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1.
Muscle Nerve ; 69(1): 55-63, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37933889

RESUMO

INTRODUCTION/AIMS: Merosin is a protein complex located in the basement membrane of skeletal muscles and laminin α2-containing regions of the central and peripheral nervous systems. However, because of the prominence of muscle-related symptoms, peripheral neuropathy associated with merosin-deficient congenital muscular dystrophy type 1A (MDC1A) has received little clinical attention. This study aimed to present pathological changes in intramuscular nerves of three patients with MDC1A and discuss their relationship with electrophysiological findings to provide new evidence of peripheral nerve involvement in MDC1A. METHODS: MDC1A was confirmed by clinical features, muscle biopsy, and genetic testing for variants in LAMA2. To clarify peripheral nerve involvement, we statistically evaluated electrophysiological and muscle pathology findings of intramuscular nerves. These findings were compared with those of age-matched boys with Duchenne muscular dystrophy (DMD) as controls with normal nerves. Nerve conduction studies (NCS) were performed before biopsy. Biopsied intramuscular nerves were examined with electron microscopy using g-ratio, which is the ratio of axon diameter to myelinated fiber diameter. RESULTS: The myelin sheaths were significantly thinner in MDC1A patients than in age-matched DMD patients, with a mean g-ratio of 0.76 ± 0.07 in MDC1A patients and 0.65 ± 0.14 in DMD patients (p < .0001). No neuropathic changes were identified in muscle pathology. Low compound muscle action potential amplitudes, positive sharp waves and fibrillation potentials, and low-amplitude motor unit potentials with increased polyphasia indicated myopathic changes; no neurogenic changes were seen. DISCUSSION: We postulate that the thin myelin associated with MDC1A reflects the role of merosin in myelin maturation.


Assuntos
Distrofia Muscular de Duchenne , Doenças do Sistema Nervoso Periférico , Masculino , Humanos , Bainha de Mielina , Músculo Esquelético/patologia , Laminina/genética , Laminina/metabolismo , Distrofia Muscular de Duchenne/patologia , Doenças do Sistema Nervoso Periférico/patologia
2.
Genet Med ; 24(12): 2453-2463, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36305856

RESUMO

PURPOSE: Cerebellar hypoplasia and atrophy (CBHA) in children is an extremely heterogeneous group of disorders, but few comprehensive genetic studies have been reported. Comprehensive genetic analysis of CBHA patients may help differentiating atrophy and hypoplasia and potentially improve their prognostic aspects. METHODS: Patients with CBHA in 176 families were genetically examined using exome sequencing. Patients with disease-causing variants were clinically evaluated. RESULTS: Disease-causing variants were identified in 96 of the 176 families (54.5%). After excluding 6 families, 48 patients from 42 families were categorized as having syndromic associations with CBHA, whereas the remaining 51 patients from 48 families had isolated CBHA. In 51 patients, 26 aberrant genes were identified, of which, 20 (76.9%) caused disease in 1 family each. The most prevalent genes were CACNA1A, ITPR1, and KIF1A. Of the 26 aberrant genes, 21 and 1 were functionally annotated to atrophy and hypoplasia, respectively. CBHA+S was more clinically severe than CBHA-S. Notably, ARG1 and FOLR1 variants were identified in 2 families, leading to medical treatments. CONCLUSION: A wide genetic and clinical diversity of CBHA was revealed through exome sequencing in this cohort, which highlights the importance of comprehensive genetic analyses. Furthermore, molecular-based treatment was available for 2 families.


Assuntos
Exoma , Malformações do Sistema Nervoso , Criança , Humanos , Exoma/genética , Mutação , Malformações do Sistema Nervoso/genética , Atrofia/genética , Receptor 1 de Folato/genética , Cinesinas
3.
J Med Genet ; 58(8): 505-513, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-32732225

RESUMO

BACKGROUND: Variants in the type IV collagen gene (COL4A1/2) cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with COL4A1/2 variants remain unclear. METHODS: We examined COL4A1/2 in 218 individuals with suspected COL4A1/2-related brain defects. Among those arising from COL4A1/2 variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail. RESULTS: Pathogenic COL4A1/2 variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with COL4A1/2 variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly. CONCLUSIONS: Prenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and COL4A1/2 gene testing should be considered when pathogenic variants are strongly suspected.


Assuntos
Colágeno Tipo IV/genética , Mutação/genética , Síndrome de Dandy-Walker/genética , Feminino , Humanos , Masculino , Gravidez , Ultrassonografia Pré-Natal/métodos
4.
Hum Mutat ; 42(1): 50-65, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33131168

RESUMO

Many algorithms to detect copy number variations (CNVs) using exome sequencing (ES) data have been reported and evaluated on their sensitivity and specificity, reproducibility, and precision. However, operational optimization of such algorithms for a better performance has not been fully addressed. ES of 1199 samples including 763 patients with different disease profiles was performed. ES data were analyzed to detect CNVs by both the eXome Hidden Markov Model (XHMM) and modified Nord's method. To efficiently detect rare CNVs, we aimed to decrease sequencing biases by analyzing, at the same time, the data of all unrelated samples sequenced in the same flow cell as a batch, and to eliminate sex effects of X-linked CNVs by analyzing female and male sequences separately. We also applied several filtering steps for more efficient CNV selection. The average number of CNVs detected in one sample was <5. This optimization together with targeted CNV analysis by Nord's method identified pathogenic/likely pathogenic CNVs in 34 patients (4.5%, 34/763). In particular, among 142 patients with epilepsy, the current protocol detected clinically relevant CNVs in 19 (13.4%) patients, whereas the previous protocol identified them in only 14 (9.9%) patients. Thus, this batch-based XHMM analysis efficiently selected rare pathogenic CNVs in genetic diseases.


Assuntos
Variações do Número de Cópias de DNA , Exoma , Algoritmos , Exoma/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Reprodutibilidade dos Testes , Sequenciamento do Exoma
5.
Am J Med Genet A ; 185(5): 1468-1480, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33624935

RESUMO

Intellectual disability (ID) is characterized by significant limitations in both intellectual functioning and adaptive behaviors, originating before the age of 18 years. However, the genetic etiologies of ID are still incompletely elucidated due to the wide range of clinical and genetic heterogeneity. Whole genome sequencing (WGS) has been applied as a single-step clinical diagnostic tool for ID because it detects genetic variations with a wide range of resolution from single nucleotide variants (SNVs) to structural variants (SVs). To explore the causative genes for ID, we employed WGS in 45 patients from 44 unrelated Japanese families and performed a stepwise screening approach focusing on the coding variants in the genes. Here, we report 12 pathogenic and likely pathogenic variants: seven heterozygous variants of ADNP, SATB2, ANKRD11, PTEN, TCF4, SPAST, and KCNA2, three hemizygous variants of SMS, SLC6A8, and IQSEC2, and one homozygous variant in AGTPBP1. Of these, four were considered novel. Furthermore, a novel 76 kb deletion containing exons 1 and 2 in DYRK1A was identified. We confirmed the clinical and genetic heterogeneity and high frequency of de novo causative variants (8/12, 66.7%). This is the first report of WGS analysis in Japanese patients with ID. Our results would provide insight into the correlation between novel variants and expanded phenotypes of the disease.


Assuntos
Predisposição Genética para Doença , Deficiência Intelectual/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Adolescente , Heterogeneidade Genética , Genoma Humano/genética , Heterozigoto , Proteínas de Homeodomínio/genética , Homozigoto , Humanos , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/patologia , Japão/epidemiologia , Masculino , Sequenciamento Completo do Genoma , Quinases Dyrk
6.
J Neuroradiol ; 48(2): 88-93, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32335071

RESUMO

BACKGROUND AND PURPOSE: Beta-propeller protein-associated neurodegeneration (BPAN) is one subtype of neurodegeneration with brain iron accumulation. It is difficult to diagnose BPAN due to the non-specificity of their clinical findings and neuroimaging in early childhood. We experienced four pediatric patients with serial brain MRI and evaluated the alteration of the findings through their course. METHODS: We retrospectively reviewed the clinical findings and 21 MRI findings of the four patients with genetically confirmed pediatric BPAN. We also performed a quantitative MR assessment using the quantitative susceptibility mapping (QSM) values of the globus pallidus (GP), substantia nigra (SN), and deep cerebellar nuclei (DCN) compared to 10 age-matched disease controls. RESULTS: Only one patient was suspected of BPAN based on imaging findings before the genetic diagnosis was made. The other three patients could not be suspected until their Whole-exome sequencings (WES) done. In all four cases, no abnormal signals were noted in the GP and SN at the initial brain MRI, but hypointensities were observed after the ages of 4-7 years on T2-weighted images and after the ages of 2-7 years on susceptibility-weighted images. In three patients, T2 hyperintensity in the bilateral DCN was persistently observed throughout the observational period. Three patients showed transient T2 hyperintensity and swelling in the GP, SN and/or DCN during the episodes of pyrexia and seizures. The other findings included cerebral and cerebellar atrophy, thinning of the corpus callosum, and delayed myelination. The QSM values of the GP and SN were significantly higher in the patients compared to the controls (P=0.005, respectively), but that of the DCN did not differ significantly (P=0.16). CONCLUSION: Brain MRI is a useful method to establish the early diagnosis of BPAN.


Assuntos
Proteínas de Transporte , Doenças Neurodegenerativas , Criança , Pré-Escolar , Humanos , Imageamento por Ressonância Magnética , Doenças Neurodegenerativas/diagnóstico por imagem , Neuroimagem , Estudos Retrospectivos
7.
BMC Med ; 18(1): 343, 2020 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-33208172

RESUMO

BACKGROUND: Duchenne muscular dystrophy (DMD) is a progressive, degenerative muscular disorder and cognitive dysfunction caused by mutations in the dystrophin gene. It is characterized by excess inflammatory responses in the muscle and repeated degeneration and regeneration cycles. Neutral sphingomyelinase 2/sphingomyelin phosphodiesterase 3 (nSMase2/Smpd3) hydrolyzes sphingomyelin in lipid rafts. This protein thus modulates inflammatory responses, cell survival or apoptosis pathways, and the secretion of extracellular vesicles in a Ca2+-dependent manner. However, its roles in dystrophic pathology have not yet been clarified. METHODS: To investigate the effects of the loss of nSMase2/Smpd3 on dystrophic muscles and its role in the abnormal behavior observed in DMD patients, we generated mdx mice lacking the nSMase2/Smpd3 gene (mdx:Smpd3 double knockout [DKO] mice). RESULTS: Young mdx:Smpd3 DKO mice exhibited reduced muscular degeneration and decreased inflammation responses, but later on they showed exacerbated muscular necrosis. In addition, the abnormal stress response displayed by mdx mice was improved in the mdx:Smpd3 DKO mice, with the recovery of brain-derived neurotrophic factor (Bdnf) expression in the hippocampus. CONCLUSIONS: nSMase2/Smpd3-modulated lipid raft integrity is a potential therapeutic target for DMD.


Assuntos
Distrofia Muscular de Duchenne/genética , Esfingomielina Fosfodiesterase/metabolismo , Animais , Modelos Animais de Doenças , Distrofina/genética , Distrofina/metabolismo , Distrofina/farmacologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos mdx , Camundongos Knockout
8.
Muscle Nerve ; 61(2): 192-197, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31725904

RESUMO

INTRODUCTION: With improved treatments, patients with Duchenne muscular dystrophy (DMD) can survive far beyond adolescence. However, advanced-stage DMD patients are at risk of developing renal dysfunction. In this study, long-term renal function outcomes and associated risk factors in advanced stage DMD were analyzed. METHODS: Fifty-one patients were classified into three different age groups (<20, 20-29, and ≥30 years of age), and cystatin C (CysC) levels were compared among groups. RESULTS: Median serum CysC levels were 0.74 mg/L, 0.63 mg/L, and 0.76 mg/L in the age groups of <20, 20-29, and ≥30 years, respectively (P = .003). Five of the nine patients in the ≥30 years age group showed elevated serum CysC and decreased cardiac function compared with the other four in the group (P = .014). DISCUSSION: Our results indicate an association between cardiac and renal dysfunction in patients with advanced-stage DMD.


Assuntos
Nefropatias/etiologia , Distrofia Muscular de Duchenne/complicações , Adolescente , Adulto , Envelhecimento , Criança , Pré-Escolar , Cistatina C/sangue , Progressão da Doença , Feminino , Cardiopatias/etiologia , Cardiopatias/fisiopatologia , Testes de Função Cardíaca , Humanos , Nefropatias/fisiopatologia , Testes de Função Renal , Masculino , Distrofia Muscular de Duchenne/fisiopatologia , Fatores de Risco , Adulto Jovem
9.
Epilepsy Behav ; 113: 107561, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33232894

RESUMO

PURPOSE: We investigated the relationship between electroencephalographic (EEG) functional connectivity and executive function in children with frontal lobe epilepsy (FLE). METHODS: We enrolled 24 children with FLE (mean age, 11.0 years; 13 boys) and 22 sex-, age-, and intelligence-matched typically developing children (TDC) to undergo 19-channel EEG during light sleep. We estimated functional connectivity using the phase lag index (PLI) that captures the synchronization of EEG. We also performed continuous performance tests (CPTs) on the children and obtained questionnaire responses on attention deficit hyperactivity disorder and oppositional defiant disorder (ODD). RESULTS: The average gamma PLI was lower in the FLE group than in the TDC group, especially between long-distance frontoparietal pairs, between interhemispheric frontal pairs, and between interhemispheric parietotemporal pairs. Gamma PLIs with long-distance frontoparietal and interhemispheric frontal pairs were positively associated with inattention, ODD scores, omission error, and reaction time in the FLE group but not in the TDC group. Conversely, they were negatively associated with age, hyperactivity score, and commission error. CONCLUSIONS: A lack of functional connectivity of the frontal brain regions in children with FLE was associated with poor response inhibition.


Assuntos
Epilepsia do Lobo Frontal/fisiopatologia , Função Executiva , Lobo Frontal/fisiopatologia , Inibição Reativa , Adolescente , Criança , Cognição , Eletroencefalografia , Feminino , Humanos , Inteligência , Masculino , Tempo de Reação
10.
Epilepsy Behav ; 108: 107092, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32320922

RESUMO

OBJECTIVE: We aimed to clarify the strengths and weaknesses in adaptive behavior in children with focal epilepsy and show children-associated factors related to adaptive behavior. MATERIALS AND METHODS: Sixty-three children with focal epilepsy aged 5-18 years with intellectual quotient (IQ) ranging from 67 to 135 were enrolled in this study. Adaptive behavior was evaluated using the Vineland Adaptive Behavior Scale, 2nd edition (VABS-II). The children performed continuous performance test and tests of reading, writing, and IQ; parents answered questionnaires regarding attention-deficit hyperactivity disorder and autism spectrum disorder (ASD). Participants were categorized into four groups based on IQ and adaptive behavior scores for statistical comparisons. RESULTS AND DISCUSSION: Children with low adaptive behavior were more likely to show a reduction in daily living skills, and those with both low adaptive behavior and IQ were more likely to show a reduction in daily living skills and communication. Lower adaptive behavior was related to more severe autistic symptoms, lower academic achievement in children with IQ > 85, and lower executive function in children with IQ ≤ 85. There was a qualitative difference of cognitive dysfunction in adaptive behavior between both groups. CONCLUSIONS: There were differences in VABS-II domain and subdomain characteristics between children with focal epilepsy and those with ASD; however, it was more difficult for children with more severe ASD and coexisting focal epilepsy to show age-equivalent adaptive behavior.


Assuntos
Atividades Cotidianas/psicologia , Adaptação Psicológica/fisiologia , Epilepsias Parciais/diagnóstico , Epilepsias Parciais/psicologia , Adolescente , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/psicologia , Criança , Pré-Escolar , Epilepsias Parciais/epidemiologia , Feminino , Hospitalização/tendências , Humanos , Masculino , Pais/psicologia , Estudos Prospectivos , Inquéritos e Questionários
11.
Neuropediatrics ; 50(6): 387-390, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31370080

RESUMO

BACKGROUND: Leukoencephalopathy associated with dysmorphic features may be attributed to chromosomal abnormalities such as 17p13.3 microdeletion syndrome. CASE: A 19-year-old female patient was referred to our hospital for diagnostic evaluation of her leukoencephalopathy. She demonstrated moderate intellectual disability, minor dysmorphic features, and short stature. Serial brain magnetic resonance images obtained within a 16-year interval revealed prolonged T2 signals in the deep cerebral white matter with enlarged Virchow-Robin spaces. A nonsymptomatic atlas anomaly was also noted. Using microarray-based comparative genomic hybridization, we identified a 2.2-Mb terminal deletion at 17p13.3, encompassing YWHAE, CRK, and RTN4RL1 but not PAFAH1B1. CONCLUSION: Except for atlas anomaly, the patient's clinical and imaging findings were compatible with the diagnosis of 17p13.3 microdeletion syndrome. The white matter abnormality was static and nonprogressive. The association between the atlas abnormality and this deletion remains elusive. We note the importance of exploring submicroscopic chromosomal imbalance when patients show prominent but static white matter abnormalities with discrepantly mild and stable neurological signs.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Leucoencefalopatias/genética , Proteínas 14-3-3/genética , Estatura , Atlas Cervical/anormalidades , Atlas Cervical/diagnóstico por imagem , Feminino , Humanos , Deficiência Intelectual/etiologia , Deficiência Intelectual/genética , Leucoencefalopatias/diagnóstico por imagem , Imageamento por Ressonância Magnética , Receptores Nogo/genética , Proteínas Proto-Oncogênicas c-crk/genética , Substância Branca/diagnóstico por imagem , Adulto Jovem
12.
J Hum Genet ; 63(3): 263-270, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29339779

RESUMO

Misato 1, mitochondrial distribution and morphology regulator (encoded by the MSTO1 gene), is involved in mitochondrial distribution and morphology. Recently, MSTO1 mutations have been shown to cause clinical manifestations suggestive of mitochondrial dysfunction, such as muscle weakness, short stature, motor developmental delay, and cerebellar atrophy. Both autosomal dominant and recessive modes of inheritance have been suggested. We performed whole-exome sequencing in two unrelated patients showing cerebellar atrophy, intellectual disability, and pigmentary retinopathy. Three novel mutations were identified: c.836 G > A (p.Arg279His), c.1099-1 G > A (p.Val367Trpfs*2), and c.79 C > T (p.Gln27*). Both patients had compound heterozygous mutations with a combination of protein-truncation mutation and missense mutation, the latter shared by them both. This survey of two patients with recessive and novel MSTO1 mutations provides additional clinical and genetic information on the pathogenicity of MSTO1 in humans.


Assuntos
Proteínas de Ciclo Celular/genética , Doenças Cerebelares/diagnóstico , Doenças Cerebelares/genética , Proteínas do Citoesqueleto/genética , Genes Recessivos , Mutação , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/genética , Adolescente , Idade de Início , Alelos , Atrofia , Linhagem Celular , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Genótipo , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Linhagem , Fenótipo , Sequenciamento Completo do Genoma
13.
Muscle Nerve ; 58(6): 824-827, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30019482

RESUMO

INTRODUCTION: Needle electromyography (EMG) has been an important diagnostic tool, although discomfort may limit its use in some children. We investigated the diagnostic utility of the clustering index (CI) method, a quantitative analysis for surface EMG (SEMG), in children. METHODS: SEMG was recorded from the tibialis anterior muscle. Discriminant analysis between patients with neurogenic disorders and patients with myopathy was performed for whole epochs by using the CI and area values. RESULTS: Forty-five children (29 with myopathy, 16 with neurogenic disorders; age 9 ± 3.9 years) were enrolled. The mean discriminant function value of the neurogenic group was 0.58 ± 0.88 (-0.48-2.30), whereas that of the myopathic group was -0.55 ± 0.70 (-2.38-0.68). When the cutoff value was set at the limit of the other group, 17 of 29 children with myopathy and 7 of 16 children with neurogenic disorders were correctly classified. DISCUSSION: The CI method can be a useful noninvasive diagnostic tool in children with neuromuscular disorders. Muscle Nerve 58:824-827, 2018.


Assuntos
Eletromiografia/métodos , Potencial Evocado Motor/fisiologia , Músculo Esquelético/fisiopatologia , Doenças Neuromusculares/diagnóstico , Doenças Neuromusculares/fisiopatologia , Adolescente , Criança , Pré-Escolar , Análise Discriminante , Feminino , Humanos , Lactente , Masculino
14.
Epilepsy Behav ; 84: 122-126, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29791879

RESUMO

Diagnosis of seizure imitators in children is often challenging, and individuals with intellectual disability (ID) could be at additional risk of seizure imitator misdiagnosis. We aimed to elucidate distinct features of clinical semiology among children of different intellectual levels, which may help in distinguishing seizure imitators from epilepsy in such individuals. We retrospectively compared semiological features of seizure imitators in children with and without ID captured using video-electroencephalography (video-EEG). Seizure imitators were classified based on the definition of the International League Against Epilepsy (ILAE). A total of 67 individuals (mean age: 8.4 years, SD: 4.2 years) with seizure imitators documented using long-term video-EEG were identified, in which 27 patients had normal IQ/DQ, 20 had moderate ID, and 20 had severe ID. There was no statistically significant difference in the semiological features of seizure imitators between individuals with ID and those without ID; similarly, no difference was found between those with moderate ID and severe ID compared with individuals with normal IQ/DQ. Among all the patients, altered responsiveness mimicking cognitive or absence seizures was most frequently observed (36%), followed by jerks mimicking myoclonic seizures (22%). The most common seizure imitators among all the patients were unclassifiable nonepileptic seizures per the ILAE definition (28 cases, 42%), followed by day dreaming (24 cases, 36%) and physiological myoclonus (14 cases, 21%). In summary, the present study found no marked difference in semiological features of seizure imitators between patients with ID and those without ID regardless of ID severity, suggesting the necessity of early video-EEG for correct diagnosis.


Assuntos
Eletroencefalografia , Epilepsias Mioclônicas/diagnóstico , Deficiência Intelectual/complicações , Convulsões/diagnóstico , Adolescente , Criança , Pré-Escolar , Diagnóstico Diferencial , Epilepsias Mioclônicas/complicações , Epilepsias Mioclônicas/fisiopatologia , Feminino , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Monitorização Fisiológica , Estudos Retrospectivos , Convulsões/complicações , Convulsões/fisiopatologia , Gravação de Videoteipe
15.
Neuropathology ; 38(3): 300-304, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29250844

RESUMO

A rosette-forming glioneuronal tumor (RGNT) was initially reported as an infratentorial tumor that comprised both small neurocytic rosettes and astrocytic components. However, a few studies have reported supratentorial RGNTs arising in the cerebral hemispheres. Here, we report an unusual case involving a 9-year-old boy with a supratentorial RGNT who presented with intractable epilepsy and behavioral changes. Brain MRI revealed a well-circumscribed space-occupying lesion with septae in the right inferomedial parietal lobe. Electroencephalography showed multifocal spikes over the right frontal, temporal and parietal regions. The seizure frequency decreased dramatically after tumorectomy. Histopathological examination revealed prominent neurocytic rosette formation appearing with the specific glioneuronal element of a dysembryoplastic neuroepithelial tumor (DNT). Although the pathogenesis has not been elucidated, a supratentorial RGNT presenting with epilepsy may exhibit a rosette component, which is the major feature of this tumor, against the background of a specific glioneuronal element mimicking DNT. However, RGNT arising in regions other than the fourth ventricle is rare, and the pathogenesis of epilepsy due to RGNT has not been fully elucidated. Further clinical and histological studies are required to understand the pathology underlying epilepsy caused by RGNT.


Assuntos
Neoplasias Encefálicas/patologia , Epilepsia Resistente a Medicamentos/etiologia , Neoplasias Neuroepiteliomatosas/patologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Neoplasias Encefálicas/complicações , Criança , Humanos , Masculino , Neoplasias Neuroepiteliomatosas/complicações
17.
Epilepsia ; 57(4): 566-73, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26918889

RESUMO

OBJECTIVE: GABRA1 mutations have been identified in patients with familial juvenile myoclonic epilepsy, sporadic childhood absence epilepsy, and idiopathic familial generalized epilepsy. In addition, de novo GABRA1 mutations were recently reported in a patient with infantile spasms and four patients with Dravet syndrome. Those reports suggest that GABRA1 mutations are associated with infantile epilepsy including early onset epileptic encephalopathies. In this study, we searched for GABRA1 mutations in patients with infantile epilepsy to investigate the phenotypic spectrum of GABRA1 mutations. METHODS: In total, 526 and 145 patients with infantile epilepsy were analyzed by whole-exome sequencing and GABRA1-targeted resequencing, respectively. RESULTS: We identified five de novo missense GABRA1 mutations in six unrelated patients. A p.R112Q mutation in the long extracellular N-terminus was identified in a patient with infantile epilepsy; p.P260L, p.M263T, and p.M263I in transmembrane spanning domain 1 (TM1) were identified in three unrelated patients with West syndrome and a patient with Ohtahara syndrome, respectively; and p.V287L in TM2 was identified in a patient with unclassified early onset epileptic encephalopathy. Four of these mutations have not been observed previously. SIGNIFICANCE: Our study suggests that de novo GABRA1 mutations can cause early onset epileptic encephalopathies, including Ohtahara syndrome and West syndrome.


Assuntos
Mutação de Sentido Incorreto/genética , Receptores de GABA-A/genética , Espasmos Infantis/diagnóstico , Espasmos Infantis/genética , Sequência de Aminoácidos , Criança , Pré-Escolar , Eletroencefalografia , Feminino , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Espasmos Infantis/fisiopatologia
18.
No To Hattatsu ; 48(4): 277-81, 2016 Jul.
Artigo em Japonês | MEDLINE | ID: mdl-30011142

RESUMO

A 6-year-old boy with normal development experienced tonic-clonic seizures and myoclonus. His electroencephalogram showed epileptic discharge and he was administered antiepileptic drugs ; however, they were ineffective. Antiepileptic drugs were discontinued temporarily because of no ictal recordings. He could not walk unaided and his speech reduced gradually. He was admitted to our hospital at the age of seven years and eight months. He experienced daily tonic-clonic seizures and myoclonus. Epileptic encephalopathy related to autoimmunity was suspected as he had psychomotor regression and his cerebrospinal and serum anti-glutamate receptor antibody (anti-GluR) levels were elevated. After being administered immunoglobulins, his motor and cognitive functions improved and his seizures almost stopped. After one year, he could walk unaided and speak fluently. We strongly suspect an autoimmune reaction to be the pathological cause because of the effectiveness of immunoglobulin treatment. Immunoglobulin interventions should be considered in patients with unknown-cause, sub-acute onset, and destructively progressive epileptic encephalopathy.


Assuntos
Epilepsia/tratamento farmacológico , Imunização Passiva , Imunoglobulinas/uso terapêutico , Criança , Eletroencefalografia , Epilepsia/complicações , Epilepsia/diagnóstico por imagem , Epilepsia/fisiopatologia , Humanos , Masculino , Tomografia por Emissão de Pósitrons , Resultado do Tratamento
19.
J Hum Genet ; 60(12): 739-42, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26354034

RESUMO

Recently, de novo KIF1A mutations were identified in patients with intellectual disability, spasticity and cerebellar atrophy and/or optic nerve atrophy. In this study, we analyzed a total of 62 families, including 68 patients with genetically unsolved childhood cerebellar atrophy, by whole-exome sequencing (WES). We identified five de novo missense KIF1A mutations, including only one previously reported mutation (p.Arg316Trp). All the mutations are located in the motor domain of KIF1A. In all patients, initial symptom onset was during the infantile period, and included developmental delay in three patients and gait disturbance in two. Thereafter, they showed gait disturbances, exaggerated deep tendon reflexes, cerebellar symptoms and cerebellar atrophy on brain magnetic resonance imaging. Four patients showed lower limb spasticity, upper limb clumsiness and visual disturbances. Nerve conduction study revealed peripheral neuropathy in three patients. This study further delineates clinical features of de novo KIF1A mutations. Genetic testing of KIF1A should be considered in children with developmental delay, cerebellar atrophy and pyramidal features.


Assuntos
Doenças Cerebelares/genética , Deficiência Intelectual/genética , Cinesinas/genética , Espasticidade Muscular/genética , Mutação de Sentido Incorreto , Transtornos da Visão/genética , Substituição de Aminoácidos , Doenças Cerebelares/patologia , Doenças Cerebelares/fisiopatologia , Feminino , Humanos , Deficiência Intelectual/patologia , Deficiência Intelectual/fisiopatologia , Extremidade Inferior/patologia , Extremidade Inferior/fisiopatologia , Masculino , Espasticidade Muscular/patologia , Espasticidade Muscular/fisiopatologia , Transtornos da Visão/patologia , Transtornos da Visão/fisiopatologia
20.
Am J Med Genet A ; 167A(5): 1100-6, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25712306

RESUMO

Distal arthrogryposis (DA) encompasses a heterogeneous group of hereditary disorders with multiple congenital contractures predominant in the distal extremities. A total of 10 subtypes are proposed based on the pattern of contractures and association with extraarticular symptoms. DA5 is defined as a subtype with ptosis/oculomotor limitation. However, affected individuals have a variety of non-ocular features as well. We report on a two-generation family, including four affected individuals who all had congenital contractures of the distal joints, ptosis, restricted ocular movements, distinct facial appearance with deep-set eyes, and shortening of the 1st and 5th toes. The proband and her affected mother had restrictive lung disease, a recently recognized syndromic component of DA5, while younger patients did not. The proband had metacarpal and metatarsal synostosis, and the mother showed excavation of the optic disk. Whole-exome sequencing revealed a novel heterozygous mutation c.4456G>C (p.A1486P) of PIEZO2. PIEZO2 encodes a mechanosensitive ion channel, malfunction of which provides pleiotropic effects on joints, ocular muscles, lung function, and bone development.


Assuntos
Artrogripose/genética , Canais Iônicos/genética , Mutação/genética , Nervo Óptico/fisiopatologia , Adolescente , Adulto , Artrogripose/etiologia , Artrogripose/fisiopatologia , Criança , Exoma/genética , Feminino , Humanos , Masculino , Doenças Musculares/genética , Doenças Musculares/fisiopatologia , Linhagem , Análise de Sequência de DNA , Sinostose/genética , Sinostose/fisiopatologia
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