RESUMEN
Anxiety is being increasingly identified in Angelman syndrome (AS). Qualitative questions and quantitative assessments were used to evaluate for anxiety in 50 subjects with AS. In-person evaluations assessed behaviors concerning for anxiety and circumstances wherein they occurred. Caregivers completed anxiety and other behavioral rating scales. Caregiver responses were categorized and compared to items from anxiety rating scales. The most common behavioral manifestation of anxiety was "aggression." The most common circumstance was "separation from caregiver/parent." Subjects had elevated scores on anxiety, irritability and hyperactivity scales with lower mean scores among subjects with a maternal deletion. The Pediatric Anxiety Rating Scale best captured behaviors described by caregivers. Existing anxiety scales should be adapted for use in AS.
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Síndrome de Angelman , Trastorno del Espectro Autista , Síndrome de Angelman/diagnóstico , Ansiedad , Cuidadores , Niño , Humanos , Padres , Escalas de Valoración PsiquiátricaRESUMEN
OBJECTIVE: To evaluate safety and tolerability and exploratory efficacy end points for gaboxadol (OV101) compared with placebo in individuals with Angelman syndrome (AS). METHODS: Gaboxadol is a highly selective orthosteric agonist that activates δ-subunit-containing extrasynaptic γ-aminobutyric acid type A (GABAA) receptors. In a multicenter, double-blind, placebo-controlled, parallel-group trial, adolescent and adult individuals with a molecular diagnosis of AS were randomized (1:1:1) to 1 of 3 dosing regimens for a duration of 12 weeks: placebo morning dose and gaboxadol 15 mg evening dose (qd), gaboxadol 10 mg morning dose and 15 mg evening dose (bid), or placebo morning and evening dose. Safety and tolerability were monitored throughout the study. Prespecified exploratory efficacy end points included adapted Clinical Global Impression-Severity and Clinical Global Impression-Improvement (CGI-I) scales, which documented the clinical severity at baseline and change after treatment, respectively. RESULTS: Eighty-eight individuals were randomized. Of 87 individuals (aged 13-45 years) who received at least 1 dose of study drug, 78 (90%) completed the study. Most adverse events (AEs) were mild to moderate, and no life-threatening AEs were reported. Efficacy of gaboxadol, as measured by CGI-I improvement in an exploratory analysis, was observed in gaboxadol qd vs placebo (p = 0.0006). CONCLUSION: After 12 weeks of treatment, gaboxadol was found to be generally well-tolerated with a favorable safety profile. The efficacy as measured by the AS-adapted CGI-I scale warrants further studies. CLINICALTRIALSGOV IDENTIFIER: NCT02996305. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that, for individuals with AS, gaboxadol is generally safe and well-tolerated.
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Síndrome de Angelman/tratamiento farmacológico , Agonistas del GABA/administración & dosificación , Isoxazoles/administración & dosificación , Adolescente , Adulto , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Isoxazoles/efectos adversos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
Angelman Syndrome (AS) is a severe neurodevelopmental disorder due to impaired expression of UBE3A in neurons. There are several genetic mechanisms that impair UBE3A expression, but they differ in how neighboring genes on chromosome 15 at 15q11-q13 are affected. There is evidence that different genetic subtypes present with different clinical severity, but a systematic quantitative investigation is lacking. Here we analyze natural history data on a large sample of individuals with AS (n = 250, 848 assessments), including clinical scales that quantify development of motor, cognitive, and language skills (Bayley Scales of Infant Development, Third Edition; Preschool Language Scale, Fourth Edition), adaptive behavior (Vineland Adaptive Behavioral Scales, Second Edition), and AS-specific symptoms (AS Clinical Severity Scale). We found that clinical severity, as captured by these scales, differs between genetic subtypes: individuals with UBE3A pathogenic variants and imprinting defects (IPD) are less affected than individuals with uniparental paternal disomy (UPD); of those with UBE3A pathogenic variants, individuals with truncating mutations are more impaired than those with missense mutations. Individuals with a deletion that encompasses UBE3A and other genes are most impaired, but in contrast to previous work, we found little evidence for an influence of deletion length (class I vs. II) on severity of manifestations. The results of this systematic analysis highlight the relevance of genomic regions beyond UBE3A as contributing factors in the AS phenotype, and provide important information for the development of new therapies for AS. More generally, this work exemplifies how increasing genetic irregularities are reflected in clinical severity.
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Síndrome de Angelman , Síndrome de Angelman/genética , Cromosomas Humanos Par 15 , Impresión Genómica/genética , Genotipo , Humanos , Fenotipo , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Duplication of 15q11.2-q13.1 (dup15q syndrome) is one of the most common copy number variations associated with autism spectrum disorders (ASD) and intellectual disability (ID). As with many neurogenetic conditions, accurate behavioral assessment is challenging due to the level of impairment and heterogeneity across individuals. Large-scale phenotyping studies are necessary to inform future clinical trials in this and similar ID syndromes. This study assessed developmental and behavioral characteristics in a large cohort of children with dup15q syndrome, and examined differences based on genetic subtype and epilepsy status. Participants included 62 children (2.5-18 years). Across individuals, there was a wide range of abilities. Although adaptive behavior was strongly associated with cognitive ability, adaptive abilities were higher than cognitive scores. Measures of ASD symptoms were associated with cognitive ability, while parent report of challenging behavior was not. Both genetic subtype and epilepsy were related to degree of impairment across cognitive, language, motor, and adaptive domains. Children with isodicentric duplications and epilepsy showed the greatest impairment, while children with interstitial duplications showed the least. On average, participants with epilepsy experienced seizures over 53% of their lives, and half of children with epilepsy had infantile spasms. Parents of children with isodicentric duplications reported more concerns regarding challenging behaviors. Future trials in ID syndromes should employ a flexible set of assessments, allowing each participant to receive assessments that capture their skills. Multiple sources of information should be considered, and the impact of language and cognitive ability should be taken into consideration when interpreting results.
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Trastorno del Espectro Autista/genética , Variaciones en el Número de Copia de ADN/genética , Epilepsia/genética , Discapacidad Intelectual/genética , Adolescente , Trastorno del Espectro Autista/patología , Niño , Preescolar , Aberraciones Cromosómicas , Duplicación Cromosómica/genética , Cromosomas Humanos Par 15/genética , Estudios de Cohortes , Epilepsia/patología , Femenino , Humanos , Discapacidad Intelectual/patología , Masculino , LinajeRESUMEN
Fumarate hydratase deficiency (FHD) is a rare metabolic disease caused by two defective copies of the FH gene, which encodes the Krebs cycle enzyme fumarase. FHD is associated with brain and developmental abnormalities, seizures, and high childhood mortality. We describe the symptoms and treatment of a patient with FHD. While infantile spasms are common in FHD, the patient presented with epileptic spasms later in childhood. Also unexpectedly, the patient responded excellently to lacosamide for her non-convulsive status epilepticus and epileptic spasms after three first-line medication trials failed. We biochemically analyzed the patient's two fumarase variants (E432Kfs*17 and D65G). While E432Kfs*17 was extremely enzymatically defective, D65G exhibited only a mild defect, possibly playing a role in the patient's longer survival.
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Fumarato Hidratasa/deficiencia , Fumarato Hidratasa/genética , Errores Innatos del Metabolismo/genética , Hipotonía Muscular/genética , Trastornos Psicomotores/genética , Espasmos Infantiles/genética , Encéfalo/patología , Niño , Femenino , Humanos , Recién Nacido , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/mortalidad , Hipotonía Muscular/diagnóstico , Hipotonía Muscular/mortalidad , Mutación/genética , Trastornos Psicomotores/diagnóstico , Trastornos Psicomotores/mortalidad , Convulsiones/diagnóstico , Convulsiones/genética , Convulsiones/mortalidad , Espasmos Infantiles/diagnóstico , Espasmos Infantiles/mortalidadRESUMEN
OBJECTIVES: Angelman syndrome (AS) is a neurogenetic disorder associated with impaired expression of the ubiquitin-protein ligase E3A gene on chromosome 15. AS results in intellectual disability with limited expressive language, epilepsy, ataxia, sleep impairment, and problematic behavior which may include anxiety. Buspirone is a serotonin (5-HT)1A receptor partial agonist used in the treatment of anxiety disorders and may, therefore, have a treatment role for patients with AS. METHODS: We describe three patients who were given open-label buspirone for the treatment of behaviors thought to be related to anxiety. RESULTS: We found significant improvement in symptoms of anxiety with buspirone. Patients tolerated long-term usage of the medication. CONCLUSION: The findings of this study suggest that buspirone may be effective for the amelioration of behaviors related to anxiety in patients with AS, and well tolerated. Limitations include the open-label nature of these treatments, the small sample size and the absence of a control group.
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Síndrome de Angelman/tratamiento farmacológico , Ansiedad/tratamiento farmacológico , Buspirona/farmacología , Adulto , Síndrome de Angelman/complicaciones , Trastornos de Ansiedad/tratamiento farmacológico , Femenino , Humanos , Discapacidad Intelectual , Masculino , Receptor de Serotonina 5-HT1A , Serotonina , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder characterized by intellectual disability, specific facial features, and marked autonomic nervous system dysfunction, especially with disturbances of regulating respiration and intestinal mobility. It is caused by variants in the transcription factor TCF4. Heterogeneity in the clinical and molecular diagnostic criteria and care practices has prompted a group of international experts to establish guidelines for diagnostics and care. For issues, for which there was limited information available in international literature, we collaborated with national support groups and the participants of a syndrome specific international conference to obtain further information. Here, we discuss the resultant consensus, including the clinical definition of PTHS and a molecular diagnostic pathway. Recommendations for managing particular health problems such as dysregulated respiration are provided. We emphasize the need for integration of care for physical and behavioral issues. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimization of diagnostics and care.
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Hiperventilación/diagnóstico , Hiperventilación/terapia , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/terapia , Factores de Edad , Terapia Combinada , Diagnóstico Diferencial , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Facies , Pruebas Genéticas , Humanos , Hiperventilación/etiología , Discapacidad Intelectual/etiología , Mutación , Fenotipo , Factor de Transcripción 4/genéticaAsunto(s)
Encefalitis Antirreceptor N-Metil-D-Aspartato/diagnóstico , Autoanticuerpos/sangre , Encéfalo/diagnóstico por imagen , Imagen por Resonancia Magnética , Receptores de N-Metil-D-Aspartato/inmunología , Convulsiones/etiología , Encefalitis Antirreceptor N-Metil-D-Aspartato/complicaciones , Encefalitis Antirreceptor N-Metil-D-Aspartato/tratamiento farmacológico , Anticonvulsivantes/uso terapéutico , Análisis Químico de la Sangre , Preescolar , Diagnóstico Diferencial , Electroencefalografía , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Factores Inmunológicos/uso terapéutico , Masculino , Convulsiones/tratamiento farmacológico , Vómitos/etiologíaRESUMEN
Angelman syndrome is a neurogenetic disorder with varying clinical presentations and symptoms as the individual ages. The goal of this study was to characterize changes over time in the natural history of this syndrome in a large population. We reviewed the medical records of the 53 patients who were born prior to 2000 and seen at the Angelman Syndrome Clinic at Massachusetts General Hospital to assess neurological, sleep, behavioral, gastrointestinal, orthopedic, and ophthalmologic functioning. The average age of this cohort was 24 years. Active seizures were present in 35%, nonepileptic myoclonus in 42%, and clinically significant tremors in 55%. Anxiety was present in 57%, increasing to 71% in those ages 26-43 years. In terms of sleep, 56% reported 8 hr of sleep or more, although 43% reported frequent nocturnal awakenings. Gastrointestinal issues remain problematic with 81% having constipation and 53% gastroesophageal reflux. The majority lived in a parent's home and remained independently mobile, though scoliosis was reportedly present in 30%, and 20% had reported low bone density/osteoporosis. The results of this study suggest that the prevalence of active seizures may decrease in adulthood but that the prevalence of movement disorders such as tremor and nonepileptic myoclonus may increase. Anxiety increases significantly as individuals age while defiant behaviors appear to decrease. Sleep dysfunction typically improves as compared to childhood but remains a significant issue for many adults. Other areas that require monitoring into adulthood include gastrointestinal dysfunction, and orthopedic/mobility issues, such as reported scoliosis and bone density, and ophthalmologic disorders.
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Síndrome de Angelman/etiología , Ansiedad/etiología , Convulsiones/etiología , Adolescente , Adulto , Síndrome de Angelman/tratamiento farmacológico , Anticonvulsivantes/uso terapéutico , Ansiedad/tratamiento farmacológico , Estreñimiento/etiología , Femenino , Reflujo Gastroesofágico/etiología , Humanos , Masculino , Estudios Retrospectivos , Escoliosis/etiología , Convulsiones/tratamiento farmacológico , Trastornos del Sueño-Vigilia/tratamiento farmacológico , Trastornos del Sueño-Vigilia/etiologíaRESUMEN
Angelman syndrome (AS) is a neurogenetic imprinting disorder caused by loss of the maternally inherited Ube3a gene and is characterized by generalized epilepsy, limited expressive speech, sleep dysfunction, and movement disorders. Myoclonic seizures are often the first seizure type to appear, and myoclonic status, associated with developmental regression, may occur in the first few years of life. Additionally, there have been rare reports of prolonged episodes of myoclonus without electrographic correlate in adults with AS. The medical records of 200 individuals seen in the Angelman Syndrome Clinic at the Massachusetts General Hospital and the Lurie Center for Autism were retrospectively reviewed to identify and characterize myoclonic seizures and episodes of nonepileptic myoclonus. Myoclonic seizures were reported in 14% of individuals with age of onset occurring before 8years. These are brief events, unless the individual was experiencing myoclonic status, and electroencephalographs show interictal generalized spike and wave activity. Nonepileptic myoclonus occurred in 40% of individuals over 10years of age, and prevalence appears to increase with age. The episodes of nonepileptic myoclonus arise during puberty or later, with age of onset ranging from 10 to 26years. These events were captured on 5 video electroencephalographs and had no electrographic correlate. They can last from seconds to hours, always occurring in the hands and spreading to the face and all extremities in some individuals. Episodes of nonepileptic myoclonus have a discrete beginning and end, lacks a postictal period, and are not associated with significant alteration of consciousness or developmental regression. These episodes can be difficult to treat and are often refractory to medication; however, levetiracetam, clobazam, and clonazepam appear to be effective for some individuals. Myoclonic seizures are common in AS, typically occurring in young children and associated with epileptiform changes on electroencephalographs. Prolonged episodes are associated with developmental regression. In contrast, nonepileptic myoclonus typically begins in adolescence or early adulthood and has no electroencephalogram (EEG) correlate, alteration in consciousness, or regression but can significantly impact quality of life.
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Síndrome de Angelman/complicaciones , Epilepsias Mioclónicas , Adolescente , Adulto , Distribución por Edad , Síndrome de Angelman/fisiopatología , Anticonvulsivantes/uso terapéutico , Niño , Preescolar , Electroencefalografía , Epilepsias Mioclónicas/tratamiento farmacológico , Epilepsias Mioclónicas/epidemiología , Epilepsias Mioclónicas/fisiopatología , Femenino , Humanos , Lactante , Masculino , Prevalencia , Calidad de Vida , Estudios Retrospectivos , Convulsiones/tratamiento farmacológico , Convulsiones/epidemiología , Trastornos del Sueño-Vigilia , Adulto JovenRESUMEN
Angelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability, expressive speech impairment, movement disorder, epilepsy, and a happy demeanor. Children with AS are frequently reported to be poor feeders during infancy and as having gastrointestinal issues such as constipation, reflux, and abnormal food related behaviors throughout their lifetime. To assess the prevalence of gastrointestinal disorders in individuals with AS, we retrospectively analyzed medical records of 120 individuals seen at the Angelman Syndrome Clinic at Massachusetts General Hospital and 43 individuals seen at the University of North Carolina Comprehensive Angelman Clinic. The majority of patients' medical records indicated at least one symptom of gastrointestinal dysfunction, with constipation and gastroesophageal reflux disease (GERD) the most common. Other gastrointestinal issues reported were cyclic vomiting episodes, difficulty swallowing, excessive swallowing, and eosinophilic esophagitis. Upper gastrointestinal symptoms such as GERD, swallowing difficulties, cyclic vomiting, and eosinophilic esophagitis were more common in those with deletions and uniparental disomy, likely related to the involvement of multiple genes and subsequent hypotonia. The frequency of constipation is consistent among all genetic subtypes while early feeding issues appear to mainly affect those with deletions. Caregivers and healthcare providers should be aware of the high prevalence of these issues, as proper treatment may improve not only gastrointestinal dysfunction but also sleep and behavioral issues.
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Síndrome de Angelman/complicaciones , Enfermedades Gastrointestinales/epidemiología , Adolescente , Adulto , Síndrome de Angelman/fisiopatología , Niño , Preescolar , Femenino , Enfermedades Gastrointestinales/etiología , Enfermedades Gastrointestinales/patología , Humanos , Lactante , Masculino , Massachusetts/epidemiología , Prevalencia , Pronóstico , Estudios Retrospectivos , Adulto JovenRESUMEN
[This corrects the article DOI: 10.1186/s11689-017-9195-8.].
RESUMEN
BACKGROUND: Clinicians have qualitatively described rhythmic delta activity as a prominent EEG abnormality in individuals with Angelman syndrome, but this phenotype has yet to be rigorously quantified in the clinical population or validated in a preclinical model. Here, we sought to quantitatively measure delta rhythmicity and evaluate its fidelity as a biomarker. METHODS: We quantified delta oscillations in mouse and human using parallel spectral analysis methods and measured regional, state-specific, and developmental changes in delta rhythms in a patient population. RESULTS: Delta power was broadly increased and more dynamic in both the Angelman syndrome mouse model, relative to wild-type littermates, and in children with Angelman syndrome, relative to age-matched neurotypical controls. Enhanced delta oscillations in children with Angelman syndrome were present during wakefulness and sleep, were generalized across the neocortex, and were more pronounced at earlier ages. CONCLUSIONS: Delta rhythmicity phenotypes can serve as reliable biomarkers for Angelman syndrome in both preclinical and clinical settings.
RESUMEN
The low glycemic index treatment, a dietary therapy that focuses on glycemic index and reduced carbohydrate intake, has been successful in reducing seizure frequency in the general epilepsy population. Epilepsy is a common feature of Angelman syndrome and seizures are often refractory to multiple medications, especially in those with maternal deletions. Dietary therapy has become a more frequently used option for treating epilepsy, often in combination with other antiepileptic drugs, due to its efficacy and favorable side effect profile. This study aimed to assess the effectiveness of the low glycemic index treatment for seizure control in Angelman syndrome. Through a retrospective medical record review of 23 subjects who utilized the low glycemic index treatment at the Clinic and Center for Dietary Therapy of Epilepsy at the Massachusetts General Hospital, we found that the high level of seizure control and favorable side effect profile make the low glycemic index treatment a viable treatment for seizures in Angelman syndrome. The majority of subjects in our cohort experienced some level of seizure reduction after initiating the diet, 5 (22%) maintained complete seizure freedom, 10 (43%) maintained seizure freedom except in the setting of illness or non-convulsive status epilepticus, 7 (30%) had a decrease in seizure frequency, and only 1 (4%) did not have enough information to determine seizure control post-initiation. The low glycemic index treatment monotherapy was successful for some subjects in our cohort but most subjects used an antiepileptic drug concurrently. Some subjects were able to maintain the same level of seizure control on a liberalized version of the low glycemic index treatment which included a larger amount of low glycemic carbohydrates. No correlation between the level of carbohydrate restriction and level of seizure control was found. Few subjects experienced side effects and those that did found them to be mild and easily treated. The efficacy of the low glycemic index treatment and its favorable side effect profile make it an excellent alternative or supplement to antiepileptic drug therapy for the treatment of seizures in Angelman syndrome.
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Síndrome de Angelman/dietoterapia , Dieta Cetogénica , Índice Glucémico , Convulsiones/dietoterapia , Adolescente , Adulto , Síndrome de Angelman/complicaciones , Niño , Preescolar , Femenino , Humanos , Masculino , Massachusetts , Estudios Retrospectivos , Convulsiones/etiología , Resultado del Tratamiento , Adulto JovenRESUMEN
Chromosome 15q11-q13.1 duplication is a common copy number variant associated with autism spectrum disorder (ASD). Most cases are de novo, maternal in origin and fully penetrant for ASD. Here, we describe a unique family with an interstitial 15q11.2-q13.1 maternal duplication and the presence of somatic mosaicism in the mother. She is typically functioning, but formal autism testing showed mild ASD. She had several congenital anomalies, and she is the first 15q Duplication case reported in the literature to develop unilateral renal carcinoma. Her two affected children share some of these clinical characteristics, and have severe ASD. Several tissues in the mother, including blood, skin, a kidney tumor, and normal kidney margin tissues were studied for the presence of the 15q11-q13.1 duplication. We show the mother has somatic mosaicism for the duplication in several tissues to varying degrees. A growth competition assay in two types of stem cells from duplication 15q individuals was also performed. Our results suggest that the presence of this interstitial duplication 15q chromosome may confer a previously unknown growth advantage in this particular individual, but not in the general interstitial duplication 15q population.
RESUMEN
BACKGROUND: Duplications of 15q11.2-q13.1 (Dup15q syndrome) are highly penetrant for autism spectrum disorder (ASD). A distinct electrophysiological (EEG) pattern characterized by excessive activity in the beta band has been noted in clinical reports. We asked whether EEG power in the beta band, as well as in other frequency bands, distinguished children with Dup15q syndrome from those with non-syndromic ASD and then examined the clinical correlates of this electrophysiological biomarker in Dup15q syndrome. METHODS: In the first study, we recorded spontaneous EEG from children with Dup15q syndrome (n = 11), age-and-IQ-matched children with ASD (n = 10) and age-matched typically developing (TD) children (n = 9) and computed relative power in 6 frequency bands for 9 regions of interest (ROIs). Group comparisons were made using a repeated measures analysis of variance. In the second study, we recorded spontaneous EEG from a larger cohort of individuals with Dup15q syndrome (n = 27) across two sites and examined age, epilepsy, and duplication type as predictors of beta power using simple linear regressions. RESULTS: In the first study, spontaneous beta1 (12-20 Hz) and beta2 (20-30 Hz) power were significantly higher in Dup15q syndrome compared with both comparison groups, while delta (1-4 Hz) was significantly lower than both comparison groups. Effect sizes in all three frequency bands were large (|d| > 1). In the second study, we found that beta2 power was significantly related to epilepsy diagnosis in Dup15q syndrome. CONCLUSIONS: Here, we have identified an electrophysiological biomarker of Dup15q syndrome that may facilitate clinical stratification, treatment monitoring, and measurement of target engagement for future clinical trials. Future work will investigate the genetic and neural underpinnings of this electrophysiological signature as well as the functional consequences of excessive beta oscillations in Dup15q syndrome.
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Corteza Cerebral/fisiopatología , Electrodiagnóstico/métodos , Electroencefalografía/métodos , Discapacidad Intelectual/diagnóstico , Adolescente , Trastorno del Espectro Autista/fisiopatología , Biomarcadores , Niño , Preescolar , Aberraciones Cromosómicas , Cromosomas Humanos Par 15 , Femenino , Humanos , Lactante , Discapacidad Intelectual/fisiopatología , Masculino , Adulto JovenRESUMEN
Epilepsy is a common feature of Angelman syndrome (~80-90%), with the most common seizure types including myoclonic, atonic, atypical absence, focal, and generalized tonic-clonic. Seizure types are similar among the various genetic subtypes, but epilepsy in those with maternal deletions is more frequent and more refractory to medication. Treatment with older antiepileptic drugs such as valproic acid and clonazepam is effective, but these medications tend to have less favorable side effect profiles in Angelman syndrome compared with those in newer medications. This study aimed to assess the use of newer antiepileptic drug therapies in individuals with Angelman syndrome followed at the Angelman Syndrome Clinic at the Massachusetts General Hospital. Many of the subjects in this study were on valproic acid therapy prior to their initial evaluation and exhibited increased tremor, decreased balance, and/or regression of motor skills, which resolved after tapering off of this medication. Newer antiepileptic drugs such as levetiracetam, lamotrigine, and clobazam, and to a lesser extent topiramate, appeared to be as effective - if not more so - as valproic acid and clonazepam while offering more favorable side effect profiles. The low glycemic index treatment also provided effective seizure control with minimal side effects. The majority of subjects remained on combination therapy with levetiracetam, lamotrigine, and clobazam being the most commonly used medications, indicating a changing trend when compared with prior studies.
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Síndrome de Angelman/tratamiento farmacológico , Síndrome de Angelman/epidemiología , Anticonvulsivantes/uso terapéutico , Hospitales Generales/métodos , Convulsiones/tratamiento farmacológico , Convulsiones/epidemiología , Adolescente , Adulto , Instituciones de Atención Ambulatoria , Síndrome de Angelman/diagnóstico , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Masculino , Massachusetts/epidemiología , Estudios Retrospectivos , Convulsiones/diagnóstico , Resultado del Tratamiento , Adulto JovenRESUMEN
Mutations in mitochondrial aminoacyl-tRNA synthetases are an increasingly recognized cause of human diseases, often arising in individuals with compound heterozygous mutations and presenting with system-specific phenotypes, frequently neurologic. FARS2 encodes mitochondrial phenylalanyl transfer ribonucleic acid (RNA) synthetase (mtPheRS), perturbations of which have been reported in 6 cases of an infantile, lethal disease with refractory epilepsy and progressive myoclonus. Here the authors report the case of juvenile onset refractory epilepsy and progressive myoclonus with compound heterozygous FARS2 mutations. The authors describe the clinical course over 6 years of care at their institution and diagnostic studies including electroencephalogram (EEG), brain magnetic resonance imaging (MRI), serum and cerebrospinal fluid analyses, skeletal muscle biopsy histology, and autopsy gross and histologic findings, which include features shared with Alpers-Huttenlocher syndrome, Leigh syndrome, and a previously published case of FARS2 mutation associated infantile onset disease. The authors also present structure-guided analysis of the relevant mutations based on published mitochondrial phenylalanyl transfer RNA synthetase and related protein crystal structures as well as biochemical analysis of the corresponding recombinant mutant proteins.
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Epilepsia Refractaria/genética , Epilepsias Mioclónicas/genética , Heterocigoto , Proteínas Mitocondriales/genética , Mutación , Fenilalanina-ARNt Ligasa/genética , Adolescente , Epilepsia Refractaria/diagnóstico por imagen , Epilepsia Refractaria/patología , Epilepsia Refractaria/fisiopatología , Epilepsias Mioclónicas/diagnóstico por imagen , Epilepsias Mioclónicas/patología , Epilepsias Mioclónicas/fisiopatología , Resultado Fatal , Femenino , Humanos , FenotipoRESUMEN
BACKGROUND: The objective was to determine if it is useful to routinely add magnetic resonance spectroscopy (MRS) to magnetic resonance imaging (MRI) in the evaluation of seizure in the pediatric patient. Specifically, how often does MRS contribute information to conventional MRI? METHODS: A retrospective search, over a period of 3 years, of patients <18 years of age who underwent both MRI and MRS as part of the evaluation of seizures yielded a total of 233 cases in 216 patients. The medical records were reviewed to determine how many patients carried a diagnosis relevant to seizures. The MRIs and MRSs were reviewed by two neuroradiologists and an MR physicist/spectroscopist who determined by consensus in how many cases MRS contributed information regarding management, diagnosis, or prognosis, in addition to the findings on MRI alone. RESULTS: In 100 of 233 cases (43%), MRS contributed information additional to MRI. In 40 cases, MRS contributed information relevant to patient management by prompting an evaluation for an underlying inborn error of metabolism. MRS contributed information relevant to diagnosis in 24 of 100 cases (e.g., neoplasm versus dysplasia). MRS contributed information relevant to prognosis in 36 cases (e.g., hypoxic-ischemic injury). MRS added more information in cases where the patients had a diagnosis relevant to seizure before imaging. Interestingly, in 25 cases where the MRI was normal, MRS was found to be abnormal, which prompted evaluation for an inborn error of metabolism. CONCLUSIONS: These results suggest that MRS is a useful evaluation tool in addition to MRI for children undergoing imaging for the evaluation of seizures.