Publications by authors named "Joël Fluss"

75 Publications

haploinsufficiency causes a recognisable neurodevelopmental phenotype at the mild end of the Joubert syndrome spectrum.

J Med Genet 2021 Oct 21. Epub 2021 Oct 21.

Unit of Neurorehabilitation, Department of Neurosciences, IRCCS Bambino Gesù Children's Hospital, Roma, Italy.

Background: Joubert syndrome (JS) is a recessively inherited ciliopathy characterised by congenital ocular motor apraxia (COMA), developmental delay (DD), intellectual disability, ataxia, multiorgan involvement, and a unique cerebellar and brainstem malformation. Over 40 JS-associated genes are known with a diagnostic yield of 60%-75%.In 2018, we reported homozygous hypomorphic missense variants of the gene in two families with mild JS. Recently, heterozygous truncating variants were identified in families with dominantly inherited COMA, occasionally associated with mild DD and subtle cerebellar anomalies.

Methods: We reanalysed next generation sequencing (NGS) data in two cohorts comprising 1097 probands referred for genetic testing of JS genes.

Results: Heterozygous truncating and splice-site variants were detected in 22 patients from 17 families (1.5%) with strong male prevalence (86%), and in 8 asymptomatic parents. Patients presented with COMA, hypotonia, ataxia and mild DD, and only a third manifested intellectual disability of variable severity. Brain MRI showed consistent findings characterised by vermis hypoplasia, superior cerebellar dysplasia and subtle-to-mild abnormalities of the superior cerebellar peduncles. The same pattern was observed in two out of three tested asymptomatic parents.

Conclusion: Heterozygous truncating or splice-site variants cause a novel neurodevelopmental syndrome encompassing COMA and mild JS, which likely represent overlapping entities. Variants can arise de novo or be inherited from a healthy parent, representing the first cause of JS with dominant inheritance and reduced penetrance. Awareness of this condition will increase the diagnostic yield of JS genetic testing, and allow appropriate counselling about prognosis, medical monitoring and recurrence risk.
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http://dx.doi.org/10.1136/jmedgenet-2021-108114DOI Listing
October 2021

Structural brain abnormalities in epilepsy with myoclonic atonic seizures.

Epilepsy Res 2021 Sep 21;177:106771. Epub 2021 Sep 21.

Pediatric Neurology and Neurorehabilitation Unit, Woman-Mother-Child Department, Lausanne University Hospital and University of Lausanne (CHUV-UNIL), Lausanne, Switzerland. Electronic address:

Objective: Epilepsy with myoclonic atonic seizure (EMAS) occurs in young children with previously normal to subnormal development. The outcome ranges from seizure freedom with preserved cognitive abilities to refractory epilepsy with intellectual disability (ID). Routine brain imaging typically shows no abnormalities. We aimed to compare the brain morphometry of EMAS patients with healthy subjects several years after epilepsy onset, and to correlate it to epilepsy severity and cognitive findings.

Methods: Fourteen EMAS patients (4 females, 5-14 years) and 14 matched healthy controls were included. Patients were classified into three outcome groups (good, intermediate, poor) according to seizure control and cognitive and behavioral functioning. Individual anatomical data (T1-weighted sequence) were processed using the FreeSurfer pipeline. Cortical volume (CV), cortical thickness (CT), local gyrification index (LGI), and subcortical volumes were used for group-comparison and linear regression analyses.

Results: Morphometric comparison between EMAS patients and healthy controls revealed that patients have 1) reduced CV in frontal, temporal and parietal lobes (p = <.001; 0.009 and 0.024 respectively); 2) reduced CT and LGI in frontal lobes (p = 0.036 and 0.032 respectively); and 3) a neat cerebellar volume reduction (p = 0.011). Neither the number of anti-seizure medication nor the duration of epilepsy was related to cerebellar volume (both p > 0.62). Poor outcome group was associated with lower LGI. Patients in good and intermediate outcome groups had a comparable LGI to their matched healthy controls (p > 0.27 for all lobes).

Conclusions: Structural brain differences were detectable in our sample of children with EMAS, mainly located in the frontal lobes and cerebellum. These findings are similar to those found in patients with genetic/idiopathic generalized epilepsies. Outcome groups correlated best with LGI. Whether these anatomical changes reflect genetically determined abnormal neuronal networks or a consequence of sustained epilepsy remains to be solved with prospective longitudinal studies.
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http://dx.doi.org/10.1016/j.eplepsyres.2021.106771DOI Listing
September 2021

High rate of hypomorphic variants as the cause of inherited ataxia and related diseases: study of a cohort of 366 families.

Genet Med 2021 Jul 7. Epub 2021 Jul 7.

Department of Clinical Genetics, Centre de Référence Maladies Rares Anomalies du Développement, CHU de Rennes, Rennes, France.

Purpose: Diagnosis of inherited ataxia and related diseases represents a real challenge given the tremendous heterogeneity and clinical overlap of the various causes. We evaluated the efficacy of molecular diagnosis of these diseases by sequencing a large cohort of undiagnosed families.

Methods: We analyzed 366 unrelated consecutive patients with undiagnosed ataxia or related disorders by clinical exome-capture sequencing. In silico analysis was performed with an in-house pipeline that combines variant ranking and copy-number variant (CNV) searches. Variants were interpreted according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines.

Results: We established the molecular diagnosis in 46% of the cases. We identified 35 mildly affected patients with causative variants in genes that are classically associated with severe presentations. These cases were explained by the occurrence of hypomorphic variants, but also rarely suspected mechanisms such as C-terminal truncations and translation reinitiation.

Conclusion: A significant fraction of the clinical heterogeneity and phenotypic overlap is explained by hypomorphic variants that are difficult to identify and not readily predicted. The hypomorphic C-terminal truncation and translation reinitiation mechanisms that we identified may only apply to few genes, as it relies on specific domain organization and alterations. We identified PEX10 and FASTKD2 as candidates for translation reinitiation accounting for mild disease presentation.
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http://dx.doi.org/10.1038/s41436-021-01250-6DOI Listing
July 2021

Truncating variants in the SHANK1 gene are associated with a spectrum of neurodevelopmental disorders.

Genet Med 2021 10 10;23(10):1912-1921. Epub 2021 Jun 10.

Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA.

Purpose: In this study, we aimed to characterize the clinical phenotype of a SHANK1-related disorder and define the functional consequences of SHANK1 truncating variants.

Methods: Exome sequencing (ES) was performed for six individuals who presented with neurodevelopmental disorders. Individuals were ascertained with the use of GeneMatcher and Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources (DECIPHER). We evaluated potential nonsense-mediated decay (NMD) of two variants by making knock-in cell lines of endogenous truncated SHANK1, and expressed the truncated SHANK1 complementary DNA (cDNA) in HEK293 cells and cultured hippocampal neurons to examine the proteins.

Results: ES detected de novo truncating variants in SHANK1 in six individuals. Evaluation of NMD resulted in stable transcripts, and the truncated SHANK1 completely lost binding with Homer1, a linker protein that binds to the C-terminus of SHANK1. These variants may disrupt protein-protein networks in dendritic spines. Dispersed localization of the truncated SHANK1 variants within the spine and dendritic shaft was also observed when expressed in neurons, indicating impaired synaptic localization of truncated SHANK1.

Conclusion: This report expands the clinical spectrum of individuals with truncating SHANK1 variants and describes the impact these variants may have on the pathophysiology of neurodevelopmental disorders.
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http://dx.doi.org/10.1038/s41436-021-01222-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487955PMC
October 2021

Bi-allelic loss of ERGIC1 causes relatively mild arthrogryposis.

Clin Genet 2021 09 14;100(3):329-333. Epub 2021 Jun 14.

Genetic Medicine division, Diagnostic Department, Hôpitaux Universitaires de Genève, Genève (CH), Switzerland.

Arthrogryposis describes the presence of multiple joint-contractures. Clinical severity of this phenotype is variable, and more than 400 causative genes have been proposed. Among these, ERGIC1 is a recently reported candidate encoding a putative transmembrane protein of the ER-Golgi interface. Two homozygous missense variants have been reported in patients with relatively mild non-syndromic arthrogryposis. In a consanguineous family with two affected siblings presenting congenital arthrogryposis and some facial dysmorphism we performed prenatal array-CGH, postnatal targeted exome and genome sequencing. Genome sequencing identified a homozygous 22.6 Kb deletion encompassing the promoter and first exon of ERGIC1. mRNA quantification showed the complete absence of ERGIC1 expression in the two affected siblings and a decrease in heterozygous parents. Our observations validate the pathogenic role of ERGIC1 in congenital arthrogryposis and demonstrate that complete loss of function causes a relatively mild phenotype. These findings will contribute to improve genetic counseling of ERGIC1 mutations.
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http://dx.doi.org/10.1111/cge.14004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453841PMC
September 2021

Recognition, identification, and diagnosis announcement of neonatal arterial ischemic stroke: A combined exploratory quantitative and qualitative study on parents' lived experiences.

Arch Pediatr 2021 May 11;28(4):285-290. Epub 2021 Mar 11.

Pediatric Neurology Unit, Paediatric subspecialties Service, Geneva University Hospitals, Rue Willy-Donzé 6, 1211 Geneva 14, Switzerland. Electronic address:

Objectives: To examine the epidemiology of neonatal arterial ischemic stroke (NAIS) and the chronology of care from early reported manifestations to formal diagnosis obtained by imaging. To explore how parents experienced the sequence of events, their own perception of potential diagnostic delay, diagnosis announcement, and prognosis discussion, and their current view of their child's quality of life.

Methods: We retrospectively analyzed data of all NAIS cases that have been treated in our institution. Quantitative data came from both newborns' and mothers' medical records. Qualitative data were collected from parents in semi-structured interviews based on a standardized questionnaire composed of open-ended questions.

Results: A total of 14 neonates were treated for NAIS in our institution between January 2008 and December 2017. The incidence of NAIS during this period was one out of 4258 births. The majority of neonates presented within 48 hours with a mean of 27h after birth, most often in the form of repetitive focal clonus (13/14). The mean time before diagnosis consideration and confirmation was 5 and 33h, respectively. Late consideration of early reported symptoms was identified as the main source of delay. Despite good reported health outcome, NAIS was associated with significant acute and long-standing parental emotional stress.

Conclusion: Maternity hospital caregivers' awareness of NAIS is crucial to reach early diagnosis. Improving this aspect would not only allow better early management, but also make it possible to set up acute neuroprotective strategies. Clinicians should be attentive to the modalities of diagnosis and prognosis announcements, which are associated with considerable stress and misconceptions.
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http://dx.doi.org/10.1016/j.arcped.2021.02.002DOI Listing
May 2021

Trigeminal nerve chronic motor denervation caused by cerebellar peduncle pilocytic astrocytoma.

Childs Nerv Syst 2021 04 22;37(4):1035-1037. Epub 2021 Jan 22.

Department of Pediatrics, Gynecology and Obstetrics, Division of General Pediatrics, Pediatric Hematology and Oncology Unit, University Hospitals of Geneva, Geneva, Switzerland.

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http://dx.doi.org/10.1007/s00381-021-05047-5DOI Listing
April 2021

Making sense of missense variants in TTN-related congenital myopathies.

Acta Neuropathol 2021 03 15;141(3):431-453. Epub 2021 Jan 15.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

Mutations in the sarcomeric protein titin, encoded by TTN, are emerging as a common cause of myopathies. The diagnosis of a TTN-related myopathy is, however, often not straightforward due to clinico-pathological overlap with other myopathies and the prevalence of TTN variants in control populations. Here, we present a combined clinico-pathological, genetic and biophysical approach to the diagnosis of TTN-related myopathies and the pathogenicity ascertainment of TTN missense variants. We identified 30 patients with a primary TTN-related congenital myopathy (CM) and two truncating variants, or one truncating and one missense TTN variant, or homozygous for one TTN missense variant. We found that TTN-related myopathies show considerable overlap with other myopathies but are strongly suggested by a combination of certain clinico-pathological features. Presentation was typically at birth with the clinical course characterized by variable progression of weakness, contractures, scoliosis and respiratory symptoms but sparing of extraocular muscles. Cardiac involvement depended on the variant position. Our biophysical analyses demonstrated that missense mutations associated with CMs are strongly destabilizing and exert their effect when expressed on a truncating background or in homozygosity. We hypothesise that destabilizing TTN missense mutations phenocopy truncating variants and are a key pathogenic feature of recessive titinopathies that might be amenable to therapeutic intervention.
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http://dx.doi.org/10.1007/s00401-020-02257-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882473PMC
March 2021

Risk Factors for Postprocedural Arterial Ischemic Stroke in Children With Cardiac Disease.

Stroke 2020 09 19;51(9):e242-e245. Epub 2020 Aug 19.

Department of Neonatology, University of Basel Children's Hospital (UKBB), Switzerland (M.I.H.).

Background And Purpose: Cardiac pathologies are the second most frequent risk factor (RF) in children with arterial ischemic stroke (AIS). This study aimed to analyze RFs for AIS in children with cardiac disease and cardiac intervention.

Methods: Data were drawn from the Swiss Neuropediatric Stroke Registry. Patients with cardiac disease and postprocedural AIS registered from 2000 until 2015 were analyzed for the cause of cardiac disease and for potential RFs.

Results: Forty-seven out of 78 children with cardiac disease had a cardiac intervention. Of these, 36 presented a postprocedural AIS. Median time from cardiac intervention to symptom onset was 4 days (interquartile range, 2-8.5); time to diagnosis of AIS was 2 days (interquartile range, 0-5.8). Main RFs for postprocedural AIS were hypotension, prosthetic cardiac material, right-to-left shunt, arrhythmias, low cardiac output, and infections.

Conclusions: In children with postprocedural AIS, time to diagnosis was delayed. Most patients presented multiple potentially modifiable RFs as hemodynamic alterations and infections.
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http://dx.doi.org/10.1161/STROKEAHA.120.029447DOI Listing
September 2020

Cognitive and academic profiles in children with cerebral palsy: A narrative review.

Ann Phys Rehabil Med 2020 Feb 19. Epub 2020 Feb 19.

Clinic of Paediatric Medicine, Department of Paediatric Neurology, Development, Rehabilitation, University Children's Hospital Berne, Switzerland.

Background: Considerable effort has recently been made to improve the accurate diagnosis of cerebral palsy (CP) in childhood and to establish early intervention aiming to improve functional outcome. Besides the visible motor impairments, cognitive abilities are frequently affected but might remain unrecognised in children with mild forms. On the other hand, some severely disabled children with presumed intellectual disabilities might demonstrate normal-range reasoning capacities. Most studies on this topic have emphasized a variety of cognitive profiles (cognitive level) related to the type of cerebral palsy and the underlying brain lesions (biological level). However, little is known at the behavioural level, namely learning skills and educational achievement.

Objective: This narrative review aimed to discuss cognitive and scholastic skills typically affected in children with CP.

Methods: Online literature research for studies of cerebral palsy, cognition and academic achievement, extracting all relevant articles regardless of article type.

Results: In children with CP, intellectual disability is frequent and correlated with the degree of motor impairment and early epilepsy. Speech and language problems are prevalent in all forms of CP and might hamper everyday participation on varying levels depending on the degree of motor disability. Most children with CP have neuropsychological deficits affecting predominantly visuospatial functions, attention, and/or executive functions. These problems relate to academic performance and social participation.

Discussion: An adequate interdisciplinary follow-up of children with CP requires a sensitization of clinicians to the complex topic of cognitive and academic problems in this population and a better synergy between the medical and educational worlds.
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http://dx.doi.org/10.1016/j.rehab.2020.01.005DOI Listing
February 2020

MCF2 is linked to a complex perisylvian syndrome and affects cortical lamination.

Ann Clin Transl Neurol 2020 01 17;7(1):121-125. Epub 2019 Dec 17.

Department of Psychiatry, University of Geneva Medical School, Geneva, 4 CH-1211, Switzerland.

The combination of congenital bilateral perisylvian syndrome (CBPS) with lower motor neuron dysfunction remains unusual and suggests a potential common genetic insult affecting basic neurodevelopmental processes. Here we identify a putatively pathogenic missense mutation in the MCF2 gene in a boy with CBPS. Using in utero electroporation to genetically manipulate cortical neurons during corticogenesis, we demonstrate that the mouse Mcf2 gene controls the embryonic migration of cortical projection neurons. Strikingly, we find that the CBPS-associated MCF2 mutation impairs cortical laminar positioning, supporting the hypothesis that alterations in the process of embryonic neuronal migration can lead to rare cases of CBPS.
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http://dx.doi.org/10.1002/acn3.50949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952308PMC
January 2020

From congenial paralysis to post-early brain injury developmental condition: Where does cerebral palsy actually stand?

Ann Phys Rehabil Med 2019 Aug 14. Epub 2019 Aug 14.

Département de médecine physique et de réadaptation, Centre national de référence de l'AVC de l'enfant, CHU d'Angers, CHU Angers-Capucins, 49000 Angers, France; Laboratoire Angevin de recherche en ingénierie des systèmes (LARIS) EA7315, Univ Angers, 49000 Angers, France.

Cerebral palsy (CP), an umbrella term for a developmental motor disorder caused by early brain injury (EBI)/interference, remains debated. In this essay, we present a narrative, beginning with the original anatomical-clinical description of the so-called paralysie congéniale (congenial paralysis) by the French psychiatrist Jean-Baptiste Cazauvieilh. We then discuss how the concept has evolved over the last 2 centuries. We aim to illustrate these ideas with the biopsychosocial model of health, especially in light of the current neuroscientific and sociological knowledge of human development. We endeavour to integrate 3 connected but distinct entities: (1) the EBI as a seminal turning point of the individual's story; (2) the clinical findings we call CP, when motor impairment and activity limitation related to post-EBI (or other early non-progressive brain interference) appears, and; (3) a post-EBI developmental condition that encompasses the overall consequences of an EBI. This framework should guide individual, familial and collective care discussions and research strategies beyond the scope of CP.
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http://dx.doi.org/10.1016/j.rehab.2019.07.003DOI Listing
August 2019

Perinatal stroke syndromes: Similarities and diversities in aetiology, outcome and management.

Eur J Paediatr Neurol 2019 May 27;23(3):368-383. Epub 2019 Feb 27.

CHU Saint-Étienne, French Centre for Paediatric Stroke, Paediatric Physical and Rehabilitation Medicine Department, INSERM, CIC 1408, F-42055, Saint-Étienne, France; INSERM, U1059 Sainbiose, Univ Saint-Étienne, Univ Lyon, F-42023, Saint-Étienne, France. Electronic address:

With a birth-prevalence of 37-67/100,000 (mostly term-born), perinatal stroke encompasses distinct disease-states with diverse causality, mechanism, time of onset, mode of presentation and outcome. Neonatal primary haemorrhagic stroke and ischemic events (also divided into neonatal arterial ischemic stroke and neonatal cerebral sinus venous thrombosis) that manifest soon after birth are distinguished from presumed perinatal - ischemic or haemorrhagic - stroke. Signs of the latter become apparent only beyond the neonatal period, most often with motor asymmetry or milestones delay, and occasionally with seizures. Acute or remote MRI defines the type of stroke and is useful for prognosis. Acute care relies on homeostatic maintenance. Seizures are often self-limited and anticonvulsant agents might be discontinued before discharge. Prolonged anticoagulation for a few weeks is an option in some cases of sinovenous thrombosis. Although the risk of severe impairment is low, many children develop mild to moderate multimodal developmental issues that require a multidisciplinary approach.
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http://dx.doi.org/10.1016/j.ejpn.2019.02.013DOI Listing
May 2019

The effects of dual tasks on gait in children with cerebral palsy.

Gait Posture 2019 05 21;70:148-155. Epub 2019 Feb 21.

Willy Taillard Laboratory of Kinesiology, Geneva University Hospitals and University of Geneva, Geneva 1211, Switzerland. Electronic address:

Aim: To assess the gait and cognitive performances of children with cerebral palsy (CP) during dual tasks (DT) in comparison to typically developing (TD) children.

Method: This prospective, observational, case-control study included 18 children with CP (7 girls, 11 boys; median age 12 [10:13] years and 19 controls (9 girls, 10 boys; median age 12 [10:13y6mo] years). Performances were recorded during a simple walking task, 5 DT (walking + cognitive tasks with increasing cognitive load), and 5 simple cognitive tasks (while sitting). Gait parameters were computed using an optoelectronic system during walking tasks. Six parameters were selected for analysis by a principal component analysis. Cognitive performance was measured for each cognitive task. The dual-task cost (DTC) was calculated for each DT.

Results: Gait performance decreased in both groups as DT cognitive load increased (e.g., walking speed normalized by leg length, in simple task: 1.25 [1.15:1.46] s for CP, 1.53 [1.38:1.62] s for TD; DT with highest load: 0.64 [0.53:0.80] s for CP, 0.95 [0.75:1.08] s for TD). The CP group performed significantly worse than TD group in every task (including the simple task), but DTC were similar in both groups. A task effect was found for the majority of the gait parameters.

Interpretation: The reduced gait performance induced by DT may generate underestimated difficulties for children with CP in daily-life situations, where DT are common. This should be considered in clinical assessments.
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http://dx.doi.org/10.1016/j.gaitpost.2019.02.014DOI Listing
May 2019

Modalities of reading acquisition in three siblings with infantile-onset saccade initiation delay (Cogan congenital ocular motor apraxia): A longitudinal study.

Eur J Paediatr Neurol 2019 May 8;23(3):517-524. Epub 2019 Feb 8.

Pediatric Neurology Unit, Pediatric Subspecialties Service, Children's Hospital of Geneva, Switzerland.

This study aims to ascertain the impact of congenital ocular motor apraxia (COMA), alternatively called infantile-onset saccade initiation delay (ISID), on reading acquisition. More specifically, the consequence of defective initiation of horizontal saccades during reading acquisition was investigated. Three siblings (A: male, 11y3m at the first time-point of testing (i.e. T1 hereafter); B: female, 7y3m at T1 and C: male, 5y9m at T1) suffering from ISID were assessed longitudinally over 3 years in various reading tests and their eye movements simultaneously registered. At each time-point, they were compared to control participants matched on reading level. Eye movements during reading tasks were markedly abnormal in children with ISID at the beginning of reading acquisition and their reading scores were poor. With time, the number of fixations, small amplitude saccades and their reading abilities became comparable to those of control children. Despite the abnormal eye movements and difficulties in specifically directing the eyes to the appropriate position, children with ISID do not seem to encounter major difficulties during reading acquisition, although mild delays might be observed during the early stages.
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http://dx.doi.org/10.1016/j.ejpn.2019.01.008DOI Listing
May 2019

Dexterity and Finger Sense: A Possible Dissociation in Children With Cerebral Palsy.

Percept Mot Skills 2018 Aug 3;125(4):718-731. Epub 2018 Jun 3.

3 Institute of Psychology, University of Lausanne, Switzerland.

Both hand and finger sensory perception and motor abilities are essential for the development of skilled gestures and efficient bimanual coordination. While finger dexterity and finger sensory perception can be impaired in children with cerebral palsy (CP), the relationship between these two functions in this population is not clearly established. The common assumption that CP children with better sensory function also demonstrate better motor outcomes has been recently challenged. To study these questions further, we assessed both finger dexterity and finger gnosia, the ability to perceive one's own fingers by touch, in groups of 11 children with unilateral (i.e., hemiplegic CP) and 11 children with bilateral spastic CP (i.e., diplegic CP) and compared them with typical children. In our sample, children with hemiplegia exhibited finger dexterity deficit in both hands and finger gnosia deficit only in their paretic hand. In contrast, children with diplegia exhibited finger gnosia deficits in both hands and finger dexterity deficit only in their dominant hand. Thus, our results indicated that children with spastic hemiplegia and diplegia present different sensory and motor profiles and suggest that these two subgroups of CP should be considered separately in future experimental and clinical research. We discuss the implications of our results for rehabilitation.
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http://dx.doi.org/10.1177/0031512518779473DOI Listing
August 2018

Novel NEXMIF pathogenic variant in a boy with severe autistic features, intellectual disability, and epilepsy, and his mildly affected mother.

J Hum Genet 2018 Jul 1;63(7):847-850. Epub 2018 May 1.

Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.

Intellectual disability (ID) and autism spectrum disorders are complex neurodevelopmental disorders occurring among all ethnic and socioeconomic groups. Pathogenic variants in the neurite extension and migration factor (NEXMIF) gene (formerly named KIAA2022) on the X chromosome are responsible for ID, autistic behavior, epilepsy, or dysmorphic features in males. Most affected females described had a milder phenotype or were asymptomatic obligate carriers. We report here for the first time mother-to-son transmission of a novel NEXMIF truncating variant without X-inactivation skewing in the blood. Truncating gene variant leads to symptomatic mother to severely affected son transmission. Our findings emphasize that NEXMIF sequencing should be strongly considered in patients with unexplained autism spectrum disorder, ID, and epilepsy, irrespective of gender. Such testing could increase our knowledge of the pathogenicity of NEXMIF variants and improve genetic counseling.
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http://dx.doi.org/10.1038/s10038-018-0459-2DOI Listing
July 2018

Feasibility, safety, and outcome of recanalization treatment in childhood stroke.

Ann Neurol 2018 06;83(6):1125-1132

Department of Pediatrics, Division of Child Neurology, University Children's Hospital Bern, University of Bern, Bern.

Objective: Intravenous thrombolysis and endovascular therapy (IVT/EVT) are evidence-based treatments for adults with arterial ischemic stroke (AIS). However, randomized controlled trials in pediatric patients are lacking. This study aimed to describe feasibility, safety, and outcome of IVT/EVT in children with AIS.

Methods: This retrospective study (01/2000-12/2015) included a multicenter, population-based consecutive cohort of patients aged 1 month to 16 years, diagnosed with AIS and presenting with pediatric National Institutes of Health Stroke Scale (pedNIHSS) ≥ 4. Clinical and radiological data of patients receiving IVT/EVT were compared to those receiving standard care (SC) using linear regression to adjust for potential confounders. EVT included intra-arterial thrombolysis and/or mechanical thrombectomy. Outcome was assessed 6 months after stroke using the pediatric stroke outcome measure (PSOM).

Results: Overall, 150 patients (age 7.1 ± 4.9 years, 55 [37%] females) presented with pedNIHSS ≥ 4. Recanalization treatment was performed in 16 (11%), of whom 5 (3%) were treated with IVT and 11 (7%) with EVT. Patients receiving recanalization treatment were older (mean age = 11.0 vs 6.9 years, p = 0.01) and more severely affected (median pedNIHSS = 13.5 vs 8.0, p < 0.001). Death and bleeding complications did not differ between the 2 groups. Median (interquartile range) PSOM 6 months after AIS was 2.5 (1-4.3) and 1 (0-2) in the IVT/EVT and SC groups, respectively (p = 0.014). However, after multiple linear regression analysis, only higher baseline pedNIHSS remained associated with an unfavorable outcome (p < 0.001).

Interpretation: Recanalization treatment is feasible and seems to be safe in severely affected pediatric AIS patients. The assessment of efficacy of IVT/EVT in pediatric stroke patients requires larger studies. Ann Neurol 2018;83:1125-1132.
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http://dx.doi.org/10.1002/ana.25242DOI Listing
June 2018

Intracranial Hemorrhage and Autoimmune Thrombocytopenia in a Neonate: A Rare "Unpredictable" Event.

Child Neurol Open 2018 5;5:2329048X18768693. Epub 2018 Apr 5.

Pediatric Neurology Unit, Pediatric Subspecialties Service, University Hospitals of Geneva, Geneva, Switzerland.

Neonatal thrombocytopenia is a rare complication of maternal autoimmune thrombocytopenia, and no maternal predictors of its gravity and potential complications have been identified. Neonatal cerebral hemorrhage, a feared event in the setting of autoimmune thrombocytopenia, is fortunately uncommon, but it can occur in utero or in the perinatal period, with potentially serious consequences. The authors report the case of a boy born to a mother affected by autoimmune thrombocytopenia, who presented with severe thrombocytopenia at birth and developed intracranial hemorrhage despite mild maternal thrombocytopenia at delivery and a prompt preventive treatment of the newborn. Platelet count should be tested at birth in all babies born from mothers with autoimmune thrombocytopenia, irrespective of maternal platelets counts during pregnancy or at delivery, and should be closely monitored during the first days of life. Systematic early and serial cranial ultrasound might be advocated in the setting of neonatal thrombocytopenia.
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http://dx.doi.org/10.1177/2329048X18768693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5894894PMC
April 2018

Manual dexterity, but not cerebral palsy, predicts cognitive functioning after neonatal stroke.

Dev Med Child Neurol 2018 10 6;60(10):1045-1051. Epub 2018 Apr 6.

INSERM, UMR1059 Sainbiose, University of Saint-Étienne, University of Lyon, Saint-Étienne.

Aim: To disentangle the respective impacts of manual dexterity and cerebral palsy (CP) in cognitive functioning after neonatal arterial ischaemic stroke.

Method: The population included 60 children (21 females, 39 males) with neonatal arterial ischaemic stroke but not epilepsy. The presence of CP was assessed clinically at the age of 7 years and 2 months (range 6y 11mo-7y 8mo) using the definition of the Surveillance of CP in Europe network. Standardized tests (Nine-Hole Peg Test and Box and Blocks Test) were used to quantify manual (finger and hand respectively) dexterity. General cognitive functioning was evaluated with the Wechsler Intelligence Scale for Children, Fourth Edition. Simple and multiple linear regression models were performed while controlling for socio-economic status, lesion side, and sex.

Results: Fifteen children were diagnosed with CP. In simple regression models, both manual dexterity and CP were associated with cognitive functioning (β=0.41 [p=0.002] and β=0.31 [p=0.019] respectively). However, in multiple regression models, manual dexterity was the only associated variable of cognitive functioning, whether or not a child had CP (β=0.35; p=0.007). This result was reproduced in models with other covariables (β=0.31; p=0.017).

Interpretation: As observed in typically developing children, manual dexterity is related to cognitive functioning in children having suffered a focal brain insult during the neonatal period.

What This Paper Adds: Manual dexterity predicts cognitive functioning after neonatal arterial ischaemic stroke. Correlations between manual dexterity and cognitive functioning occur irrespective of sex, lesion side, presence of cerebral palsy, and socio-economic status. Residual motor ability may support cognitive functioning.
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http://dx.doi.org/10.1111/dmcn.13752DOI Listing
October 2018

MRI of the first event in pediatric acquired demyelinating syndromes with antibodies to myelin oligodendrocyte glycoprotein.

J Neurol 2018 Apr 8;265(4):845-855. Epub 2018 Feb 8.

Department of Pediatric Neurology, Children's Hospital Datteln, Witten/Herdecke University, Datteln, Germany.

Antibodies against the myelin oligodendrocyte glycoprotein (MOG-Ab) can be detected in various pediatric acquired demyelinating syndromes (ADS). Here, we analyze the spectrum of neuroradiologic findings in children with MOG-Ab and a first demyelinating event. The cerebral and spinal MRI of 69 children with different ADS was assessed in regard to the distribution and characteristics of lesions. Children with acute disseminated encephalomyelitis (n = 36) or neuromyelitis optica spectrum disorder (n = 5) presented an imaging pattern characterized predominantly by poorly demarcated lesions with a wide supra- and infratentorial distribution. Younger children also tended to have poorly defined and widespread lesions. The majority of patients with an isolated optic neuritis (n = 16) only presented small non-specific brain lesions or none at all. A longitudinally extensive transverse myelitis mainly affecting the cervical, and less often so the thoracic, lumbar, and conus regions, was detected in 31 children. The three children of our cohort who were then finally diagnosed with multiple sclerosis had at onset already demarcated white matter lesions as well as transverse myelitis. In conclusion, children with MOG seropositive ADS present disparate, yet characteristic imaging patterns. These patterns have been seen to correlate to the disease entity as well as to age of symptom onset.
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http://dx.doi.org/10.1007/s00415-018-8781-3DOI Listing
April 2018

Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects.

Am J Hum Genet 2017 Oct 28;101(4):552-563. Epub 2017 Sep 28.

Neurogenetics Unit, IRCCS Santa Lucia Foundation, Rome 00143, Italy; Department of Molecular Medicine, University of Pavia, Pavia 27100, Italy. Electronic address:

The Sonic Hedgehog (SHH) pathway is a key signaling pathway orchestrating embryonic development, mainly of the CNS and limbs. In vertebrates, SHH signaling is mediated by the primary cilium, and genetic defects affecting either SHH pathway members or ciliary proteins cause a spectrum of developmental disorders. SUFU is the main negative regulator of the SHH pathway and is essential during development. Indeed, Sufu knock-out is lethal in mice, and recessive pathogenic variants of this gene have never been reported in humans. Through whole-exome sequencing in subjects with Joubert syndrome, we identified four children from two unrelated families carrying homozygous missense variants in SUFU. The children presented congenital ataxia and cerebellar vermis hypoplasia with elongated superior cerebellar peduncles (mild "molar tooth sign"), typical cranio-facial dysmorphisms (hypertelorism, depressed nasal bridge, frontal bossing), and postaxial polydactyly. Two siblings also showed polymicrogyria. Molecular dynamics simulation predicted random movements of the mutated residues, with loss of the native enveloping movement of the binding site around its ligand GLI3. Functional studies on cellular models and fibroblasts showed that both variants significantly reduced SUFU stability and its capacity to bind GLI3 and promote its cleavage into the repressor form GLI3R. In turn, this impaired SUFU-mediated repression of the SHH pathway, as shown by altered expression levels of several target genes. We demonstrate that germline hypomorphic variants of SUFU cause deregulation of SHH signaling, resulting in recessive developmental defects of the CNS and limbs which share features with both SHH-related disorders and ciliopathies.
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http://dx.doi.org/10.1016/j.ajhg.2017.08.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630196PMC
October 2017

Is there an excess of left-handedness after neonatal stroke?

Cortex 2017 11 16;96:161-164. Epub 2017 Aug 16.

INSERM, UMR1059 Sainbiose, Université de Lyon, Équipe Dysfonction Vasculaire et Hémostase (DVH), Université Jean Monnet, Saint-Étienne, F-42023, France; CHU Saint-Étienne, Service de Médecine Physique et de Réadaptation Pédiatrique, Saint-Étienne, F-42055, France; CHU Saint-Étienne, Centre national de référence de l'AVC de l'enfant, INSERM, CIC1408, Saint-Étienne, F-42055, France. Electronic address:

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http://dx.doi.org/10.1016/j.cortex.2017.08.007DOI Listing
November 2017

Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections.

J Clin Invest 2017 Sep 7;127(9):3543-3556. Epub 2017 Aug 7.

Laboratory of Experimental Hematology, Vaccine & Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.

Varicella zoster virus (VZV) typically causes chickenpox upon primary infection. In rare cases, VZV can give rise to life-threatening disease in otherwise healthy people, but the immunological basis for this remains unexplained. We report 4 cases of acute severe VZV infection affecting the central nervous system or the lungs in unrelated, otherwise healthy children who are heterozygous for rare missense mutations in POLR3A (one patient), POLR3C (one patient), or both (two patients). POLR3A and POLR3C encode subunits of RNA polymerase III. Leukocytes from all 4 patients tested exhibited poor IFN induction in response to synthetic or VZV-derived DNA. Moreover, leukocytes from 3 of the patients displayed defective IFN production upon VZV infection and reduced control of VZV replication. These phenotypes were rescued by transduction with relevant WT alleles. This work demonstrates that monogenic or digenic POLR3A and POLR3C deficiencies confer increased susceptibility to severe VZV disease in otherwise healthy children, providing evidence for an essential role of a DNA sensor in human immunity.
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http://dx.doi.org/10.1172/JCI92280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669568PMC
September 2017

SERPINI1 pathogenic variants: An emerging cause of childhood-onset progressive myoclonic epilepsy.

Am J Med Genet A 2017 Sep 20;173(9):2456-2460. Epub 2017 Jun 20.

Pediatric Neurology Unit, Department of Child and Adolescent, Geneva University Hospitals, Geneva, Switzerland.

Progressive myoclonic epilepsies are rare neurodegenerative diseases with a wide spectrum of clinical presentations and genetic heterogeneity that render their diagnosis perplexing. Discovering new imputable genes has been an ongoing process in recent years. We present two pediatric cases of progressive myoclonic epilepsy with SERPINI1 pathogenic variants that lead to a severe presentation; we highlight the importance of including this gene, previously known as causing an adult-onset dementia-epilepsy syndrome, in the genetic work-up of childhood-onset progressive myoclonic epilepsies.
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http://dx.doi.org/10.1002/ajmg.a.38317DOI Listing
September 2017

Author's response: Extracerebral thrombi in symptomatic neonatal arterial ischemic stroke.

Eur J Paediatr Neurol 2017 07;21(4):689-690

CHU Saint-Étienne, Centre national de référence de l'AVC de l'enfant, Inserm, CIC1408, F-42055 Saint-Étienne, France; Inserm, Univ Lyon, U1059 SAINBIOSE, Univ Jean Monnet, F-42023 Saint-Étienne, France.

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http://dx.doi.org/10.1016/j.ejpn.2017.05.005DOI Listing
July 2017

Thalamic Hemorrhagic Stroke in the Term Newborn: A Specific Neonatal Syndrome With Non-uniform Outcome.

J Child Neurol 2017 07 21;32(8):746-753. Epub 2017 Apr 21.

2 Pediatric Neurology, University Hospital of Geneva, Geneva, Switzerland.

Background: Neonatal thalamic hemorrhagic stroke is related to cerebral sinus venous thrombosis and associated with neurological sequelae. Predicting factors are however lacking.

Methods: Clinical and radiological findings at onset and on follow-up of 5 neonates with thalamic hemorrhage stroke are described.

Results: All neonates presented with abrupt lethargy, ophistotonos, irritability and/or seizures. The thalamic hemorrhagic stroke was most often unilateral (4/5), involving the posterior/entire thalamus in 3 cases and the anterior thalamus in 2. Cerebral venous thrombosis was identified in a single patient. At follow-up, children with unilateral anterior thalamic hemorrhagic stroke demonstrated thalamic atrophy without neurological symptoms, whereas children whose thalamus lesion was extensive exhibit a porencephalic cavity and presented with late-onset epilepsy.

Discussion: Although deep cerebral venous thrombosis is probably the cause of neonatal thalamic hemorrhagic stroke, its radiological evidence is challenging. Outcome seems dependent of the size and location of thalamic hemorrhagic stroke. Epilepsy is a frequent morbidity after thalamic hemorrhagic stroke.
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http://dx.doi.org/10.1177/0883073817703503DOI Listing
July 2017

Secondary Prevention of Childhood Arterial Ischemic Stroke.

J Child Neurol 2017 04 27;32(5):488-493. Epub 2017 Jan 27.

1 INSERM, UMR 1059, SAINBIOSE, Dysfonction Vasculaire et Hémostase, Université Jean Monnet, Saint-Étienne, France.

This study aimed to know how frontline physicians in France, Belgium, and Switzerland implement guidelines regarding the secondary prevention of childhood arterial ischemic stroke and to introduce physicians' point of view on a clinical trial assessing the efficacy of aspirin as a preventive strategy. The authors conducted an online survey directed at specialists throughout dedicated networks and used a mixed method for data analysis. Overall, 63 physicians responded, and 88% prescribe aspirin when sickle cell disease, cardio-embolic stroke, and dissection of cervical arteries are excluded. Prescribing habits vary among respondents with respect to their specialty. A majority would choose placebo or a treatment given to historical controls to compare with an aspirin arm in a trial. In studied countries, there seems to be good adherence to guidelines regarding the secondary prevention of childhood stroke. A trial assessing the efficacy of aspirin could be well accepted if several factors regarding study design were taken into account.
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http://dx.doi.org/10.1177/0883073816686911DOI Listing
April 2017

Transient Cerebral Arteriopathy, Postvaricella Arteriopathy, and Focal Cerebral Arteriopathy or the Unique Susceptibility of the M1 Segment in Children With Stroke.

Stroke 2016 10 15;47(10):2439-41. Epub 2016 Sep 15.

From the CHU Saint-Étienne, French Center for Pediatric Stroke, Hôpital Bellevue, Saint-Étienne F-42055, France (S.C.); Child Neurology Division, Montreal Children's Hospital, McGill University, Canada (G.S.); and Pediatric Neurology Unit, Geneva University Hospitals, Children's Hospital, Genève, Switzerland (J.F.).

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http://dx.doi.org/10.1161/STROKEAHA.116.014606DOI Listing
October 2016

Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy.

Eur J Hum Genet 2016 12 29;24(12):1761-1770. Epub 2016 Jun 29.

Human Genetics Laboratory, "Mina Minovici" National Institute of Forensic Medicine, Bucharest, Romania.

Genetic generalized epilepsy (GGE), formerly known as idiopathic generalized epilepsy, is the most common form of epilepsy and is thought to have predominant genetic etiology. GGE are clinically characterized by absence, myoclonic, or generalized tonic-clonic seizures with electroencephalographic pattern of bilateral, synchronous, and symmetrical spike-and-wave discharges. Despite their strong heritability, the genetic basis of generalized epilepsies remains largely elusive. Nevertheless, recent advances in genetic technology have led to the identification of numerous genes and genomic defects in various types of epilepsies in the past few years. In the present study, we performed whole-exome sequencing in a family with GGE consistent with the diagnosis of eyelid myoclonia with absences. We found a nonsense variant (c.196C>T/p.(Arg66*)) in RORB, which encodes the beta retinoid-related orphan nuclear receptor (RORβ), in four affected family members. In addition, two de novo variants (c.218T>C/p.(Leu73Pro); c.1249_1251delACG/p.(Thr417del)) were identified in sporadic patients by trio-based exome sequencing. We also found two de novo deletions in patients with behavioral and cognitive impairment and epilepsy: a 52-kb microdeletion involving exons 5-10 of RORB and a larger 9q21-microdeletion. Furthermore, we identified a patient with intellectual disability and a balanced translocation where one breakpoint truncates RORB and refined the phenotype of a recently reported patient with RORB deletion. Our data support the role of RORB gene variants/CNVs in neurodevelopmental disorders including epilepsy, and especially in generalized epilepsies with predominant absence seizures.
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http://dx.doi.org/10.1038/ejhg.2016.80DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5117930PMC
December 2016
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