Ceroid lipofuscinosis type 2 disease: Effective presymptomatic therapy-Oldest case of a presymptomatic enzyme therapy.

Neuronal ceroid lipofuscinosis type 2 (CLN2) disease is a rare, lysosomal storage disorder that causes pediatric onset neurodegenerative disease. It is characterized by mutations in the TPP1 gene. Symptoms begin between 2 and 4 years of age with loss of previously acquired motor, cognitive, and language abilities. Cerliponase alfa, a recombinant human TPP1 enzyme, is the only approved therapy. We report the first presymptomatic cerliponase alfa intraventricular treatment in a familial case of CLN2 related to a classical TPP1 variant. Sister 1 presented with motor, cognitive, and language decline and progressive myoclonic epilepsy since the age of 3 years, evolved with severe diffuse encephalopathy, received no specific treatment, and died at 11 years. Sister 2 had a CLN2 presymptomatic diagnosis and has been treated with cerliponase since she was 12 months old. She is now 6 years 8 months and has no CLN2 symptom except one generalized seizure 1 year ago. No serious adverse event has occurred. Repeated Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition standardized index scores are heterogeneous in the extremely low to low average ranges. Mean length of utterances, a global index of sentence complexity, showed a delay, but a gradual improvement. The reported case enhances the major contribution of presymptomatic diagnosis and significant middle-term treatment benefit for patients with CLN2.

The longitudinal evolution of cerebral blood flow in children with tuberous sclerosis assessed by arterial spin labeling magnetic resonance imaging may be related to cognitive performance.

OBJECTIVE: To study longitudinal changes in tuber and whole-brain perfusion in children with tuberous sclerosis complex (TSC) using arterial spin labeling (ASL) perfusion MRI and correlate them with pathological EEG slow wave activity and neurodevelopmental outcomes. METHODS: Retrospective longitudinal cohort study of 13 children with TSC, 3 to 6 serial ASL-MRI scans between 2 months and 7 years of age (53 scans in total), and an EEG examination performed within 2 months of the last MRI. Tuber cerebral blood flow (CBF) values were calculated in tuber segmentation masks, and tuber:cortical CBF ratios were used to study tuber perfusion. Logistic regression analysis was performed to identify which initial tuber characteristics (CBF value, volume, location) in the first MRI predicted tubers subsequently associated with EEG slow waves. Whole-brain and lobar CBF values were extracted for all patient scans and age-matched controls. CBF ratios were compared in patients and controls to study longitudinal changes in whole-brain CBF. RESULTS: Perfusion was reduced in tubers associated with EEG slow waves compared with other tubers. Low tuber CBF values around 6 months of age and large tuber volumes were predictive of tubers subsequently associated with EEG slow waves. Patients with severe developmental delay had more severe whole-brain hypoperfusion than those with no/mild delay, which became apparent after 2 years of age and were not associated with a higher tuber load. CONCLUSIONS: Dynamic changes in tuber and brain perfusion occur over time. Perfusion is significantly reduced in tubers associated with EEG slow waves. Whole-brain perfusion is significantly reduced in patients with severe delay. KEY POINTS: • Tubers associated with EEG slow wave activity were significantly more hypoperfused than other tubers, especially after 1 year of age. • Larger and more hypoperfused tubers at 6 months of age were more likely to subsequently be associated with pathological EEG slow wave activity. • Patients with severe developmental delay had more extensive and severe global hypoperfusion than those without developmental delay.

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.

Fetal Brain Magnetic Resonance Imaging Findings Predict Neurodevelopment in Children with Tuberous Sclerosis Complex.

OBJECTIVE: To correlate fetal brain magnetic resonance imaging (MRI) findings with epilepsy characteristics and neurodevelopment at 2 years of age in children with tuberous sclerosis complex (TSC) to improve prenatal counseling. STUDY DESIGN: This retrospective cohort study was performed in a collaboration between centers of the EPISTOP consortium. We included children with definite TSC, fetal MRIs, and available follow-up data at 2 years of age. A pediatric neuroradiologist masked to the patient's clinical characteristics evaluated all fetal MRIs. MRIs were categorized for each of the 10 brain lobes as score 0: no (sub)cortical lesions or doubt; score 1: a single small lesion; score 2: more than one small lesion or at least one large lesion (>5 mm). Neurologic manifestations were correlated to lesion sum scores. RESULTS: Forty-one children were included. Median gestational age at MRI was 33.3 weeks; (sub)cortical lesions were detected in 97.6%. Mean lesion sum score was 4.5. At 2 years, 58.5% of patients had epilepsy and 22% had drug-resistant epilepsy. Cognitive, language, and motor development were delayed in 38%, 81%, and 50% of patients, respectively. Autism spectrum disorder (ASD) was diagnosed in 20.5%. Fetal MRI lesion sum scores were significantly associated with cognitive and motor development, and with ASD diagnosis, but not with epilepsy characteristics. CONCLUSIONS: Fetal cerebral lesion scores correlate with neurodevelopment and ASD at 2 years in children with TSC.

Expanding the genetic and phenotypic relevance of KCNB1 variants in developmental and epileptic encephalopathies: 27 new patients and overview of the literature.

Developmental and epileptic encephalopathies (DEE) refer to a heterogeneous group of devastating neurodevelopmental disorders. Variants in KCNB1 have been recently reported in patients with early-onset DEE. KCNB1 encodes the α subunit of the delayed rectifier voltage-dependent potassium channel Kv 2.1. We review the 37 previously reported patients carrying 29 distinct KCNB1 variants and significantly expand the mutational spectrum describing 18 novel variants from 27 unreported patients. Most variants occur de novo and mainly consist of missense variants located on the voltage sensor and the pore domain of Kv 2.1. We also report the first inherited variant (p.Arg583*). KCNB1-related encephalopathies encompass a wide spectrum of neurodevelopmental disorders with predominant language difficulties and behavioral impairment. Eighty-five percent of patients developed epilepsies with variable syndromes and prognosis. Truncating variants in the C-terminal domain are associated with a less-severe epileptic phenotype. Overall, this report provides an up-to-date review of the mutational and clinical spectrum of KCNB1, strengthening its place as a causal gene in DEEs and emphasizing the need for further functional studies to unravel the underlying mechanisms.

Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome.

OBJECTIVE: We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy. METHODS: We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association "KCNB1 France." Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the long-term outcome in patients older than 12 years from our series and from literature. RESULTS: Our series included 36 patients (21 males, median age = 10 years, range = 1.6 months-34 years). Twenty patients (56%) had DEE with infantile onset seizures (seizure onset = 10 months, range = 10 days-3.5 years), whereas 16 (33%) had DE with late onset epilepsy in 10 (seizure onset = 5 years, range = 18 months-25 years) and without epilepsy in six. Cognitive impairment was more severe in individuals with DEE compared to those with DE. Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports) showed developmental delay in all with severe to profound intellectual disability in 67% (n = 41/61) and autistic features in 56% (n = 32/57). Long-term outcome in 22 individuals older than 12 years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome. Epilepsy course was variable. Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants. SIGNIFICANCE: Our study describes the phenotypic spectrum of KCNB1 encephalopathy, which varies from severe DEE to DE with or without epilepsy. Although cognitive impairment is worse in patients with DEE, long-term outcome is poor for most and missense variants are associated with more severe epilepsy outcome. Further understanding of disease mechanisms should facilitate the development of targeted therapies, much needed to improve the neurodevelopmental prognosis.

Transition of patients with childhood onset epilepsy: Perspectives from pediatric and adult neurologists.

Transition from pediatric to adult care systems is a major challenge in the management of adolescents with epilepsy. The comparison of pediatric and adult physicians' points of view on this issue is scarcely described. The aim of this study was to understand pediatric and adult neurologists' experience and opinions on transition in epilepsy in France. We investigate the age at which they usually transfer patients, their opinion on the factors that positively or negatively impact transition, on the help provided during this transition period, and their propositions to improve this process. We prepared a targeted questionnaire with two versions, one adapted for neurologists and the other for child neurologists. The questionnaires were diffused through the Reference Centre for Rare Epilepsies, the French Chapter of the League Against Epilepsy, the French Association for Office-based Neurologists, and the French Pediatric Neurology Society. A total of sixty-eight physicians involved mostly in epilepsy care answered this questionnaire: 39 child neurologists and 29 neurologists. Questionnaires were filled at 96.8%. Twenty-six child neurologists followed patients aged over 18 years (70%), and 18 neurologists followed patients under the age of 12 years (66.6%). Cognitive impairment in childhood led significantly to a later transfer to adult care. The major factors believed to delay the transfer were attachment between child neurologists and families as reported in 96.3% by neurologists and in 81.1% by child neurologists, p = 0.07 and lack of adaptation of adult neurology facilities to adolescents especially with intellectual disability (59.3% neurologists, 75.7% child neurologists, p = 0.16). Factors that helped a transfer around 18-19 years were mainly pharmacoresistant epilepsy (71% for neurologists vs. 19% for child neurologists, p < 105) and pregnancy (72% for child neurologists versus 50% for neurologists, p = 0.08). Factors that negatively impacted transition were the lack of information about daily life in adulthood (driving license, contraception, sexuality, carrier guidance, etc.), the weak transition preparation in pediatric system, the lack of knowledge of pediatric epilepsy syndromes, and the lack of global support for patients with intellectual disability and multidisciplinary care needs in adult system. Both groups proposed joint clinics (>65% of providers) and development of care networks between pediatric and adult care for patients with epilepsy (>55%) to improve transition as well as introducing courses on transition. Few physicians were aware of transition and transfer recommendations. Although child and adult neurologists still have some preconceived beliefs, they were able to identify the strengths and weaknesses of both care systems paving the way for proposals to improve transition and transfer of patients with epilepsy from pediatric to adult care.

Usefulness of preschool and school versions of the Behavioral Rating Inventory of Executive Functions in the evaluation of the daily life executive function in myoclonic-atonic epilepsy.

PURPOSE: Executive functions (EF) are high-order cognitive skills that have a major influence on quality of life, social skills, and school achievement. We aimed to screen EF daily life abilities in young patients with myoclonic-atonic epilepsy (MAE) using an ecological questionnaire and to correlate EF to epilepsy characteristics. METHODS: Behavioral Rating Inventory of Executive Functions - Preschool (BRIEF-P) and BRIEF - for school-aged patients - parental questionnaires were proposed to patients with MAE and typically developing children (TDC) including Inhibit, Shift, Emotional control, Working memory (WM), Plan/Organize, Initiate, Organization of materials, and Monitor subscales. We included prospectively 12 patients with MAE and 44 TDC aged 3 to 5 years and seven patients with MAE and 21 TDC aged 6-7 years. We performed in addition for all patients an intellectual efficiency evaluation using WPPSI-IV (Wechsler intelligence scale for preschool children version IV) and collected demographics, age at onset of epilepsy, epilepsy duration, response to treatment, number and type of treatments including AEDs (antiepileptic drugs), and ketogenic diet. RESULTS: Four out of 12 patients for BRIEF-P and 6/7 patients for BRIEF had pathological scores for at least one domain. Behavioral Rating Inventory of Executive Functions' questionnaires showed higher pathological scores for WM, Plan/Organize, Initiate, Monitor, and Metacognition Index in patients with MAE compared to TDC suggesting higher problems reported by parents. Working memory scores were higher in the group with MAE than TDC for both BRIEF-P and BRIEF. Response to treatment is a predictor of multiple BRIEF-P domains. Epilepsy duration predicts Shift and WM domains while age at onset predicts WM domain on BRIEF in this syndrome. CONCLUSIONS: This study is the first to assess prospectively EF in young patients with MAE. We show everyday deficits in EF reported by parents. Metacognition and more specifically WM, appear to be a core deficit. Early evaluation of EF using both questionnaires and standardized tools is necessary for early detection of EF deficit and initiating tailored rehabilitation. Given the normal development before seizure onset and the absence of cerebral lesion in MAE, these results are in favor of the impact of epilepsy on EF.

Autism spectrum disorder phenotype and intellectual disability in females with epilepsy and PCDH-19 mutations.

INTRODUCTION: Autism features and various degrees of cognitive deficit are reported in patients with PCDH-19 mutations and epilepsy. Autism spectrum disorder (ASD) and, often, cognitive profile are usually assessed clinically. We studied autism phenotype and cognitive outcome in a series of patients using standardized tools for development and ASD. We aimed to describe the phenotype of ASD in this series and to understand whether ASD is strictly linked to intellectual disability (ID) or is present as a comorbidity. METHODS: Eight females aged 5 to 17years old with PCDH-19 mutations and epilepsy were recruited. For ASD diagnosis, the Autism Diagnostic Interview - Revised (ADI-R) and the Autism Diagnosis Observation Schedule (ADOS) were administered. Patients underwent a neuropsychological examination with tests measuring global intellectual efficiency (WPPSI-III and WISC-IV), language, and executive and social cognition abilities. Parental adaptive behavioral questionnaires were also obtained (VABS, CBCL, and BRIEF). RESULTS: Six out of eight patients presented with ASD and ID. Two patients had neither ASD nor ID, and both had the latest age of onset for their epilepsy. All cognitive functions were deficient, but theory-of-mind abilities compared to other cognitive features were even impaired. Features of ASD lacked major repetitive and stereotyped behaviors and show some differences with the classical ASD features related to ID. CONCLUSION: Our results show a large spectrum of ID and a very high rate of ASD in patients with epilepsy and PCDH-19 mutations. Autism spectrum disorder seems to be a genuine comorbidity, more than a consequence of ID. It highlights the importance of standardized psychiatric and cognitive evaluation in order to establish a tailored rehabilitation program.

Autism spectrum disorder and cognitive profile in children with Dravet syndrome: Delineation of a specific phenotype.

OBJECTIVE: We aimed to assess a cohort of young patients with Dravet syndrome (DS) for intellectual disability (ID) and autism spectrum disorder (ASD) using standardized tools and parental questionnaires to delineate their specific profiles. METHODS: We included 35 patients with DS aged 24 months to 7 years, excluding patients with a developmental age (DA) <18 months (n = 5). We performed specific tests adapted for ID (Psychoeducational Profile, Third Edition [PEP-3]), in addition to the Child Development Inventory (CDI) and Vineland Adaptive Behavior Scales, Second Edition (VABS-II) questionnaires. We used 2 standardized tools for ASD: the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2) and the Autism Diagnostic Interview-Revised (ADI-R). We compared the with parental questionnaires and the VABS-II, and with ASD characteristics. RESULTS: PEP-3 subscales showed pathologic development in all but one patient (97%): ID in 23 of 30 (77%), and borderline cognitive functioning in 6 of 30 (22%). Eleven patients (39%) had ASD and 2 (7%) had a Social Communication Disorder (SCD) diagnosis. We found no difference between PEP-3 and CDI categorization except for fine motor skills. We found significant negative correlations between ADOS-2 and PEP-3 for the majority of scores. For patients aged older than 50 months, 2 groups emerged (ASD/no ASD) with significant difference in DA. The logistic regression for ASD diagnosis explained by VABS-II showed a significant effect for Socialization, Motor Skills, and Adaptive Behavior. SIGNIFICANCE: We found a high prevalence of ID in patients with DS. ID is characterized by expressive and comprehensive communication deficits in addition to visuospatial difficulties. ASD showed a specific profile with a relative preservation of social skills, emphasizing a possible underdiagnosis. Parental questionnaires can provide a good assessment of cognitive profile and might allow the difficulty of addressing cognitive scales in DS to be overcome. The profile of ID and ASD should help to establish early adapted rehabilitation programs and emphasizes the global need for care beyond seizures in DS and other developmental epileptic encephalopathies.