RESUMEN
ATP1A3 encodes the α3 subunit of the sodium-potassium ATPase, one of two isoforms responsible for powering electrochemical gradients in neurons. Heterozygous pathogenic ATP1A3 variants produce several distinct neurological syndromes, yet the molecular basis for phenotypic variability is unclear. We report a novel recurrent variant, ATP1A3(NM_152296.5):c.2324C>T; p.(Pro775Leu), in nine individuals associated with the primary clinical features of progressive or non-progressive spasticity and developmental delay/intellectual disability. No patients fulfil diagnostic criteria for ATP1A3-associated syndromes, including alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism or cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss (CAPOS), and none were suspected of having an ATP1A3-related disorder. Uniquely among known ATP1A3 variants, P775L causes leakage of sodium ions and protons into the cell, associated with impaired sodium binding/occlusion kinetics favouring states with fewer bound ions. These phenotypic and electrophysiologic studies demonstrate that ATP1A3:c.2324C>T; p.(Pro775Leu) results in mild ATP1A3-related phenotypes resembling complex hereditary spastic paraplegia or idiopathic spastic cerebral palsy. Cation leak provides a molecular explanation for this genotype-phenotype correlation, adding another mechanism to further explain phenotypic variability and highlighting the importance of biophysical properties beyond ion transport rate in ion transport diseases.
Asunto(s)
Ataxia Cerebelosa , Discapacidad Intelectual , Humanos , Mutación/genética , Síndrome , Discapacidad Intelectual/genética , Ataxia Cerebelosa/genética , Fenotipo , Espasticidad Muscular/genética , Cationes , ATPasa Intercambiadora de Sodio-Potasio/genéticaRESUMEN
BACKGROUND: Epilepsy with eyelid myoclonia(EEM) or Jeavons syndrome is considered a genetic generalized epilepsy with a typical age of onset in childhood. Many types of seizures can be observed, including eyelid myoclonia, absence, generalized tonic-clonic, and myoclonic seizures. Seizures tend to be difficult to control requiring polypharmacy treatment or become drug-resistant. Dietary therapy, particularly with Modified Atkins Diet (MAD), as a treatment of seizures in this syndrome has rarely been studied. We report efficacy and tolerability of MAD in children with epilepsy with eyelid myoclonia. METHODS: We reviewed medical records of children with EEM treated at the University of Chicago Ketogenic Diet program from 2017 to 2022. Patient's demography, seizure characteristics, EEG findings, response to treatment, and adverse effects were reviewed. RESULT: Six patients with EEM were identified. Average age of seizure onset was 6 (2-11) years and an average age when the MAD started was 10.7 (6-15) years. All patients were started on MAD and completed at least 6 months on the diet at the time of report. An average of 4 (0-9) anti-seizure medications (ASM) had been tried prior to the MAD. All patients achieved ketosis with an average level of serum beta-hydroxybutyrate of 1.9 (1.03-3.61) mmol/L. At the 6-month follow-up visit, all patients (100%) experienced a greater than 50% seizure reduction, 3/6 patients (50%) had more than 90% seizure reduction, 1/6 patients (17%) became seizure-free. All seizure types demonstrated a greater than 80% reduction in frequency.Absence and myoclonic seizures showed the greatest reduction with 100% seizure reduction. Eyelid myoclonia and generalized tonic-clonic seizures showed more than 80% seizure reduction.Moreover, all patients reported improvement in alertness, mood, and concentration. Initial weight loss and mild gastrointestinal disturbances were reported in 2/6 patients (33%) and corrected with dietary adjustment. CONCLUSION: The Modified Atkins Diet has shown to be effective and welltolerated for children with EEM in our study. Cognitive improvement has also been subjectively reported in all patients. Adverse effects are tolerable and correctable. The MAD, therefore, may be considered as a treatment option for patients with epilepsy with eyelid myoclonia.
Asunto(s)
Dieta Rica en Proteínas y Pobre en Hidratos de Carbono , Dieta Cetogénica , Epilepsias Mioclónicas , Epilepsia Generalizada , Epilepsia Refleja , Oftalmopatías , Mioclonía , Humanos , Niño , Adolescente , Estudios Retrospectivos , Epilepsia Generalizada/tratamiento farmacológico , Dieta Cetogénica/efectos adversos , Epilepsias Mioclónicas/complicaciones , Dieta Baja en Carbohidratos , Convulsiones/complicaciones , Párpados , Resultado del TratamientoRESUMEN
OBJECTIVE: Within the spectrum of developmental and epileptic encephalopathy (DEE), there are a group of infants with features that are distinct from the well-recognized syndromes of early infantile developmental and epileptic encephalopathy (EIDEE), infantile epileptic spasm syndrome (IESS), and Lennox-Gastaut syndrome (LGS). We refer to this condition as late infantile epileptic encephalopathy (LIEE). Our objective was to highlight the characteristics of this group by analyzing patients who exhibit prototypical features. METHODS: From July 2022 to May 2023, we searched for LIEE features in pediatric patients who underwent epilepsy follow-up at the University of Chicago Comer Children's Hospital. RESULTS: Out of 850 patients evaluated, thirty patients (3.5%) were identified with LIEE based on electroclinical characteristics. These patients had an average onset of epilepsy at 6.8 months and an average onset of LIEE features at 18.1 months. The epilepsy etiology was most commonly genetic and metabolic (50%), followed by congenital cortical malformations (23%), acquired structural abnormalities (20%), and unknown (7%). The predominant seizure types were myoclonic-tonic (70%), spasm-tonic (50%), epileptic spasms (47%), tonic (43%), and myoclonic (43%) seizures. All patients reported a history of either spasm-tonic or myoclonic-tonic seizures in addition to other types. All patients had EEGs showing discontinuity, electrodecrements, or both along with diffuse slowing, background voltages between 100 and 300 µV, and superimposed multifocal, diffuse epileptiform discharges. Every patient, except one, fulfilled the definition of drug-resistant epilepsy, and all reported either moderate-to-severe or severe developmental delay. SIGNIFICANCE: Late infantile epileptic encephalopathy (LIEE) is characterized by several unique clinical and electrographic features. Typically, LIEE manifests in patients during the second year of life and occurs before two years of age, hence late infantile onset. The condition is commonly observed in infants with symptomatic epilepsy. Myoclonic-tonic and spasm-tonic seizures are the quintessential seizure types. The inter-ictal EEG exhibits more organization and lower voltages than seen with hypsarrhythmia and lacks the defining EEG characteristics of EIDEE, IESS, or LGS. We propose that LIEE is a distinct electroclinical syndrome within the spectrum of developmental and epileptic encephalopathies.
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Epilepsias Mioclónicas , Epilepsia , Síndrome de Lennox-Gastaut , Espasmos Infantiles , Lactante , Humanos , Niño , Epilepsia/diagnóstico , Epilepsia/genética , Espasmos Infantiles/diagnóstico , Convulsiones , Espasmo , ElectroencefalografíaRESUMEN
Myoclonic-tonic (MT) and spasm-tonic (ST) seizures represent distinctive features in late infantile epileptic encephalopathy (LIEE). This commentary aims to delineate the electroclinical characteristics of MT and ST seizures, setting them apart from other seizure types. Our analysis encompasses 211 ST and MT seizures observed in 31 patients diagnosed with LIEE, providing a comprehensive overview of video-EEG features and polygraphic signatures. In MT seizures, EEG findings reveal a high-voltage diffuse spike/polyspike and wave discharge, often succeeded by diffuse electrodecrements. The amplitude-integrated EEG (aEEG) signature is described as a "reversed checkmark." Conversely, ST seizures exhibit EEG findings such as a vertex positive deflection after a slow-wave and relative electrodecrement, with intermixed epileptiform discharges. In comparison to MT seizures, polygraphic characteristics in ST seizures appear more distinct, featuring a brief rhomboid shape corresponding to the spasm, followed by a lengthier rectangular shape indicative of the tonic phase of the ST seizure. While the pathophysiology of ST and MT seizures remains inadequately understood, their concurrent occurrence and association with other seizure types (tonic, epileptic spasm, myoclonic) within the temporal context of LIEE and other epileptic encephalopathies prompt us to anticipate advancements in our understanding through future research. We hope that this study serves as a foundation for unraveling these complexities in the times to come.
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Electroencefalografía , Epilepsias Mioclónicas , Convulsiones , Humanos , Electroencefalografía/métodos , Epilepsias Mioclónicas/fisiopatología , Epilepsias Mioclónicas/diagnóstico , Convulsiones/fisiopatología , Convulsiones/diagnóstico , Lactante , Preescolar , Niño , Espasmos Infantiles/fisiopatología , Espasmos Infantiles/diagnóstico , Masculino , FemeninoRESUMEN
The ketogenic diet is a time-tested, potent, nonpharmacological treatment of epilepsy. However, the use of the ketogenic diet in premature neonates with epilepsy has not been previously reported. We share our experience with the use of ketogenic diet therapy in two premature neonates. Two identical twin premature neonates with SCN2A-related developmental and epileptic encephalopathy, whose seizures were refractory to multiple anti-seizure medications, were started on the classic ketogenic diet at the conceptual age of 35 weeks. Ketosis was achieved and maintained (range 2-5 mmol/L of serum beta-hydroxybutyrate level). Seizure frequency was significantly reduced (>90% reduction in both patients), and some anti-seizure medications were able to be discontinued. Initial transient weight loss and one episode of asymptomatic hypoglycemia were observed and corrected. The ketogenic diet was found to be a safe, well-tolerated, and effective treatment for seizures in two premature neonates. The side effects are tolerable and correctable. The ketogenic diet, therefore, is a treatment option for refractory seizures in this age group, when administered under expert guidance.
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Dieta Cetogénica , Epilepsia , Cetosis , Recién Nacido , Humanos , Lactante , Dieta Cetogénica/efectos adversos , Cuerpos Cetónicos/uso terapéutico , Epilepsia/tratamiento farmacológico , Resultado del TratamientoRESUMEN
At the time of graduation from medical school, medical students have been exposed primarily to adult neurology and have limited exposure to child neurology. Child neurology is a unique field that encompasses caring for children with neurological conditions ranging from routine to rare. There are many opportunities for a variety of unique careers in child neurology including both in the inpatient and outpatient setting. This article aims to provide practical advice for the medical student interested in child neurology to best prepare for a successful match and rewarding career.
RESUMEN
OBJECTIVE: The ketogenic diet therapy is a time-tested and potent non-pharmacologic treatment for epilepsy. However, the study of the ketogenic diet in patients with genetic generalized epilepsy (GGE) is not widely established. The aim of this study was to evaluate the efficacy and tolerability of the modified Atkins diet, a variation of the ketogenic diets, as a treatment for drug-resistant GGE. METHODS: A retrospective chart review was performed in patients with epilepsy treated with the modified Atkins diet at the University of Chicago from 2017 to 2020. For three months following diet initiation, participants were monitored for diet tolerability and effect on seizures. Response to the treatment was recorded by self-reporting patients and guardians. RESULTS: Thirteen patients with a diagnosis of drug-resistant GGE were identified. An average of 3.8 anti-seizure medications (ASMs) had been tried and 3.4 years had elapsed from seizure onset before dietary therapy was attempted. Patients were receiving a mean of 2.2 ASMs at the time of diet initiation. After undergoing dietary treatment for three months, 12/13 (92%) patients experienced a greater than 50% reduction in seizure frequency, 6/13 (46%) patients became seizure-free, and 7/13 (54%) were able to discontinue at least one ASM. All patients completed at least three months of dietary therapy with an average duration of 9.3 months at the time of report. One patient reported side effects of fatigue which may be attributed to the diet. SIGNIFICANCE: The modified Atkins diet has shown to be an effective and well-tolerated treatment for children with drug-resistant GGE. The diet provides the additional benefit of aiding to discontinue ASMs and, therefore, minimize the side effects from polypharmacy. Given these results, it seems reasonable to consider the modified Atkins diet as an alternative and possibly earlier treatment option for patients with drug-resistant GGE.
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Dieta Rica en Proteínas y Pobre en Hidratos de Carbono , Dieta Cetogénica , Epilepsia Refractaria , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Epilepsia Generalizada , Epilepsia , Niño , Dieta Rica en Proteínas y Pobre en Hidratos de Carbono/efectos adversos , Dieta Rica en Proteínas y Pobre en Hidratos de Carbono/métodos , Dieta Cetogénica/efectos adversos , Dieta Cetogénica/métodos , Epilepsia Refractaria/diagnóstico , Epilepsia Refractaria/tratamiento farmacológico , Humanos , Estudios Retrospectivos , Convulsiones , Resultado del TratamientoRESUMEN
Seizures are a common neonatal neurological disorder with an incidence of 1 to 5 in 1,000 live births. Genetic and metabolic epilepsies account for 10% to 12% of all neonatal seizures. Correct identification and diagnosis are important factors, as they carry treatment and management implications. Clinical history, neurological examination, seizure types, epilepsy syndromes, and electroencephalogram findings can be used to guide the diagnosis of epilepsy. Genetic and metabolic epilepsies in neonates can be categorized practically into two groups: amenably treatable disorders, and the most common genetic epilepsies. The treatable disorders primarily consist of inborn errors of metabolism that have a specific therapy. The most common genetic epilepsies include monogenic disorders, which usually result from channelopathies, synaptic vesicle docking/release defect, or dysfunction of cell signaling. A step-wise diagnostic approach to genetic and metabolic epilepsies is proposed in this article to aid clinicians in providing care for newborns with seizures. [Pediatr Ann. 2020;50(6):e245-e253.].
Asunto(s)
Epilepsia , Epilepsia/diagnóstico , Epilepsia/genética , Epilepsia/terapia , Humanos , Incidencia , Recién Nacido , Examen Neurológico , ConvulsionesRESUMEN
BACKGROUND: Several studies showed that inhaled corticosteroids (ICS) may be a potential treatment in acute asthma exacerbation in children. This study was an update meta-analysis on the roles of ICS in the management of acute asthma exacerbation in children presenting to the hospital. MATERIALS AND METHODS: Published articles with key words of ICS for asthma exacerbation, asthma attacks, and acute asthma in children aged under 18 years in the hospital setting with outcome of hospital admission between 2009 and 2018 were enrolled. The databases used in this study were Medline, Scopus, and Web of Science. Odds ratio of comparison between ICS and other treatments on hospital admissions was calculated. RESULTS: There were 311 eligible studies met the searching criteria; seven eligible studies for the analysis; comprised of three meta-analysis and four added studies. The ICS had a significant reduction in hospital admission compared with placebo in overall with odds ratio of 0.63 (95% confidence interval [CI]: 0.41-0.96) and in moderate-to-severe group with odds ratio of 0.17 (95% CI: 0.05-0.51). Comparing with systemic corticosteroid (SC), ICS had significantly lower hospital admissions overall and in mild-to-moderate group with odds ratios of 0.63 and 0.26, respectively. The combination of ICS and SC had odds ratio of 0.75 (95% CI: 0.57-0.99) over SC in moderate-to-severe asthma exacerbation. CONCLUSIONS: ICS significantly reduced hospital admission in asthma exacerbation in children. It may be used alone for mild-to-moderate asthma exacerbation and combination with SC for moderate-to-severe asthma exacerbation.
RESUMEN
The metabolic syndrome (MS) is commonly found in clinical practice. There are many criteria to diagnose MS. The authors did a cross-sectional study to study the difference among the WHO criteria, the National Cholesterol Educational Program (NCEP) Adult Treatment Panel (ATP III), and the International Diabetes Foundation (IDF) in hypertensive patients. Between July and September 2005, 100 patients (62 women) treated at the hypertension clinic, Srinagarind Hospital were included. The WHO, NCEP A TP III and IDF criteria gave the diagnosis of MS in 37, 33, 60 cases, respectively. The IDF criteria had the significantly highest yield among those three criteria (p < 0.0001). Body mass index (BMI) was the only significant correlated with the diagnosis of MS by the IDF criteria (p-value = 0.04). It also had moderately positive correlated with waist circumference, WC (p < 0.0001, Pearson Correlation 0.58). At the cut point of BMI 23 kg/m2, we suggested the appropriate WC cut-point for Thai hypertensive men and women was 82.5 cm (32.5") and 79.5 cm (31.3"), respectively.