining Typically Developing (TD) children displacing a bottle with or without knowledge of its weight prior to movement onset, we provide kinematic evidence that the sub-phases of this displacing action (reaching + moving the bottle) manifest a structure akin to linguistic embedded dependencies. Then, using the same motor task, we reveal that children suffering from specific language impairment (SLI), whose core deficit affects syntactic embedding and dependencies, manifest specific structural motor anomalies parallel to their linguistic deficits. In contrast to TD children, SLI children performed the displacing-action as if its sub-phases were juxtaposed rather than embedded. The specificity of SLI's structural motor deficit was confirmed by testing an additional control group: Fragile-X Syndrome patients, whose language capacity, though delayed, comparatively spares embedded dependencies, displayed slower but structurally normal motor performances. By identifying the presence of structural representations and dependency computations in the motor system and by showing their selective deficit in SLI patients, these findings point to a potential motor origin for language syntax.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0072677PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749983PMC
June 2014

Simultaneous action execution and observation optimise grasping actions.

Exp Brain Res 2013 Jun 25;227(3):407-19. Epub 2013 Apr 25.

Laboratoire sur le Langage, le Cerveau et la Cognition UMR 5304, CNRS/University of Lyon 1, 67, Boulevard Pinel, 69675 Bron Cedex, France.

Action observation and execution share overlapping neural resonating mechanisms. In the present study, we sought to examine the effect of the activation of this system during concurrent movement observation and execution in a prehension task, when no a priori information about the requirements of grasping action was available. Although it is known that simultaneous activation by observation and execution influences motor performance, the importance of the delays of these two events and the specific effect of movement observation itself (and not the prediction of the to-be-observed movement) on action performance are poorly known. Fine-grained kinematic analysis of both the transport and grasp components of the movement should provide knowledge about the influence of movement observation on the precision and the performance of the executed movement. The experiment involved two real participants who were asked to grasp a different side of a single object that was composed of a large and a small part. In the first experiment, we measured how the transport component and the grasp component were affected by movement observation. We tested whether this influence was greater if the observed movement occurred just before the onset of movement (200 ms) or well before the onset of movement (1 s). In a second experiment, to reproduce the previous experiment and to verify the specificity of the grasping movements, we also included a condition consisting of pointing towards the object. Both experiments showed two main results. A general facilitation of the transport component was found when observing a simultaneous action, independent of its congruency. Moreover, a specific facilitation of the grasp component was present during the observation of a congruent action when movement execution and observation were nearly synchronised. While the general facilitation may arise from a competition between the two participants as they reached for the object, the specific facilitation of the grasp component seems to be directly related to mirror neuron system activity induced by action observation itself. Moreover, the time course of the events appears to be an essential factor for this modulation, implying the transitory activation of the mirror neuron system.
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http://dx.doi.org/10.1007/s00221-013-3523-3DOI Listing
June 2013

Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056.

Sci Transl Med 2011 Jan;3(64):64ra1

Service de Génétique Médicale, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland.

Fragile X syndrome (FXS) is an X-linked condition associated with intellectual disability and behavioral problems. It is caused by expansion of a CGG repeat in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene. This mutation is associated with hypermethylation at the FMR1 promoter and resultant transcriptional silencing. FMR1 silencing has many consequences, including up-regulation of metabotropic glutamate receptor 5 (mGluR5)-mediated signaling. mGluR5 receptor antagonists have shown promise in preclinical FXS models and in one small open-label study of FXS. We examined whether a receptor subtype-selective inhibitor of mGluR5, AFQ056, improves the behavioral symptoms of FXS in a randomized, double-blind, two-treatment, two-period, crossover study of 30 male FXS patients aged 18 to 35 years. We detected no significant effects of treatment on the primary outcome measure, the Aberrant Behavior Checklist-Community Edition (ABC-C) score, at day 19 or 20 of treatment. In an exploratory analysis, however, seven patients with full FMR1 promoter methylation and no detectable FMR1 messenger RNA improved, as measured with the ABC-C, significantly more after AFQ056 treatment than with placebo (P < 0.001). We detected no response in 18 patients with partial promoter methylation. Twenty-four patients experienced an adverse event, which was mostly mild to moderately severe fatigue or headache. If confirmed in larger and longer-term studies, these results suggest that blockade of the mGluR5 receptor in patients with full methylation at the FMR1 promoter may show improvement in the behavioral attributes of FXS.
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http://dx.doi.org/10.1126/scitranslmed.3001708DOI Listing
January 2011

[Problems posed by genetic diseases, concerning DNA instability disorders: fragile X syndrome].

Rev Prat 2010 Feb;60(2):243-4

Service de génétique moléculaire et clinique, hôpital Edouard-Herriot et service de génétique, hôpital Femme-Mère-Enfant, Lyon.

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February 2010

Impairment of cerebello-thalamo-frontal pathway in Rab-GDI mutated patients with pure mental deficiency.

Eur J Med Genet 2009 Jan-Feb;52(1):6-13. Epub 2008 Sep 25.

Institut des Sciences Cognitives, CNRS UMR5230, Université Claude Bernard Lyon 1 and Hospices Civils de Lyon, Lyon, France.

Background: Rab-GDI mutations are responsible for "pure" mental deficiency, without any specific clinical features or brain malformation. Therefore, screening for mutations in mentally retarded patients is not available on a routine basis. Moreover, neuronal networks involved in mental deficiency still remain largely unknown.

Methods: We performed a fine neuropsychological and imaging study in five patients from two unrelated families, affected with mental deficiency due to a mutation in the Rab-GDI gene. High resolution 3D brain MRI of the five mentally retarded adult males (mean age 33 years) were compared to MRI of 14 healthy males (mean age 35 years) using a Voxel-Based Morphometric analysis (VBM).

Results: All patients had isolated moderate mental retardation (WAIS-III IQ range, 41-50; mean 45) without specific morphological or behavioural features. No obvious brain abnormality was observed on visual inspection of individual scans. Using VBM analysis, Rab-GDI mutated patients' MRIs exhibited significant brain changes compared to normal subjects (p<0.05, corrected for multiple comparisons): increased grey matter density in left cerebellum and in left angular gyrus, decreased grey matter volume in thalami, decreased white matter density in prefrontal lobes, right fusiform occipito-temporal gyrus, and decreased white matter volume in cerebellar peduncles.

Conclusions: These morphological changes observed in Rab-GDI mutated patients, mainly localized in the cerebello-thalamo-prefrontal pathway, are consistent with the hypothesis that the cerebellum is one of the critical components of a global learning network. Our results open new avenues in the diagnosis of non-specific mental deficiency using gene-specific "brain maps" as endophenotypes.
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http://dx.doi.org/10.1016/j.ejmg.2008.09.003DOI Listing
April 2009

Long-term follow-up in 12 children with pulmonary arteriovenous malformations: confirmation of hereditary hemorrhagic telangiectasia in all cases.

J Pediatr 2007 Sep 25;151(3):299-306. Epub 2007 Jul 25.

Department of Clinical Genetics and National Reference Centre of Rendu-Osler Disease, Hôtel-Dieu Hospital, Civil Hospices of Lyon, University of Claude-Bernard Lyon 1, France.

Objective: To assess whether pulmonary arteriovenous malformation (PAVM) is associated with hereditary hemorrhagic telangiectasia (HHT).

Study Design: This study was a review of 12 children (sex ratio = 1) including family history, mutation analysis, and long-term follow-up.

Results: Five children were under age 3 years when PAVM was diagnosed. Presentations included pulmonary symptoms (n = 8), cerebral abscess (n = 2), and transient ischemic attack (TIA) (n = 1); 1 patient was asymptomatic. Nine of the 12 children (75%) had a family history of PAVM. The diagnosis of HHT was confirmed in all cases. A mutation in ENG was found in 9 of the 10 children available for testing. No mutation in ACVRL1 was found. During long-term follow-up (mean, 16 years), the following complications occurred: TIA (n = 2), hemoptysis (n = 2), and cerebral abscess (n = 2). Nine children experienced recurrence of PAVM. The children with no recurrence were those without a family history of PAVM.

Conclusions: The diagnosis of HHT should be considered in a child with an apparently isolated PAVM. Because serious complications may occur at any age, we recommend screening for PAVM and long-term follow-up in children from families with HHT, especially those with an ENG mutation.
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http://dx.doi.org/10.1016/j.jpeds.2007.03.021DOI Listing
September 2007
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