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1.
J Neuroinflammation ; 21(1): 260, 2024 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-39396010

RESUMO

Haploinsufficiency of the transcriptional repressor ZBTB18/RP58 is associated with intellectual disability. However, the mechanisms causing this disability are unknown, and preventative measures and treatments are not available. Here, we assessed multiple behaviors in Zbtb18/Rp58 heterozygous-knockout mice, and examined local field potentials, DNA fragmentation, mitochondrial morphology, and performed histochemical and transcriptome analyses in the hippocampus to evaluate chronic inflammation. In wild-type mice, object location memory was present at a similar level at 2 and 4-5 months of age, and became impaired at 12-18 months. In contrast, Zbtb18/Rp58 heterozygous-knockout mice displayed early onset impairments in object location memory by 4-5 months of age. These mice also exhibited earlier accumulation of DNA and mitochondrial damage, and activated microglia in the dentate gyrus, which are associated with defective DNA repair. Notably, chronic minocycline therapy, which has neuroprotective and anti-inflammatory effects, attenuated age-related phenotypes, including accumulation of DNA damage, increased microglial activation, and impairment of object location memory. Our results suggest that Zbtb18/Rp58 activity is required for DNA repair and its reduction results in DNA and mitochondrial damage, increased activation of microglia, and inflammation, leading to accelerated declines in cognitive functions. Minocycline has potential as a therapeutic agent for the treatment of ZBTB18/RP58 haploinsufficiency-associated cognitive dysfunction.


Assuntos
Disfunção Cognitiva , Modelos Animais de Doenças , Haploinsuficiência , Deficiência Intelectual , Minociclina , Animais , Minociclina/farmacologia , Minociclina/uso terapêutico , Camundongos , Deficiência Intelectual/genética , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/prevenção & controle , Disfunção Cognitiva/patologia , Camundongos Endogâmicos C57BL , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Camundongos Knockout , Envelhecimento/genética , Envelhecimento/metabolismo , Envelhecimento/efeitos dos fármacos , Masculino , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/patologia
2.
Mol Psychiatry ; 28(6): 2370-2381, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36721027

RESUMO

ZBTB18/RP58 (OMIM *608433) is one of the pivotal genes responsible for 1q43q44 microdeletion syndrome (OMIM #612337) and its haploinsufficiency induces intellectual disability. However, the underlying pathological mechanism of ZBTB18/RP58 haploinsufficiency is unknown. In this study, we generated ZBTB18/RP58 heterozygous mice and found that these mutant mice exhibit multiple behavioral deficits, including impairment in motor learning, working memory, and memory flexibility, which are related to behaviors in people with intellectual disabilities, and show no gross abnormalities in their cytoarchitectures but dysplasia of the corpus callosum, which has been reported in certain population of patients with ZBTB18 haploinsufficiency as well as in those with 1q43q44 microdeletion syndrome, indicating that these mutant mice are a novel model of ZBTB18/RP58 haploinsufficiency, which reflects heterozygotic ZBTB18 missense, truncating variants and some phenotypes of 1q43q44 microdeletion syndrome based on ZBTB18/RP58 haploinsufficiency. Furthermore, these mice show glutamatergic synaptic dysfunctions, including a reduced glutamate receptor expression, altered properties of NMDA receptor-mediated synaptic responses, a decreased saturation level of long-term potentiation of excitatory synaptic transmission, and distinct morphological characteristics of the thick-type spines. Therefore, these results suggest that ZBTB18/RP58 haploinsufficiency leads to impaired excitatory synaptic maturation, which in turn results in cognitive dysfunction in ZBTB18 haploinsufficiency.


Assuntos
Disfunção Cognitiva , Deficiência Intelectual , Humanos , Camundongos , Animais , Deficiência Intelectual/genética , Haploinsuficiência/genética , Corpo Caloso , Transmissão Sináptica/genética , Síndrome , Disfunção Cognitiva/genética
3.
Surg Today ; 51(3): 439-446, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32876734

RESUMO

PURPOSE: Tissue disaggregation and the cell sorting technique by surface markers has played an important role in isolating lymphatic endothelial cells (LECs) from lymphatic malformation (LM). However, this technique may have the drawback of impurities or result in isolation failure because it is dependent on surface marker expressions, the heterogeneity of which has been found in the lymphatic system. We developed a novel method for isolating LM-LECs without using whole tissue disaggregation. METHODS: Seven LM surgical specimens were collected from seven patients with LMs. LM-LECs were detached from the LM cyst wall by "lumen digestion" and irrigating the cystic cavity with trypsin, and maintained in culture. RESULTS: The cells formed a monolayer with a cobblestone-like appearance. Immunohistochemistry and quantitative RT-PCR of these cells revealed high expression of lymphatic-specific genes, confirming their identity as LM-LECs. The whole-exome sequencing and PIK3CA sequencing of these cells revealed somatic mutations in PIK3CA in all cases. CONCLUSIONS: We established a novel technique for isolating LM-LECs from LM tissue by "lumen digestion" without whole-tissue disaggregation. The limited incorporation of non-LM LECs in the isolate in our method could make it an important tool for investigating the heterogeneity of gene expression as well as mutations in LM-LECs.


Assuntos
Separação Celular/métodos , Classe I de Fosfatidilinositol 3-Quinases/genética , Células Endoteliais , Anormalidades Linfáticas/genética , Anormalidades Linfáticas/patologia , Sistema Linfático/citologia , Sistema Linfático/patologia , Mutação , Adolescente , Criança , Feminino , Expressão Gênica/genética , Heterogeneidade Genética , Humanos , Lactente , Masculino
4.
Pharm Res ; 37(3): 61, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32124083

RESUMO

PURPOSE: Cyclocreatine, a creatine analog, is a candidate drug for treating patients with cerebral creatine deficiency syndromes (CCDSs) caused by creatine transporter (CRT, SLC6A8) deficiency, which reduces brain creatine level. The purpose of this study was to clarify the characteristics of cyclocreatine transport in HEK293 cells, which highly express endogenous CRT, in hCMEC/D3 cells, a human blood-brain barrier (BBB) model, and in CCDSs patient-derived fibroblasts with CRT mutations. METHODS: Cells were incubated at 37°C with [14C]cyclocreatine (9 µM) and [14C]creatine (9 µM) for specified periods of times in the presence or absence of inhibitors, while the siRNAs were transfected by lipofection. Protein expression and mRNA expression were quantified using targeted proteomics and quantitative PCR, respectively. RESULTS: [14C]Cyclocreatine was taken up by HEK293 cells in a time-dependent manner, while exhibiting saturable kinetics. The inhibition and siRNA knockdown studies demonstrated that the uptake of [14C]cyclocreatine by both HEK293 and hCMEC/D3 cells was mediated predominantly by CRT as well as [14C]creatine. In addition, uptake of [14C]cyclocreatine and [14C]creatine by the CCDSs patient-derived fibroblasts was found to be largely reduced. CONCLUSION: The present study suggests that cyclocreatine is a CRT substrate, where CRT is the predominant contributor to influx of cyclocreatine into the brain at the BBB. Our findings provide vital insights for the purposes of treating CCDSs patients using cyclocreatine.


Assuntos
Barreira Hematoencefálica/metabolismo , Creatina/deficiência , Creatinina/análogos & derivados , Fibroblastos/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Transporte Biológico , Barreira Hematoencefálica/citologia , Linhagem Celular , Células Cultivadas , Creatina/metabolismo , Creatinina/metabolismo , Creatinina/farmacocinética , Células HEK293 , Humanos
5.
Tohoku J Exp Med ; 236(3): 225-32, 2015 07.
Artigo em Inglês | MEDLINE | ID: mdl-26118651

RESUMO

Mitochondria are key organelles implicated in a variety of processes related to energy and free radical generation, the regulation of apoptosis, and various signaling pathways. Mitochondrial dysfunction increases cellular oxidative stress and depletes ATP in a variety of inherited mitochondrial diseases and also in many other metabolic and neurodegenerative diseases. Mitochondrial diseases are characterized by the dysfunction of the mitochondrial respiratory chain, caused by mutations in the genes encoded by either nuclear DNA or mitochondrial DNA. We have hypothesized that chemicals that increase the cellular ATP levels may ameliorate the mitochondrial dysfunction seen in mitochondrial diseases. To search for the potential drugs for mitochondrial diseases, we screened an in-house chemical library of indole-3-acetic-acid analogs by measuring the cellular ATP levels in Hep3B human hepatocellular carcinoma cells. We have thus identified mitochonic acid 5 (MA-5), 4-(2,4-difluorophenyl)-2-(1H-indol-3-yl)-4-oxobutanoic acid, as a potential drug for enhancing ATP production. MA-5 is a newly synthesized derivative of the plant hormone, indole-3-acetic acid. Importantly, MA-5 improved the survival of fibroblasts established from patients with mitochondrial diseases under the stress-induced condition, including Leigh syndrome, MELAS (myopathy encephalopathy lactic acidosis and stroke-like episodes), Leber's hereditary optic neuropathy, and Kearns-Sayre syndrome. The improved survival was associated with the increased cellular ATP levels. Moreover, MA-5 increased the survival of mitochondrial disease fibroblasts even under the inhibition of the oxidative phosphorylation or the electron transport chain. These data suggest that MA-5 could be a therapeutic drug for mitochondrial diseases that exerts its effect in a manner different from anti-oxidant therapy.


Assuntos
Trifosfato de Adenosina/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Descoberta de Drogas , Fibroblastos/efeitos dos fármacos , Ácidos Indolacéticos/química , Ácidos Indolacéticos/farmacologia , Doenças Mitocondriais/tratamento farmacológico , Fenilbutiratos/farmacologia , Análise de Variância , Linhagem Celular Tumoral , Sobrevivência Celular/fisiologia , Fibroblastos/fisiologia , Humanos , Fosforilação Oxidativa , Fenilbutiratos/química , Bibliotecas de Moléculas Pequenas
6.
J Hum Genet ; 59(7): 408-10, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24898829

RESUMO

In clinical practice, it is important to diagnose the carrier state of female patients with X-linked diseases for genetic counseling to calculate the recurrent risk of offspring. Because some X-linked diseases show high rates of gonadal mosaicism, this diagnosis is sometimes difficult, when there are few offspring in a family and no mutation is detected in the maternal genomic DNA. Here, we report two male siblings with ATR-X syndrome carrying an intragenic deletion of 78.6 kb involving exons 2-5 out of the 35 exons in the ATRX, as revealed by PCR amplification of these exons. The mother was expected to be an obligate carrier, but we could not confirm her as a mutation carrier by quantitative PCR (qPCR) for the exons. However, we identified the breakpoint of ATRX, and qPCR with breakpoint-specific primers revealed gonosomal mosaicism, with a relative frequency of the mutation of <1% in genomic DNA of her peripheral blood. For these obligate carriers of X-linked disease, we should aggressively investigate the maternal genomic status, not only because her genetic condition is important for estimating the recurrent risk of her offspring but also because a diagnosis of her gonosomal mosaicism can render negligible the possibility that her female siblings are carriers. We should reconfirm that a female who has a risk of being a carrier has a gonosomal or somatic mutation, even if she is an obligate carrier or apparently harbors a mutation.


Assuntos
DNA Helicases/genética , Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico , Deficiência Intelectual Ligada ao Cromossomo X/genética , Mosaicismo , Proteínas Nucleares/genética , Deleção de Sequência , Talassemia alfa/diagnóstico , Talassemia alfa/genética , Alelos , Criança , Pré-Escolar , Pontos de Quebra do Cromossomo , Análise Mutacional de DNA , Éxons , Frequência do Gene , Genótipo , Humanos , Masculino , Linhagem , Fenótipo , Irmãos , Translocação Genética , Proteína Nuclear Ligada ao X
8.
J Psychiatr Res ; 163: 74-79, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37207434

RESUMO

Schizophrenia (SZ) and bipolar disorder (BD), which are both psychiatric disorders, share some common clinical evidence. We recently discovered that brain capillary angiopathy is another common feature of these psychiatric disorders using fibrin accumulation in vascular endothelial cells as an indicator. This study aimed to characterize the similarities and differences in cerebral capillary injuries in various brain diseases to provide new diagnostic methods for SZ and BD and to develop new therapeutic strategies. We evaluated whether discrepancies exist in the degree of vascular damage among SZ and BD and other brain disorders (amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD)) using postmortem brains. Our results demonstrate that fibrin was strongly accumulated in the capillaries of the grey matter (GM) of brains of patients with SZ and AD and in the capillaries of the white matter (WM) in those of patients with SZ, BD, and AD when compared with control subjects without any psychiatric or neurological disease history. However, ALS and PD brains did not present a significant increase in the amount of accumulated fibrin, either in the capillaries of WM or GM. Furthermore, significant leakage of fibrin into the brain parenchyma, indicating a vascular physical disruption, was observed in the brains of patients with AD but not in the brains of other patients compared with control subjects. In conclusion, our work reveals that Fibrin-accumulation in the brain capillaries are observed in psychiatric disorders, such as SZ, BD, and AD. Furthermore, fibrin-accumulating, nonbreaking type angiopathy is characteristic of SZ and BD, even though there are regional differences between these diseases.


Assuntos
Doença de Alzheimer , Esclerose Lateral Amiotrófica , Transtorno Bipolar , Lesões Encefálicas Traumáticas , Esquizofrenia , Humanos , Transtorno Bipolar/complicações , Esquizofrenia/complicações , Doença de Alzheimer/complicações , Capilares , Células Endoteliais , Encéfalo
9.
Mol Genet Metab ; 106(1): 43-7, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22472424

RESUMO

We report here a 6-year-old boy exhibiting severe dystonia, profound intellectual and developmental disability with liver disease, and sensorineural deafness. A deficient creatine peak in brain (1)H-MR spectroscopy and high ratio of creatine/creatinine concentration in his urine lead us to suspect a creatine transporter (solute carrier family 6, member 8; SLC6A8) deficiency, which was confirmed by the inability to take up creatine into fibroblasts. We found a large ~19 kb deletion encompassing exons 5-13 of SLC6A8 and exons 5-8 of the B-cell receptor-associated protein (BAP31) gene. This case is the first report in which the SLC6A8 and BAP31 genes are both deleted. The phenotype of BAP31 mutations has been reported only as a part of Xq28 deletion syndrome or contiguous ATP-binding cassette, sub-family D, member 1 (ABCD1)/DXS1375E (BAP31) deletion syndrome [MIM ID #300475], where liver dysfunction and sensorineural deafness have been suggested to be attributed to the loss of function of BAP31. Our case supports the idea that the loss of BAP31 is related to liver dysfunction and hearing loss.


Assuntos
Distonia , Deleção de Genes , Perda Auditiva Neurossensorial , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Criança , Creatina/urina , Creatinina/urina , Distonia/genética , Distonia/metabolismo , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/metabolismo , Humanos , Fígado/metabolismo , Fígado/patologia , Masculino
10.
Amino Acids ; 43(2): 993-7, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22080216

RESUMO

Cerebral creatine deficiency syndromes (CCDS) are caused by genetic defects in L-arginine:glycine amidinotransferase, guanidinoacetate methyltransferase or creatine transporter 1. CCDS are characterized by abnormal concentrations of urinary creatine (CR), guanidinoacetic acid (GA), or creatinine (CN). In this study, we describe a simple HPLC method to determine the concentrations of CR, GA, and CN using a weak-acid ion chromatography column with a UV detector without any derivatization. CR, GA, and CN were separated clearly with the retention times (mean ± SD, n = 3) of 5.54 ± 0.0035 min for CR, 6.41 ± 0.0079 min for GA, and 13.53 ± 0.046 min for CN. This new method should provide a simple screening test for the diagnosis of CCDS.


Assuntos
Encefalopatias Metabólicas Congênitas/diagnóstico , Encefalopatias Metabólicas Congênitas/urina , Creatina/urina , Creatinina/urina , Glicina/análogos & derivados , Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico , Deficiência Intelectual Ligada ao Cromossomo X/urina , Cromatografia Líquida de Alta Pressão , Cromatografia por Troca Iônica , Creatina/deficiência , Creatina/isolamento & purificação , Creatinina/isolamento & purificação , Glicina/isolamento & purificação , Glicina/urina , Humanos , Masculino , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiência , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/urina , Transferases/deficiência
11.
J Med Genet ; 48(9): 606-9, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21415082

RESUMO

BACKGROUND: Conventional PCR-based direct sequencing of candidate genes for a family with X-linked leucoencephalopathy with unknown aetiology failed to identify any causative mutations. OBJECTIVE: To carry out exome sequencing of entire transcripts of the whole X chromosome to investigate a family with X linked leucoencephalopathy. METHODS AND RESULTS: Next-generation sequencing of all the transcripts of the X chromosome, after liquid-based genome partitioning, was performed on one of the two affected male subjects (the proband) and an unaffected male subject (his brother). A nonsense mutation in MCT8 (c.1102A→T (p.R368X)) was identified in the proband. Subsequent PCR-based direct sequencing of other family members confirmed the presence of this mutation, hemizygous in the other affected brother and heterozygous in the proband's mother and maternal grandmother. MCT8 mutations usually cause abnormal thyroid function in addition to neurological abnormalities, but this proband had normal thyroid function. CONCLUSION: Single-lane exome next-generation sequencing is sufficient to fully analyse all the transcripts of the X chromosome. This method is particularly suitable for mutation screening of X-linked recessive disorders and can avoid biases in candidate gene choice.


Assuntos
Exoma , Doenças Genéticas Ligadas ao Cromossomo X/genética , Leucoencefalopatias/genética , Transportadores de Ácidos Monocarboxílicos/genética , Mutação , Adolescente , Povo Asiático , Sequência de Bases , Cromossomos Humanos X/genética , Genótipo , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Simportadores
12.
Hum Genome Var ; 9(1): 33, 2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36104326

RESUMO

The ATRX variant c.21-1G>A was detected by an exome analysis of a patient with Cockayne syndrome without alpha thalassemia X-linked intellectual disability syndrome (ATR-XS). In addition, variants in ERCC6 were detected. ATRX c.21-1G>A is localized at the splicing acceptor site of intron 1. This splicing event, NM_000489.6: c.21_133del p.S7Rfs*1, induces exon 2 deletion and early termination. The start codon in exon 3 of ATRX is presumed to produce a slightly shorter but functional ATRX protein.

13.
Ann Neurol ; 68(2): 250-4, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20695017

RESUMO

Mutations in the gap junction protein gamma-2 gene, GJC2, cause a central hypomyelinating disorder; Pelizaeus-Merzbacher-like disease (PMLD; MIM311601). Using a homozygosity mapping and positional candidate gene approach, we identified a homozygous mutation (c.-167A>G) within the GJC2 promoter at a potent SOX10 binding site in a patient with mild PMLD. Functionally, this mutation completely abolished the SOX10 binding and attenuated GJC2 promoter activity. These findings suggest not only that the SOX10-to-GJC2 transcriptional dysregulation is a cause of PMLD, but also that GJC2 may be in part responsible for the central hypomyelination caused by SOX10 mutations.


Assuntos
Conexinas/genética , Conexinas/metabolismo , Doença de Pelizaeus-Merzbacher/genética , Doença de Pelizaeus-Merzbacher/metabolismo , Fatores de Transcrição SOXE/fisiologia , Transcrição Gênica , Adulto , Feminino , Humanos , Mutação , Bainha de Mielina/genética , Bainha de Mielina/metabolismo , Doença de Pelizaeus-Merzbacher/patologia , Elementos Reguladores de Transcrição/genética , Fatores de Transcrição SOXE/genética , Transcrição Gênica/genética
14.
Sci Adv ; 7(46): eabl6077, 2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34757783

RESUMO

Metabolic dysfunction is thought to contribute to the severity of psychiatric disorders; however, it has been unclear whether current high­simple sugar diets contribute to pathogenesis of these diseases. Here, we demonstrate that a high-sucrose diet during adolescence induces psychosis-related behavioral endophenotypes, including hyperactivity, poor working memory, impaired sensory gating, and disrupted interneuron function in mice deficient for glyoxalase-1 (GLO1), an enzyme involved in detoxification of sucrose metabolites. Furthermore, the high-sucrose diet induced microcapillary impairments and reduced brain glucose uptake in brains of Glo1-deficient mice. Aspirin protected against this angiopathy, enhancing brain glucose uptake and preventing abnormal behavioral phenotypes. Similar vascular damage to our model mice was found in the brains of randomly collected schizophrenia and bipolar disorder patients, suggesting that psychiatric disorders are associated with angiopathy in the brain caused by various environmental stresses, including metabolic stress.

15.
Pediatr Neurol ; 113: 33-41, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32980745

RESUMO

BACKGROUND: We aimed to demonstrate the biochemical characteristics of vitamin B6-dependent epilepsy, with a particular focus on pyridoxal 5'-phosphate and pyridoxal in the cerebrospinal fluid. METHODS: Using our laboratory database, we identified patients with vitamin B6-dependent epilepsy and extracted their data on the concentrations of pyridoxal 5'-phosphate, pyridoxal, pipecolic acid, α-aminoadipic semialdehyde, and monoamine neurotransmitters. We compared the biochemical characteristics of these patients with those of other epilepsy patients with low pyridoxal 5'-phosphate concentrations. RESULTS: We identified seven patients with pyridoxine-dependent epilepsy caused by an ALDH7A1 gene abnormality, two patients with pyridoxal 5'-phosphate homeostasis protein deficiency, and 28 patients with other epilepsies with low cerebrospinal fluid pyridoxal 5'-phosphate concentrations. Cerebrospinal fluid pyridoxal and pyridoxal 5'-phosphate concentrations were low in patients with vitamin B6-dependent epilepsy but cerebrospinal fluid pyridoxal concentrations were not reduced in most patients with other epilepsies with low cerebrospinal fluid pyridoxal 5'-phosphate concentrations. Increase in 3-O-methyldopa and 5-hydroxytryptophan was demonstrated in some patients with vitamin B6-dependent epilepsy, suggestive of pyridoxal 5'-phosphate deficiency in the brain. CONCLUSIONS: Low cerebrospinal fluid pyridoxal concentrations may be a better indicator of pyridoxal 5'-phosphate deficiency in the brain in vitamin B6-dependent epilepsy than low cerebrospinal fluid pyridoxal 5'-phosphate concentrations. This finding is especially helpful in individuals with suspected pyridoxal 5'-phosphate homeostasis protein deficiency, which does not have known biomarkers.


Assuntos
Epilepsia/metabolismo , Fosfato de Piridoxal/líquido cefalorraquidiano , Piridoxal/líquido cefalorraquidiano , 5-Hidroxitriptofano/metabolismo , Adolescente , Criança , Pré-Escolar , Epilepsia/diagnóstico , Epilepsia/etiologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Ácidos Pipecólicos/metabolismo , Estudos Retrospectivos , Tirosina/análogos & derivados , Tirosina/metabolismo , Vitamina B 6 , Adulto Jovem
16.
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
17.
Brain Dev ; 41(2): 195-200, 2019 Feb.
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.


Assuntos
Doença de Alexander/genética , Doença de Alexander/patologia , Encéfalo/patologia , Proteína Glial Fibrilar Ácida/genética , Doença de Alexander/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Criança , Feminino , Humanos , Mutação
18.
Congenit Anom (Kyoto) ; 58(1): 33-35, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28220539

RESUMO

Saethre-Chotzen syndrome (SCS) is an autosomal dominant craniosynostotic disorder characterized by coronal synostosis, facial asymmetry, ptosis, and limb abnormalities. Haploinsufficiency of TWIST1, a basic helix-loop-helix transcription factor is responsible for SCS. Here, we report a 15-month-old male patient with typical clinical features of SCS in addition to developmental delay, which is a rare complication in SCS. He showed a de novo 0.9-Mb microdeletion in 7p21, in which TWIST1, NPMIP13, FERD3L, TWISTNB, and HDAC9 were included. In comparison with previously reported patients, HDAC9 was suggested to contribute to developmental delay in SCS patients with 7p21 mirodeletions.


Assuntos
Acrocefalossindactilia/genética , Deleção Cromossômica , Cromossomos Humanos Par 7 , Deficiências do Desenvolvimento/genética , Transtornos do Neurodesenvolvimento/genética , Proteínas Nucleares/genética , Proteína 1 Relacionada a Twist/genética , Acrocefalossindactilia/diagnóstico por imagem , Acrocefalossindactilia/patologia , Tomografia Computadorizada de Feixe Cônico , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/patologia , Genes Dominantes , Haploinsuficiência , Histona Desacetilases/deficiência , Histona Desacetilases/genética , Humanos , Lactente , Masculino , Fatores de Regulação Miogênica/genética , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Transtornos do Neurodesenvolvimento/patologia , Proteínas Nucleares/deficiência , Proteínas/genética , Proteínas/metabolismo , Proteínas Repressoras/deficiência , Proteínas Repressoras/genética , Proteína 1 Relacionada a Twist/deficiência
19.
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.

20.
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.

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