Publications by authors named "Sylvie Nguyen"

14 Publications

  • Page 1 of 1

Three cases of adult-onset Brown-Vialetto-Van Laere syndrome: Novel variants in SLC52A3 gene and MRI abnormalities.

Neuromuscul Disord 2021 08 26;31(8):752-755. Epub 2021 Jun 26.

Univ. Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience & Cognition, F-59000 Lille, France; Centre de référence des maladies neuromusculaires Nord Est Ile de France, Lille University Medical Centre, Lille, France; Neurology Department, Lille University Medical Center, Lille, France.

Brown-Vialetto-Van Laere syndrome is a rare, autosomal, recessive neurological condition caused by variants in the riboflavin transporter genes SLC52A2 and SLC52A3. Here, we report on three cases. Case 1 was a 35-year-old woman from a consanguineous family who presented with progressive deafness, subacute multiple cranial nerve impairments (III, VII, IX, XII), and MRI abnormalities (including as hypersignal from the cranial nerves). The patient was homozygous for a novel SLC52A3variant. Case 2 was the woman's brother, who presented similar symptoms. Case 3 was an 18-year-old woman experiencing progressive hearing loss, bilateral steppage gait and a cranial nerves impairment (VII and XII). MRI revealed hypersignal in the root nerves and cauda equina. A novel heterozygous variant in SLC52A3 was identified. A subacute history of polyradiculoneuropathy along with progressive deafness, cranial nerve impairment, and MRI abnormalities should raise suspicion for Brown-Vialetto-Van Laere syndrome.
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http://dx.doi.org/10.1016/j.nmd.2021.06.009DOI Listing
August 2021

Haploinsufficiency of ARFGEF1 is associated with developmental delay, intellectual disability, and epilepsy with variable expressivity.

Genet Med 2021 10 10;23(10):1901-1911. Epub 2021 Jun 10.

Inserm UMR1231 team GAD, University of Burgundy and Franche-Comté, Dijon, France.

Purpose: ADP ribosylation factor guanine nucleotide exchange factors (ARFGEFs) are a family of proteins implicated in cellular trafficking between the Golgi apparatus and the plasma membrane through vesicle formation. Among them is ARFGEF1/BIG1, a protein involved in axon elongation, neurite development, and polarization processes. ARFGEF1 has been previously suggested as a candidate gene for different types of epilepsies, although its implication in human disease has not been well characterized.

Methods: International data sharing, in silico predictions, and in vitro assays with minigene study, western blot analyses, and RNA sequencing.

Results: We identified 13 individuals with heterozygous likely pathogenic variants in ARFGEF1. These individuals displayed congruent clinical features of developmental delay, behavioral problems, abnormal findings on brain magnetic resonance image (MRI), and epilepsy for almost half of them. While nearly half of the cohort carried de novo variants, at least 40% of variants were inherited from mildly affected parents who were clinically re-evaluated by reverse phenotyping. Our in silico predictions and in vitro assays support the contention that ARFGEF1-related conditions are caused by haploinsufficiency, and are transmitted in an autosomal dominant fashion with variable expressivity.

Conclusion: We provide evidence that loss-of-function variants in ARFGEF1 are implicated in sporadic and familial cases of developmental delay with or without epilepsy.
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http://dx.doi.org/10.1038/s41436-021-01218-6DOI Listing
October 2021

A survey of the European Reference Network EpiCARE on clinical practice for selected rare epilepsies.

Epilepsia Open 2021 03 13;6(1):160-170. Epub 2021 Jan 13.

IRCCS Mondino Foundation Pavia Italy.

Objective: Clinical care of rare and complex epilepsies is challenging, because evidence-based treatment guidelines are scarce, the experience of many physicians is limited, and interdisciplinary treatment of comorbidities is required. The pathomechanisms of rare epilepsies are, however, increasingly understood, which potentially fosters novel targeted therapies. The objectives of our survey were to obtain an overview of the clinical practice in European tertiary epilepsy centers treating patients with 5 arbitrarily selected rare epilepsies and to get an estimate of potentially available patients for future studies.

Methods: Members of the ( were invited to participate in a web-based survey on clinical practice of patients with Dravet syndrome, tuberous sclerosis complex (TSC), autoimmune encephalitis, and progressive myoclonic epilepsies including Unverricht Lundborg and Unverricht-like diseases. A consensus-based questionnaire was generated for each disease.

Results: Twenty-six of 30 invited epilepsy centers participated. Cohorts were present in most responding centers for TSC (87%), Dravet syndrome (85%), and autoimmune encephalitis (71%). Patients with TSC and Dravet syndrome represented the largest cohorts in these centers. The antiseizure drug treatments were rather consistent across the centers especially with regard to Dravet syndrome, infantile spasms in TSC, and Unverricht Lundborg / Unverricht-like disease. Available, widely used targeted therapies included everolimus in TSC and immunosuppressive therapies in autoimmune encephalitis. Screening for comorbidities was routinely done, but specific treatment protocols were lacking in most centers.

Significance: The survey summarizes the current clinical practice for selected rare epilepsies in tertiary European epilepsy centers and demonstrates consistency as well as heterogeneity in the treatment, underscoring the need for controlled trials and recommendations. The survey also provides estimates for potential participants of clinical trials recruited via EpiCARE, emphasizing the great potential of Reference Networks for future studies to evaluate new targeted therapies and to identify novel biomarkers.
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http://dx.doi.org/10.1002/epi4.12459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918306PMC
March 2021

Cohen Syndrome-Associated Cataract Is Explained by VPS13B Functions in Lens Homeostasis and Is Modified by Additional Genetic Factors.

Invest Ophthalmol Vis Sci 2020 09;61(11):18

INSERM UMR1231, Equipe GAD, Université de Bourgogne Franche Comté, Dijon, France.

Purpose: Cohen syndrome (CS) is a rare genetic disorder caused by variants of the VPS13B gene. CS patients are affected with a severe form of retinal dystrophy, and in several cases cataracts also develop. The purpose of this study was to investigate the mechanisms and risk factors for cataract in CS, as well as to report on cataract surgeries in CS patients.

Methods: To understand how VPS13B is associated with visual impairments in CS, we generated the Vps13b∆Ex3/∆Ex3 mouse model. Mice from 1 to 3 months of age were followed by ophthalmoscopy and slit-lamp examinations. Phenotypes were investigated by histology, immunohistochemistry, and western blot. Literature analysis was performed to determine specific characteristic features of cataract in CS and to identify potential genotype-phenotype correlations.

Results: Cataracts rapidly developed in 2-month-old knockout mice and were present in almost all lenses at 3 months. Eye fundi appeared normal until cataract development. Lens immunostaining revealed that cataract formation was associated with the appearance of large vacuoles in the cortical area, epithelial-mesenchymal transition, and fibrosis. In later stages, cataracts became hypermature, leading to profound retinal remodeling due to inflammatory events. Literature analysis showed that CS-related cataracts display specific features compared to other forms of retinitis pigmentosa-related cataracts, and their onset is modified by additional genetic factors. Corroboratively, we were able to isolate a subline of the Vps13b∆Ex3/∆Ex3 model with delayed cataract onset.

Conclusions: VPS13B participates in lens homeostasis, and the CS-related cataract development dynamic is linked to additional genetic factors.
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http://dx.doi.org/10.1167/iovs.61.11.18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488618PMC
September 2020

Fetal sheep cerebral electrical activity: A new technique to record EEG.

J Neurosci Methods 2020 11 2;345:108888. Epub 2020 Aug 2.

Univ. Lille, CHU Lille, ULR 2694 - METRICS, F-59000, Lille, France; CHU Lille, Department of Obstetrics, F-59000, Lille, France.

Background: Sheep models are commonly used to study fetal cortical activity, including response to hypoxia. The standard technique consists of recording electrocorticogram (ECOG) in utero using electrodes placed on the dura mater.

New Method: We propose a new method for recording the electroencephalogram (EEG) of fetal sheep, using electrodes placed above the skull bone and fixed to the cranial periosteum.

Results: Twelve animals were instrumented with this new technique. The EEG signal recorded in utero was of sufficient quality for visual and quantitative analysis of the fetal cortical activity.

Comparison With Existing Method: This new method is less invasive than the standard method commonly used to record cerebral activity in fetal sheep, because it avoids drilling the skull by hand. The EEG signal recorded in utero had visual and quantitative characteristics comparable to ECOG.

Conclusions: We present a new method of EEG recording that appears to be an acceptable alternative to the standard ECOG recording method. Fetal sheep EEG can be used to better understand the physiological mechanisms involved in the cerebral response to hypoxia.
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http://dx.doi.org/10.1016/j.jneumeth.2020.108888DOI Listing
November 2020

Heterogeneous clinical and functional features of GRIN2D-related developmental and epileptic encephalopathy.

Brain 2019 10;142(10):3009-3027

Department of Pediatrics and Pediatric Epilepsy Center, Peking University First Hospital, Beijing, China.

N-methyl d-aspartate receptors are ligand-gated ionotropic receptors mediating a slow, calcium-permeable component of excitatory synaptic transmission in the CNS. Variants in genes encoding NMDAR subunits have been associated with a spectrum of neurodevelopmental disorders. Here we report six novel GRIN2D variants and one previously-described disease-associated GRIN2D variant in two patients with developmental and epileptic encephalopathy. GRIN2D encodes for the GluN2D subunit protein; the GluN2D amino acids affected by the variants in this report are located in the pre-M1 helix, transmembrane domain M3, and the intracellular carboxyl terminal domain. Functional analysis in vitro reveals that all six variants decreased receptor surface expression, which may underline some shared clinical symptoms. In addition the GluN2D(Leu670Phe), (Ala675Thr) and (Ala678Asp) substitutions confer significantly enhanced agonist potency, and/or increased channel open probability, while the GluN2D(Ser573Phe), (Ser1271Phe) and (Arg1313Trp) substitutions result in a mild increase of agonist potency, reduced sensitivity to endogenous protons, and decreased channel open probability. The GluN2D(Ser573Phe), (Ala675Thr), and (Ala678Asp) substitutions significantly decrease current amplitude, consistent with reduced surface expression. The GluN2D(Leu670Phe) variant slows current response deactivation time course and increased charge transfer. GluN2D(Ala678Asp) transfection significantly decreased cell viability of rat cultured cortical neurons. In addition, we evaluated a set of FDA-approved NMDAR channel blockers to rescue functional changes of mutant receptors. This work suggests the complexity of the pathological mechanisms of GRIN2D-mediated developmental and epileptic encephalopathy, as well as the potential benefit of precision medicine.
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http://dx.doi.org/10.1093/brain/awz232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763743PMC
October 2019

Relationship between somatosensory deficit and brain somatosensory system after early brain lesion: A morphometric study.

Eur J Paediatr Neurol 2016 May 19;20(3):403-11. Epub 2016 Jan 19.

LUNAM, Université d'Angers, Laboratoire Angevin de Recherche en Ingénierie des Systèmes (LARIS), EA7315, F-49000, France; LUNAM, Université d'Angers, CHU Angers Département de Médecine Physique et de Réadaptation, F-49933, France. Electronic address:

Cerebral Palsy (CP) is a group of permanent motor disorders due to non-progressive damage to the developing brain. Poor tactile discrimination is common in children with unilateral CP. Previous findings suggest the crucial role of structural integrity of the primary (S1) and secondary (S2) somatosensory areas located in the ipsilesional hemisphere for somatosensory function processing. However, no focus on the relationship between structural characteristics of ipsilesional S1 and S2 and tactile discrimination function in paretic hands has been proposed. Using structural MRI and a two-point discrimination assessment (2 PD), we explore this potential link in a group of 21 children (mean age 13 years and 7 months) with unilateral CP secondary to a periventricular white matter injury (PWMI) or middle cerebral artery infarct (MCA). For our whole sample there was a significant negative correlation between the 2 PD and the gray matter volume in the ipsilesional S2 (rho = -0.50 95% confidence interval [-0.76, -0.08], one-tailed p-value = 0.0109) and in the ipsilesional S1 (rho = -0.57, 95% confidence interval [-0.81, -0.19], one-tailed p-value = 0.0032). When studying these relationships with regard to the lesion types, we found these correlations were non-significant in the patients with PWMI but stronger in patients with MCA. According to our results, the degree of sensory impairment is related to the spared gray matter volume in ipsilesional S1 and S2 and is marked after an MCA stroke. Our work contributes to a better understanding of why some patients with CP have variable somatosensory deficit following an early brain lesion.
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http://dx.doi.org/10.1016/j.ejpn.2015.11.013DOI Listing
May 2016

Dermatologic features of Smith-Magenis syndrome.

Pediatr Dermatol 2015 May-Jun;32(3):337-41. Epub 2015 Feb 12.

Department of Dermatology, University Hospital of Angers, Angers, France.

Smith-Magenis syndrome (SMS) is characterized by distinctive facial and skeletal features, developmental delay, cognitive impairment, and behavioral abnormalities, including self-injurious behaviors. We aimed to investigate whether cutaneous features are common in SMS. We performed a complete skin examination in 20 young SMS patients. Skin features secondary to self-injurious behavior, such as bites, abrasions, dystrophic scars, limited spots of hyperkeratosis, anomalies of the nails, and whitlows, were found in the majority of patients. Acral pachydermia and fissured plantar keratoderma were common. Xerosis was constant and associated with extensive keratosis pilaris in the majority of patients. Dermatofibromas were frequent in older patients. The hair was dense and shiny, with an unusual hairline. Eyelash trichomegaly and heavy brows were common, as well as folliculitis on the back. The skin features of SMS have rarely been reported in the literature. Some of these are the consequence of neurobehavioral features, but some cutaneous features and abnormalities of appendages have not been reported in other related syndromes. Skin manifestations of SMS are varied, sometimes induced by self-injurious behavior and sometimes more specific. It remains to be determined whether the combination of the two kinds of signs could contribute to early diagnosis of the syndrome.
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http://dx.doi.org/10.1111/pde.12517DOI Listing
April 2016

Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations.

Ann Neurol 2015 Apr 13;77(4):675-83. Epub 2015 Mar 13.

Sorbonne Universités, Pierre and Marie Curie University, UPMC Univ Paris 06, UM 75, ICM, Paris, France; National Institute of Health and Medical Research, INSERM U1127, ICM, Paris, France; National Center for Scientific Research, CNRS, UMR 7225, ICM, Paris, France; Brain and Spine Institute, Institut du Cerveau et de la Moelle (ICM), Paris, France.

Objective: The DEPDC5 (DEP domain-containing protein 5) gene, encoding a repressor of the mTORC1 signaling pathway, has recently emerged as a major gene mutated in familial focal epilepsies. We aimed to further extend the role of DEPDC5 to focal cortical dysplasias (FCDs).

Methods: Seven patients from 4 families with DEPDC5 mutations and focal epilepsy associated with FCD were recruited and investigated at the clinical, neuroimaging, and histopathological levels. The DEPDC5 gene was sequenced from genomic blood and brain DNA.

Results: All patients had drug-resistant focal epilepsy, 5 of them underwent surgery, and 1 had a brain biopsy. Electroclinical phenotypes were compatible with FCD II, although magnetic resonance imaging (MRI) was typical in only 4 cases. Histopathology confirmed FCD IIa in 2 patients (including 1 MRI-negative case) and showed FCD I in 2 other patients, and remained inconclusive in the last 2 patients. Three patients were seizure-free postsurgically, and 1 had a worthwhile improvement. Sequencing of blood DNA revealed truncating DEPDC5 mutations in all 4 families; 1 mutation was found to be mosaic in an asymptomatic father. A brain somatic DEPDC5 mutation was identified in 1 patient in addition to the germline mutation.

Interpretation: Germline, germline mosaic, and brain somatic DEPDC5 mutations may cause epilepsy associated with FCD, reinforcing the link between mTORC1 pathway and FCDs. Similarly to other mTORopathies, a "2-hit" mutational model could be responsible for cortical lesions. Our study also indicates that epilepsy surgery is a valuable alternative in the treatment of drug-resistant DEPDC5-positive focal epilepsies, even if the MRI is unremarkable.
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http://dx.doi.org/10.1002/ana.24368DOI Listing
April 2015

A new virtual reality tool for unilateral cerebral palsy rehabilitation: two single-case studies.

Dev Neurorehabil 2013 Dec 11;16(6):418-22. Epub 2013 Jul 11.

Laboratoire d'Ingénierie des Systèmes Automatisés (LISA), LUNAM, Université d'Angers , Angers , France .

Objective: To examine the "clinical utility" of a new virtual rehabilitation tool in order to treat upper-limb motor deficit in cerebral palsy (CP) patient.

Methods: Single-case experimental designs. Virtual reality intervention was performed in two left unilateral spastic CP adolescent patients. The virtual reality intervention was given for 60 minutes per session, two sessions a day, and 5 days a week over 2 weeks.

Results: For each patient and for both hands, the number of blocks transported within one minute (box and block test scores) is increased. The nonoverlap of all pairs indices for the paretic hand were calculated as 0.95 for subject 1 and 0.93 for subject 2, and the nonoverlap of all pairs indices for the nonparetic hand were calculated, respectively, as 0.92 and 1.

Conclusion: We provide empirical evidence in support of a new simple Virtual Rehabilitation system in CP patient to improve upper-limb motor function.
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http://dx.doi.org/10.3109/17518423.2013.778347DOI Listing
December 2013

Severe bronchiolitis in infants born very preterm and neurodevelopmental outcome at 2 years.

Eur J Pediatr 2013 May 22;172(5):639-44. Epub 2013 Jan 22.

Department of Neonatal Medicine, Nantes University Hospital, Nantes, France.

Preterm infants are at greater risk of bronchopulmonary dysplasia, which is associated with neurodevelopmental impairment. These infants are also more likely to develop severe bronchiolitis, which can contribute to neurodevelopmental impairment. The aim of this study was to determine whether severe bronchiolitis in very preterm infants (born before 33 weeks of gestation) was associated with an increased risk of neurodevelopmental impairment at 2 years of age. We analyzed a population-based cohort of infants (the Loire Infant Follow-up Team cohort) born between 1 January 2003 and 31 December 2009. Severe bronchiolitis was defined as hospitalization due to bronchiolitis during the first year of life. Neurodevelopmental outcome was assessed at 2 years of corrected age. A total of 2,405 infants were included in this analysis and categorized based on neonatal respiratory status: 1,308 (54.4 %) received no respiratory assistance, 864(35.9 %) received oxygen for <28 days, and 167 (6.9 %) had mild and 66 (2.7) moderate or severe bronchopulmonary dysplasia. At 2 years, 502 children displayed non-optimal neurodevelopmental outcome (20.9 %). Moderate or severe bronchopulmonary dysplasia was significantly associated with non-optimal neurodevelopmental outcome at 2 years (adjusted odds ratios (OR) = 2.3 [95 % confidence interval (CI): 1.3-3.9], p = 0.003). In the first year, 318 infants acquired severe bronchiolitis (13.2 %), which was not associated with non-optimal neurodevelopmental outcome (adjusted OR = 1.0 [95 % CI: 0.8-1.4]; p = 0.88). In conclusion, respiratory status in the neonatal period was significantly associated with non-optimal neurodevelopmental outcome at 2 years, while severe bronchiolitis was not.
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http://dx.doi.org/10.1007/s00431-013-1940-8DOI Listing
May 2013

The American Clinical Neurophysiology Society's Guideline on Continuous Electroencephalography Monitoring in Neonates.

J Clin Neurophysiol 2011 Dec;28(6):611-7

Department of Pediatrics and Communicable Diseases, Mott Children's Hospital, University of Michigan, Ann Arbor, MI 48109, USA.

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http://dx.doi.org/10.1097/WNP.0b013e31823e96d7DOI Listing
December 2011
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