Inflammatory Type Focal Cerebral Arteriopathy of the Posterior Circulation in Children: A Comparative Cohort Study.

BACKGROUND: Inflammatory type focal cerebral arteriopathy (FCA-i) in the anterior circulation (AC) is well characterized, and the focal cerebral arteriopathy severity score (FCASS) reflects the severity of the disease. We identified cases of FCA-i in the posterior circulation (PC) and adapted the FCASS to describe these cases. METHODS: In this comparative cohort study, patients from the Swiss NeuroPaediatric Stroke Registry with ischemic stroke due to FCA-i between January 2000 and December 2018 were analyzed. A comparison between PC and AC cases regarding pediatric National Institutes of Health Stroke Scale score and pediatric stroke outcome measure and FCASS was performed. We estimated infarct size by the modified pediatric Alberta Stroke Program Early Computed Tomography Score in children with AC stroke and the adapted Bernese posterior diffusion-weighted imaging score in the PC. RESULTS: Thirty-five children with a median age of 6.3 (interquartile range, 2.7-8.2 [95% CI, 0.9-15.6]; 20 male; 57.1%) years with FCA-i were identified. The total incidence rate was 0.15/100 000/year (95% CI, 0.11-0.21). Six had PC-FCA-i. Time to final FCASS was longer in the PC compared with AC; the evolution of FCASS did not differ. Initial pediatric National Institutes of Health Stroke Scale score was higher in children with FCA-i in the PC with a median of 10.0 (interquartile range, 5.75-21.0) compared with 4.5 (interquartile range, 2.0-8.0) in those with AC-FCA-i. Different from the anterior cases, PC infarct volume did not correlate with higher discharge, maximum, or final FCASS scores (Pearson correlation coefficient [r], 0.25, 0.35, and 0.54). CONCLUSIONS: FCA-i also affects the PC. These cases should be included in future investigations into FCA-i. Although it did not correlate with clinical outcomes in our cohort, the modified FCASS may well serve as a marker for the evolution of the arteriopathy in posterior FCA-i.

CAMTA1-related disorder: Phenotypic and molecular characterization of 26 new individuals and literature review.

Calmodulin-binding transcriptional activator 1 (CAMTA1) is highly expressed in the brain and plays a role in cell cycle regulation, cell differentiation, regulation of long-term memory, and initial development, maturation, and survival of cerebellar neurons. The existence of human neurological phenotypes, including cerebellar dysfunction with variable cognitive and behavioral abnormalities (CECBA), associated with CAMTA1 variants, has further supported its role in brain functions. In this study, we phenotypically and molecularly characterize the largest cohort of individuals (n = 26) with 23 novel CAMTA1 variants (frameshift-7, nonsense-6, splicing-1, initiation codon-1, missense-5, and intragenic deletions-3) and compare the findings with all previously reported cases (total = 53). We show that the most notable phenotypic findings are developmental delay/intellectual disability, unsteady or uncoordinated gait, hypotonia, behavioral problems, and eye abnormalities. In addition, there is a high incidence of dysarthria, dysgraphia, microcephaly, gastrointestinal abnormalities, sleep difficulties, and nonspecific brain MRI findings; a few of which have been under-reported. More than one third of the variants in this cohort were inherited from an asymptomatic or mildly affected parent suggesting reduced penetrance and variable expressivity. Our cohort provides a comprehensive characterization of the spectrum of phenotypes and genotypes among individuals with CECBA and the large data will facilitate counseling and formulating management plans and surveillance recommendations for these individuals.

Fatal cervical myelopathy in a child with glutaric aciduria type 1.

We report the case of a Syrian female refugee with late diagnosis of glutaric aciduria type 1 characterised by massive axial hypotonia and quadriplegia who only started adequate diet upon arrival in Switzerland at the age of 4 years, after a strenuous migration journey. Soon after arrival, she died from an unexpected severe upper cervical myelopathy, heralded by acute respiratory distress after a viral infection. This was likely due to repeated strains on her hypotonic neck and precipitated by an orthotopic os odontoideum who led to atlanto-axial subluxation. This case reminds us not to omit handling patients with insufficient postural control and hypotonia with great care to avoid progressive cervical myelopathy.

Successful heart transplant in a child with congenital core myopathy and delayed-onset restrictive cardiomyopathy due to recessive mutations in the titin (TTN) gene.

BACKGROUND: Mutations in the TTN gene, encoding the muscle filament titin, are a major cause of inherited dilated cardiomyopathy. Early-onset skeletal muscle disorders due to recessive TTN mutations have recently been described, sometimes associated with cardiomyopathies. CASE DESCRIPTION: We report the case of a boy with congenital core myopathy due to compound heterozygosity for TTN variants. He presented in infancy with rapidly evolving restrictive cardiomyopathy, requiring heart transplantation at the age of 5 years with favorable long-term cardiac and neuromuscular outcome. CONCLUSION: Heart transplantation may have a role in selected patients with TTN-related congenital myopathy with disproportionally severe cardiac presentation compared to skeletal and respiratory muscle involvement.

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

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 SUFU gene in two families with mild JS. Recently, heterozygous truncating SUFU 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 SUFU 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 SUFU 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.

Decompressive hemicraniectomy in pediatric malignant arterial ischemic stroke: a case-based review.

PURPOSE: Malignant stroke is a life-threatening emergency, with a high mortality rate (1-3). Despite strong evidence showing decreased morbidity and mortality in the adult population, decompressive hemicraniectomy (DCH) has been scarcely reported in the pediatric stroke population, and its indication remains controversial, while it could be a potential lifesaving option. METHODS AND RESULTS: We performed an extensive literature review on pediatric malignant arterial ischemic stroke (pmAIS) and selected 26 articles reporting 97 cases. Gathering the data together, a 67% mortality rate is observed without decompressive therapy, contrasting with a 95.4% survival rate with it. The median modified Rankin score (mRS) is 2.1 after surgery with a mean follow-up of 31.8 months. For the 33% of children who survived without surgery, the mRS is 3 at a mean follow-up of 19 months. As an illustrative case, we report on a 2-year-old girl who presented a cardioembolic right middle cerebral artery stroke with subsequent malignant edema and ongoing cerebral transtentorial herniation in the course of a severe myocarditis requiring ECMO support. A DCH was done 32 h after symptom onset. At the age of 5 years, she exhibits an mRS of 3. CONCLUSION: Pediatric stroke with malignant edema is a severe condition with high mortality rate if left untreated and often long-lasting consequences. DCH might minimize the vicious circle of cerebral swelling, increasing intracranial pressure and brain ischemia. Our literature review underscores DCH as an efficient therapeutic measure management of pmAIS even when performed after a significant delay; however, long-lasting morbidities remain high.

Movement disorders in valine métabolism diseases caused by HIBCH and ECHS1 deficiencies.

BACKGROUND AND PURPOSE: HIBCH and ECHS1 genes encode two enzymes implicated in the critical steps of valine catabolism, 3-hydroxyisobutyryl-coenzyme A (CoA) hydrolase (HIBCH) and short-chainenoyl-CoA hydratase (ECHS1), respectively. HIBCH deficiency (HIBCHD) and ECHS1 deficiency (ECHS1D) generate rare metabolic dysfunctions, often revealed by neurological symptoms. The aim of this study was to describe movement disorders spectrum in patients with pathogenic variants in ECHS1 and HIBC. METHODS: We reviewed a series of 18 patients (HIBCHD: 5; ECHS1D: 13) as well as 105 patients from the literature. We analysed the detailed phenotype of HIBCHD (38 patients) and ECHS1D (85 patients), focusing on MDs. RESULTS: The two diseases have a very similar neurological phenotype, with an early onset before 10 years of age for three clinical presentations: neonatal onset, Leigh-like syndrome (progressive onset or acute neurological decompensation), and isolated paroxysmal dyskinesia. Permanent or paroxysmal MDs were recorded in 61% of HIBCHD patients and 72% of ECHS1D patients. Patients had a variable combination of either isolated or combined MD, and dystonia was the main MD. These continuous MDs included dystonia, chorea, parkinsonism, athetosis, myoclonus, tremors, and abnormal eye movements. Patients with paroxysmal dyskinesia (HIBCHD: 4; ECHS1D: 9) usually had pure paroxysmal dystonia with normal clinical examination and no major impairment in psychomotor development. No correlation could be identified between clinical pattern (especially MD) and genetic pathogenic variants. CONCLUSIONS: Movement disorders, including abnormal ocular movements, are a hallmark of HIBCHD and ECHS1D. MDs are not uniform; dystonia is the most frequent, and various types of MD are combined in single patient.

Adaptive behavior and psychiatric comorbidities in KCNB1 encephalopathy.

AIM: KCNB1 encephalopathy encompasses a broad phenotypic spectrum associating intellectual disability, behavioral disturbances, and epilepsies of various severity. Using standardized parental questionnaires, we aimed to capture the heterogeneity of the adaptive and behavioral features in a series of patients with KCNB1 pathogenic variants. METHODS: We included 25 patients with a KCNB1 encephalopathy, aged from 3.2 to 34.1 years (median = 10 years). Adaptive functioning was assessed in all patients using the French version of the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) questionnaire. We screened global behavior with the Childhood Behavioral Check-List (CBCL, Achenbach) and autism spectrum disorder (ASD) with the Social Communication Questionnaire (SCQ). We used a cluster analysis to identify subgroups of adaptive profiles. RESULTS: VABS-II questionnaire showed pathological adaptive behavior in all participants with a severity of adaptive deficiency ranging from mild in 8/20 to severe in 7/20. Eight out of 16 were at risk of Attention Problems at the CBCL and 13/18 were at risk of autism spectrum disorder (ASD). The adaptive behavior composite score significantly decreased with age (Spearman's Rho=-0.72, p<0.001) but not the equivalent ages, suggesting stagnation and slowing but no regression over time. The clustering analysis identified two subgroups of patients, one showing more severe adaptive behavior. The severity of the epilepsy phenotype predicted the severity of the behavioral profile with a sensitivity of 70% and a specificity of 90.9%. CONCLUSION: This study confirms the deleterious consequences of early-onset epilepsy in addition to the impact of the gene dysfunction in patients with KCNB1 encephalopathy. ASD and attention disorders are frequent. Parental questionnaires should be considered as useful tools for early screening and care adaptation.

[Medical and educational challenges in the care of children with disabilities]. / Enjeux médico-éducatifs dans la prise en charge de l'enfant en situation de handicap.

The International Classification of Functioning, Disability and Health (ICF) serves as a useful tool to describe the numerous challenges that pediatricians face when dealing with disabled children. In this review article, we will first discuss the issues of diagnosis announcement and communication modalities. In a second part, we will expose the challenges posed by newly available therapies for rare disorders, and innovative technologies in the field of disability, which are at the crossroads of medicine, engineering and education. Finally, we will address the question of schooling of disabled children and advocate for a close and early cooperation between health care professionals and educational stakeholders.

La Classification internationale du fonctionnement, du handicap et de la santé (CIF) permet de souligner les nombreux défis auxquels les professionnels de la santé sont confrontés face à un enfant atteint d'un handicap. Dans cet article, nous abordons les défis liés au processus de diagnostic en mettant l'accent sur les modalités de communication. Dans une deuxième partie, nous exposons les défis posés, d'une part par les nouvelles thérapies disponibles pour les maladies rares et, d'autre part, par les technologies innovantes dans le domaine du handicap, qui sont au carrefour de la médecine, de l'ingénierie et de l'éducation. Nous discutons finalement de divers aspects liés à la scolarisation des enfants en situation de handicap et de la nécessité d'une étroite collaboration entre professionnels de la santé et de l'éducation.

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

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.

Bi-allelic loss of ERGIC1 causes relatively mild arthrogryposis.

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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 (ß=0.41 [p=0.002] and ß=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 (ß=0.35; p=0.007). This result was reproduced in models with other covariables (ß=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.

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

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.

Multimodal Outcome at 7 Years of Age after Neonatal Arterial Ischemic Stroke.

OBJECTIVES: To evaluate the epileptic, academic, and developmental status at age 7 years in a large population of term-born children who sustained neonatal arterial ischemic stroke (NAIS), and to assess the co-occurrence of these outcomes. STUDY DESIGN: A cohort study including 100 term newborns with NAIS was designed. Two infants died during the neonatal period, 13 families were lost to follow-up, and 5 families declined to participate in this evaluation. Thus, 80 families completed the 7-year clinical assessment. Epileptic status, schooling, motor abilities, global intellectual functioning, spoken language, and parental opinions were recorded. Principal component analysis was applied. RESULTS: Rates of impaired language, cerebral palsy, low academic skills, active epilepsy, and global intellectual deficiency were 49%, 32%, 28%, 11%, and 8%, respectively. All were highly correlated. Eventually, 59% of children were affected by at least 1 of the aforementioned conditions. In 30% of cases, the viewpoints of health practitioners and parents did not match. CONCLUSION: The prevalence of severe disabilities at 7 years after NAIS is low, but most children exhibit some impairment in developmental profile. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02511249), Programme Hospitalier de Recherche Clinique Régional (0308052), Programme Hospitalier de Recherche Clinique Interrégional (1008026), and EudraCT (2010-A00329-30).