Epilepsy in Duchenne and Becker muscular dystrophies.

OBJECTIVE: Duchenne and Becker muscular dystrophies (DMD and BMD) are dystrophinopathies caused by variants in DMD gene, resulting in reduced or absent dystrophin. These conditions, characterized by muscle weakness, also manifest central nervous system (CNS) comorbidities due to dystrophin expression in the CNS. Prior studies have indicated a higher prevalence of epilepsy in individuals with dystrophinopathy compared to the general population. Our research aimed to investigate epilepsy prevalence in dystrophinopathies and characterize associated electroencephalograms (EEGs) and seizures. METHODS: We reviewed 416 individuals with dystrophinopathy, followed up at three centers between 2010 and 2023, to investigate the lifetime epilepsy prevalence and characterize EEGs and seizures in those individuals diagnosed with epilepsy. Associations between epilepsy and type of dystrophinopathy, genotype, and cognitive involvement were studied. RESULTS: Our study revealed a higher epilepsy prevalence than the general population (1.4%; 95% confidence interval: 0.7-3.2%), but notably lower than previously reported in smaller dystrophinopathy cohorts. No significant differences were found in epilepsy prevalence between DMD and BMD or based on underlying genotypes. Cognitive impairment was not found to be linked to higher epilepsy rates. The most prevalent epilepsy types in dystrophinopathies resembled those observed in the broader pediatric population, with most individuals effectively controlled through monotherapy. INTERPRETATION: The actual epilepsy prevalence in dystrophinopathies may be markedly lower than previously estimated, possibly half or even less. Our study provides valuable insights into the epilepsy landscape in individuals with dystrophinopathy, impacting medical care, especially for those with concurrent epilepsy.

Severity of GNAO1-Related Disorder Correlates with Changes in G-Protein Function.

OBJECTIVE: GNAO1-related disorders (OMIM #615473 and #617493), caused by variants in the GNAO1 gene, are characterized by developmental delay or intellectual disability, hypotonia, movement disorders, and epilepsy. Neither a genotype-phenotype correlation nor a clear severity score have been established for this disorder. The objective of this prospective and retrospective observational study was to develop a severity score for GNAO1-related disorders, and to delineate the correlation between the underlying molecular mechanisms and clinical severity. METHODS: A total of 16 individuals with GNAO1-related disorders harboring 12 distinct missense variants, including four novel variants (p.K46R, p.T48I, p.R209P, and p.L235P), were examined with repeated clinical assessments, video-electroencephalogram monitoring, and brain magnetic resonance imaging. The molecular pathology of each variant was delineated using a molecular deconvoluting platform. RESULTS: The patients displayed a wide variability in the severity of their symptoms. This heterogeneity was well represented in the GNAO1-related disorders severity score, with a broad range of results. Patients with the same variant had comparable severity scores, indicating that differences in disease profiles are not due to interpatient variability, but rather, to unique disease mechanisms. Moreover, we found a significant correlation between clinical severity scores and molecular mechanisms. INTERPRETATION: The clinical score proposed here provides further insight into the correlation between pathophysiology and phenotypic severity in GNAO1-related disorders. We found that each variant has a unique profile of clinical phenotypes and pathological molecular mechanisms. These findings will contribute to better understanding GNAO1-related disorders. Additionally, the severity score will facilitate standardization of patients categorization and assessment of response to therapies in development. ANN NEUROL 2023;94:987-1004.

Expanding the phenotypic spectrum of TRAPPC11-related muscular dystrophy: 25 Roma individuals carrying a founder variant.

BACKGROUND: Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetically determined muscle disorders. TRAPPC11-related LGMD is an autosomal-recessive condition characterised by muscle weakness and intellectual disability. METHODS: A clinical and histopathological characterisation of 25 Roma individuals with LGMD R18 caused by the homozygous TRAPPC11 c.1287+5G>A variant is reported. Functional effects of the variant on mitochondrial function were investigated. RESULTS: The c.1287+5G>A variant leads to a phenotype characterised by early onset muscle weakness, movement disorder, intellectual disability and elevated serum creatine kinase, which is similar to other series. As novel clinical findings, we found that microcephaly is almost universal and that infections in the first years of life seem to act as triggers for a psychomotor regression and onset of seizures in several individuals with TRAPPC11 variants, who showed pseudometabolic crises triggered by infections. Our functional studies expanded the role of TRAPPC11 deficiency in mitochondrial function, as a decreased mitochondrial ATP production capacity and alterations in the mitochondrial network architecture were detected. CONCLUSION: We provide a comprehensive phenotypic characterisation of the pathogenic variant TRAPPC11 c.1287+5G>A, which is founder in the Roma population. Our observations indicate that some typical features of golgipathies, such as microcephaly and clinical decompensation associated with infections, are prevalent in individuals with LGMD R18.

New genes involved in Angelman syndrome-like: Expanding the genetic spectrum.

Angelman syndrome (AS) is a neurogenetic disorder characterized by severe developmental delay with absence of speech, happy disposition, frequent laughter, hyperactivity, stereotypies, ataxia and seizures with specific EEG abnormalities. There is a 10-15% of patients with an AS phenotype whose genetic cause remains unknown (Angelman-like syndrome, AS-like). Whole-exome sequencing (WES) was performed on a cohort of 14 patients with clinical features of AS and no molecular diagnosis. As a result, we identified 10 de novo and 1 X-linked pathogenic/likely pathogenic variants in 10 neurodevelopmental genes (SYNGAP1, VAMP2, TBL1XR1, ASXL3, SATB2, SMARCE1, SPTAN1, KCNQ3, SLC6A1 and LAS1L) and one deleterious de novo variant in a candidate gene (HSF2). Our results highlight the wide genetic heterogeneity in AS-like patients and expands the differential diagnosis.

Epilepsy in LAMA2-related muscular dystrophy: An electro-clinico-radiological characterization.

OBJECTIVE: To delineate the epileptic phenotype of LAMA2-related muscular dystrophy (MD) and correlate it with the neuroradiological and muscle biopsy findings, as well as the functional motor phenotype. METHODS: Clinical, electrophysiological, neuroradiological, and histopathological data of 25 patients with diagnosis of LAMA2-related MD were analyzed. RESULTS: Epilepsy occurred in 36% of patients with LAMA2-related MD. Mean age at first seizure was 8 years. The most common presenting seizure type was focal-onset seizures with or without impaired awareness. Visual aura and autonomic signs, including vomiting, were frequently reported. Despite a certain degree of variability, bilateral occipital or temporo-occipital epileptiform abnormalities were by far the most commonly observed. Refractory epilepsy was found in 75% of these patients. Epilepsy in LAMA2-related MD was significantly more prevalent in those patients in whom the cortical malformations were more extensive. In contrast, the occurrence of epilepsy was not found to be associated with the patients' motor ability, the size of their white matter abnormalities, or the amount of residual merosin expressed on muscle. SIGNIFICANCE: The epileptic phenotype of LAMA2-related MD is characterized by focal seizures with prominent visual and autonomic features associated with EEG abnormalities that predominate in the posterior quadrants. A consistent correlation between epileptic phenotype and neuroimaging was identified, suggesting that the extension of the polymicrogyria may serve as a predictor of epilepsy occurrence.

Retrospective natural history of thymidine kinase 2 deficiency.

BACKGROUND: Thymine kinase 2 (TK2) is a mitochondrial matrix protein encoded in nuclear DNA and phosphorylates the pyrimidine nucleosides: thymidine and deoxycytidine. Autosomal recessive TK2 mutations cause a spectrum of disease from infantile onset to adult onset manifesting primarily as myopathy. OBJECTIVE: To perform a retrospective natural history study of a large cohort of patients with TK2 deficiency. METHODS: The study was conducted by 42 investigators across 31 academic medical centres. RESULTS: We identified 92 patients with genetically confirmed diagnoses of TK2 deficiency: 67 from literature review and 25 unreported cases. Based on clinical and molecular genetics findings, we recognised three phenotypes with divergent survival: (1) infantile-onset myopathy (42.4%) with severe mitochondrial DNA (mtDNA) depletion, frequent neurological involvement and rapid progression to early mortality (median post-onset survival (POS) 1.00, CI 0.58 to 2.33 years); (2) childhood-onset myopathy (40.2%) with mtDNA depletion, moderate-to-severe progression of generalised weakness and median POS at least 13 years; and (3) late-onset myopathy (17.4%) with mild limb weakness at onset and slow progression to respiratory insufficiency with median POS of 23 years. Ophthalmoparesis and facial weakness are frequent in adults. Muscle biopsies show multiple mtDNA deletions often with mtDNA depletion. CONCLUSIONS: In TK2 deficiency, age at onset, rate of weakness progression and POS are important variables that define three clinical subtypes. Nervous system involvement often complicates the clinical course of the infantile-onset form while extraocular muscle and facial involvement are characteristic of the late-onset form. Our observations provide essential information for planning future clinical trials in this disorder.

[Epilepsy and cognition: the role of antiepileptic drugs]. / Epilepsia y cognición: el papel de los fármacos antiepilépticos.

INTRODUCTION: Multiple factors underlie the cognitive changes associated with epilepsy, including the effect of antiepileptic drug (AED) therapy itself. The use of AEDs in the management of epilepsy requires an ongoing risk-benefit analysis that attempts to maximize seizure control while minimizing adverse cognitive side-effects. AIM: This review focuses on the global and specific cognitive effects of the classic and the new AEDs. DEVELOPMENT: All of the established AEDs can produce cognitive side effects, which are increased with polypharmacy and with increasing dosage and anticonvulsant blood levels. The main disorders are a diminished reaction and information processing time with alterations affecting memory, attention and language. Further, there is much debate concerning the existence and clinical importance of differential AED cognitive side effects and a large portion of the literature examining the comparative cognitive effects of AEDs is limited by inadequate study designs. CONCLUSIONS: Cognitive side effects of antiepileptic drugs are common and can negatively affect tolerability, compliance, and long-term retention of the treatment. The role of cognitive side effects should be kept in proper perspective when choosing AED therapy. It is important to be able to recognize early these effects and to put them into perspective as to how they affect our patients.

TITLE: Epilepsia y cognicion: el papel de los farmacos antiepilepticos.Introduccion. Multiples y muy diversos factores se relacionan con la alteracion cognitiva en la epilepsia, incluyendo el efecto adverso directo de los farmacos antiepilepticos (FAE). El uso de los FAE requiere de un riguroso equilibrio entre riesgo y beneficio para conseguir asi el mejor control de las crisis con el menor numero de efectos adversos neurocognitivos. Objetivo. Analizar los efectos adversos cognitivos generales y especificos de los FAE de primera, segunda y tercera generacion. Desarrollo. Todos los FAE disponibles pueden producir efectos adversos cognitivos, que son mas frecuentes en politerapia, con dosis totales altas y niveles sericos elevados. Las alteraciones mas comunes son el descenso de la capacidad de reaccion y de la velocidad de procesamiento con afectacion concomitante de la memoria, la atencion y el lenguaje. Sin embargo, hay gran controversia sobre la existencia o no de perfiles cognitivos especificos para cada uno de los distintos FAE y se dispone de una informacion contradictoria al respecto por la inadecuada metodologia de los estudios comparativos. Conclusiones. Los efectos adversos cognitivos de los FAE son frecuentes y pueden afectar negativamente la tolerabilidad, el cumplimiento y el mantenimiento a largo plazo del tratamiento antiepileptico. Se debe considerar el potencial efecto adverso cognitivo de los distintos FAE a la hora de elegir un tratamiento y es importante reconocer e identificar precozmente estos efectos adversos y saber como pueden afectar a los pacientes.

Epilepsia mioclónica benigna del lactante: evolución natural y pronóstico neurocognitivo y conductual / Benign myoclonic epilepsy in infancy: natural history and behavioral and cognitive outcome

Introducción. La epilepsia mioclónica benigna del lactante (EMBL) es un síndrome electroclínico de características homogéneas y bien definidas, considerado clásicamente de buen pronóstico. Sin embargo, en los últimos años se han publicado estudios con resultados variables en cuanto a evolución neuropsicológica. Objetivo. Analizar la evolución natural y el pronóstico neurocognitivo y conductual de los pacientes con EMBL. Pacientes y métodos. Estudio retrospectivo de 10 pacientes con EMBL, con un período de seguimiento de más de cinco años, durante los cuales se realizó una evaluación neurocognitiva y conductual. Resultados. En el 60% de los pacientes las crisis se controlaron con ácido valproico en monoterapia, y el 80% no presentó nuevas crisis durante su seguimiento. El cociente intelectual de la cohorte se situó entre 74 y 93; tres pacientes tuvieron un cociente intelectual en rango de inteligencia límite, y seis, en rango de inteligencia media-baja. Nueve pacientes cumplieron criterios de trastorno por déficit de atención/hiperactividad y dos asociaban otro trastorno del aprendizaje, uno de ellos trastorno de aprendizaje no verbal, y el otro, trastorno específico de la lectoescritura. Todos los pacientes presentaron datos de pobre coordinación motriz y visuoespacial, y tres fueron diagnosticados de trastorno de conducta. Conclusiones. El término ‘benigno’ en la EMBL debe utilizarse con precaución en cuanto a su pronóstico neurocognitivo y conductual. El inicio precoz y un peor control de las crisis podrían suponer factores de riesgo de evolución neuropsicológica desfavorable (AU)

Introduction. Benign myoclonic epilepsy in infancy (BMEI) is a well-defined electro-clinical syndrome, classically associated with a good prognosis. However, in the last years several studies have been published with variable results of neuropsychological outcome in BMEI. Aim. To analyze the natural history and the cognitive and behavioral outcome in BMEI patients. Patients and methods. We report a long-term follow-up of 10 patients with BMEI. During the follow-up, all the patients underwent neurocognitive and behavioral evaluations. Results. Sixty percent of patients became seizure free on valproic acid. The intelligence quotient of the whole cohort was between 74 and 93, with three patients in the range of borderline intelligence and six in the range of medium-to-low intelligence. Nine of the 10 patients met criteria for attention deficit hyperactivity disorder, and two patients associated another learning disorder. All patients showed poor motor and visuospatial coordination signs and three patients had a behavior disorder. Conclusions. The term ‘benign’ in BMEI has to be used with caution in refer to its behavioral and cognitive outcome. Early onset of seizures and a worse epilepsy control may be risk factors of a poor neuropsychological outcome (AU)

Epilepsia y cognición: el papel de los fármacos antiepilépticos / Epilepsy and cognition: the role of antiepileptic drugs

Introducción. Múltiples y muy diversos factores se relacionan con la alteración cognitiva en la epilepsia, incluyendo el efecto adverso directo de los fármacos antiepilépticos (FAE). El uso de los FAE requiere de un riguroso equilibrio entre riesgo y beneficio para conseguir así el mejor control de las crisis con el menor número de efectos adversos neurocognitivos. Objetivo. Analizar los efectos adversos cognitivos generales y específicos de los FAE de primera, segunda y tercera generación. Desarrollo. Todos los FAE disponibles pueden producir efectos adversos cognitivos, que son más frecuentes en politerapia, con dosis totales altas y niveles séricos elevados. Las alteraciones más comunes son el descenso de la capacidad de reacción y de la velocidad de procesamiento con afectación concomitante de la memoria, la atención y el lenguaje. Sin embargo, hay gran controversia sobre la existencia o no de perfiles cognitivos específicos para cada uno de los distintos FAE y se dispone de una información contradictoria al respecto por la inadecuada metodología de los estudios comparativos. Conclusiones. Los efectos adversos cognitivos de los FAE son frecuentes y pueden afectar negativamente la tolerabilidad, el cumplimiento y el mantenimiento a largo plazo del tratamiento antiepiléptico. Se debe considerar el potencial efecto adverso cognitivo de los distintos FAE a la hora de elegir un tratamiento y es importante reconocer e identificar precozmente estos efectos adversos y saber cómo pueden afectar a los pacientes (AU)

Introduction. Multiple factors underlie the cognitive changes associated with epilepsy, including the effect of antiepileptic drug (AED) therapy itself. The use of AEDs in the management of epilepsy requires an ongoing risk-benefit analysis that attempts to maximize seizure control while minimizing adverse cognitive side-effects. Aim. This review focuses on the global and specific cognitive effects of the classic and the new AEDs. Development. All of the established AEDs can produce cognitive side effects, which are increased with polypharmacy and with increasing dosage and anticonvulsant blood levels. The main disorders are a diminished reaction and information processing time with alterations affecting memory, attention and language. Further, there is much debate concerning the existence and clinical importance of differential AED cognitive side effects and a large portion of the literature examining the comparative cognitive effects of AEDs is limited by inadequate study designs. Conclusions. Cognitive side effects of antiepileptic drugs are common and can negatively affect tolerability, compliance, and long-term retention of the treatment. The role of cognitive side effects should be kept in proper perspective when choosing AED therapy. It is important to be able to recognize early these effects and to put them into perspective as to how they affect our patients (AU)

[Benign myoclonic epilepsy in infancy: natural history and behavioral and cognitive outcome]. / Epilepsia mioclónica benigna del lactante: evolución natural y pronóstico neurocognitivo y conductual.

INTRODUCTION: Benign myoclonic epilepsy in infancy (BMEI) is a well-defined electro-clinical syndrome, classically associated with a good prognosis. However, in the last years several studies have been published with variable results of neuropsychological outcome in BMEI. AIM. To analyze the natural history and the cognitive and behavioral outcome in BMEI patients. PATIENTS AND METHODS: We report a long-term follow-up of 10 patients with BMEI. During the follow-up, all the patients underwent neurocognitive and behavioral evaluations. RESULTS: Sixty percent of patients became seizure free on valproic acid. The intelligence quotient of the whole cohort was between 74 and 93, with three patients in the range of borderline intelligence and six in the range of medium-to-low intelligence. Nine of the 10 patients met criteria for attention deficit hyperactivity disorder, and two patients associated another learning disorder. All patients showed poor motor and visuospatial coordination signs and three patients had a behavior disorder. CONCLUSIONS: The term 'benign' in BMEI has to be used with caution in refer to its behavioral and cognitive outcome. Early onset of seizures and a worse epilepsy control may be risk factors of a poor neuropsychological outcome.

TITLE: Epilepsia mioclonica benigna del lactante: evolucion natural y pronostico neurocognitivo y conductual.Introduccion. La epilepsia mioclonica benigna del lactante (EMBL) es un sindrome electroclinico de caracteristicas homogeneas y bien definidas, considerado clasicamente de buen pronostico. Sin embargo, en los ultimos años se han publicado estudios con resultados variables en cuanto a evolucion neuropsicologica. Objetivo. Analizar la evolucion natural y el pronostico neurocognitivo y conductual de los pacientes con EMBL. Pacientes y metodos. Estudio retrospectivo de 10 pacientes con EMBL, con un periodo de seguimiento de mas de cinco años, durante los cuales se realizo una evaluacion neurocognitiva y conductual. Resultados. En el 60% de los pacientes las crisis se controlaron con acido valproico en monoterapia, y el 80% no presento nuevas crisis durante su seguimiento. El cociente intelectual de la cohorte se situo entre 74 y 93; tres pacientes tuvieron un cociente intelectual en rango de inteligencia limite, y seis, en rango de inteligencia media-baja. Nueve pacientes cumplieron criterios de trastorno por deficit de atencion/hiperactividad y dos asociaban otro trastorno del aprendizaje, uno de ellos trastorno de aprendizaje no verbal, y el otro, trastorno especifico de la lectoescritura. Todos los pacientes presentaron datos de pobre coordinacion motriz y visuoespacial, y tres fueron diagnosticados de trastorno de conducta. Conclusiones. El termino 'benigno' en la EMBL debe utilizarse con precaucion en cuanto a su pronostico neurocognitivo y conductual. El inicio precoz y un peor control de las crisis podrian suponer factores de riesgo de evolucion neuropsicologica desfavorable.

[Abnormalities of synaptogenesis in autism. Pathogenic and therapeutic implications]. / Alteraciones de la sinaptogenesis en el autismo. Implicaciones etiopatogenicas y terapeuticas.

INTRODUCTION: The social, language, and behavioural problems that occur with autism suggest that this syndrome affects a functionally diverse and widely distributed set of neural systems. AIMS: To review the molecular pathways involved in synaptic growth, development, and stability of human synapses. We also examine the genes implicated in synaptogenesis which have been associated with autism. In particular, we highlight the role of these genes in synaptic cell adhesion, organization of presynaptic and postsynaptic specializations, growth signaling pathways, and endosomal function. DEVELOPMENT: Proper brain function requires stringent balance of excitatory and inhibitory synapse formation during neural circuit assembly. Mutation of genes that normally sculpt and maintain this balance results in severe dysfunction, causing neurodevelopmental disorders including autism, epilepsy, Angelman syndrome, fragile X syndrome, and Rett syndrome. Such mutations may result in defective architectural structuring of synaptic connections, molecular assembly of synapses and/or functional synaptogenesis. CONCLUSIONS: Increased knowledge of abnormal mechanisms of human synaptogenesis may lead to define different etio-pathogenic models of autism and to understand how far abnormal cell/synaptic growth and synaptic function could be reversed.

Alteraciones de la sinaptogénesis en el autismo. Implicaciones etiopatogénicas y terapéuticas / Abnormalities of synaptogenesis in autism. Pathogenic and therapeutic implications

Introducción. Los trastornos de interacción social recíproca, lenguaje y comportamiento que aparecen en el autismo sugieren que este síndrome es la expresión de un trastorno neurobiológico complejo relacionado con la afectación de diversos circuitos neuronales. Objetivos. Revisar las vías moleculares que regulan el crecimiento, desarrollo y estabilidad de las sinapsis, examinar las alteraciones de los genes que modulan la sinaptogénesis en el cerebro autista y repasar principalmente aquellos genes que codifican adhesividad sináptica, organización de estructuras presinápticas y postsinápticas, crecimiento axonal y maduración de los endosomas. Desarrollo. El adecuado balance entre sinapsis excitatorias e inhibidoras es básico durante el desarrollo de los circuitos neuronales. Las mutaciones en los genes que regulan este balance causan diversos trastornos del neurodesarrollo como autismo, epilepsia, síndrome de Angelman, síndrome del cromosoma X frágil y síndrome de Rett. Estas mutaciones van a originar alteraciones en la sinaptogénesis estructural y funcional y en la plasticidad sináptica. Conclusiones. El mejor conocimiento de los mecanismos patológicos de la sinaptogénesis puede permitir definir distintos subtipos de autismo y llegar a conocer si estas anomalías del desarrollo y función de las sinapsis pudieran ser o no reversibles con tratamiento farmacológico (AU)

Introduction. The social, language, and behavioural problems that occur with autism suggest that this syndrome affects a functionally diverse and widely distributed set of neural systems. Aims. To review the molecular pathways involved in synaptic growth, development, and stability of human synapses. We also examine the genes implicated in synaptogenesis which have been associated with autism. In particular, we highlight the role of these genes in synaptic cell adhesion, organization of presynaptic and postsynaptic specializations, growth signaling pathways, and endosomal function. Development. Proper brain function requires stringent balance of excitatory and inhibitory synapse formation during neural circuit assembly. Mutation of genes that normally sculpt and maintain this balance results in severe dysfunction, causing neurodevelopmental disorders including autism, epilepsy, Angelman syndrome, fragile X syndrome, and Rett syndrome. Such mutations may result in defective architectural structuring of synaptic connections, molecular assembly of synapses and/or functional synaptogenesis. Conclusions. Increased knowledge of abnormal mechanisms of human synaptogenesis may lead to define different etiopathogenic models of autism and to understand how far abnormal cell/synaptic growth and synaptic function could be reversed (AU)