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BACKGROUND: To summarize the clinical and genetic characteristics of patients with pyridox(am)ine-5'-phosphate oxidase (PNPO) deficiency. METHODS: Clinical and genetic data of the patients were collected and analyzed. RESULTS: Eighteen patients from 17 families with variants in PNPO were collected, and 15 cases survived to date. The age of onset ranged from 1 day to 5 months (median age 6.5 days) and seven of them presented with seizures <24 h. About 7/18 (39%) of patients showed seizure-free with pyridoxine (PN) or pyridoxal-5'-phosphate treatment. Two patients showed surprised therapeutic responses to antiseizure medications therapy: one could be controlled for up to 1 year and 5 months, and the other showed seizure-free for >8 years. The neurodevelopment was normal in one patient, mild delay in four, in whom responded well to PN. Severe delay could be seen in the remaining 10 surviving patients. Genetic analysis revealed 14 variants of PNPO, seven of which were novel. Five pairs of unrelated patients were observed to carry the same variants, respectively, and had similar developmental status and onset age of seizures in some degree in each pair, whereas also had differences. CONCLUSIONS: The clinical characteristics, including age of onset, treatment response and prognosis, were variable and difficult to classify into different types clearly. Patients with PNPO deficiency who used PN as their main treatment and being able to control seizures seemed to be associated with better outcomes. Patients with the same genotype tended to show the correlation of phenotype-genotype.
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Encefalopatías Metabólicas , Hipoxia-Isquemia Encefálica , Enfermedades Metabólicas , Piridoxaminafosfato Oxidasa , Humanos , Encefalopatías Metabólicas/genética , Hipoxia-Isquemia Encefálica/genética , Oxidorreductasas , Fosfatos/uso terapéutico , Fosfato de Piridoxal/uso terapéutico , Piridoxaminafosfato Oxidasa/deficiencia , Piridoxaminafosfato Oxidasa/genética , Piridoxina , Convulsiones/tratamiento farmacológico , Convulsiones/genéticaRESUMEN
BACKGROUND: PHACTR1 (phosphatase and actin regulators) plays a key role in cortical migration and synaptic activity by binding and regulating G-actin and PPP1CA. This study aimed to expand the genotype and phenotype of patients with de novo variants in PHACTR1 and analyse the impact of variants on protein-protein interaction. METHODS: We identified seven patients with PHACTR1 variants by trio-based whole-exome sequencing. Additional two subjects were ascertained from two centres through GeneMatcher. The genotype-phenotype correlation was determined, and AlphaFold-Multimer was used to predict protein-protein interactions and interfaces. RESULTS: Eight individuals carried missense variants and one had CNV in the PHACTR1. Infantile epileptic spasms syndrome (IESS) was the unifying phenotype in eight patients with missense variants of PHACTR1. They could present with other types of seizures and often exhibit drug-resistant epilepsy with a poor prognosis. One patient with CNV displayed a developmental encephalopathy phenotype. Using AlphaFold-Multimer, our findings indicate that PHACTR1 and G-actin-binding sequences overlap with PPP1CA at the RPEL3 domain, which suggests possible competition between PPP1CA and G-actin for binding to PHACTR1 through a similar polymerisation interface. In addition, patients carrying missense variants located at the PHACTR1-PPP1CA or PHACTR1-G-actin interfaces consistently exhibit the IESS phenotype. These missense variants are mostly concentrated in the overlapping sequence (RPEL3 domain). CONCLUSIONS: Patients with variants in PHACTR1 can have a phenotype of developmental encephalopathy in addition to IESS. Moreover, our study confirmed that the variants affect the binding of PHACTR1 to G-actin or PPP1CA, resulting in neurological disorders in patients.
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Secuenciación del Exoma , Estudios de Asociación Genética , Proteínas de Microfilamentos , Mutación Missense , Fenotipo , Espasmos Infantiles , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Actinas/genética , Predisposición Genética a la Enfermedad , Genotipo , Proteínas de Microfilamentos/genética , Mutación Missense/genética , Enfermedades del Sistema Nervioso/genética , Proteína Fosfatasa 1/genética , Espasmos Infantiles/genéticaRESUMEN
Biallelic variants in EEF1B2 have recently been shown to cause a novel form of non-syndromic intellectual disability (ID) in two unrelated families. More patients are needed to delineate the genotypic and phenotypic spectrum of this gene. In this study, two patients in a family harboring pathogenic compound heterozygous variants in EEF1B2 were identified. They were characterized by non-syndromic ID and fever-sensitive seizures in childhood. Quantitative real-time polymerase chain reaction (QPCR) analysis showed significantly reduced levels of mRNA expression in two patients compared with unaffected controls. The level of EEF1B2 protein was hardly detected in both patients and their unaffected parents. The eef1b2 F0 knockout (crispant) zebrafish presented with abnormal development and light-induced hyperactivity. We identified novel pathogenic EEF1B2 variants within two siblings in a new family. The findings of the expression experiment and first crispant eef1b2 zebrafish model provided further clues to the role of EEF1B2 variants in the pathogenesis of autosomal-recessive ID.
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Discapacidad Intelectual , Animales , Genes Recesivos , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Linaje , Hermanos , Pez Cebra/genéticaRESUMEN
AGO1, as one of the rare genes in neurodevelopmental disorders, is involved in the microRNA-induced silencing complex. Here, we describe the clinical and genetic features of 18 individuals with de novo AGO1 variants: four new and 14 previously reported. Three variants are identified: two in-frame deletion variants and one missense variant. The spectrum of AGO1-related disorders included global development delay (GDD), intellectual disability (ID) with or without epilepsy, autism spectrum disorder, hypotonia and dysmorphisms. Focal seizures are the most common type of seizure, occasionally with atypical absence. Mild deafness may be a new phenotype of AGO1-releated disease. Gly199Ser may be a hot-spot variant of AGO1 with the same phenotype: GDD/ID, intractable epilepsy, remarkably with Rolandic discharges, and even reaching electrical status epilepticus during sleep.
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Proteínas Argonautas , Trastorno del Espectro Autista , Factores Eucarióticos de Iniciación , Discapacidad Intelectual , Trastornos del Neurodesarrollo , Trastorno del Espectro Autista/genética , Humanos , Discapacidad Intelectual/genética , Hipotonía Muscular/genética , Trastornos del Neurodesarrollo/genética , Fenotipo , Convulsiones/genéticaRESUMEN
AIM: To further identify and broaden the phenotypic characteristics and genotype spectrum of the dehydrodolichol diphosphate synthase (DHDDS) gene. METHOD: Pathogenic variants of DHDDS were identified by whole-exome sequencing; clinical data of 10 patients (six males, four females; age range 2-14y; mean age 5y 9mo, SD 3y 3mo) were collected and analysed. RESULTS: All patients had seizures, and myoclonic seizures could be seen in eight patients, with myoclonic status epilepticus in three. The interictal electroencephalogram (EEG) in four patients at seizure onset showed generalized slow waves, slow wave mixed spikes, and spike and waves. Tremor, ataxia, and hypertonia was observed in six, five, and three patients respectively. The results of short-latency somatosensory evoked potential in two patients were normal, and the symptom of tremor was captured on EEG without time-locked discharges in one patient, suggesting that the tremor in both patients was a motor impairment rather than myoclonic seizures. Global developmental delay occurred in all patients, among whom nine showed severe intellectual disability and one moderate. Five DHDDS variants were identified, three of which have not been reported previously. INTERPRETATION: Myoclonic seizure is the most common seizure type in heterozygous DHDDS variants, while myoclonic status epilepticus can also occur. The pattern of interictal EEG discharges is characterized by slow waves rather than spike and waves, and generalized discharges was prominent.
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Transferasas Alquil y Aril/genética , Epilepsias Mioclónicas/genética , Convulsiones/genética , Estado Epiléptico/genética , Temblor/genética , Adolescente , Encéfalo/fisiopatología , Niño , Preescolar , Electroencefalografía , Epilepsias Mioclónicas/fisiopatología , Potenciales Evocados Somatosensoriales/genética , Femenino , Genotipo , Humanos , Masculino , Fenotipo , Convulsiones/fisiopatología , Estado Epiléptico/fisiopatología , Temblor/fisiopatología , Secuenciación del ExomaRESUMEN
AIM: To characterize the clinical and genetic characteristics of a large cohort of patients with pyridoxine-dependent epilepsy (PDE). METHOD: We retrospectively collected clinical and genetic information of 33 (15 males, 18 females; mean [SD] age 4y 11mo [2y 5mo]; 1y 3mo-10y 4mo) patients with PDE from 31 unrelated families at a single centre. RESULTS: There were many types of seizures, with focal seizures in 32 cases. Dravet syndrome was suspected clinically in two patients. Electroencephalogram (EEG) was normal in seven patients at the initial stage and then in 17 patients during pyridoxine maintenance therapy. Genetic studies revealed 26 kinds of variants in ALDH7A1 and four in PLPBP with 18 variants unreported previously, and 48 ALDH7A1 variants were located in exon 11, 12, 14, and 17 or intron 9 and 11. In addition, three patients carried different exons deletion. Among these, seizures could be controlled for several years in one patient by levetiracetam monotherapy. Another patient remained seizure free for up to 7 months without therapy. All patients received oral pyridoxine treatment, with only one case (with exon 8-13 deletion) showing poor control. INTERPRETATION: This study illustrates the range of clinical presentations and genetic causes in PDE, as well as responsiveness to antiepileptic drugs. A relationship between EEG and pyridoxine therapy could be seen in many cases. Seizure control was seen in all with pyridoxine monotherapy except for one patient. WHAT THIS PAPER ADDS: There is a parallel relationship between electroencephalogram and pyridoxine therapy in many patients. Patients with pyridoxine-dependent epilepsy may respond well to low-dose pyridoxine.
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Aldehído Deshidrogenasa/genética , Epilepsia/diagnóstico , Proteínas/genética , Encéfalo/fisiopatología , Niño , Preescolar , China , Análisis Mutacional de ADN , Electroencefalografía , Epilepsia/genética , Epilepsia/fisiopatología , Femenino , Humanos , Lactante , Masculino , Mutación , Estudios RetrospectivosRESUMEN
BACKGROUND AND PURPOSE: To test the hypothesis that myoclonic seizures can evolve to tonic seizures, we documented the electroclinical features of this under-recognized seizure type. METHODS: We observed a distinct seizure pattern starting with myoclonus without returning to an interictal state, which subsequently evolved into generalized tonic seizures. The detailed symptomatic and electroencephalographic characteristics of this seizure were extracted, and the clinical manifestations, drug curative responses in patients with this seizure were reviewed and analyzed. RESULTS: The onset of all seizures was characterized by a preceding period of myoclonus and bursts of generalized spike or poly-spike slow wave discharges with high amplitude. This was closely followed by the occurrence of tonic seizures, which were distinguished by bursts of generalized fast activity at 10 Hz or higher frequency. This under-recognized seizure type has been designated as myoclonic-to-tonic (MT) seizure. The number of patients identified with MT seizures in this study was 34. The prevalence rate of MT seizures was found to be higher in males. While MT seizures typically included a tonic component, it should be noted that some patients experiencing this seizure type never presented with isolated tonic seizures. Generalized Epilepsy not further defined (GE) accounted for approximately one-third of the diagnosed cases, followed by Lennox-Gastaut syndrome and Epilepsy with Myoclonic-Atonic seizures. In comparison to other types of epilepsy, GE with MT seizures demonstrated a more favorable prognosis. CONCLUSIONS: The classification of myoclonic-to-tonic seizure represents a novel approach in comprehending the ictogenesis of generalized seizures and can provide valuable assistance to clinicians in epilepsy diagnosis.
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Electroencefalografía , Epilepsias Mioclónicas , Convulsiones , Humanos , Masculino , Femenino , Electroencefalografía/métodos , Adulto , Adolescente , Convulsiones/fisiopatología , Convulsiones/diagnóstico , Niño , Adulto Joven , Epilepsias Mioclónicas/fisiopatología , Epilepsias Mioclónicas/diagnóstico , Epilepsia Generalizada/fisiopatología , Epilepsia Generalizada/diagnóstico , Preescolar , Persona de Mediana Edad , Mioclonía/fisiopatología , Mioclonía/diagnóstico , LactanteRESUMEN
OBJECTIVE: Lennox-Gastaut Syndrome (LGS) is characterized by the presence of multiple seizure types and encompasses a heterogenous group of etiologies. The aim of our study was to evaluate the etiological profile of LGS and investigate seizure outcomes based on different clinical variables. METHODS: The clinical features, neuroimaging findings, genetic testing and other testing results of LGS patients were systematically reviewed. The identifiable etiology was categorized as either acquired or nonacquired. Univariate and multivariate regression analyses were performed to explore the association between clinical variables and seizure outcome at the last follow-up. RESULTS: We enrolled 156 patients diagnosed with LGS, of whom 66% were male. The mean age of patients was 34.2 months and the median follow-up duration was 29.5 months (interquartile range = 14-56.25 months). The initial seizure type was epileptic spasm in 61 patients, among which 33 of them met the criteria for infantile epileptic spasm syndrome. All patients underwent neuroimaging test, with 25% falling into the acquired structural category. Etiology could be identified in 84 individuals, including pathogenetic variants found in 34 out of 117 patients with nonacquired etiology. CHD2 mutations were most frequently observed among these pathogenetic variants. At the last follow-up, favorable outcomes were observed in 27 patients. The identification of etiology emerged as a significant determinant influencing LGS outcome; specifically, patients with unknown etiology had a higher likelihood of experiencing favorable outcomes compared to those with known cause (p = 0.041). Early onset age and longer epilepsy duration significantly increased the odds of an unfavorable outcome (p = 0.006 and 0.024). SIGNIFICANCE: We present novel data on the clinical and etiological spectrum of LGS, with determined etiology observed in over half of the patients. Epileptic spasms were found to be more prevalent than tonic seizures as seizure onset types in LGS. The presence of a known etiology, earlier age at onset, and longer duration of epilepsy were associated with a poorer long-term epileptological outcome.
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Síndrome de Lennox-Gastaut , Humanos , Masculino , Síndrome de Lennox-Gastaut/fisiopatología , Femenino , Preescolar , Lactante , Niño , Estudios de Seguimiento , Estudios Retrospectivos , Espasmos Infantiles/etiología , Espasmos Infantiles/fisiopatología , ElectroencefalografíaRESUMEN
This systematic review and meta-analysis aimed to evaluate the efficacy of vigabatrin (VGB) in treating infantile epileptic spasms syndrome (IESS). Databases of PubMed, Embase, Web of Science, MEDLINE, and Cochrane Library were systematically searched. All the relevant randomized controlled trials (RCTs) and observational studies (OSs) of VGB for IESS were included and analyzed separately. The primary outcome was the cessation of epileptic spasms (ES). Five RCTs and nine OSs compared the efficacy of VGB vs hormonal monotherapy for IESS. Meta-analysis of the five RCTs showed that hormonal monotherapy was significantly better than VGB monotherapy (OR = 0.37, 95% CI = 0.20-0.67) for patients with new-onset IESS. Meta-analysis of the nine OSs agrees with the result from RCTs (OR = 0.61, 95% CI = 0.43-0.85). VGB was more effective in patients with TSC than in those with other etiologies (five OSs, OR = 5.59, 95% CI = 2.17-14.41). There was no significant difference in the efficiency of VGB combined with hormonal therapy vs hormonal monotherapy for IESS (two RCTs, OR = 0.75, 95% CI = 0.09-6.45). Hormonal monotherapy is better than VGB monotherapy for non-TSC-associated IESS. But for patients with IESS due to TSC, VGB is the first choice. VGB combined with hormone therapy does not definitely increase ES control rates compared with that of hormonal monotherapy.
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Espasmos Infantiles , Vigabatrin , Humanos , Vigabatrin/uso terapéutico , Anticonvulsivantes/uso terapéutico , Espasmos Infantiles/tratamiento farmacológico , Síndrome , Espasmo/complicaciones , Espasmo/tratamiento farmacológicoRESUMEN
BACKGROUND: To investigate electroclinical phenotypes and long-term photosensitivity outcome in a large pediatric cohort of patients with epilepsy with photosensitivity. METHODS: Patients with epilepsy with photosensitivity with four or more years of follow-up were included. Sustained terminal remission (STR) of photosensitivity (≥3.5 years) and seizure control were investigated, as well as the prognostic factors of photosensitivity. Furthermore, a cluster analysis was used to study the different subgroups of photoparoxysmal responses (PPR). RESULTS: We included 190 individuals with a median age at diagnosis of photosensitivity of 93.1 months (interquartile range [IQR] 62.8 to 120 months) and a median follow-up duration of 68.5 months (IQR 51.8 to 84 months). STR of photosensitivity was achieved in 97 (51.1%) patients, and the mean time from age at diagnosis of photosensitivity onset to STR was 16.5 months. Age at the last follow-up (9 to 18 years [P = 0.001]), a history of photoconvulsive response (PCR) (P = 0.009), and posterior epileptiform discharges (EDs) of PPRs (P = 0.05) were significantly associated with a lower chance of entering STR according to a Cox proportional hazards model. The subgroup of generalized epilepsy syndrome exhibited 46.2% of eye closure sensitivity and 47.7% of PCR. The rates of focal epilepsy syndrome (cluster 1), generalized epilepsy syndrome (cluster 2), and unclassified epilepsy (cluster 3) were similar and not statistically different in photosensitive outcome (P = 0.527). CONCLUSIONS: Age nine to 18 years, a history of PCR, and posterior EDs of PPRs were the adverse factors affecting photosensitivity, suggesting the effect of age-related brain changes in STR. There was no difference in the prognosis of photosensitivity in different epileptic syndromes.
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Epilepsias Parciales , Epilepsia Generalizada , Epilepsia , Síndromes Epilépticos , Humanos , Epilepsia/tratamiento farmacológico , ConvulsionesRESUMEN
OBJECTIVE: To study the relationship between eye closure sensitivity (ECLS), photosensitivity, and the mechanism of Jeavons syndrome (JS). METHODS: The interictal and the ictal epileptiform discharges (EDs) of 80 patients with electroencephalograms were classified (I: focal posterior EDs; II: the posterior spread into the frontal EDs; and III: generalized EDs) and analyzed under different provoked conditions. RESULTS: During the interictal and the ictal period, the positive rates of ECLS were higher than those of photosensitivity (100% vs 57.5%, P = 0.001; 97.5% vs 27.4%, P = 0.001). After a one-year interval, eyelid-myoclonia with ECLS remitted in 16 out of 21 patients (P = 0.002), and eyelid-myoclonia with photo-convulsion response (PCR) disappeared in all the previous six patients (P = 0.021). For the interictal EDs with ECLS, grade I accounted for 11.2%; grade I, II, and III 51.3%; and grade III 32.5%. Interictal EDs classification of photosensitivity showed a similar trend as that of ECLS. For the ictal EDs, grade I accounted for 10.2% of patients with ECLS and 6.7% of patients with PCR; grade I, II, and III, 33.3% of patients with ECLS and 46.6% of patients with PCR; and grade III, 53.9% of patients with ECLS and 40% of patients with PCR. CONCLUSION: ECLS was more common than photosensitivity in JS. Photosensitivity was more likely to disappear than ECLS. Both eye closure and intermittent-photic-stimulation could induce three grades of EDs, confirming that visual stimuli could trigger occipital cortex originating epileptic neural network to varying degrees, which further recognizes JS as another continuum epilepsy.
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Epilepsias Parciales , Epilepsia Generalizada , Epilepsia , Trastornos por Fotosensibilidad , Electroencefalografía , Humanos , Lóbulo Occipital/diagnóstico por imagen , ConvulsionesRESUMEN
Objective: To analyze the clinical feature, treatment, and prognosis of epileptic spasms (ES) in vitamin B6-dependent epilepsy, including patients with pyridoxine-dependent epilepsy (PDE) caused by ALDH7A1 mutation, pyridox(am)ine-5'-phosphate oxidase (PNPO) deficiency, and PLPBP deficiency. Methods: We analyzed data from a cohort of 54 cases with PDE, 13 cases with PNPO deficiency, and 2 cases with PLPBP deficiency and looked for the presentation of ES among them. Results: A total of 11 patients with the seizure presentation of ES have been collected. Among them, four patients carried mutations in ALDH7A1, six carried mutations in PNPO, and the remaining one carried mutation in PLPBP. The analysis of this cohort identified nine cases presenting as infantile spasms distributed in the three diseases and two cases presenting as Ohtahara syndrome diagnosed with PDE and PNPO deficiency, respectively. In the PDE and PLPBP deficiency groups, seizures were controlled by pyridoxine monotherapy, and the remaining one had refractory seizures due to secondary brain atrophy. In the groups with PNPO deficiency, one patient showed seizure-free when treated by PLP combined with valproic acid, three still had infrequent seizures treated by PLP monotherapy or pyridoxine or PLP combined with other antiseizure medications, and two died. In two cases presenting as Ohtahara syndrome, after regular treatment, one showed seizure-free, the others showed a marked decrease in seizure frequency, and they both showed an improvement in EEG. Significance: ES might be a common form of seizures in PNPO deficiency, and EEG presented as hypsarrhythmia or a burst suppression pattern. It is difficult for pyridoxine to control frequent seizures caused by secondary brain injury. In our PNPO deficiency cohort, patients with infantile spasms did not respond better to PLP than pyridoxine. Timely and correct treatment could prevent the transformation of the child's disease from Ohtahara syndrome and infantile spasms to subsequent epileptic encephalopathy or refractory epilepsy.
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Objective: This study aimed to delineate the detailed characteristics of startle-induced epileptic spasms (ES) and explore the brain regions where startle-induced ES originated. Methods: Among 581 patients with ES registered in our database, 30 were diagnosed with startle-induced ES according to video-electroencephalogram (EEG) and seizure semiology and were included in this study. Patients' clinical characteristics and ictal high-frequency oscillations (HFOs) were analyzed. Results: Mean age at the onset of startle-induced ES was 28.1 months. Half of the patients had structural etiology, two of whom were diagnosed with co-existing structural and genetic etiologies. The focal neuroimaging abnormalities were predominant in the frontal cortex (9/15, 60.0%). Fifteen patients (50%) had prominent interictal epileptiform discharges in the frontal and anterior temporal. Ictal HFOs counts of the startle-induced ES in the anterior region were significantly higher than those in the posterior regions (p < 0.05). Five patients (16.7%) became seizure-free ≥6 months, and ten (33.3%) showed startle-induced ES cessation ≥6 months. All patients except one had mild to severe psychomotor developmental delay after the onset of seizures. Conclusion: Patients with startle-induced ES typically had brain lesions and showed drug-resistant. The neuroimaging and EEG findings, including ictal HFOs, support that startle-induced ES often originates from the frontal cortex.
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Objective: To analyze the clinical features, treatment, and prognosis of patients with vitamin B6-responsive infantile spasms (IS). Methods: The clinical features, genetics, and follow-up data of 30 patients were collected and analyzed. Results: The age of epileptic spasms (ES) onset was from 3 months to 12 months. They all received high doses of vitamin B6 at different times after the onset of ES, ranging from 1 day to 5 months. ES were controlled within 11 days in 93% (28/30) patients, and as late as 1 month and 2 months in the other two patients. In the course of treatment, 28 patients were seizure-free all the time, and seizures of other two patients recurred due to withdrawal of vitamin B6. The available follow-up EEG results of 28 patients were normal in 26 cases, and 81% (21/26) had suppressed epileptic discharges within 6 months. Of the 26 cases with normal follow up EEG, 4 had developmental delay and 22 had normal development. The time for EEG to return to normal in 22 patients with normal development ranged from 14 days to 2 years (mean = 111.5 days; median = 52.5 days). The time for EEG to return to normal in the other 4 patients with development delay ranged from 4 months to 2 years (mean = 375 days; median = 330 days). To the last follow-up, seizures were controlled well in 29 surviving patients, and 21 patients were able to deactivate from all medications without seizures recurrence. Sixteen patients showed varying degrees of developmental delay after onset. After seizure control, the psychomotor development was delayed in 7 patients (one died) until the last follow-up. Genetic analysis did not show any meaningful results. Conclusion: An observation period of 1-2 weeks is essential to identify patients with vitamin B6-responsive IS. The treatment time could be extended according to the treatment response and EEG changes. It might take a longer time for EEG to return to normal and to stop taking drugs in patients with persistent or unimproved developmental delay. Neurodevelopmental outcomes and prognosis of vitamin B6-responsive IS were relatively favorable.
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Objective: To determine the contribution of genetic etiologies in epilepsy with photosensitivity. Methods: A total of 35 epileptic patients with genetic photosensitivity from January 2019 to May 2021 were analyzed. Results: Pathogenic variants were identified in 35 patients, including SCN1A(7) CHD2(6), TPP1(3), SYNGAP1(3), GABRA1(2), GABRG2(1), KCTD7(1), MFSD8(1), KCNC1(1) GBA(1), CACNA1A(1), KCNMA1(1), FLNA(1), SZT2(1), SLC2A1(1), 5q33.2-34del(1), and mitochondrial variants(3). The predominant epileptic syndrome was progressive myoclonus epilepsy (PME) and Dravet syndrome, while the most common seizure type in both spontaneous seizures and photoconvulsive response (PCR) was myoclonic seizures. The abnormal EEG background and brain MRI were mainly seen in the PME patients. In PME, initial low-frequencies (1-6 Hz) photosensitivity was observed in 70% (7/10) of patients. Among the other patients, 12 patients (48.0%, 12/25) had photosensitivity at initial low -frequencies and 12 patients (48.0%, 12/25) had photosensitivity at initial middle frequencies (6-20 Hz). At the 1-year follow-up, 77.7% (21/27) still remained photosensitive. Conclusion: The most common genes for epilepsy with genetic photosensitivity are SCN1A and CHD2, and the most common syndromes are PME and Dravet syndrome. MFSD8, KCNMA1, SZT2, FLNA, and SLC2A1 variants might be candidate genes for photosensitivity. PPRs at initial low-frequencies may be a marker of PME, and the most typical feature of genetic photosensitivity may be low- or middle- frequencies induced PPRs. Photosensitivity in epilepsy with genetic photosensitivity may be difficult to disappear in a short period of time.
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Objective: KCNT2 gene mutations had been described to cause developmental and epileptic encephalopathies (DEEs). In this study, we presented the detailed clinical features and genetic analysis of two unrelated patients carrying two de novo variants in KCNT2 and reviewed eight different cases available in publications. Methods: Likely pathogenic variants were identified by whole exome sequencing; clinical data of the patients were retrospectively collected and analyzed. Results: Our two unrelated patients were diagnosed with Ohtahara syndrome followed by infantile spasms (IS) and possibly the epilepsy of infancy with migrating focal seizures (EIMFS), respectively. They both manifested dysmorphic features with hirsute arms, thick hair, prominent eyebrows, long and thick eyelashes, a broad nasal tip, and short and smooth philtrum. In the eight patients reported previously, two was diagnosed with IS carrying a 'change-of-function' mutation and a gain-of-function mutation, respectively, two with EIMFS-like carrying a gain-of-function mutation and a loss-of-function mutation, respectively, one with EIMFS carrying a loss-of-function mutation, three with DEE without functional analysis. Among them, two patients with gain-of-function mutations both exhibited dysmorphic features and presented epilepsy phenotype, which was similar to our patients. Conclusion: Overall, the most common phenotypes associated with KCNT2 mutation were IS and EIMFS. Epilepsy phenotype associated with gain- and loss-of-function mutations could overlap. Additional KCNT2 cases will help to make genotype-phenotype correlations clearer.
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OBJECTIVE: To describe the clinical characteristics of 12 patients from six families with pyridoxine-dependent epilepsy (PDE) carrying ALDH7A1 mutations, and analyze the impact of early diagnosis and treatment, as well as possible genotype-phenotype relationship. METHODS: Clinical and genetics data of 12 patients were collected. RESULTS: Family 1-3 presented with symptoms in the neonatal period, while family 4-6 presented during early infancy. In the same family, the age of onset was similar. The focal motor seizure appeared in all patients. The affected identical twins from family 4 were diagnosed with infantile spasms. Mutation analysis identified nine different ALDH7A1 mutations among six families. The neurodevelopment of siblings in family 1 was mild delay and normal separately due to the minor difference of delayed diagnosis time. Siblings in family 2 showed severely delayed and normal development respectively due to the significant difference of a delayed diagnosis for 4 years. In family 5, although the difference of the delayed diagnosis time is up to 7 years, the nearly normal psychomotor development in both patients might be due to infrequent seizures before the delayed diagnosis. A severe phenotype exhibited in family 3, 4, and 6. The survived affected patients presented with severe developmental delay or refractory seizures and their twins or older sisters presented a similar clinical history and died in the early days of life. Mutation analysis showed D511N and IVS11 + 1G > A in family 3, V188A and exon1 deletion in family 4, and Y354C and exon 8-13 deletion in family 6. CONCLUSION: Patients from the same family often have the same phenotype, including onset age and seizure type. Early treatment with pyridoxine and infrequent seizures showed positive relationship with prognosis. The deletion of exon 1 and exon 8-13 might be associated with the severe phenotype.
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BACKGROUND: Recently, the electroencephalogram pattern of electrical status epilepticus during sleep (ESES) had been reported in some genetic disorders, and most of them were noted with developmental and epileptic encephalopathy (DEE) or epileptic encephalopathy (EE). This study aimed to determine the genetic etiologies and clinical characteristics of ESES in DEE/EE. METHODS: We performed a cohort study in cases of DEE or EE with ESES. Tio-based genetic testing was performed in 74 cases and was analyzed to identify underlying variants. RESULTS: Pathogenic or likely pathogenic variants were identified in 17/74 cases, including KCNQ2 (n = 6), KCNA2 (n = 5), GRIN2A (n = 3), SLC9A6 (n = 1), HIVEP2 (n = 1), and RARS2 (n = 1). Eleven were boys. The median age at seizure onset was 6 months. ESES occurred at the mean age of 2.0 ± 1.2 years, predominant in the Rolandic region in 14 years. Twelve of 17 cases had the first stage of different epilepsy preceding ESES: 2/12 were diagnosed as Ohtahara syndrome, 2/12 were diagnosed as infantile spasms, 3/12 were diagnosed as DEE, and 5/12 were diagnosed as EE without the epileptic syndrome. CONCLUSION: Monogenic variants explained over 20% of DEE/EE with ESES. ESES could be an age-related feature in genetic disorders and occurred after the first stage of different epilepsy. Both age-related factors and genetic etiology were suggested to play a role in the occurrence of ESES in genetic DEE/EE.
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The study aimed to review the clinical, radiological, and pathological findings and electroencephalogram (EEG) of pediatric epilepsy patients with temporal onset focal seizures induced by intermittent photic stimulation (IPS). Four patients with temporal onset photosensitivity focal seizures were analyzed. Three (75%) of the four patients were female. The average age of seizure-onset was 4.4 years. The interictal EEG showed both generalized and focal spike and waves in one patient and focal or multifocal spike and waves alone in three patients. Photoparoxysmal response (PPR) was evoked in all patients and showed generalized discharges (patients 2-4), both generalized and posterior discharges (patient 1). Both generalized and focal discharges could coexist in interictal discharges and PPR. The sensitive frequencies of PPR and photoconvulsive response (PCR) were 12-30 and 10-16 Hz, respectively, which were close to the occipital rhythm. In all patients, the onset of PCR was recorded, namely, the left anterior and mesial temporal lobe (TL), the left posterior TL, and the whole left TL, which showed two forms: the seizure of two patients was the onset of slow waves in the temporal area without spreading generalized discharges (patients 1 and 4), and the other one was fast rhythmic activities in the temporal area, spreading to the occipital area or gradually evolving into the generalized discharges (patients 2 and 3). During follow-up, except for patient 3 who had occasional seizures, the seizures of the remaining patients were under control. Temporal onset focal seizures could be induced by IPS. Temporal onset photosensitivity seizures were mostly easy to control with antiseizure drugs.
RESUMEN
Objective: The DYNC1H1 gene is related to a variety of diseases, including spinal muscular atrophy with lower extremity-predominant 1, Charcot-Marie-Tooth disease type 2O, and mental retardation, autosomal dominant13 (MRD13). Some patients with DYNC1H1 variant also had epilepsy. This study aimed to detect DYNC1H1 variants in Chinese patients with infantile spasms (ISs). Methods: We reviewed clinical information, video electroencephalogram (V-EEG), and neuroimaging of a newly identified cohort of five patients with de novo DYNC1H1gene variants. Results: Five patients with four DYNC1H1variants from four families were included. All patients had epileptic spasms (ESs), the median age at seizure onset was 7.5 months (range from 5 months to 2 years 7 months), and the interictal V-EEG results were hypsarrhythmia. Four of five patients had brain magnetic resonance imaging (MRI) abnormalities. Four de novo DYNC1H1 variants were identified, including two novel variants (p.N1117K, p.M3405L) and two reported variants (p.R1962C, p.F1093S). As for the variant site, two variants are located in the tail domain, one variant is located in the motor domain, and one variant is located in the stalk domain. All patients had tried more than five kinds of antiepileptic drugs. One patient has been controlled well by vigabatrin (VGB) for 4 years, and another patient by VGB and steroids for 1.5 years. The other three patients still had frequent ESs. All patients had severe intellectual disability and development delays. Significance: IS was one of the phenotypes of DYNC1H1 variants. Most patients had non-specific brain MRI abnormality. Two of four DYNC1H1 variants were novel, expanding the variant spectrum. The IS phenotype was related to the variant's domains of DYNC1H1 variant sites. All patients were drug-refractory and showed development delays.