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OBJECTIVE: This study aimed to identify the recurrence rate of genetic generalized epilepsy (GGE) and risk factors for recurrence after antiseizure medication (ASM) withdrawal in adolescent patients. METHODS: We retrospectively reviewed medical records of patients with GGE who were included in the registry at the Department of Child Neurology, National Hospital Organization Nishiniigata Chuo Hospital from 2000 through 2020. The eligibility criteria were as follows: onset of epileptic seizures at <15 years of age, treatment with an ASM, and attempted treatment withdrawal at 10-19 years of age. The rates of seizure recurrence after drug withdrawal were evaluated. Moreover, several variables were evaluated as predictors of recurrence. RESULTS: In total, 77 patients with GGE (21, 13, and 43 patients with juvenile myoclonic epilepsy [JME], juvenile absence epilepsy [JAE], and epilepsy with generalized tonic-clonic seizures alone [EGTCSA], respectively) were included in this study. Recurrence was detected in 68% of patients with GGE (86%, 31%, and 70% of patients with JME, JAE, and EGTCSA, respectively). Recurrence rates for patients who developed epilepsy at ≥13 years of age, those who started dose reduction at ≥16 years of age, those who exhibited a seizure-free period of <36 months before withdrawal, and those who chose to discontinue treatment at their own discretion were significantly higher than those for their counterparts. Multivariate analysis revealed that initiation of dose reduction at ≥16 years of age was associated with increased recurrence risk. Meanwhile, a diagnosis of JAE was associated with decreased recurrence risk. All patients with JAE were treated with valproic acid. SIGNIFICANCE: Antiseizure medication withdrawal at ≥16 years of age and a diagnosis other than JAE may be independent risk factors for seizure recurrence after drug withdrawal in adolescent patients.
Assuntos
Epilepsia Tipo Ausência , Epilepsia Generalizada , Epilepsia Mioclônica Juvenil , Síndrome de Abstinência a Substâncias , Adolescente , Adulto , Anticonvulsivantes/uso terapêutico , Criança , Pré-Escolar , Epilepsia Generalizada/tratamento farmacológico , Epilepsia Generalizada/genética , Humanos , Estudos Retrospectivos , Fatores de Risco , Convulsões/tratamento farmacológico , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Adulto JovemRESUMO
BACKGROUND: Pallister-Killian syndrome (PKS) is a rare disorder caused by the mosaic tetrasomy of chromosome 12p, and is characterized by facial dysmorphism, developmental delay, hypotonia and seizures. RESULTS: We report a patient with PKS showing unique polymicrogyria with calcification. He had delayed development and dysmorphic facial features including frontal bossing, hypertelorism, and high arched palate at 6 months of age. Neuroimaging revealed unilateral polymicrogyria with spot calcifications, which predominantly affected the right perisylvian region. Chromosome G-banding showed the karyotype 46,XY, however, array-based comparative genomic hybridization analysis showed mosaic duplication of chromosome 12p, in which CCND2, which encodes cyclin D2 and is a downstream mediator of PI3K-AKT pathway, is located. Supernumerary chromosome of 12p was detected in 58% of buccal mucosa cells by the interphase fluorescence in situ hybridization analysis using chromosome 12 centromere-specific D12Z3 probe. The diagnosis of PKS was made based on distinctive clinical features of our patient and the results of cytogenetic analyses. CONCLUSION: This report is, to our knowledge, the first case of a patient with PKS who clearly demonstrates polymicrogyria colocalized with calcifications, as shown by CT scans and MRI, and suggests that a patient with PKS could show structural brain anomalies with calcification. We assume that somatic mosaicism of tetrasomy could cause asymmetrical polymicrogyria in our patient, and speculate that increased dosages of CCND2 at chromosome 12p might be involved in the abnormal neuronal migration in PKS.
Assuntos
Calcinose/genética , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/patologia , Polimicrogiria/genética , Encefalopatias/genética , Encefalopatias/patologia , Cromossomos Humanos Par 12/genética , Hibridização Genômica Comparativa , Humanos , Lactente , Masculino , Análise em MicrossériesRESUMO
OBJECTIVE: Epilepsy with continuous spikes and waves during slow sleep (ECSWS) is associated with cognitive deficits. The underlying mechanism is thought to relate to disturbance of functions of the foci by the persistent epileptic activity. However, the relationship between epileptic foci and cognitive deficits remains largely unknown, except for in Landau-Kleffner syndrome. The aim of this study was to evaluate the relationship of epileptic foci estimated from magnetoencephalography (MEG) with cognitive functions at the period of diagnosis in non-lesional ECSWS children, excluding those with Landau-Kleffner syndrome. METHODS: MEG data and the Wechsler intelligence scale for children-III scores at ECSWS diagnosis, and medical records, were reviewed. Multiple regression analysis was performed to examine the relationship of parameters of MEG spike dipole clusters, including anatomical location or laterality, with the Wechsler intelligence scale for children-III scores at ECSWS diagnosis. RESULTS: Sixteen patients were included, all of whom were right-handed. Epilepsy onset (first unprovoked seizure) ranged from 31 to 110â¯months (mean, 68.5). The age at ECSWS diagnosis ranged from 72 to 156â¯months (mean, 108.9). The dipole clusters were estimated on the right Rolandic area (RA) in 4 patients (25%), right supramarginal gyrus (SMG) in 3 (19%), left RA in 2 (13%), left SMG in 2 (13%), bilateral RA in 3 (19%), multiple anatomical locations in 2 (13%). The age at epilepsy onset had the strongest prognostic effect, and full-scale intelligence quotient was relatively less-affected if the cluster was found on the SMG (ßâ¯=â¯14.7, pâ¯=â¯0.031). Cases with only a right side cluster exhibited reduced impairment of perceptual organization compared with those with only a left side cluster or bilateral clusters (ßâ¯=â¯17.48, pâ¯=â¯0.02). In 12 patients, long-term intellectual prognosis was evaluated, and was associated with intellectual level at the period of ECSWS diagnosis. CONCLUSION: In non-lesional ECSWS, the relationship between epileptic focus and cognitive deficits differs from that observed in adults. Rather, it is similar to epilepsies associated with congenital or early infantile brain insults, in that the left epileptic foci in right-handed patients were associated with lower non-verbal functions. Future studies are required to determine the role of plasticity of the immature brain in driving these differences.
Assuntos
Encéfalo/fisiopatologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , Epilepsia/complicações , Epilepsia/diagnóstico , Magnetoencefalografia , Criança , Disfunção Cognitiva/fisiopatologia , Epilepsia/fisiopatologia , Feminino , Humanos , Masculino , Cuidados Pré-Operatórios , Sono de Ondas Lentas , Escalas de WechslerRESUMO
Immune-mediated central nervous system manifestations of group A ß-hemolytic Streptococcus (GABHS) infection include Sydenham's chorea, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS)-which includes tic and obsessive compulsive disorders-and a variety of neurobehavioral disorders. We report a case of Streptococcus dysgalactiae subspecies equisimilis (group G Streptococcus) (GGS) infection associated with involuntary movements, complex tics, and emotional lability in an 11-year-old Japanese girl. Serum IgM and IgG antibodies to lysoganglioside were positive, and she responded rapidly to intravenous immunoglobulin treatment. Neuropsychiatric disorder associated with GGS infection was ultimately diagnosed. The present findings suggest that neuropsychiatric disorders can result from GGS infection and that the pathogenic mechanism is similar to that of GABHS infection. Future large-scale studies should examine the relation between GGS infection and onset of neuropsychiatric disorder.
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Objective: α (CAMK2A) and ß (CAMK2B) isoforms of Calcium/calmodulin-dependent protein kinase II (CaMKII) play a pivotal role in neuronal plasticity and in learning and memory processes in the brain. Here, we explore the possible involvement of α- and ß-CaMKII variants in neurodevelopmental disorders. Methods: Whole-exome sequencing was performed for 976 individuals with intellectual disability, developmental delay, and epilepsy. The effect of CAMK2A and CAMK2B variants on CaMKII structure and firing of neurons was evaluated by computational structural analysis, immunoblotting, and electrophysiological analysis. Results: We identified a total of five de novo CAMK2A and CAMK2B variants in three and two individuals, respectively. Seizures were common to three individuals with CAMK2A variants. Using a minigene splicing assay, we demonstrated that a splice site variant caused skipping of exon 11 leading to an in-frame deletion of the regulatory segment of CaMKII α. By structural analysis, four missense variants are predicted to impair the interaction between the kinase domain and the regulatory segment responsible for the autoinhibition of its kinase activity. The Thr286/Thr287 phosphorylation as a result of release from autoinhibition was increased in three mutants when the mutants were stably expressed in Neuro-2a neuroblastoma cells. Expression of a CaMKII α mutant in primary hippocampal neurons significantly increased A-type K+ currents, which facilitated spike repolarization of single action potentials. Interpretation: Our data highlight the importance of CaMKII α and CaMKII ß and their autoinhibitory regulation in human brain function, and suggest the enhancement of A-type K+ currents as a possible pathophysiological basis.
RESUMO
Vici syndrome (VICIS) is a rare, autosomal recessive neurodevelopmental disorder with multisystem involvement characterized by agenesis of the corpus callosum, cataracts, cardiomyopathy, combined immunodeficiency, developmental delay, and hypopigmentation. Mutations in EPG5, a gene that encodes a key autophagy regulator, have been shown to cause VICIS, however, the precise pathomechanism underlying VICIS is yet to be clarified. Here, we describe detailed clinical (including brain MRI and muscle biopsy) and genetic features of nine Japanese patients with VICIS. Genetic dissection of these nine patients from seven families identified 14 causative mutations in EPG5. These included five nonsense, two frameshift, three splicing, one missense, and one multi-exon deletion mutations, and two initiation codon variants. Furthermore, cultured skin fibroblasts (SFs) from two affected patients demonstrated partial autophagic dysfunction. To investigate the function of EPG5, siRNA based EPG5 knock-down, and CRISPR/Cas9 mediated EPG5 knock-out HeLa cells were generated. EPG5-depleted cells exhibited a complete block of autophagic flux caused by defective autophagosome-lysosome fusion. Unexpectedly, endocytic degradation was normal in both VICIS SFs and EPG5 depleted cells, suggesting that EPG5 function is limited to the regulation of autophagosome-lysosome fusion.
Assuntos
Agenesia do Corpo Caloso/genética , Agenesia do Corpo Caloso/patologia , Autofagossomos/metabolismo , Catarata/genética , Catarata/patologia , Lisossomos/metabolismo , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Proteínas/genética , Povo Asiático , Proteínas Relacionadas à Autofagia , Biópsia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Células Epiteliais/patologia , Saúde da Família , Fibroblastos/patologia , Técnicas de Silenciamento de Genes , Técnicas de Inativação de Genes , Células HeLa , Humanos , Proteínas de Membrana Lisossomal , Imageamento por Ressonância Magnética , Músculos/patologia , Mutação , Proteínas de Transporte VesicularRESUMO
Cerebral folate deficiency due to folate receptor 1 gene (FOLR1) mutations is an autosomal recessive disorder resulting from a brain-specific folate transport defect. It is characterized by late infantile onset, severe psychomotor regression, epilepsy, and leukodystrophy. We describe a consanguineous girl exhibiting severe developmental regression, intractable epilepsy, polyneuropathy, and profound hypomyelination with cortical involvement. Magnetic resonance imaging showed cortical disturbances in addition to profound hypomyelination and cerebellar atrophy. Nerve conduction studies revealed both axonal degeneration and demyelinating features. A diagnosis of cerebral folate deficiency was confirmed by a homozygous c.466T>G (p.W156G) mutation in FOLR1, coupled with extremely low cerebrospinal fluid levels of 5-methyltetrahydrofolate. Her symptoms, neuroradiological findings, and polyneuropathy were alleviated by oral folinic acid treatment in conjunction with intravenous and intramuscular administration therapy. Our patient shows that folinic acid therapy can ameliorate the clinical symptoms, white matter disturbances, cortical insults, and peripheral neuropathy of cerebral folate deficiency caused by FOLR1 mutation. It is important to recognize these clinical symptoms and make a precise diagnosis early on, because cerebral folate deficiency is treatable.
Assuntos
Receptor 1 de Folato/metabolismo , Deficiência de Ácido Fólico/genética , Leucoencefalopatias/genética , Mutação/genética , Doenças do Sistema Nervoso Periférico/genética , Criança , Epilepsia/complicações , Epilepsia/genética , Feminino , Receptor 1 de Folato/deficiência , Deficiência de Ácido Fólico/diagnóstico , Humanos , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/patologia , Imageamento por Ressonância Magnética/métodos , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/patologiaRESUMO
Megalencephalic polymicrogyria syndromes include megalencephaly-capillary malformation and megalencephaly-polymicrogyria-polydactyly-hydrocephalus. Recent genetic studies have identified that genes in the PI3K-AKT pathway are involved in the pathogenesis of these disorders. Herein, we report a patient who presented with developmental delay, epilepsy and peculiar neuroimaging findings of megalencephaly, polymicrogyria, and symmetrical band heterotopia in the periventricular region. The heterotopias exhibited inhomogeneous signals with undulatory mixtures of gray and white matter, resembling ribbon-like heterotopia, with a predominance in the temporal to occipital regions. These neuroradiological findings were not consistent with those in known megalencephalic polymicrogyria syndromes. No genetic abnormality was identified through whole-exome sequencing. The neuroimaging findings of this patient may represent a novel cortical malformation involving megalencephaly with polymicrogyria and ribbon-like band heterotopia.
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Encéfalo/diagnóstico por imagem , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/diagnóstico por imagem , Megalencefalia/diagnóstico por imagem , Polimicrogiria/diagnóstico por imagem , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/genética , Feminino , Técnicas de Genotipagem , Humanos , Lactente , Imageamento por Ressonância Magnética , Megalencefalia/genética , Análise em Microsséries , Polimicrogiria/genéticaRESUMO
OBJECTIVE: Recent studies have elucidated causative roles for genetic abnormalities in early-onset epileptic encephalopathies (EOEE). Accompanying characteristic features, in addition to seizures, have also been suggested to provide important clues for an early and accurate genetic diagnosis of affected patients. In this study, we investigated the underlying genetic causes in patients with EOEE associated with infantile movement disorders. METHODS: We examined 11 patients with EOEE and involuntary movements (nine with West syndrome and two with nonsyndromic epileptic encephalopathy). All showed severe developmental delay, cognitive impairment, and involuntary movements such as chorea, ballism, dyskinesia or myoclonus, and hand stereotypies. We performed whole-exome sequencing of 10 patients, while the other patient underwent high-resolution melting analysis of candidate EOEE genes. RESULTS: We identified mutations in CDKL5, SCN2A, SETD5, ALG13, and TBL1XR1 in seven patients with West syndrome, and in SCN1A and GRIN1 in the two patients with unclassified epileptic encephalopathy. All mutations were validated as de novo events. The genetic cause was undetermined in the remaining two patients. CONCLUSIONS: We found pathogenic mutations in seven genes, in nine of 11 patients with EOEE and involuntary movements. Although the results of our study are preliminary because of the small number of patients, they nevertheless suggest that specific accompanying phenotypes such as hyperkinetic movements or hand stereotypies could be important in narrowing the disease spectrum and identifying causative genetic abnormalities.
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Espasmos Infantis/genética , Espasmos Infantis/fisiopatologia , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Eletroencefalografia , Exoma , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Movimento , Transtornos dos Movimentos/genética , Mutação , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Proteínas do Tecido Nervoso/genética , Prevalência , Proteínas Serina-Treonina Quinases/genética , Receptores de N-Metil-D-Aspartato/genética , Análise de Sequência de DNARESUMO
Gómez-López-Hernández syndrome (GLHS) is a rare neurocutaneous syndrome characterized by the triad of rhombencephalosynapsis, trigeminal anesthesia, and bilateral parieto-occipital alopecia. We herein describe the first Japanese patient with GLHS characterized by the standard triad with typical craniofacial anomaly including hypertelorism, brachyturricephaly and midface retrusion, and a short stature. This female patient had also exhibited fever-induced convulsive seizures and psychomotor developmental delay since infancy. Brain magnetic resonance imaging showed severe rhombencephalosynapsis, supratentorial abnormalities (aplasia of the septum pellucidum, severe ventricular enlargement, and hypoplasia of the corpus callosum), and hippocampus atrophy. Bilateral ectopic cerebellums were also observed. This report describes the long-term clinical outcome of GLHS and a new neuroradiological finding regarding rhombencephalosynapsis.
Assuntos
Anormalidades Múltiplas/diagnóstico , Alopecia/diagnóstico , Cerebelo/anormalidades , Anormalidades Craniofaciais/diagnóstico , Transtornos do Crescimento/diagnóstico , Síndromes Neurocutâneas/diagnóstico , Anormalidades Múltiplas/patologia , Anormalidades Múltiplas/fisiopatologia , Alopecia/patologia , Alopecia/fisiopatologia , Cerebelo/patologia , Cerebelo/fisiopatologia , Pré-Escolar , Anormalidades Craniofaciais/patologia , Anormalidades Craniofaciais/fisiopatologia , Feminino , Transtornos do Crescimento/patologia , Transtornos do Crescimento/fisiopatologia , Humanos , Japão , Imageamento por Ressonância Magnética , Síndromes Neurocutâneas/patologia , Síndromes Neurocutâneas/fisiopatologia , Rombencéfalo/patologia , Rombencéfalo/fisiopatologiaRESUMO
We report a case of infantile refractory epilepsy associated with Turner syndrome (TS), showing very frequent, focal clonic seizures of the left upper extremity. Characteristically, in addition to spontaneous fits, her seizure was inducible by rubbing her left hand and forearm for a few seconds. Accordingly, she was diagnosed with a rare form of reflex epilepsy, "rub epilepsy". Neuroradiological investigation indicated the existence of cortical abnormalities, such as focal cortical dysplasia of the right parietal lobe. Patients with TS are reported to have neuroanatomical abnormalities, especially of the parietal lobe. Thus, our case may imply a causal relationship between potential cortical hyperexcitability of the parietal lobe and epilepsy in TS. This is the first reported infantile case of rub epilepsy, and more generally, reflex epilepsy associated with TS.
Assuntos
Encéfalo/patologia , Encéfalo/fisiopatologia , Epilepsia Reflexa/patologia , Epilepsia Reflexa/fisiopatologia , Síndrome de Turner/patologia , Síndrome de Turner/fisiopatologia , Eletroencefalografia , Epilepsia Reflexa/complicações , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Síndrome de Turner/complicaçõesRESUMO
We report a female patient who presented with intractable epileptic seizures, profound developmental delay since early infancy, and hyperkinetic movements with hand stereotypies. The patient initially developed focal seizures with multiple foci at 3 months of age. Thereafter, the seizures evolved to frequent episodes of hyperthermia-induced status epilepticus. A novel de novo SCN1A mutation was identified by whole-exome sequence analysis. This case demonstrates that SCN1A mutations may cause movement disorders as an atypical phenotype and the case history of this patient may expand our understanding of the clinical spectrum of SCN1A-associated epileptic encephalopathy. [Published with video sequences].
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Epilepsia/complicações , Epilepsia/genética , Hipercinese/complicações , Hipercinese/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Comportamento Estereotipado/fisiologia , Atrofia , Encéfalo/patologia , Deficiências do Desenvolvimento/complicações , Discinesias/fisiopatologia , Epilepsia/patologia , Feminino , Humanos , Hipercinese/patologia , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Mutação/genética , Mutação/fisiologia , Estado Epiléptico/complicaçõesRESUMO
Pseudohypoparathyroidism (PHP) type Ia is characterized by hypocalcemia due to PTH resistance and by features of Albright's hereditary osteodystrophy, including short stature, obesity, subcutaneous calcification and brachydactyly. A wide variety of clinical and biochemical manifestations have been reported. We report two cases of PHP type Ia in duozygotic twins with different phenotypes. The proband was a 10-yr-old girl. She showed subcutaneous ossification, shortening of the metacarpal bone, short stature, obesity and round face. She had normocalcemia (8.9 mg/dl), high-normal phosphate (5.0 mg/dl) and increased levels of serum intact PTH (152 pg/ml) and TSH (9.17 µIU/ml) levels. Her twin younger brother had atypical Albright's hereditary osteodystrophy with only mild obesity and subcutaneous calcifications, but he showed a low level of serum calcium (7.0 mg/dl) and high levels of serum phosphate (7.6 mg/dl), intact PTH (377 pg/ml) and TSH (6.9 µIU/ml). We diagnosed them as having PHP type Ia on the basis of clinical and biochemical findings, Ellsworth-Howard test and family history. There is considerable variability in clinical and biochemical features of PHP type Ia even among affected duozygotic twins. The differences of intrauterine environment and growth history cannot account for the variable phenotypes of PHP type Ia. Even if a patient shows no AHO features, examination of all family members should be undertaken.