Vincent des Portes

University of Lyon, Lyons, Rhône-Alpes, France

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Publications (155)623.87 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: West syndrome (WS), defined by the triad of infantile spasms, pathognomonic hypsarrhythmia and developmental regression, is a rare epileptic disease affecting about 1:3500 live births. To get better insights on the genetic of this pathology, we exome-sequenced the members of a consanguineous family affected with isolated WS. We identified a homozygous variant (c.1825G>T/p.(Ala609Ser)) in the GUF1 gene in the three affected siblings. GUF1 encodes a protein essential in conditions that counteract faithful protein synthesis: it is able to remobilize stuck ribosomes and transiently inhibit the elongation process to optimize protein synthesis. The variant identified in the WS family changes an alanine residue conserved in all eukaryotic organisms and positioned within the tRNA-binding moiety of this nuclear genome-encoded mitochondrial translational elongation factor. Yeast complementation assays show that the activity of GUF1(A609S) is modified in suboptimal environments. We suggest a new link between improper assembly of respiratory chain complexes and WS.European Journal of Human Genetics advance online publication, 21 October 2015; doi:10.1038/ejhg.2015.227.
    European journal of human genetics: EJHG 10/2015; DOI:10.1038/ejhg.2015.227 · 4.35 Impact Factor
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    ABSTRACT: Xq28 duplications encompassing MECP2 have been described in male patients with a severe neurodevelopmental disorder associated with hypotonia and spasticity, severe learning disability, stereotyped movements, and recurrent pulmonary infections. We report on standardized brain magnetic resonance imaging (MRI) data of 30 affected patients carrying an Xq28 duplication involving MECP2 of various sizes (228 kb to 11.7 Mb). The aim of this study was to seek recurrent malformations and attempt to determine whether variations in imaging features could be explained by differences in the size of the duplications. We showed that 93% of patients had brain MRI abnormalities such as corpus callosum abnormalities (n = 20), reduced volume of the white matter (WM) (n = 12), ventricular dilatation (n = 9), abnormal increased hyperintensities on T2-weighted images involving posterior periventricular WM (n = 6), and vermis hypoplasia (n = 5). The occipitofrontal circumference varied considerably between >+2SD in five patients and <-2SD in four patients. Among the nine patients with dilatation of the lateral ventricles, six had a duplication involving L1CAM. The only patient harboring bilateral posterior subependymal nodular heterotopia also carried an FLNA gene duplication. We could not demonstrate a correlation between periventricular WM hyperintensities/delayed myelination and duplication of the IKBKG gene. We thus conclude that patients with an Xq28 duplication involving MECP2 share some similar but non-specific brain abnormalities. These imaging features, therefore, could not constitute a diagnostic clue. The genotype-phenotype correlation failed to demonstrate a relationship between the presence of nodular heterotopia, ventricular dilatation, WM abnormalities, and the presence of FLNA, L1CAM, or IKBKG, respectively, in the duplicated segment. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 09/2015; DOI:10.1002/ajmg.a.37384 · 2.16 Impact Factor
  • K. Chevreul · K. Berg Brigham · M. Brunn · V des Portes ·
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    ABSTRACT: Background Fragile X syndrome (FXS) is the main hereditary cause of intellectual disability. Although the associated burden appears to be considerable, to date no study has comprehensively assessed the cost incurred because of FXS, including its specific impact on health-related quality of life and the burden on caregivers using standardised quantitative tools. The aim of this article is to provide data in order to increase awareness of the repercussions of FXS on patients and caregivers as well as on the health and social care systems in France.MethodsA retrospective cross-sectional study was carried out on 145 patients recruited through Le Goëland X-Fragile and Mosaïques, the French FXS patient associations. Data on their demographic characteristics and resource use were obtained from an online questionnaire, and costs were estimated by a bottom-up approach. The EQ-5D health questionnaire was used to measure patients' and caregivers' health-related quality of life. Perceived burden of care was measured using the Zarit Caregiver Burden Interview. The Barthel index, a non-utility-based assessment, was used to measure patients' level of dependence.ResultsThe annual total direct cost of FXS was estimated at €25 800 per patient. The main contributors were informal care provided by the main caregiver (€10 500) and social services (€8400). Healthcare costs, estimated at €2700, represented only a minor share. Mean EQ-5D utility scores were 0.49 for patients and 0.75 for caregivers. The mean burden for caregivers as measured by the Zarit Caregiver Burden Interview was 39.9.Conclusions Fragile X syndrome requires significant resources that are mainly of a non-medical nature and are higher for children than for adults. Compared with related diseases, it constitutes a particularly high burden for caregivers. Using a bottom-up approach and a wide range of standardised measures, this study underscores the need for greater awareness of the burden of FXS as well as an assessment of new and existing interventions to address it.
    Journal of Intellectual Disability Research 09/2015; DOI:10.1111/jir.12215 · 2.41 Impact Factor
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    ABSTRACT: 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. 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.
    Orphanet Journal of Rare Diseases 09/2015; 10(1):111. DOI:10.1186/s13023-015-0330-x · 3.36 Impact Factor
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    ABSTRACT: Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a rare genetic disorder due to mutations or deletions in SLC2A1, resulting in impaired glucose uptake through the blood brain barrier. The classic phenotype includes pharmacoresistant epilepsy, intellectual deficiency, microcephaly and complex movement disorders, with hypoglycorrhachia, but milder phenotypes have been described (carbohydrate-responsive phenotype, dystonia and ataxia without epilepsy, paroxysmal exertion-induced dystonia).
    European journal of medical genetics 08/2015; 58(9):443-54. DOI:10.1016/j.ejmg.2015.06.007 · 1.47 Impact Factor
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    ABSTRACT: 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.
    PLoS ONE 08/2015; 10(7):e0133316. DOI:10.1371/journal.pone.0133316 · 3.23 Impact Factor
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    ABSTRACT: Infantile spasms syndrome (ISs) is characterized by clinical spasms with ictal electrodecrement, usually occurring before the age of 1 year and frequently associated with cognitive impairment. Etiology is widely heterogeneous, the cause remaining elusive in 40% of patients. We searched for de novo mutations in 10 probands with ISs and their parents using whole-exome sequencing (WES). Patients had neither consanguinity nor family history of epilepsy. Common causes of ISs were excluded by brain MRI, metabolic screening, array-CGH and testing for mutations in CDKL5, STXBP1, and for ARX duplications. We found a probably pathogenic mutation in four patients. Missense mutations in SCN2A (p.Leu1342Pro) and KCNQ2 (p.Ala306Thr) were found in two patients with no history of epilepsy before the onset of ISs. The p.Asn107Ser missense mutation of ALG13 had been previously reported in four females with ISs. The fourth mutation was an in-frame deletion (p.Phe110del) in NR2F1, a gene whose mutations cause intellectual disability, epilepsy, and optic atrophy. In addition, we found a possibly pathogenic variant in KIF3C that encodes a kinesin expressed during neural development. Our results confirm that WES improves significantly the diagnosis yield in patients with sporadic ISs. This article is protected by copyright. All rights reserved.
    Clinical Genetics 07/2015; DOI:10.1111/cge.12636 · 3.93 Impact Factor
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    ABSTRACT: Dendritic cells (DCs) play a critical role in the immune response to viral infection through the facilitation of cell-intrinsic antiviral activity and the activation of adaptive immunity. HIV-1 infection of DCs triggers an IRF3-dependent innate immune response, which requires the activity of cyclic GAMP synthase (cGAS). We report the results of a targeted RNAi screen utilizing primary human monocyte-derived DCs (MDDCs) to identify immune regulators that directly interface with HIV-1-encoded features to initiate this innate response. Polyglutamine binding protein 1 (PQBP1) emerged as a strong candidate through this analysis. We found that PQBP1 directly binds to reverse-transcribed HIV-1 DNA and interacts with cGAS to initiate an IRF3-dependent innate response. MDDCs derived from Renpenning syndrome patients, who harbor mutations in the PQBP1 locus, possess a severely attenuated innate immune response to HIV-1 challenge, underscoring the role of PQBP1 as a proximal innate sensor of a HIV-1 infection. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 06/2015; 161(6):1293-1305. DOI:10.1016/j.cell.2015.04.050 · 32.24 Impact Factor

  • European Journal of Paediatric Neurology 05/2015; 19:S80. DOI:10.1016/S1090-3798(15)30265-8 · 2.30 Impact Factor

  • European Journal of Paediatric Neurology 05/2015; 19:S33-S34. DOI:10.1016/S1090-3798(15)30107-0 · 2.30 Impact Factor
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    ABSTRACT: Le syndrome de Smith-Magenis (SMS) est une affection génétique se manifestant essentiellement par une déficience intellectuelle associée à un important retard de langage, des signes morphologiques reconnaissables, des troubles du comportement et du sommeil. Il est lié dans 90 % des cas à une microdélétion localisée sur le bras court du chromosome 17 en 17p11.2. Plus rarement, il s’agit d’une mutation ponctuelle du gène RAI1, situé dans cette même région chromosomique. Les troubles du comportement sont variés, majorés par le retard de langage et les troubles du sommeil. Ces derniers sont liés à une inversion de la sécrétion de mélatonine perturbant le cycle nycthéméral et entraînant une agitation nocturne et diurne. L’association des troubles du sommeil et des troubles comportementaux, qui en résultent partiellement, met en péril le parcours scolaire de l’enfant et impacte l’équilibre familial. Il n’y a actuellement aucune recommandation clinique pour ce syndrome. Néanmoins, avec une prise en charge adaptée, il est possible de rétablir un rythme de sommeil normal et d’améliorer le comportement. La prescription médicamenteuse associe généralement la prise de β-bloquants le matin (pour limiter la sécrétion diurne de mélatonine) et de mélatonine le soir (pour remplacer le pic déficitaire). Parallèlement, il faut identifier et prendre en charge de manière spécifique une éventuelle hyperactivité ou agressivité. L’amélioration des capacités de communication et les soins de stimulation (orthophonie, psychomotricité, remédiation cognitive) sont un élément thérapeutique central. Cet article reprend les principaux éléments cliniques et paracliniques du syndrome de Smith-Magenis et propose une prise en charge adaptée aux différentes étapes de la vie de l’enfant.
    Archives de Pédiatrie 04/2015; 22(6). DOI:10.1016/j.arcped.2015.03.015 · 0.41 Impact Factor
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    ABSTRACT: Intellectual disability is a neurodevelopmental disorder of impaired adaptive skills and low intelligence quotient. The overall prevalence is estimated at 2-3% in the general population with extreme clinical and genetic heterogeneity, and it has been associated with possibly causative mutations in more than 700 identified genes. In a recent review, among over 100 X-linked intellectual disability causative genes, eight were reported as "awaiting replication." Exome sequencing in a large family identified a missense mutation in RPL10 highly suggestive of X-linked intellectual disability. Herein, we report on the clinical description of four affected males. All patients presented apparent intellectual disability (4/4), psychomotor delay (4/4) with syndromic features including amniotic fluid excess (3/4), microcephaly (2/4), urogenital anomalies (3/4), cerebellar syndrome (2/4), and facial dysmorphism. In the literature, two mutations were reported in three families with affected males presenting with autism. This report confirms the implication of RPL10 mutations in neurodevelopmental disorders and extends the associated clinical spectrum from autism to syndromic intellectual disability. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 04/2015; 167(8). DOI:10.1002/ajmg.a.37094 · 2.16 Impact Factor
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    ABSTRACT: 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. 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. 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. 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to
    Journal of Neurology Neurosurgery & Psychiatry 01/2015; 86(7). DOI:10.1136/jnnp-2014-309025 · 6.81 Impact Factor
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    ABSTRACT: Infantile Spasms syndrome (ISs) is a characterized by epileptic spasms occurring in clusters with an onset in the first year of life. West syndrome represents a subset of ISs that associates spasms in clusters, a hypsarrhytmia EEG pattern and a developmental arrest or regression. Etiology of ISs is widely heterogeneous including many genetic causes. Many patients, however, remain without etiological diagnosis, which is critical for prognostic purpose and genetic counselling. In the present study, we performed genetic screening of 73 patients with different types of ISs by array-CGH and molecular analysis of 5 genes: CDKL5, STXBP1, KCNQ2, and GRIN2A, whose mutations cause different types of epileptic encephalopathies, including ISs, as well as MAGI2, which was suggested to be related to a subset of ISs. In total, we found a disease-causing mutation or CNV (Copy Number Variation) in 15% of the patients. These included 6 point mutations found in CDKL5 (n=3) and STXBP1 (n=3), 3 microdeletions (10Mb in 2q24.3, 3.2Mb in 5q14.3 including the region upstream to MEF2C, and 256kb in 9q34 disrupting EHMT1), and 2 microduplications (671kb in 2q24.3 encompassing SCN2A, and 11.93Mb in Xq28). In addition, we discuss 3 CNVs as potential risk factors, including one 16p12.1 deletion, one intronic deletion of the NEDD4 gene, and one intronic deletion of CALN1 gene. The present findings highlight the efficacy of combined cytogenetic and targeted mutation screening to improve the diagnostic yield in patient with ISs. Copyright © 2014. Published by Elsevier Masson SAS.
    European Journal of Medical Genetics 12/2014; 58(2). DOI:10.1016/j.ejmg.2014.11.007 · 1.47 Impact Factor
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    A Drouet · F Le Moigne · D Salamé · L Quesnel · C Motolese · V des Portes · L Guilloton · S Pinson ·
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    ABSTRACT: Neurofibromatosis type 2 (NF2) is a rare dominantly inherited disease. Its clinical presentation can be completely different in children and adults and early diagnosis is often difficult. The NF2 gene molecular analysis can help for diagnosis, but its result can be negative in case of NF2 mosaicism. We report the case of a 43-year-old man who had developed a severe phenotype with bilateral vestibular schwannomas at 19years of age. His son presented a retinal hamartoma with loss of vision in his right eye at 2months of age. At 9years of age, asymptomatic schwannomas of the cranial nerves were discovered: cranial nerves X (left), XI (left), and VIII (bilateral). Partial constitutional NF2 deletion (from exons 2-7) was detected in his son. The deletion was not detectable in the DNA blood of his father and we strongly suspect a mosaic form of NF2. Ophthalmological manifestations can be the initial sign of NF2 in childhood. These features must be actively sought during the first year of life in individuals at risk of NF2. NF2 mosaicism is often described as a mild form of NF2 with a very low risk of transmission to the carrier's children. We show that NF2 mosaicism can sometimes develop severe NF2 symptoms and we confirm that the transmission risk to the offspring depends on the proportion of zygotes carrying the mutation. NF2 remains a life-limiting and life-spoiling condition. Early diagnosis is necessary to prevent complications and the follow-up of NF2 patients must be organized throughout life in specialty centers. Copyright © 2014 Elsevier Masson SAS. All rights reserved.
    Archives de Pédiatrie 11/2014; 21(11):1233-40. DOI:10.1016/j.arcped.2014.08.031 · 0.41 Impact Factor
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    ABSTRACT: The strong positive-allometric relationship between brain size, cortical extension and gyrification complexity, recently highlighted in the general population, could be modified by brain developmental disorders. Indeed, in case of brain growth insufficiency, the pathophysiological relevance of the “simplified gyral pattern” phenotype is strongly disputed since almost no genotype–phenotype correlations have been found in primary microcephalies. Using surface scaling analysis and newly-developed spectral analysis of gyrification (Spangy), we tested whether the gyral simplification in groups of severe microcephalies related to ASPM, PQBP1 or fetal-alcohol-syndrome could be fully explained by brain size reduction according to the allometric scaling law established in typically-developing control groups, or whether an additional disease effect was to be suspected. We found the surface area reductions to be fully explained by scaling effect, leading to predictable folding intensities measured by gyrification indices. As for folding pattern assessed by spectral analysis, scaling effect also accounted for the majority of the variations, but an additional negative or positive disease effect was found in the case of ASPM and PQBP1-linked microcephalies, respectively. Our results point out the necessity of taking allometric scaling into account when studying the gyrification variability in pathological conditions. They also show that the quantitative analysis of gyrification complexity through spectral analysis can enable distinguishing between even (predictable, non-specific) and uneven (unpredictable, maybe disease-specific) gyral simplifications.
    NeuroImage 11/2014; 102:317–331. DOI:10.1016/j.neuroimage.2014.07.057 · 6.36 Impact Factor
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    ABSTRACT: Background Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with an estimated prevalence of about 1/3000, independent of ethnicity, race, or gender. Attention Deficit Hyperactivity like Disorder (ADHD)-like characteristics are often reported in patients with NF1. We hypothesised that learning disabilities in NF1 children were related to ADHD symptoms. Treatment with methylphenidate (MPD) has improved learning disabilities in ADHD by acting on neurotransmitters. Our objective was to evaluate its efficacy on ADHD-like symptoms in neurofibromatosis type 1 children (7¿12 years).Methods This was a randomised, double blind, placebo controlled, and crossover trial comparing 0.5 to 0.8 mg/kg/d of MPD as it is indicated for ADHD to placebo in NF1 children with ADHD-like symptoms. Children aged 7 to 12 years were eligible when their IQ was between 80 and 120. The total follow-up was 9 weeks including 4 weeks for each period and 1 week wash out. Fifty subjects (25 for each period) were required for testing the primary study hypothesis. The main outcome was an improvement in scores on the simplified Conners¿ Parent Rating Scale.ResultsThirty-nine patients were included between April 2004 and December 2010. Twenty participants received MPD and 19 placebo during the first period. They all completed the trial. MPD decreased the simplified Conners by 3.9 points (±1.1, p¿=¿0. 0003).Conclusions This is the first randomised controlled trial showing the short-term benefit of MPD on simplified Conners scores in NF1 children.Trial NCT00169611.
    Orphanet Journal of Rare Diseases 09/2014; 9(1):142. DOI:10.1186/s13023-014-0142-4 · 3.36 Impact Factor
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    ABSTRACT: Mutations of the CDKL5 gene cause early epileptic encephalopathy. Patients manifest refractory epilepsy, beginning before the age of 3 months, which is associated with severe psychomotor delay and features that overlap with Rett syndrome. We report here a patient with mosaicism for CDKL5 exonic deletion, with the presence of two mutant alleles. The affected 4-year-old girl presented with infantile spasms, beginning at the age of 9 months, but subsequent progression of the disease was consistent with the classical CDKL5-related phenotype. A deletion of exons 17 and 18 was suspected on the basis of Multiplex Ligation Probe Amplification analysis, but unexpected results for cDNA analysis, which showed the presence of an abnormal transcript with the deletion of exon 18 only, led us to suspect that two distinct events might have occurred. We used custom array-CGH to determine the size and breakpoints of these deletions. Exon 18 was deleted from one of the abnormal alleles, and exon 17 was deleted from the other. A Fork Stalling and Template Switching (FoSTeS) mechanism was proposed to explain the two events, given the presence of regions of microhomology at the breakpoints. We propose here an original involvement of the FoSTeS mechanism to explain the co-occurrence of these two events in the CDKL5 gene in a single patient. This patient highlights the difficulties involved in the detection of such abnormalities, particularly when they occur in a mosaic state and involve two distinct mutational events in a single gene. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 08/2014; 164A(8). DOI:10.1002/ajmg.a.36547 · 2.16 Impact Factor
  • A. Drouet · F. Le Moigne · L. Quesnel · C. Motolese · V. Des Portes · L. Guilloton · S. Pinson ·

    Revue Neurologique 04/2014; 170:A150. DOI:10.1016/j.neurol.2014.01.400 · 0.66 Impact Factor
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    ABSTRACT: 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. 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. 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. These findings suggest that the ARX c.429_452dup24 mutation may be a developmental model for Limb Kinetic Apraxia.
    Orphanet Journal of Rare Diseases 02/2014; 9(1):25. DOI:10.1186/1750-1172-9-25 · 3.36 Impact Factor

Publication Stats

4k Citations
623.87 Total Impact Points


  • 2008-2015
    • University of Lyon
      Lyons, Rhône-Alpes, France
  • 2006-2015
    • Claude Bernard University Lyon 1
      • • Institut des Sciences Cognitives
      • • Laboratoire d'anatomie pathologique
      Villeurbanne, Rhône-Alpes, France
  • 2004-2015
    • Hospices Civils de Lyon
      Lyons, Rhône-Alpes, France
  • 2006-2014
    • CHU de Lyon - Hôpital Femme-Mère-Enfant
      Lyons, Rhône-Alpes, France
    • French National Centre for Scientific Research
      • • Laboratoire sur le langage, le cerveau et la cognition (L2C2)
      • • Institut des sciences cognitives
      Lutetia Parisorum, Île-de-France, France
  • 2004-2014
    • HCL
      Noida, Uttar Pradesh, India
  • 2008-2013
    • Centre Hospitalier Universitaire de Lyon
      Lyons, Rhône-Alpes, France
  • 2012
    • Hôpital Universitaire Robert Debré
      • Département de Génétique
      Lutetia Parisorum, Île-de-France, France
  • 2007
    • CHU de Lyon - Hôpital Renée Sabran
      Lyons, Rhône-Alpes, France
    • Institut Cochin
      Lutetia Parisorum, Île-de-France, France
  • 2005
    • Centre Hospitalier Lyon Sud
      Lyons, Rhône-Alpes, France
    • St. Vincent Hospital
      Green Bay, Wisconsin, United States
  • 2003
    • University of California, Davis
      • School of Medicine
      Davis, California, United States
  • 2000-2003
    • Unité Inserm U1077
      Caen, Lower Normandy, France
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2000-2002
    • Hôpital Saint-Vincent-de-Paul – Hôpitaux universitaires Paris Centre
      Lutetia Parisorum, Île-de-France, France
  • 1996-2000
    • Institut de Génétique Moléculaire de Montpellier
      Montpelhièr, Languedoc-Roussillon, France