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1.
Brain Dev ; 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31735425

RESUMO

We report the first three Japanese patients with missense variants in the GNB1 gene. Patients exhibited severe dyskinetic quadriplegia with cortical blindness and epileptic spasms, West syndrome (but with good outcomes), and hypotonic quadriplegia that later developed into spastic diplegia. Whole-exome sequencing revealed two recurrent GNB1 variants (p.Leu95Pro and p.Ile80Thr) and one novel variant (p.Ser74Leu). A recent investigation revealed large numbers of patients with GNB1 variants. Functional studies of such variants and genotype-phenotype correlation are required to enable future precision medicine.

2.
BMC Neurol ; 19(1): 253, 2019 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-31656175

RESUMO

BACKGROUND: We encountered two unrelated individuals suffering from neurological disorders, including epilepsy and scoliosis. CASE PRESENTATION: Whole-exome sequencing identified the same recurrent, de novo, pathogenic variant in NUS1 [NM_138459.4:c.691 + 1C > A] in both individuals. This variant is located in the conserved cis-prenyltransferase domain of the nuclear undecaprenyl pyrophosphate synthase 1 gene (NUS1), which encodes the Nogo-B receptor, an essential catalyst for protein glycosylation. This variant was confirmed to create a new splice donor site, resulting in aberrant RNA splicing resulting in a 91-bp deletion in exon 3 in both individuals. The mutant mRNA was partially degraded by nonsense mediated mRNA decay. To date, only four de novo variants and one homozygous variant have been reported in NUS1, which cause developmental and epileptic encephalopathy, early onset Parkinson's disease, and a congenital disorder of glycosylation. Seven patients, including our two patients, have presented with epileptic seizures and intellectual disabilities. CONCLUSIONS: Our study strongly supports the finding that this recurrent, de novo, variant in NUS1 causes developmental and epileptic encephalopathy with involuntary movement, ataxia and scoliosis.

3.
J Hum Genet ; 64(11): 1127-1132, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31420595

RESUMO

RAC3 is a member of the Rho GTPases family, which has important regulatory functions in aspects of neuronal morphogenesis. Rho GTPases show a conformational change in two regions (switch I and II) through GTP binding, which provides a platform for selective interactions with functionally diverse proteins. Missense variants in the switch I and II regions of RAC3 were recently suggested to cause severe intellectual disability and brain malformations. Here, we report an individual with a novel de novo RAC3 variant (c.101 C>G, p.(Pro34Arg)), which substitutes for an evolutionarily conserved amino acid within the switch I region. The patient showed severe global developmental delay, intellectual disability, epilepsy, and laryngeal dystonia. An imaging study revealed characteristic brain dysplasia, including coexistence of the middle interhemispheric variant of holoprosencephaly and brainstem dysmorphism. Our study supports that RAC3 variants cause syndromic neurodevelopmental disorders and brain structural abnormality, and expands the phenotypic spectrum of RAC3-related disorders.

5.
Neurology ; 93(3): e237-e251, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31197031

RESUMO

OBJECTIVE: Intensive genetic analysis was performed to reveal comprehensive molecular insights into hypothalamic hamartoma (HH). METHODS: Thirty-eight individuals with HH were investigated by whole exome sequencing, target capture-based deep sequencing, or single nucleotide polymorphism (SNP) array using DNA extracted from blood leukocytes or HH samples. RESULTS: We identified a germline variant of KIAA0556, which encodes a ciliary protein, and 2 somatic variants of PTPN11, which forms part of the RAS/mitogen-activated protein kinase (MAPK) pathway, as well as variants in known genes associated with HH. An SNP array identified (among 3 patients) one germline copy-neutral loss of heterozygosity (cnLOH) at 6p22.3-p21.31 and 2 somatic cnLOH; one at 11q12.2-q25 that included DYNC2H1, which encodes a ciliary motor protein, and the other at 17p13.3-p11.2. A germline heterozygous variant and an identical somatic variant of DYNC2H1 arising from cnLOH at 11q12.2-q25 were confirmed in one patient (whose HH tissue, therefore, contains biallelic variants of DYNC2H1). Furthermore, a combination of a germline and a somatic DYNC2H1 variant was detected in another patient. CONCLUSIONS: Overall, our cohort identified germline/somatic alterations in 34% (13/38) of patients with HH. Disruption of the Shh signaling pathway associated with cilia or the RAS/MAPK pathway may lead to the development of HH.

6.
Seizure ; 71: 20-23, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31176277

RESUMO

PURPOSE: Early myoclonic encephalopathy (EME) is a form of developmental and epileptic encephalopathy with myoclonic seizures and a suppression burst on electroencephalogram, which occurs during the neonatal or early infantile period and is characterized by highly intractable seizures and severe development impairment. Although multiple genetic aetiologies of EME have been identified, no SCN1A mutation has been reported. METHODS: We described a female patient with EME due to an SCN1A mutation. RESULTS: She developed frequent myoclonic and apnoeic seizures during the neonatal period. As her seizures were refractory to many antiepileptic drugs, she underwent a tracheotomy and has since been treated with continuous mechanical ventilation. Eventually, perampanel was added, which resulted in the cessation of the apnoeic seizures. Genetic analysis revealed a heterozygous de novo missense mutation in the SCN1A gene (c.2588 T > C:p.Leu863Ser). CONCLUSION: This is the first patient with EME due to anSCN1A mutation to be successfully treated with perampanel. Recently, perampanel was reported to be effective in treating Dravet syndrome, including cases with an SCN1A mutation. Perampanel may contribute to seizure reduction in patients with intractable epilepsy carrying the SCN1A mutation.

7.
Epilepsy Res ; 155: 106149, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31185419

RESUMO

SMC1A variants causing Cornelia de Lange syndrome (CdLS) produce another phenotype characterized by moderate to severe neurological impairment and severe early-onset epilepsy without morphological characteristics of CdLS. The patients are all female and have truncation mutations in SMC1A. The epilepsy also follows a characteristic clinical course with pharmaco-resistant cluster seizures since infancy, mimicking that of PCDH19-related epilepsy. We report here that a missense variant of the SMC1A gene affecting a daughter (proband) and her mother caused similar phenotypes of early-onset (2 years and 1 month of age) and late-onset (12 years of age) epilepsy, respectively. Both patients lacked the morphological characteristics of CdLS, and had severe and moderate intellectual disability, respectively. The cluster seizures were characteristic, occurring approximately every 2-4 weeks (interval; mean ±â€¯SD: 20.2 ±â€¯8.3 days) at the peak of the clinical course, especially in the proband. Thus, SMC1A-related encephalopathy is caused not only by truncation mutations but also by missense variants of the SMC1A gene. The periodicity of cluster seizures mimicking that of PCDH19-related epilepsy may characterize SMC1A-related encephalopathy.

8.
J Hum Genet ; 64(8): 821-827, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31110234

RESUMO

We identified a de novo frameshift variant (NM_015048.1:c.5644_5647del:p.(Ile1882Serfs*118)) in the last exon of SETD1B in a Japanese patient with autistic behavior, developmental delay, intellectual disability, and myoclonic seizures. This variant is predicted to disrupt a well-conserved carboxyl-terminus SET domain, which is known to modulate gene activities and/or chromatin structure. Previously, two de novo missense mutations in SETD1B were reported in two patients with epilepsy. All three patients including the current patient share similar clinical features. Herein, we report a first epilepsy patient with a frameshift variant in SETD1B, emphasizing a possible pathomechanistic association of SETD1B abnormality with neurodevelopmental delay with epilepsy.

9.
J Hum Genet ; 64(7): 701-702, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31028281

RESUMO

Since the publication of this article, it has been brought to our attention, that the identified mutation (NM_015277: c.2617 G > A; p.Glu873Lys) is identical with the mutation (NM_001144967: c.2677 G > A; p.Glu893Lys) reported by Broix et al (Nature Genetics 48, 1349-1358, 2016 https://doi.org/10.1038/ng.3676 ). Therefore the mutation is not novel but recurrent. Accordingly, the word "novel" should be deleted throughout the article including the title. Thus, the title should read "A missense mutation in the HECT domain of NEDD4L identified in a girl with periventricular nodular heterotopia, polymicrogyria, and cleft palate."

10.
Seizure ; 65: 118-123, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30684875

RESUMO

PURPOSE: In rare cases, patients with epilepsy of infancy withmigrating focal seizures (EIMFS) exhibit suppression-burst (SB) patterns on electroencephalography (EEG), similar to the findings observed in patients with Ohtahara syndrome and early myoclonic encephalopathy. In this report, we discuss six cases of EIMFS in which patients exhibited two types of SB patterns. METHODS: We evaluated six patients with EIMFS who had been admitted to the NHO Shizuoka Institute of Epilepsy and Neurological Disorders between 2011 and 2018. We retrospectively examined clinical characteristics and EEG findings for each patient. In all patients, the first EEG was performed within 1 month after seizure onset. Afterwards, EEG examinations were performed at irregular intervals (ranging from 1 to 5 months). RESULTS: Age at seizure onset ranged from 2 days to 3 months. SB was first detected within 1 month of age in two patients, and within the range of 3-14 months in the remaining four patients. Among the latter four patients, SB patterns persisted at the final EEG recording in three patients (34-54 months). In all patients, SB patterns were observed during sleep only. Interhemispheric asynchrony in SB was observed in the two patients who exhibited SB within 1 month of age, while synchronous SB patterns were observed in the remaining four patients. CONCLUSIONS: Our findings indicate that EIMFS may be associated with two types of SB patterns (early-onset and late-onset), which can be distinguished based on the stage of emergence and level of synchrony.


Assuntos
Ondas Encefálicas/fisiologia , Convulsões/diagnóstico , Convulsões/fisiopatologia , Idade de Início , Pré-Escolar , Eletroencefalografia , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos
12.
Brain ; 142(2): 322-333, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30689738

RESUMO

In patients with aromatic l-amino acid decarboxylase (AADC) deficiency, a decrease in catecholamines and serotonin levels in the brain leads to developmental delay and movement disorders. The beneficial effects of gene therapy in patients from 1 to 8 years of age with homogeneous severity of disease have been reported from Taiwan. We conducted an open-label phase 1/2 study of population including adolescent patients with different degrees of severity. Six patients were enrolled: four males (ages 4, 10, 15 and 19 years) and one female (age 12 years) with a severe phenotype who were not capable of voluntary movement or speech, and one female (age 5 years) with a moderate phenotype who could walk with support. The patients received a total of 2 × 1011 vector genomes of adeno-associated virus vector harbouring DDC via bilateral intraputaminal infusions. At up to 2 years after gene therapy, the motor function was remarkably improved in all patients. Three patients with the severe phenotype were able to stand with support, and one patient could walk with a walker, while the patient with the moderate phenotype could run and ride a bicycle. This moderate-phenotype patient also showed improvement in her mental function, being able to converse fluently and perform simple arithmetic. Dystonia disappeared and oculogyric crisis was markedly decreased in all patients. The patients exhibited transient choreic dyskinesia for a couple of months, but no adverse events caused by vector were observed. PET with 6-[18F]fluoro-l-m-tyrosine, a specific tracer for AADC, showed a persistently increased uptake in the broad areas of the putamen. In our study, older patients (>8 years of age) also showed improvement, although treatment was more effective in younger patients. The genetic background of our patients was heterogeneous, and some patients suspected of having remnant enzyme activity showed better improvement than the Taiwanese patients. In addition to the alleviation of motor symptoms, the cognitive and verbal functions were improved in a patient with the moderate phenotype. The restoration of dopamine synthesis in the putamen via gene transfer provides transformative medical benefit across all patient ages, genotypes, and disease severities included in this study, with the most pronounced improvements noted in moderate patients.10.1093/brain/awy331_video1awy331media15991361892001.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Descarboxilases de Aminoácido-L-Aromático/deficiência , Terapia Genética/métodos , Processos Mentais/fisiologia , Destreza Motora/fisiologia , Adolescente , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico por imagem , Descarboxilases de Aminoácido-L-Aromático/genética , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Adulto Jovem
13.
J Med Genet ; 56(6): 388-395, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30573562

RESUMO

BACKGROUND: In this study, we aimed to identify the gene abnormality responsible for pathogenicity in an individual with an undiagnosed neurodevelopmental disorder with megalencephaly, ventriculomegaly, hypoplastic corpus callosum, intellectual disability, polydactyly and neuroblastoma. We then explored the underlying molecular mechanism. METHODS: Trio-based, whole-exome sequencing was performed to identify disease-causing gene mutation. Biochemical and cell biological analyses were carried out to elucidate the pathophysiological significance of the identified gene mutation. RESULTS: We identified a heterozygous missense mutation (c.173C>T; p.Thr58Met) in the MYCN gene, at the Thr58 phosphorylation site essential for ubiquitination and subsequent MYCN degradation. The mutant MYCN (MYCN-T58M) was non-phosphorylatable at Thr58 and subsequently accumulated in cells and appeared to induce CCND1 and CCND2 expression in neuronal progenitor and stem cells in vitro. Overexpression of Mycn mimicking the p.Thr58Met mutation also promoted neuronal cell proliferation, and affected neuronal cell migration during corticogenesis in mouse embryos. CONCLUSIONS: We identified a de novo c.173C>T mutation in MYCN which leads to stabilisation and accumulation of the MYCN protein, leading to prolonged CCND1 and CCND2 expression. This may promote neurogenesis in the developing cerebral cortex, leading to megalencephaly. While loss-of-function mutations in MYCN are known to cause Feingold syndrome, this is the first report of a germline gain-of-function mutation in MYCN identified in a patient with a novel megalencephaly syndrome similar to, but distinct from, CCND2-related megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. The data obtained here provide new insight into the critical role of MYCN in brain development, as well as the consequences of MYCN defects.

14.
Epilepsia Open ; 3(4): 495-502, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30525118

RESUMO

Objective: Vitamin B6-dependent epilepsies are treatable disorders caused by variants in several genes, such as ALDH7A1,PNPO, and others. Recently, biallelic variants in PLPBP, formerly known as PROSC, were identified as a novel cause of vitamin B6-dependent epilepsies. Our objective was to further delineate the phenotype of PLPBP mutation. Methods: We identified 4 unrelated patients harboring a total of 4 variants in PLPBP, including 3 novel variants, in a cohort of 700 patients with developmental and epileptic encephalopathies. Clinical information in each case was collected. Results: Each patient had a different clinical course of epilepsy, with seizure onset from the first day of life to 3 months of age. Generalized tonic-clonic seizures were commonly noted. Myoclonic seizures or focal seizures were also observed in 2 patients. Interictal electroencephalography showed variable findings, such as suppression burst, focal or multifocal discharges, and diffuse slow activity. Unlike previous reports, all the patients had some degree of intellectual disability, although some of them had received early treatment with vitamin B6, suggesting that different mutation types influence the severity and outcome of the seizures. Significance: PLPBP variants should be regarded as among the causative genes of developmental and epileptic encephalopathy, even when it occurs after the neonatal period. Early diagnosis and proper treatment with pyridoxine or pyridoxal phosphate is essential to improve the neurologic prognosis in neonates or young children with poorly controlled seizures.

15.
Eur J Hum Genet ; 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30487643

RESUMO

Potocki-Shaffer syndrome (PSS) is a contiguous gene syndrome caused by 11p11.2 deletions. PSS is clinically characterized by intellectual disability, craniofacial anomalies, enlarged parietal foramina, and multiple exostoses. PSS occasionally shows autism spectrum disorder, epilepsy, and overgrowth. Some of the clinical features are thought to be associated with haploinsufficiency of two genes in the 11p11.2 region; variants affecting the function of ALX4 cause enlarged parietal foramina and EXT2 lead to multiple exostoses. However, the remaining clinical features were still yet to be linked to specific genetic alterations. In this study, we identified de novo truncating variants in an 11p11.2 gene, PHF21A, in three cases with intellectual disability and craniofacial anomalies. Among these three cases, autism spectrum disorder was recognized in one case, epilepsy in one case, and overgrowth in two cases. This study shows that PHF21A haploinsufficiency results in intellectual disability and craniofacial anomalies and possibly contributes to susceptibility to autism spectrum disorder, epilepsy, and overgrowth, all of which are PSS features.

16.
Genet Med ; 2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30349098

RESUMO

PURPOSE: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin-Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. METHODS: Clinicians entered clinical data in an extensive web-based survey. RESULTS: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. CONCLUSION: There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features.

17.
Clin Genet ; 94(6): 538-547, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30280376

RESUMO

N-methyl-d-aspartate (NMDA) receptors are glutamate-activated ion channels that are widely distributed in the central nervous system and essential for brain development and function. Dysfunction of NMDA receptors has been associated with various neurodevelopmental disorders. Recently, a de novo recurrent GRIN2D missense variant was found in two unrelated patients with developmental and epileptic encephalopathy. In this study, we identified by whole exome sequencing novel heterozygous GRIN2D missense variants in three unrelated patients with severe developmental delay and intractable epilepsy. All altered residues were highly conserved across vertebrates and among the four GluN2 subunits. Structural consideration indicated that all three variants are probably to impair GluN2D function, either by affecting intersubunit interaction or altering channel gating activity. We assessed the clinical features of our three cases and compared them to those of the two previously reported GRIN2D variant cases, and found that they all show similar clinical features. This study provides further evidence of GRIN2D variants being causal for epilepsy. Genetic diagnosis for GluN2-related disorders may be clinically useful when considering drug therapy targeting NMDA receptors.

18.
J Hum Genet ; 63(12): 1259-1267, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30266950

RESUMO

Essential hypersomnia (EHS) is a lifelong disorder characterized by excessive daytime sleepiness without cataplexy. EHS is associated with human leukocyte antigen (HLA)-DQB1*06:02, similar to narcolepsy with cataplexy (narcolepsy). Previous studies suggest that DQB1*06:02-positive and -negative EHS are different in terms of their clinical features and follow different pathological pathways. DQB1*06:02-positive EHS and narcolepsy share the same susceptibility genes. In the present study, we report a genome-wide association study with replication for DQB1*06:02-negative EHS (408 patients and 2247 healthy controls, all Japanese). One single-nucleotide polymorphism, rs10988217, which is located 15-kb upstream of carnitine O-acetyltransferase (CRAT), was significantly associated with DQB1*06:02-negative EHS (P = 7.5 × 10-9, odds ratio = 2.63). The risk allele of the disease-associated SNP was correlated with higher expression levels of CRAT in various tissues and cell types, including brain tissue. In addition, the risk allele was associated with levels of succinylcarnitine (P = 1.4 × 10-18) in human blood. The leading SNP in this region was the same in associations with both DQB1*06:02-negative EHS and succinylcarnitine levels. The results suggest that DQB1*06:02-negative EHS may be associated with an underlying dysfunction in energy metabolic pathways.

19.
Brain ; 141(11): 3098-3114, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30256902

RESUMO

Trio-based whole exome sequencing identified two de novo heterozygous missense mutations [c.1449T > C/p.(Leu500Pro) and c.1436A > T/p.(Asn479Ile)] in PHACTR1, encoding a molecule critical for the regulation of protein phosphatase 1 (PP1) and the actin cytoskeleton, in unrelated Japanese individuals with West syndrome (infantile spasms with intellectual disability). We then examined the role of Phactr1 in the development of mouse cerebral cortex and the pathophysiological significance of these two mutations and others [c.1561C > T/p.(Arg521Cys) and c.1553T > A/p.(Ile518Asn)], which had been reported in undiagnosed patients with intellectual disability. Immunoprecipitation analyses revealed that actin-binding activity of PHACTR1 was impaired by the p.Leu500Pro, p.Asn479Ile and p.Ile518Asn mutations while the p.Arg521Cys mutation exhibited impaired binding to PP1. Acute knockdown of mouse Phactr1 using in utero electroporation caused defects in cortical neuron migration during corticogenesis, which were rescued by an RNAi-resistant PHACTR1 but not by the four mutants. Experiments using knockdown combined with expression mutants, aimed to mimic the effects of the heterozygous mutations under conditions of haploinsufficiency, suggested a dominant negative effect of the mutant allele. As for dendritic development in vivo, only the p.Arg521Cys mutant was determined to have dominant negative effects, because the three other mutants appeared to be degraded with these experimental conditions. Electrophysiological analyses revealed abnormal synaptic properties in Phactr1-deficient excitatory cortical neurons. Our data show that the PHACTR1 mutations may cause morphological and functional defects in cortical neurons during brain development, which is likely to be related to the pathophysiology of West syndrome and other neurodevelopmental disorders.

20.
Hum Genome Var ; 5: 16, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30083360

RESUMO

We report a case of two siblings with progressive myoclonus epilepsy whose parents were not consanguineous. Their clinical symptoms were typical of Lafora disease (LD), but skin biopsies revealed no Lafora bodies. Whole-exome sequencing identified a recurrent homozygous frameshift variant in the NHLRC1 gene in both siblings. The genetic analysis was useful for the diagnosis of LD, as neither consanguinity nor Lafora bodies were found.

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