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BACKGROUND: Biallelic ZBTB11 variants have previously been associated with an ultrarare subtype of autosomal recessive intellectual developmental disorder (MRT69). OBJECTIVE: The aim was to provide insights into the clinical and genetic characteristics of ZBTB11-related disorders (ZBTB11-RD), with a particular emphasis on progressive complex movement abnormalities. METHODS: Thirteen new and 16 previously reported affected individuals, ranging in age from 2 to 50 years, with biallelic ZBTB11 variants underwent clinical and genetic characterization. RESULTS: All patients exhibited a range of neurodevelopmental phenotypes with varying severity, encompassing ocular and neurological features. Eleven new patients presented with complex abnormal movements, including ataxia, dystonia, myoclonus, stereotypies, and tremor, and 7 new patients exhibited cataracts. Deep brain stimulation was successful in treating 1 patient with generalized progressive dystonia. Our analysis revealed 13 novel variants. CONCLUSIONS: This study provides additional insights into the clinical features and spectrum of ZBTB11-RD, highlighting the progressive nature of movement abnormalities in the background of neurodevelopmental phenotype. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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PURPOSE: In this study, we describe the phenotype and genotype of the largest cohort of patients with Joubert syndrome (JS) carrying pathogenic variants on one of the most frequent causative genes, CC2D2A. METHODS: We selected 53 patients with pathogenic variants on CC2D2A, compiled and analysed their clinical, neuroimaging and genetic information and compared it to previous literature. RESULTS: Developmental delay (motor and language) was nearly constant but patients had normal intellectual efficiency in 74% of cases (20/27 patients) and 68% followed mainstream schooling despite learning difficulties. Epilepsy was found in only 13% of cases. Only three patients had kidney cysts, only three had genuine retinal dystrophy and no subject had liver fibrosis or polydactyly. Brain MRIs showed typical signs of JS with rare additional features. Genotype-phenotype correlation findings demonstrate a homozygous truncating variant p.Arg950* linked to a more severe phenotype. CONCLUSION: This study contradicts previous literature stating an association between CC2D2A-related JS and ventriculomegaly. Our study implies that CC2D2A-related JS is linked to positive neurodevelopmental outcome and low rate of other organ defects except for homozygous pathogenic variant p.Arg950*. This information will help modulate patient follow-up and provide families with accurate genetic counselling.
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Anomalías Múltiples , Anomalías del Ojo , Enfermedades Renales Quísticas , Humanos , Cerebelo/diagnóstico por imagen , Cerebelo/patología , Enfermedades Renales Quísticas/diagnóstico , Enfermedades Renales Quísticas/genética , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Anomalías del Ojo/diagnóstico , Anomalías del Ojo/genética , Anomalías del Ojo/patología , Retina/diagnóstico por imagen , Retina/patología , Proteínas del CitoesqueletoRESUMEN
Children with Down syndrome (DS) show delayed acquisition of cognitive and functional skills compared to typically developing children. The objective of this study was to accurately describe early development of infants and young children (children hereafter) with DS based on a large recent sample. We carried out repeated measure analysis of the global development quotient (GDQ) and developmental age using data from the Assessment of Systematic Treatment with Folinic Acid and Thyroid Hormone on Psychomotor Development of Down Syndrome Young Children (ACTHYF) study (NCT01576705). Because there was no statistically significant difference in the primary endpoint between active treatment and placebo, data from all treatment groups were pooled for post-hoc analysis. Data of 141 children with DS aged 6-18 months at inclusion were analyzed. Mean GDQ decreased over the study period, especially in the youngest age classes ([6-9] and [9-12] months), indicating that acquisition of skills occurred at a slower pace compared to typically developing children. Strongest deficits were observed for motor and hearing and language skills. Only GDQ at baseline correlated significantly with evolution of GDQ. Future studies should aim at elucidating the mechanisms underlying motor and language development. Early pharmacological interventions together with early childhood therapies might be necessary to improve the developmental trajectory of children with DS.
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Síndrome de Down , Niño , Preescolar , Cognición , Humanos , Lactante , Desarrollo del Lenguaje , Estudios ProspectivosRESUMEN
Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5-37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden's Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution.
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Trastornos Distónicos/genética , N-Metiltransferasa de Histona-Lisina/genética , Adolescente , Adulto , Niño , Preescolar , Deleción Cromosómica , Estudios de Cohortes , Simulación por Computador , Estimulación Encefálica Profunda , Progresión de la Enfermedad , Trastornos Distónicos/terapia , Enfermedades del Sistema Endocrino/complicaciones , Enfermedades del Sistema Endocrino/genética , Femenino , Retardo del Crecimiento Fetal/genética , Trastornos Neurológicos de la Marcha/etiología , Trastornos Neurológicos de la Marcha/terapia , Humanos , Enfermedades de la Laringe/etiología , Enfermedades de la Laringe/terapia , Masculino , Mutación , Mutación Missense , Fenotipo , Calidad de Vida , Resultado del Tratamiento , Adulto JovenRESUMEN
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.
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Epilepsia/diagnóstico , Epilepsia/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Variación Genética , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/genética , Canales de Potasio Shab/genética , Alelos , Estudios de Asociación Genética/métodos , Genotipo , Humanos , Fenotipo , Canales de Potasio Shab/química , Canales de Potasio Shab/metabolismo , Relación Estructura-ActividadRESUMEN
PURPOSE: To determine whether folinic acid (FA) and thyroxine, in combination or alone, benefit psychomotor development in young patients with Down syndrome (DS). METHODS: The Assessment of Systematic Treatment With Folinic Acid and Thyroid Hormone on Psychomotor Development of Down Syndrome Young Children (ACTHYF) was a single-center, randomized, double-blind, placebo-controlled phase 3 trial in DS infants aged 6-18 months. Patients were randomly assigned to one of four treatments: placebo, folinic acid (FA), L-thyroxine, or FA+L-thyroxine, administered for 12 months. Randomization was done by age and sex. The primary endpoint was adjusted change from baseline in Griffiths Mental Development Scale global development quotient (GDQ) after 12 months. RESULTS: Of 175 patients randomized, 143 completed the study. The modified intention-to-treat (mITT) population included all randomized patients who did not prematurely discontinue due to elevated baseline thyroid stimulating hormone (TSH). Baseline characteristics in the mITT were well balanced between groups, with reliable developmental assessment outcomes. Adjusted mean change in GDQ in the mITT showed similar decreases in all groups (placebo: -5.10 [95% confidence interval (CI) -7.84 to -2.37]; FA: -4.69 [95% CI -7.73 to -1.64]; L-thyroxine: -3.89 [95% CI -6.94 to -0.83]; FA+L-thyroxine: -3.86 [95% CI -6.67 to -1.06]), with no significant difference for any active treatment group versus placebo. CONCLUSION: This trial does not support the hypotheses that thyroxine and/or folinic acid improve development of young children with DS or are synergistic. This trial is registered with ClinicalTrials.gov number, NCT01576705.
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Síndrome de Down/tratamiento farmacológico , Leucovorina/administración & dosificación , Desempeño Psicomotor/efectos de los fármacos , Tiroxina/administración & dosificación , Método Doble Ciego , Síndrome de Down/psicología , Femenino , Humanos , Lactante , Análisis de Intención de Tratar/métodos , Leucovorina/farmacología , Masculino , Tiroxina/farmacología , Tiroxina/uso terapéutico , Resultado del TratamientoRESUMEN
Mitochondrial respiratory chain integrity depends on a number of proteins encoded by nuclear and mitochondrial genomes. Mutations of such factors can result in isolated or combined respiratory chain deficits, some of which can induce abnormal morphology of the mitochondrial network or accumulation of intermediary metabolites. Consequently, affected patients are clinically heterogeneous, presenting with central nervous system, muscular, or neurodegenerative disorders. ATAD3A is a nuclear-encoded ATPase protein of the AAA+ family and has been localized to the inner mitochondrial membrane. Recently reported mutations or large deletions in the ATDA3A gene in patients have been shown to induce altered mitochondrial structure and function and abnormal cholesterol metabolism in a recessive or dominant manner. Here, we report two siblings presenting axonal sensory-motor neuropathy associated with neonatal cataract. Genetic analyses identified two novel mutations in ATAD3A; a point mutation and an intronic 15 bp deletion affecting splicing and leading to exon skipping. Biochemical analysis in patient cells and tissues showed abnormal function of the mitochondrial respiratory chain in muscle and abnormal mitochondrial cristae structure. These new cases underline the large spectrum of biochemical and clinical presentations of ATAD3A deficiency and the different modes of inheritance, making it an atypical mitochondrial disorder.
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ATPasas Asociadas con Actividades Celulares Diversas/genética , Transporte de Electrón/genética , Proteínas de la Membrana/genética , Mitocondrias/genética , Enfermedades Mitocondriales/genética , Proteínas Mitocondriales/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Mitocondrias/patología , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/patología , Mutación/genética , Corteza Sensoriomotora/patología , HermanosRESUMEN
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.
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Encefalopatías/diagnóstico por imagen , Encefalopatías/genética , Epilepsia/diagnóstico por imagen , Epilepsia/genética , Variación Genética/genética , Canales de Potasio Shab/genética , Adolescente , Adulto , Encefalopatías/fisiopatología , Niño , Preescolar , Estudios de Cohortes , Electroencefalografía/tendencias , Epilepsia/fisiopatología , Femenino , Humanos , Lactante , Masculino , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
Genetic malformations of cortical development (MCDs), such as mild MCDs (mMCD), focal cortical dysplasia (FCD), and hemimegalencephaly (HME), are major causes of severe pediatric refractory epilepsies subjected to neurosurgery. FCD2 are characterized by neuropathological hallmarks that include enlarged dysmorphic neurons (DNs) and balloon cells (BCs). Here, we provide a comprehensive assessment of the contribution of germline and somatic variants in a large cohort of surgical MCD cases. We enrolled in a monocentric study 80 children with drug-resistant epilepsy and a postsurgical neuropathological diagnosis of mMCD, FCD1, FCD2, or HME. We performed targeted gene sequencing ( ≥ 2000X read depth) on matched blood-brain samples to search for low-allele frequency variants in mTOR pathway and FCD genes. We were able to elucidate 29% of mMCD/FCD1 patients and 63% of FCD2/HME patients. Somatic loss-of-function variants in the N-glycosylation pathway-associated SLC35A2 gene were found in mMCD/FCD1 cases. Somatic gain-of-function variants in MTOR and its activators (AKT3, PIK3CA, RHEB), as well as germline, somatic and two-hit loss-of-function variants in its repressors (DEPDC5, TSC1, TSC2) were found exclusively in FCD2/HME cases. We show that panel-negative FCD2 cases display strong pS6-immunostaining, stressing that all FCD2 are mTORopathies. Analysis of microdissected cells demonstrated that DNs and BCs carry the pathogenic variants. We further observed a correlation between the density of pathological cells and the variant-detection likelihood. Single-cell microdissection followed by sequencing of enriched pools of DNs unveiled a somatic second-hit loss-of-heterozygosity in a DEPDC5 germline case. In conclusion, this study indicates that mMCD/FCD1 and FCD2/HME are two distinct genetic entities: while all FCD2/HME are mosaic mTORopathies, mMCD/FCD1 are not caused by mTOR-pathway-hyperactivating variants, and ~ 30% of the cases are related to glycosylation defects. We provide a framework for efficient genetic testing in FCD/HME, linking neuropathology to genetic findings and emphasizing the usefulness of molecular evaluation in the pediatric epileptic neurosurgical population.
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Encéfalo/patología , Epilepsia/patología , Hemimegalencefalia/patología , Malformaciones del Desarrollo Cortical/patología , Adolescente , Niño , Preescolar , Estudios de Cohortes , Epilepsia/genética , Femenino , Hemimegalencefalia/genética , Humanos , Lactante , Masculino , Malformaciones del Desarrollo Cortical/genética , Mutación/genética , Neuronas/patologíaRESUMEN
NALCN is a conserved cation channel, which conducts a permanent sodium leak current and regulates resting membrane potential and neuronal excitability. It is part of a large ion channel complex, the "NALCN channelosome", consisting of multiple proteins including UNC80 and UNC79. The predominant neuronal expression pattern and its function suggest an important role in neuronal function and disease. So far, biallelic NALCN and UNC80 variants have been described in a small number of individuals leading to infantile hypotonia, psychomotor retardation, and characteristic facies 1 (IHPRF1, OMIM 615419) and 2 (IHPRF2, OMIM 616801), respectively. Heterozygous de novo NALCN missense variants in the S5/S6 pore-forming segments lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD, OMIM 616266) with some clinical overlap. In this study, we present detailed clinical information of 16 novel individuals with biallelic NALCN variants, 1 individual with a heterozygous de novo NALCN missense variant and an interesting clinical phenotype without contractures, and 12 individuals with biallelic UNC80 variants. We report for the first time a missense NALCN variant located in the predicted S6 pore-forming unit inherited in an autosomal-recessive manner leading to mild IHPRF1. We show evidence of clinical variability, especially among IHPRF1-affected individuals, and discuss differences between the IHPRF1- and IHPRF2 phenotypes. In summary, we provide a comprehensive overview of IHPRF1 and IHPRF2 phenotypes based on the largest cohort of individuals reported so far and provide additional insights into the clinical phenotypes of these neurodevelopmental diseases to help improve counseling of affected families.
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Proteínas Portadoras/genética , Canalopatías/genética , Discapacidades del Desarrollo/genética , Marcadores Genéticos , Variación Genética , Proteínas de la Membrana/genética , Canales de Sodio/genética , Adolescente , Adulto , Canalopatías/patología , Niño , Preescolar , Discapacidades del Desarrollo/patología , Femenino , Humanos , Lactante , Recién Nacido , Canales Iónicos , Masculino , Fenotipo , Adulto JovenRESUMEN
BACKGROUND: Phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) is a multisystem inborn error of metabolism. OBJECTIVES: To better characterise the natural history of PMM2-CDG. METHODS: Medical charts of 96 patients with PMM2-CDG (86 families, 41 males, 55 females) were retrospectively reviewed. Data on clinical, laboratory and molecular parameters at diagnosis were analysed. Follow-up data at last examination were reported for 25 patients. RESULTS: The patients were born between 1963 and 2011. Diagnosis of PMM2-CDG was made at a mean (SD) age of 6.8 (8.5) years. The presenting signs were mostly neurological (hypotonia, intellectual disability, cerebellar syndrome) and observed in almost all the patients. A total of 38 patients (14 males, 24 females) exhibited, in addition to neurological signs, visceral features including at least one of these: feeding difficulty requiring a nutritional support (n=23), cardiac features (n=20; pericarditis: 14, cardiac malformation: 9, cardiomyopathy: 2), hepato-gastrointestinal features (n=12; chronic diarrhoea: 7, protein-losing enteropathy: 1, ascites: 3, liver failure: 1, portal hypertension: 1), kidney features (n=4; nephrotic syndrome: 2, tubulopathy: 2) and hydrops fetalis (n=1). Twelve patients died at a mean age of 3.8 years (especially from pericarditis and other cardiac issues). Laboratory abnormalities mostly included elevated transaminases and abnormal coagulation parameters. High thyreostimulin levels, hypocholesterolemia, hypoalbuminemia and elevated transaminases were associated with the visceral phenotype. Besides the common Arg141His PMM2 variant harboured by half of the patients, 45 different variants were observed. CONCLUSIONS: PMM2-CDG clinical phenotype is heterogeneous in terms of clinical course, with no clear division between neurological and visceral presentations.
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Trastornos Congénitos de Glicosilación/diagnóstico , Trastornos Congénitos de Glicosilación/genética , Estudios de Asociación Genética , Fosfotransferasas (Fosfomutasas)/genética , Adolescente , Alelos , Sustitución de Aminoácidos , Niño , Preescolar , Trastornos Congénitos de Glicosilación/mortalidad , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Mutación , Fenotipo , Fosfotransferasas (Fosfomutasas)/metabolismoRESUMEN
Rubinstein-Taybi syndrome (RSTS) is a developmental disorder characterized by a typical face and distal limbs abnormalities, intellectual disability, and a vast number of other features. Two genes are known to cause RSTS, CREBBP in 60% and EP300 in 8-10% of clinically diagnosed cases. Both paralogs act in chromatin remodeling and encode for transcriptional co-activators interacting with >400 proteins. Up to now 26 individuals with an EP300 mutation have been published. Here, we describe the phenotype and genotype of 42 unpublished RSTS patients carrying EP300 mutations and intragenic deletions and offer an update on another 10 patients. We compare the data to 308 individuals with CREBBP mutations. We demonstrate that EP300 mutations cause a phenotype that typically resembles the classical RSTS phenotype due to CREBBP mutations to a great extent, although most facial signs are less marked with the exception of a low-hanging columella. The limb anomalies are more similar to those in CREBBP mutated individuals except for angulation of thumbs and halluces which is very uncommon in EP300 mutated individuals. The intellectual disability is variable but typically less marked whereas the microcephaly is more common. All types of mutations occur but truncating mutations and small rearrangements are most common (86%). Missense mutations in the HAT domain are associated with a classical RSTS phenotype but otherwise no genotype-phenotype correlation is detected. Pre-eclampsia occurs in 12/52 mothers of EP300 mutated individuals versus in 2/59 mothers of CREBBP mutated individuals, making pregnancy with an EP300 mutated fetus the strongest known predictor for pre-eclampsia. © 2016 Wiley Periodicals, Inc.
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Proteína de Unión a CREB/genética , Proteína p300 Asociada a E1A/genética , Preeclampsia/genética , Síndrome de Rubinstein-Taybi/genética , Adulto , Ensamble y Desensamble de Cromatina/genética , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense/genética , Preeclampsia/fisiopatología , Embarazo , Síndrome de Rubinstein-Taybi/patología , Eliminación de SecuenciaRESUMEN
Mutations in the KCNQ2 and KCNQ3 genes encoding for Kv 7.2 (KCNQ2; Q2) and Kv 7.3 (KCNQ3; Q3) voltage-dependent K(+) channel subunits, respectively, cause neonatal epilepsies with wide phenotypic heterogeneity. In addition to benign familial neonatal epilepsy (BFNE), KCNQ2 mutations have been recently found in families with one or more family members with a severe outcome, including drug-resistant seizures with psychomotor retardation, electroencephalogram (EEG) suppression-burst pattern (Ohtahara syndrome), and distinct neuroradiological features, a condition that was named "KCNQ2 encephalopathy." In the present article, we describe clinical, genetic, and functional data from 17 patients/families whose electroclinical presentation was consistent with the diagnosis of BFNE. Sixteen different heterozygous mutations were found in KCNQ2, including 10 substitutions, three insertions/deletions and three large deletions. One substitution was found in KCNQ3. Most of these mutations were novel, except for four KCNQ2 substitutions that were shown to be recurrent. Electrophysiological studies in mammalian cells revealed that homomeric or heteromeric KCNQ2 and/or KCNQ3 channels carrying mutant subunits with newly found substitutions displayed reduced current densities. In addition, we describe, for the first time, that some mutations impair channel regulation by syntaxin-1A, highlighting a novel pathogenetic mechanism for KCNQ2-related epilepsies.
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Epilepsia Benigna Neonatal/genética , Canal de Potasio KCNQ2/genética , Canal de Potasio KCNQ3/genética , Sintaxina 1/genética , Animales , Biotinilación , Células CHO , Estudios de Cohortes , Cricetulus , Femenino , Eliminación de Gen , Mutación de Línea Germinal , Humanos , Masculino , Mutagénesis Insercional , Linaje , Alineación de SecuenciaRESUMEN
Guanidinoacetate methyltransferase deficiency (GAMT-D) is an autosomal recessively inherited disorder of creatine biosynthesis. Creatine deficiency on cranial proton magnetic resonance spectroscopy, and elevated guanidinoacetate levels in body fluids are the biomarkers of GAMT-D. In 74 patients, 50 different mutations in the GAMT gene have been identified with missense variants being the most common. Clinical and biochemical features of the patients with missense variants were obtained from their physicians using a questionnaire. In 20 patients, 17 missense variants, 25% had a severe, 55% a moderate, and 20% a mild phenotype. The effect of these variants on GAMT enzyme activity was overexpressed using primary GAMT-D fibroblasts: 17 variants retained no significant activity and are therefore considered pathogenic. Two additional variants, c.22C>A (p.Pro8Thr) and c.79T>C (p.Tyr27His) (the latter detected in control cohorts) are in fact not pathogenic as these alleles restored GAMT enzyme activity, although both were predicted to be possibly damaging by in silico analysis. We report 13 new patients with GAMT-D, six novel mutations and functional analysis of 19 missense variants, all being included in our public LOVD database. Our functional assay is important for the confirmation of the pathogenicity of identified missense variants in the GAMT gene.
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Guanidinoacetato N-Metiltransferasa/deficiencia , Trastornos del Desarrollo del Lenguaje/genética , Trastornos del Desarrollo del Lenguaje/patología , Trastornos del Movimiento/congénito , Adolescente , Adulto , Niño , Preescolar , Femenino , Fibroblastos/enzimología , Predisposición Genética a la Enfermedad , Variación Genética , Guanidinoacetato N-Metiltransferasa/genética , Guanidinoacetato N-Metiltransferasa/metabolismo , Humanos , Masculino , Trastornos del Movimiento/genética , Trastornos del Movimiento/patología , Mutación Missense , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Background: GNAO1-related disorders (GNAO1-RD) encompass a diverse spectrum of neurodevelopmental and movement disorders arising from variants in the GNAO1 gene. Dyskinetic crises, marked by sudden and intense exacerbations of abnormal involuntary movements, present a significant challenge in GNAO1-RD. Objectives: This study aimed to establish a standardized framework for understanding dyskinetic crises, addressing crucial aspects such as definition, triggers, diagnostic criteria, complications, and management strategies. Methods: A Delphi consensus process was conducted involving international experts in GNAO1-RD. The panel of thirteen experts participated in three voting rounds, discussing 90 statements generated through a literature review and clinical expertise. Results: Consensus was achieved on 31 statements, defining dyskinetic crises as abrupt, paroxysmal episodes involving distinct abnormal movements in multiple body regions, triggered by emotional stress or infections. Dyskinetic crises may lead to functional impairment and complications, emphasizing the need for prompt recognition. While individualized pharmacological recommendations were not provided, benzodiazepines and clonidine were suggested for acute crisis management. Chronic treatment options included tetrabenazine, benzodiazepines, gabapentin, and clonidine. Deep brain stimulation should be considered early in the treatment of refractory or prolonged dyskinetic crisis. Conclusion: This consensus provides a foundation for understanding and managing dyskinetic crises in GNAO1-RD for clinicians, caregivers, and researchers. The study emphasizes the importance of targeted parental and caregiver education, which enables early recognition and intervention, thereby potentially minimizing both short- and long-term complications. Future research should concentrate on differentiating dyskinetic crises from other neurological events and investigating potential risk factors that influence their occurrence and nature. The proposed standardized framework improves clinical management, stakeholder communication, and future GNAO1-RD research.
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Paediatric intracranial dural arteriovenous shunts have clinical presentations and evolutions, with angiographic characteristics that differ from those described in adults. We report our experience concerning their therapeutic management, emphasizing the relevance of early diagnosis and appropriate treatment for satisfactory neurocognitive development. Using a prospective database, we reviewed the clinical and radiological data of all children with dural arteriovenous shunts managed between 2002 and 2020. Dural shunts were categorized into three types: dural sinus malformations with arteriovenous shunts; infantile dural arteriovenous shunts; and adult-type dural arteriovenous shunts. Therapeutic strategies and outcomes were analysed depending on lesional subtypes. Modified Rankin Scale for the paediatric population was assessed pre-treatment and at last follow-up. Twenty-eight patients [16 girls (57.1%); 12 boys (42.9%)] were included: 17 dural sinus malformation [10 boys (58.8%); seven girls (41.2%)], three infantile shunts [three girls (100%)], eight adult-type shunts [four girls (50%)]; four boys (50%)], with a mean age of 19.2 ± 36.6 months at presentation. Twelve (42.9%) had a modified Rankin Scale score of 0-2, four (14.3%) had a score of 3, three (10.7%) had a score of 4 and eight (28.6%) had a score of 5. Embolization was performed in 22 children [78.6%; 12 girls (54.5%); 10 boys (45.5%)]. Fifteen patients could be cured (68.2%): 11 dural sinus malformations (73.3%), four adult-type lesions (100%) but no infantile shunt. Mean post-treatment follow-up was 39.5 months (max. 139 months): 14 patients (63.6%) presented a modified Rankin Scale score of 0-2 and eight (36.4%) had a score ≥3. In the dural sinus malformation group, the modified Rankin Scale score was improved in 11 patients (73.3%) and unchanged in three (20%). Only one patient with infantile subtype (33.3%) improved clinically. In the adult-subtype group, all children (100%) improved. Of six untreated patients [four girls (66.7%); two boys (33.3%)], four with adult-subtype shunts showed uneventful evolutions, one with dural sinus malformation died, and therapeutic abortion was conducted in an antenatally diagnosed dural sinus malformation. Paediatric dural fistulas comprise different subtypes with variable clinical courses. Proper diagnosis is mandatory for optimal therapeutic strategies within appropriate therapeutic windows.
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BACKGROUND/AIMS: Mutations in the inwardly-rectifying K+ channel KCNJ10/Kir4.1 cause an autosomal recessive disorder characterized by epilepsy, ataxia, sensorineural deafness and tubulopathy (EAST syndrome). KCNJ10 is expressed in the kidney distal convoluted tubule, cochlear stria vascularis and brain glial cells. Patients clinically diagnosed with EAST syndrome were genotyped to identify and study mutations in KCNJ10. METHODS: Patient DNA was sequenced and new mutations identified. Mutant and wild-type KCNJ10 constructs were cloned and heterologously expressed in Xenopus oocytes. Whole-cell K+ currents were measured by two-electrode voltage clamping. RESULTS: Three new mutations in KCNJ10 (p.R65C, p.F75L and p.V259fs259X) were identified, and mutation p.R297C, previously only seen in a compound heterozygous patient, was found in a homozygous state. Wild-type human KCNJ10-expressing oocytes showed strongly inwardly-rectified currents, which by comparison were significantly reduced in all the mutants (p < 0.001). Specific inhibition of KCNJ10 currents by Ba2+ demonstrated residual function in all mutant channels (p < 0.05) but V259X. CONCLUSION: This study confirms that EAST syndrome can be caused by many different mutations in KCNJ10 that significantly reduce K+ conductance. EAST syndrome should be considered in any patient with a renal Gitelman-like phenotype with additional neurological signs and symptoms like ataxia, epilepsy or sensorineural deafness.
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Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/fisiopatología , Discapacidad Intelectual/genética , Discapacidad Intelectual/fisiopatología , Canales de Potasio de Rectificación Interna/fisiología , Convulsiones/genética , Convulsiones/fisiopatología , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Femenino , Genotipo , Pérdida Auditiva Sensorineural/metabolismo , Humanos , Discapacidad Intelectual/metabolismo , Túbulos Renales Distales/metabolismo , Masculino , Datos de Secuencia Molecular , Mutación , Oocitos/fisiología , Técnicas de Placa-Clamp , Canales de Potasio de Rectificación Interna/química , Canales de Potasio de Rectificación Interna/genética , Canales de Potasio de Rectificación Interna/metabolismo , Convulsiones/metabolismo , Análisis de Secuencia de ADN , Xenopus laevis/genética , Xenopus laevis/fisiologíaRESUMEN
BACKGROUND: Torcular dural sinus malformations (tDSMs) with arteriovenous shunts are rare congenital intracranial vascular malformations that carry a high rate of neurologic impairment and death in the neonatal, infant and young pediatric population. Their impact on brain venous drainage, especially the deep venous system, is one of the key factors in the clinical prognosis and natural history of the disease. We describe our therapeutic strategy for tDSMs, disconnecting the reflux into the deep venous system by performing an endovascular straight sinus occlusion. METHODS: Among all children with dural sinus malformations seen between 2002 and 2020, we retrospectively reviewed those with tDSM in whom straight sinus occlusion had been performed. RESULTS: Our databank included nine patients with tDSM that were embolized. Mean age at the clinical onset was 8.9±9.6 months (min-max=0-31). Five patients presented a significant reflux in the straight sinus on digital subtraction angiography. Those patients were initially clinically worse (mean modified Rankin Scale (mRS) 3.8) than those who did not present with reflux (mean mRS 2.25), this reflux being responsible for intraventricular hemorrhage in three patients. The reflux was suppressed by transarterial embolization in one patient and by transvenous straight sinus occlusion in four patients. Staged endovascular treatment resulted in a complete cure in six patients without complications, and clinical improvement in all patients. CONCLUSION: Straight sinus occlusion is a feasible technique that needs to be considered in the treatment strategy for tDSM with deep venous reflux in order to avoid or minimize brain damage.
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Fístula Arteriovenosa/diagnóstico por imagen , Fístula Arteriovenosa/cirugía , Manejo de la Enfermedad , Procedimientos Endovasculares/métodos , Malformaciones Arteriovenosas Intracraneales/diagnóstico por imagen , Malformaciones Arteriovenosas Intracraneales/cirugía , Angiografía de Substracción Digital/métodos , Angiografía Cerebral/métodos , Preescolar , Senos Craneales/diagnóstico por imagen , Senos Craneales/cirugía , Femenino , Humanos , Lactante , Masculino , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
OBJECTIVE: Report of the contribution of invasive EEG (iEEG) and epileptogenicity mappings (EM) in a pediatric cohort of patients with epilepsy associated with focal polymicrogyria (PMG) and candidates for resective surgery. METHOD: Retrospective pediatric case series of patients presenting focal PMG-related refractory epilepsy undergoing an invasive exploration (iEEG) at Fondation Rothschild Hospital. We reviewed clinical data, structural MRI, and visual analysis of iEEG recordings. Moreover, time-frequency analysis of SEEG signals with a neuroimaging approach (epileptogenicity maps) was used to support visual analysis. RESULTS: Between 2012 and 2019, eight patients were selected. Five patients were explored with stereoelectroencephalography (SEEG) only, one patient with subdural exploration (SDE) only and two patients first underwent SEEG and then SDE. The mean age at seizure onset was 40.3 months (range 3-120), and the mean age for the iEEG 10.8 years (range 7-15). The epileptogenic zone (EZ) appeared concordant to the PMG lesion in only one case, was larger in three cases, smaller in two cases and different in one case. Four cases were selected for tailored resective surgery and one for total callosotomy. Two patients remained seizure-free at their last follow-up (mean 32.6 months, range 7-98). Epileptogenicity mapping (EM) refined the qualitative analysis, showing in four patients an EZ larger than visually defined. CONCLUSION: This study is the first pediatric study to analyze the value of iEEG and EM as well as operability in focal PMG-related refractory epilepsy. The results illustrate the complexity of this pathology with variable concordance between the EZ and the lesion and mixed response to surgery.
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Epilepsia Refractaria , Polimicrogiria , Adolescente , Niño , Preescolar , Epilepsia Refractaria/cirugía , Electroencefalografía , Humanos , Lactante , Polimicrogiria/complicaciones , Polimicrogiria/diagnóstico por imagen , Polimicrogiria/cirugía , Estudios Retrospectivos , Técnicas EstereotáxicasRESUMEN
The phenotypic spectrum of STXBP1-related encephalopathy ranges from infantile epileptic encephalopathy to intellectual disability with nonsyndromic or absent epilepsy. Although being frequently reported, the tremor associated with STXBP1 has not been fully characterized to date. The aim of our study was to describe it. We recruited patients with intellectual disability due to STXBP1 variants, regardless of their epileptic phenotype, who had tremor at examination and who underwent neurophysiological testing including polymyographic registration of upper limbs muscles activity at rest, during posture maintenance and action. Six patients met the inclusion criteria over four years. Clinically, all had a postural and action distal tremor increased by emotions. Neurophysiological recordings showed a specific myoclonus pattern and were highly suggestive of a subcortical generator. The tremor-like observed in STXBP1 encephalopathy is due to a subcortical pseudo-rhythmic myoclonus.