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1.
Brain Dev ; 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31787380

RESUMO

BACKGROUND: The pathogenesis of acute encephalopathy (AE) remains unclear, and a biomarker has not been identified. METHODS: Levels of 49 cytokines and chemokines, including osteopontin (OPN), were measured in serum and cerebrospinal fluid (CSF) of children with AE (n = 17) or febrile convulsion (FC; n = 8; control group). The AE group included acute necrotizing encephalopathy (n = 1), acute encephalopathy with biphasic seizures and late reduced diffusion (AESD; n = 3), clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS; n = 4), and unclassified acute encephalopathy (UCAE; n = 9) that does not meet the criteria of syndrome classification. Five individuals with AE had neurological sequelae or death (poor prognosis), whereas 12 were alive without neurological sequelae (good prognosis). RESULTS: The CSF:serum ratios of OPN, CC chemokine ligand (CCL)4, and interleukin (IL)-10 were significantly higher in AE than in FC. The CSF levels of macrophage inhibitory factor (MIF) and leukemia inhibitory factor (LIF) were significantly higher in the poor-prognosis group than in the good-prognosis group. The CSF:serum ratios of OPN were significantly higher in AESD and in MERS than in FC. The CSF:serum ratios of MIF and OPN were higher in MERS than in UCAE or FC. CONCLUSION: Our results suggest that microglia-related cytokines and chemokines such as OPN, MIF, and LIF could be novel biomarkers of AE, in addition to the previously reported IL-10 and CCL4, and that MIF and LIF may be markers of poor prognosis.

2.
J Hum Genet ; 64(12): 1173-1186, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31530938

RESUMO

Coffin-Siris syndrome (CSS, MIM#135900) is a congenital disorder characterized by coarse facial features, intellectual disability, and hypoplasia of the fifth digit and nails. Pathogenic variants for CSS have been found in genes encoding proteins in the BAF (BRG1-associated factor) chromatin-remodeling complex. To date, more than 150 CSS patients with pathogenic variants in nine BAF-related genes have been reported. We previously reported 71 patients of whom 39 had pathogenic variants. Since then, we have recruited an additional 182 CSS-suspected patients. We performed comprehensive genetic analysis on these 182 patients and on the previously unresolved 32 patients, targeting pathogenic single nucleotide variants, short insertions/deletions and copy number variations (CNVs). We confirmed 78 pathogenic variations in 78 patients. Pathogenic variations in ARID1B, SMARCB1, SMARCA4, ARID1A, SOX11, SMARCE1, and PHF6 were identified in 48, 8, 7, 6, 4, 1, and 1 patients, respectively. In addition, we found three CNVs including SMARCA2. Of particular note, we found a partial deletion of SMARCB1 in one CSS patient and we thoroughly investigated the resulting abnormal transcripts.

3.
Mitochondrion ; 49: 111-120, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31356884

RESUMO

Mitochondrial disease is a genetic disorder in which individuals suffer from energy insufficiency. The various clinical phenotypes of mitochondrial disease include Leigh syndrome (LS), myopathy encephalopathy lactic acidosis and stroke-like episodes (MELAS). Thus far, no curative treatment is available, and effective treatment options are eagerly awaited. We examined the cell protective effect of an existing commercially available chemical library on fibroblasts from four patients with LS and MELAS and identified apomorphine as a potential therapeutic drug for mitochondrial disease. We conducted a cell viability assay under oxidative stress induced by L-butionine (S, R)-sulfoximine (BSO), a glutathione synthesis inhibitor. Among the chemicals of library, 4 compounds (apomorphine, olanzapine, phenothiazine and ethopropazine) rescued cells from death induced by oxidative stress much more effectively than idebenone, which was used as a positive control. The EC50 value showed that apomorphine was the most effective compound. Apomorphine also significantly improved all of the assessed oxygen consumption rate values by the extracellular flux analyzer for fibroblasts from LS patients with complex I deficiency. In addition, the elevation of the Growth Differentiation Factor-15 (GDF-15), a biomarker of mitochondrial disease, was significantly reduced by apomorphine. Among 441 apomorphine-responsive genes identified by the microarray, apomorphine induced the expression of genes that inhibit the mammalian target of rapamycin (mTOR) activity and inflammatory responses, suggesting that apomorphine induced cell survival via a new potential pathway. In conclusion, apomorphine rescued fibroblasts from cell death under oxidative stress and improved the mitochondrial respiratory activity and appears to be potentially useful for treating mitochondrial disease.

4.
Nat Commun ; 10(1): 2506, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31175295

RESUMO

Although there are many known Mendelian genes linked to epileptic or developmental and epileptic encephalopathy (EE/DEE), its genetic architecture is not fully explained. Here, we address this incompleteness by analyzing exomes of 743 EE/DEE cases and 2366 controls. We observe that damaging ultra-rare variants (dURVs) unique to an individual are significantly overrepresented in EE/DEE, both in known EE/DEE genes and the other non-EE/DEE genes. Importantly, enrichment of dURVs in non-EE/DEE genes is significant, even in the subset of cases with diagnostic dURVs (P = 0.000215), suggesting oligogenic contribution of non-EE/DEE gene dURVs. Gene-based analysis identifies exome-wide significant (P = 2.04 × 10-6) enrichment of damaging de novo mutations in NF1, a gene primarily linked to neurofibromatosis, in infantile spasm. Together with accumulating evidence for roles of oligogenic or modifier variants in severe neurodevelopmental disorders, our results highlight genetic complexity in EE/DEE, and indicate that EE/DEE is not an aggregate of simple Mendelian disorders.


Assuntos
Variação Genética , Espasmos Infantis/genética , Proteínas Adaptadoras de Transporte Vesicular/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , DNA (Citosina-5-)-Metiltransferases/genética , Epilepsias Mioclônicas/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Lactente , Japão , Síndrome de Lennox Gastaut/genética , Modelos Logísticos , Mutação , Neurofibromina 1/genética , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal , Canais de Cátion TRPM/genética , Sequenciamento Completo do Exoma
5.
Mol Genet Genomic Med ; 7(8): e814, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31231989

RESUMO

BACKGROUND: Congenital disorders of glycosylation (CDGs) are genetic diseases caused by pathogenic variants of genes involved in protein or lipid glycosylation. De novo variants in the SLC35A2 gene, which encodes a UDP-galactose transporter, are responsible for CDGs with an X-linked dominant manner. Common symptoms related to SLC35A2 variants include epilepsy, psychomotor developmental delay, hypotonia, abnormal facial and skeletal features, and various magnetic resonance imaging (MRI) findings. METHODS: Whole-exome sequencing was performed on the patient's DNA, and candidate variants were confirmed by Sanger sequencing. cDNA analysis was performed to assess the effect of the splice site variant using peripheral leukocytes. The X-chromosome inactivation pattern was studied using the human androgen receptor assay. RESULTS: We identified a de novo splice site variant in SLC35A2 (NM_005660.2: c.274+1G>A) in a female patient who showed severe developmental delay, spastic paraplegia, mild cerebral atrophy, and delayed myelination on MRI, but no seizures. The variant led to an aberrant splicing resulting in an in-frame 33-bp insertion, which caused an 11-amino acid insertion in the presumptive cytoplasmic loop. X-inactivation pattern was random. Partial loss of galactose and sialic acid of the N-linked glycans of serum transferrin was observed. CONCLUSION: This case would expand the phenotypic spectrum of SLC35A2-related disorders to delayed myelination with spasticity and no seizures.

6.
Brain Dev ; 41(8): 726-730, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31029456

RESUMO

INTRODUCTION: Neuronal ceroid lipofuscinoses (NCLs; CLN) are mainly autosomal recessive neurodegenerative disorders characterized by the accumulation of autofluorescent lipopigments in neuronal and other cells. Symptoms include visual disabilities, motor decline, and epilepsy. Causative genes are CLN1, CLN2, CLN3, CLN5, CLN6, CLN7, CLN8, CLN10, CLN11, CLN12, CLN13, and CLN14. We present the fourth Japanese case with a CLN6 mutation. CASE PRESENTATION: At 3 years of age, our patient became clumsy and fell down easily. He developed focal seizures with impaired consciousness and was started on carbamazepine. He showed ataxic walking and dysarthria with increased deep tendon reflexes. Interictal electroencephalogram revealed slow waves in the left temporal and occipital areas. Brain magnetic resonance imaging showed cerebellar atrophy and ventriculomegaly. In optical coherence tomography (OCT), the inner layer of the retina was thick and highly reflective. Exome sequencing revealed a known homozygous mutation, C.794_976del, p. (Ser265del) in CLN6. DISCUSSION: A total of 130 cases of NCL with CLN6 mutations have been reported globally, of which only four were from Japan including the current patient. The deletion of serine at position 265 has been reported in six cases. Ser265 is located in a region of short repeated sequences that is susceptible to mutation. Clinical trials of gene therapy using adeno-associated virus serotype 9 have started for NCL6, making early diagnosis crucial. OCT examination might be helpful in achieving a diagnosis.

7.
Brain Dev ; 41(5): 465-469, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30739820

RESUMO

Mutations in the mitochondrial tRNAMet gene have been reported in only five patients to date, all of whom presented with muscle weakness and exercise intolerance as signs of myopathy. We herein report the case of a 12-year-old girl with focal epilepsy since the age of eight years. At age 11, the patient developed sudden visual disturbances and headaches accompanied by recurrent, stroke-like episodes with lactic acidosis (pH 7.279, lactic acid 11.6 mmol/L). The patient frequently developed a delirious state, exhibited regression of intellectual ability. Brain magnetic resonance imaging revealed high-intensity signals on T2-weighted images of the left occipital lobe. Mitochondrial gene analysis revealed a heteroplasmic m.4450G > A mutation in the mitochondrial tRNAMet. The heteroplasmic rate of the m.4450G > A mutation in blood, skin, urinary sediment, hair, saliva, and nail samples were 20, 38, 59, 41, 27, and 35%, respectively. The patient's fibroblast showed an approximately 53% reduction in the oxygen consumption rate, compared to a control, and decreased complex I and IV activities. Stroke-like episodes, lactic acidosis, encephalopathy with brain magnetic resonance imaging findings, and declined mitochondrial function were consistent with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. To our knowledge, the findings associated with this first patient with MELAS syndrome harboring the m.4450G > A mutation in mitochondrial tRNAMet expand the phenotypic spectrum of tRNAMet gene.


Assuntos
Síndrome MELAS/diagnóstico , Síndrome MELAS/genética , Síndrome MELAS/fisiopatologia , RNA Mitocondrial/genética , RNA de Transferência de Metionina/genética , Criança , Feminino , Humanos
8.
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
10.
Hum Genome Var ; 5: 25, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30210801

RESUMO

Approximately 80% of cases of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) harbor a heteroplasmic m.3243A>G transition in the tRNALeu (UUR) (MTTL1) gene. We report a MELAS case with a rare heteroplasmic m.3243A>T mutation found by direct sequencing of MTTL1. This mutation has been previously reported in 5 cases, of which 2 cases had the MELAS phenotype. Our case also strengthens the hypothesis that the m.3243A>T mutation can cause the MELAS phenotype.

11.
Brain Dev ; 2018 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-30213442

RESUMO

Alexander disease (AxD) is a neurodegenerative disease in astrocytes caused by a mutation in the gene encoding glial fibrillary acidic protein, GFAP. We herein present the case of a 12-year-old girl who showed intermittent exotropia at 3 years of age and central precocious puberty at 7 years of age. The periventricular and medulla oblongata showed high signal intensity on T2-weighted magnetic resonance imaging. The patient was diagnosed with AxD after direct sequencing revealing a de novo recurrent mutation, c.1246C>T (p.R416W) in GFAP. The transient expression of GFAPR416W in cells resulted in the significant formation of aggregates, which recapitulated the hallmark of AxD. We firstly utilized In Cell analyzer to prove the tendency of aggregate formation by mutants of GFAP.

12.
J Hum Genet ; 63(10): 1049-1054, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30018422

RESUMO

The mammalian Na+/H+ exchanger isoform one (NHE1), encoded by Solute Carrier Family 9, member 1 (SLC9A1), consists of 12 membrane domains and a cytosolic C-terminal domain. NHE1 plays an important role in maintaining intracellular pH homeostasis by exchanging one intracellular proton for one extracellular sodium ion. Mice with a homozygous null mutation in Slc9a1 (Nhe1) exhibited ataxia, recurrent seizures, and selective neuronal cell death. In humans, three unrelated patients have been reported: a patient with a homozygous missense mutation in SLC9A1, c.913G>A (p.Gly305Arg), which caused Lichtenstein-Knorr syndrome characterized by cerebellar ataxia and sensorineural hearing loss, a patient with compound heterozygous mutations, c.1351A>C (p.Ile451Leu) and c.1585C>T (p.His529Tyr), which caused a neuromuscular disorder, and a patient with de novo mutation, c.796A>C (p.Asn266His) which associated multiple anomalies. In this study, using whole exome sequencing, we identified a novel homozygous SLC9A1 truncating mutation, c.862del (p.Ile288Serfs*9), in two affected siblings. The patients showed cerebellar ataxia but neither of them showed sensorineural hearing loss nor a neuromuscular phenotype. The main clinical feature was similar to Lichtenstein-Knorr syndrome but deafness may not be an essential phenotypic feature of SLC9A1 mutation. Our report expands the knowledge of clinical features of SLC9A1 mutations.

13.
Brain Dev ; 40(9): 807-812, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29891405

RESUMO

BACKGROUND: Acute encephalopathy causes various sequelae, including motor disabilities and intellectual delays. Previous studies reported that cognitive impairments can also occur after acute encephalitis. Although the incidence of acute encephalopathy is high in Japan, there have been few reports on its sequelae. OBJECTIVE: To characterize the neurological outcomes of pediatric patients who sought motor rehabilitation for motor dysfunction after acute encephalopathy. METHOD: Subjects were 26 children who were healthy before suffering from motor dysfunction following acute encephalopathy and were referred to our pediatric rehabilitation institute during a 9-year period (August 2007-April 2017). We examined subjects' neurological status and followed sequelae for at least 8 months. RESULTS: Of 26 individuals, 21 became ambulatory after several months or years during the observation period. Patients who could sit without support within 5 months after the onset of acute encephalopathy were able to walk within several months or years. Patients showing high intensity on T2-weighted sequences or "bright tree appearance" in the frontal region took an average of 7 months to develop walking, which was longer than other patients. Among ambulatory subjects, 16(76%) exhibited mild to moderate intellectual delay with a developmental quotient (DQ) under 70, and 20 (95%) exhibited cognitive impairment. There was a significant correlation between DQ scores and motor disability (p = 0.013, r = -0.481). CONCLUSIONS: Although 80% of patients who had motor dysfunction caused by acute encephalopathy and visited out motor rehabilitation outpatient clinic were eventually able to walk, the time taken to develop walking ability depended on which region exhibited magnetic resonance imaging abnormalities. DQ scores and motor disability were significantly correlated.


Assuntos
Encefalopatias/complicações , Disfunção Cognitiva/etiologia , Transtornos dos Movimentos/etiologia , Encefalopatias/psicologia , Encefalopatias/reabilitação , Pré-Escolar , Disfunção Cognitiva/reabilitação , Feminino , Seguimentos , Humanos , Lactente , Modelos Lineares , Masculino , Transtornos dos Movimentos/reabilitação , Estudos Retrospectivos , Resultado do Tratamento , Caminhada
14.
Brain Dev ; 40(7): 607-611, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29661590

RESUMO

BACKGROUND: The effect of rituximab on acute disseminated encephalomyelitis (ADEM) followed by recurrent optic neuritis (ON) is not yet known. PATIENT: We are reporting the case of a 4-year-old Japanese girl who was diagnosed with anti-myelin oligodendrocyte glycoprotein (MOG) antibody positive ADEM followed by recurrent ON. She developed altered mental status, left facial paralysis, left paresis, and experienced three episodes of ON. She was treated with rituximab and azathioprine (AZA) as prevention for recurrent ON. She relapsed under treatment with AZA when CD19 cells reappeared 6 months after the first rituximab infusion. However, she has not relapsed since her CD19 count was reduced and kept low with rituximab infusion. CONCLUSIONS: It is conceivable that anti-MOG antibodies are involved in the pathology of "ADEM followed by recurrent ON," and that the early introduction of rituximab, which is involved in the suppression of antibody production and has effects on CD20 T lymphocytes, may be a feasible treatment for ON. Due to the small number of patients, additional reports on prospectively followed patients are needed.


Assuntos
Autoanticorpos/metabolismo , Encefalomielite Aguda Disseminada/terapia , Fatores Imunológicos/uso terapêutico , Glicoproteína Mielina-Oligodendrócito/imunologia , Neurite Óptica/terapia , Rituximab/uso terapêutico , Encéfalo/diagnóstico por imagem , Criança , Progressão da Doença , Encefalomielite Aguda Disseminada/complicações , Encefalomielite Aguda Disseminada/diagnóstico por imagem , Encefalomielite Aguda Disseminada/imunologia , Feminino , Humanos , Neurite Óptica/diagnóstico por imagem , Neurite Óptica/etiologia , Neurite Óptica/imunologia
15.
J Gene Med ; 20(4): e3013, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29624790

RESUMO

BACKGROUND: We generated an adeno-associated virus (AAV) vector in which the human SLC2A1 gene, encoding glucose transporter type 1 (GLUT1), was expressed under the human endogenous GLUT1 promoter (AAV-GLUT1). We examined whether AAV-GLUT1 administration could lead to functional improvement in GLUT1-deficient mice. METHODS: We extrapolated human endogenous GLUT1 promoter sequences from rat minimal Glut1 promoter sequences. We generated a tyrosine-mutant AAV9/3 vector in which human SLC2A1-myc-DDK was expressed under the human GLUT1 promoter (AAV-GLUT1). AAV-GLUT1 was administered to GLUT1-deficient mice (GLUT1+/- mice) via intracerebroventricular injection (1.85 × 1010 vg/mouse or 6.5 × 1010 vg/mouse). We analyzed exogenous GLUT1 mRNA and protein expression in the brain and other major organs. We also examined improvements of cerebral microvasculature, motor function using rota-rod and footprint tests, as well as blood and cerebrospinal fluid (CSF) glucose levels. Additionally, we confirmed exogenous GLUT1 protein distribution in the brain and other organs after intracardiac injection (7.8 × 1011 vg/mouse). RESULTS: Exogenous GLUT1 protein was strongly expressed in the cerebral cortex, hippocampus and thalamus. It was mainly expressed in endothelial cells, and partially expressed in neural cells and oligodendrocytes. Motor function and CSF glucose levels were significantly improved following intracerebroventricular injection. Exogenous GLUT1 expression was not detected in other organs after intracerebroventricular injection of AAV-GLUT1, whereas it was detected in the liver and muscle tissue after intracardiac injection. CONCLUSIONS: Exogenous GLUT1 expression after AAV-GLUT1 injection approximated that of physiological human GLUT1 expression. Local central nervous system administration of AAV-GLUT1 improved CSF glucose levels and motor function of GLUT1-deficient mice and minimized off-target effects.

16.
Hum Genome Var ; 5: 18013, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29619238

RESUMO

Pelizaeus-Merzbacher disease (PMD; MIM #312080) is a rare X-linked recessive disorder. A male neonate presented with severe respiratory distress that required tracheostomy. After the appearance of nystagmus, PMD was suspected as a diagnosis for the patient, and a missense mutation, p.Phe51Val, was identified in PLP1, the gene responsible for PMD. PMD can be a differential diagnosis in a male neonate presenting severe respiratory distress.

18.
Brain Dev ; 40(6): 498-502, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29506883

RESUMO

Leigh syndrome, which is a common phenotype of pediatric mitochondrial disease, is a progressive neurodegenerative disease. The typical neuroimaging findings of Leigh syndrome include bilateral symmetric lesions in the basal ganglia and/or the brainstem. However, there are a few reports on spinal cord involvement in patients with Leigh syndrome. In the present case, magnetic resonance imaging (MRI) obtained during infancy revealed symmetric lesions in the substantia nigra of a patient with Leigh syndrome with an NDUFA1 mutation; lesions of the bilateral putamen and brainstem were subsequently observed. Additionally, our patient presented large and extended spinal cord lesions. Therefore, this case is suggesting that we should consider the occurrence of spinal cord lesions as an atypical finding in Leigh syndrome.


Assuntos
Doença de Leigh/diagnóstico por imagem , Doença de Leigh/genética , NADH Desidrogenase/genética , Doenças da Medula Espinal/diagnóstico por imagem , Doenças da Medula Espinal/genética , Medula Espinal/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Criança , Diagnóstico Diferencial , Humanos , Doença de Leigh/terapia , Masculino , Mutação de Sentido Incorreto , Doenças da Medula Espinal/terapia
19.
Brain Dev ; 40(7): 587-591, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29573842

RESUMO

Alexander disease (AxD) is a progressive neurodegenerative disease caused by a mutation in the glial fibrillary acid protein (GFAP) gene. A 4-year-old boy presented several times with hemiclonic seizures with eye deviation for a few minutes at 28 days after birth. Electroencephalogram showed independent sharp waves in the right and left temporal area. Magnetic resonance imaging showed high intensity T1-weighted images in the white matter of the frontal lobe and basal ganglia. He showed no head control at 4 years of age, and his weight gain was insufficient. He did not show macrocephaly. At 4 years of age, he died of bacterial pneumonia and septic shock. He was diagnosed with AxD, and direct sequencing revealed a de novo known mutation, c. 239 T > C, p.(F80S), in GFAP. Hela and U2-OS cells transfected with GFAP cDNA with c. 239 T > C showed dot-like cytoplasmic aggregation, similar to R239C, a common mutation found in severe infantile AxD. Aggregation in the cytoplasm caused by a GFAP mutation is a hallmark of AxD. Although there is only one previous report of a patient with an F80S mutation, our data support that F80S can cause the severe, infantile form of AxD.


Assuntos
Doença de Alexander/genética , Proteína Glial Fibrilar Ácida/genética , Mutação , Doença de Alexander/diagnóstico por imagem , Doença de Alexander/patologia , Doença de Alexander/fisiopatologia , Encéfalo/diagnóstico por imagem , Linhagem Celular Tumoral , Pré-Escolar , Citoplasma/metabolismo , Citoplasma/patologia , Evolução Fatal , Células HeLa , Humanos , Masculino , Transfecção
20.
Cell Rep ; 22(3): 734-747, 2018 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-29346770

RESUMO

Recent studies have established important roles of de novo mutations (DNMs) in autism spectrum disorders (ASDs). Here, we analyze DNMs in 262 ASD probands of Japanese origin and confirm the "de novo paradigm" of ASDs across ethnicities. Based on this consistency, we combine the lists of damaging DNMs in our and published ASD cohorts (total number of trios, 4,244) and perform integrative bioinformatics analyses. Besides replicating the findings of previous studies, our analyses highlight ATP-binding genes and fetal cerebellar/striatal circuits. Analysis of individual genes identified 61 genes enriched for damaging DNMs, including ten genes for which our dataset now contributes to statistical significance. Screening of compounds altering the expression of genes hit by damaging DNMs reveals a global downregulating effect of valproic acid, a known risk factor for ASDs, whereas cardiac glycosides upregulate these genes. Collectively, our integrative approach provides deeper biological and potential medical insights into ASDs.

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