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1.
J Psychiatr Res ; 163: 74-79, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37207434

RESUMEN

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.


Asunto(s)
Enfermedad de Alzheimer , Esclerosis Amiotrófica Lateral , Trastorno Bipolar , Lesiones Traumáticas del Encéfalo , Esquizofrenia , Humanos , Trastorno Bipolar/complicaciones , Esquizofrenia/complicaciones , Enfermedad de Alzheimer/complicaciones , Capilares , Células Endoteliales , Encéfalo
2.
Mol Psychiatry ; 28(6): 2370-2381, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36721027

RESUMEN

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.


Asunto(s)
Disfunción Cognitiva , Discapacidad Intelectual , Humanos , Ratones , Animales , Discapacidad Intelectual/genética , Haploinsuficiencia/genética , Cuerpo Calloso , Transmisión Sináptica/genética , Síndrome , Disfunción Cognitiva/genética
3.
Hum Genome Var ; 9(1): 33, 2022 Sep 14.
Artículo en Inglés | MEDLINE | ID: mdl-36104326

RESUMEN

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.

4.
Sci Adv ; 7(46): eabl6077, 2021 Nov 12.
Artículo en Inglés | MEDLINE | ID: mdl-34757783

RESUMEN

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.

5.
Surg Today ; 51(3): 439-446, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32876734

RESUMEN

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.


Asunto(s)
Separación Celular/métodos , Fosfatidilinositol 3-Quinasa Clase I/genética , Células Endoteliales , Anomalías Linfáticas/genética , Anomalías Linfáticas/patología , Sistema Linfático/citología , Sistema Linfático/patología , Mutación , Adolescente , Niño , Femenino , Expresión Génica/genética , Heterogeneidad Genética , Humanos , Lactante , Masculino
6.
Pediatr Neurol ; 113: 33-41, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32980745

RESUMEN

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.


Asunto(s)
Epilepsia/metabolismo , Fosfato de Piridoxal/líquido cefalorraquídeo , Piridoxal/líquido cefalorraquídeo , 5-Hidroxitriptófano/metabolismo , Adolescente , Niño , Preescolar , Epilepsia/diagnóstico , Epilepsia/etiología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Ácidos Pipecólicos/metabolismo , Estudios Retrospectivos , Tirosina/análogos & derivados , Tirosina/metabolismo , Vitamina B 6 , Adulto Joven
7.
Pharm Res ; 37(3): 61, 2020 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-32124083

RESUMEN

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.


Asunto(s)
Barrera Hematoencefálica/metabolismo , Creatina/deficiencia , Creatinina/análogos & derivados , Fibroblastos/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Transporte Biológico , Barrera Hematoencefálica/citología , Línea Celular , Células Cultivadas , Creatina/metabolismo , Creatinina/metabolismo , Creatinina/farmacocinética , Células HEK293 , Humanos
9.
Brain Dev ; 41(5): 465-469, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30739820

RESUMEN

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.


Asunto(s)
Síndrome MELAS/diagnóstico , Síndrome MELAS/genética , Síndrome MELAS/fisiopatología , ARN Mitocondrial/genética , ARN de Transferencia de Metionina/genética , Niño , Femenino , Humanos
10.
Brain Dev ; 41(2): 195-200, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-30213442

RESUMEN

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.


Asunto(s)
Enfermedad de Alexander/genética , Enfermedad de Alexander/patología , Encéfalo/patología , Proteína Ácida Fibrilar de la Glía/genética , Enfermedad de Alexander/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Niño , Femenino , Humanos , Mutación
11.
Hum Genome Var ; 5: 25, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30210801

RESUMEN

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.

12.
Hum Genome Var ; 5: 18013, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29619238

RESUMEN

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.

13.
Brain Dev ; 40(2): 145-149, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-28916229

RESUMEN

BACKGROUND: Leigh syndrome is a mitochondrial disease caused by respiratory chain deficiency, and there are no proven effective therapies. EPI-743 is a potent cellular oxidative stress protectant and results of clinical trials for mitochondrial diseases are accumulating. CASE: At 5months, a girl presented with the scarce eye movement and diminished muscle tone. She was diagnosed with Leigh encephalopathy from blood and cerebrospinal fluid lactate elevation and MRI findings. Sequence analysis for mitochondrial DNA revealed a T10158C mutation in the mitochondrial encoded ND3 gene in complex I. RESULTS: At 8months, succinate was prescribed expected to restore the electron transport chain system. After that her condition got worse and succinate was discontinued. Subsequent administration of EPI-743 improved her eye movement, fine motor movements of the extremities, and bowel movement. She is now 5years old. Although brain atrophy has progressed, she has still respiratory free time. CONCLUSION: Our patient showed visible improvement with EPI-743 treatment and the only patient surviving after 4years. There is a possibility that EPI-743 is modifying the natural course of the syndrome.


Asunto(s)
Antioxidantes/uso terapéutico , Enfermedad de Leigh/tratamiento farmacológico , Ubiquinona/análogos & derivados , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Preescolar , Progresión de la Enfermedad , Complejo I de Transporte de Electrón/genética , Femenino , Humanos , Ácido Láctico/sangre , Enfermedad de Leigh/diagnóstico por imagen , Enfermedad de Leigh/genética , Enfermedad de Leigh/fisiopatología , Respiración Artificial , Ubiquinona/uso terapéutico
14.
Congenit Anom (Kyoto) ; 58(1): 33-35, 2018 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-28220539

RESUMEN

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.


Asunto(s)
Acrocefalosindactilia/genética , Deleción Cromosómica , Cromosomas Humanos Par 7 , Discapacidades del Desarrollo/genética , Trastornos del Neurodesarrollo/genética , Proteínas Nucleares/genética , Proteína 1 Relacionada con Twist/genética , Acrocefalosindactilia/diagnóstico por imagen , Acrocefalosindactilia/patología , Tomografía Computarizada de Haz Cónico , Discapacidades del Desarrollo/diagnóstico por imagen , Discapacidades del Desarrollo/patología , Genes Dominantes , Haploinsuficiencia , Histona Desacetilasas/deficiencia , Histona Desacetilasas/genética , Humanos , Lactante , Masculino , Factores Reguladores Miogénicos/genética , Trastornos del Neurodesarrollo/diagnóstico por imagen , Trastornos del Neurodesarrollo/patología , Proteínas Nucleares/deficiencia , Proteínas/genética , Proteínas/metabolismo , Proteínas Represoras/deficiencia , Proteínas Represoras/genética , Proteína 1 Relacionada con Twist/deficiencia
15.
Mol Genet Genomic Med ; 5(4): 429-437, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28717667

RESUMEN

BACKGROUND: Chromosome 2p15p16.1 deletion syndrome is a rare genetic disorder characterized by intellectual disability (ID), neurodevelopmental delay, language delay, growth retardation, microcephaly, structural brain abnormalities, and dysmorphic features. More than 30 patients with 2p15p16.1 microdeletion syndrome have been reported in the literature. METHODS: Molecular analysis was performed using microarray-based comparative genomic hybridization (array CGH). Clinical characteristics and brain magnetic resonance imaging features of these patients were also reviewed. RESULTS: We identified four patients with ID, neurodevelopmental delay, brain malformations, and dysmorphic features; two patients with 2p15p16.1 deletions (3.24 Mb, 5.04 Mb), one patient with 2p16.1 deletion (1.12 Mb), and one patient with 2p14p16.1 deletion (5.12 Mb). Three patients with 2p15p16.1 deletions or 2p16.1 deletions encompassing BCL11A,PAPOLG, and REL showed hypoplasia of the pons and cerebellum. The patient with 2p14p16.1 deletion, which did not include three genes showed normal size and shape of the cerebellar hemispheres and pons. CONCLUSION: The zinc finger transcription factor BCL11A associated with the BAF chromatin remodeling complex has been identified to be critical for neural development and BCL11A haploinsufficiency is closely related to cerebellar abnormalities.

16.
EBioMedicine ; 20: 27-38, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28579242

RESUMEN

Mitochondrial dysfunction increases oxidative stress and depletes ATP in a variety of disorders. Several antioxidant therapies and drugs affecting mitochondrial biogenesis are undergoing investigation, although not all of them have demonstrated favorable effects in the clinic. We recently reported a therapeutic mitochondrial drug mitochonic acid MA-5 (Tohoku J. Exp. Med., 2015). MA-5 increased ATP, rescued mitochondrial disease fibroblasts and prolonged the life span of the disease model "Mitomouse" (JASN, 2016). To investigate the potential of MA-5 on various mitochondrial diseases, we collected 25 cases of fibroblasts from various genetic mutations and cell protective effect of MA-5 and the ATP producing mechanism was examined. 24 out of the 25 patient fibroblasts (96%) were responded to MA-5. Under oxidative stress condition, the GDF-15 was increased and this increase was significantly abrogated by MA-5. The serum GDF-15 elevated in Mitomouse was likewise reduced by MA-5. MA-5 facilitates mitochondrial ATP production and reduces ROS independent of ETC by facilitating ATP synthase oligomerization and supercomplex formation with mitofilin/Mic60. MA-5 reduced mitochondria fragmentation, restores crista shape and dynamics. MA-5 has potential as a drug for the treatment of various mitochondrial diseases. The diagnostic use of GDF-15 will be also useful in a forthcoming MA-5 clinical trial.


Asunto(s)
Ácidos Indolacéticos/farmacología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Enfermedades Mitocondriales/metabolismo , ATPasas de Translocación de Protón Mitocondriales/metabolismo , Fenilbutiratos/farmacología , Multimerización de Proteína/efectos de los fármacos , Adenosina Trifosfato/metabolismo , Animales , Biomarcadores , Línea Celular , Supervivencia Celular/efectos de los fármacos , ADN Mitocondrial , Modelos Animales de Enfermedad , Factores de Crecimiento de Fibroblastos/metabolismo , Fibroblastos/metabolismo , Factor 15 de Diferenciación de Crecimiento/metabolismo , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Mitocondrias/genética , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/tratamiento farmacológico , Enfermedades Mitocondriales/genética , Dinámicas Mitocondriales/efectos de los fármacos , ATPasas de Translocación de Protón Mitocondriales/química , Complejos Multiproteicos/metabolismo , Mutación , Biogénesis de Organelos , Pronóstico , Sustancias Protectoras , Unión Proteica
17.
Brain Dev ; 38(9): 871-4, 2016 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27056292

RESUMEN

BACKGROUND: Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder that affects the degradation of gamma-aminobutyric acid and leads to the accumulation of gamma-hydroxybutyric acid (GHB) in body fluids. Diagnosis of SSADH deficiency is challenging, since the neurological symptoms are non-specific. CASE: The patient is a nine-year-old Japanese boy who presented with developmental delay, autism, epilepsy, and episodic gait disturbance. Brain magnetic resonance imaging showed hyperintense lesions in the bilateral thalami, globus pallidi, substantia nigra, and dentate nuclei. Urine metabolome analysis revealed elevated GHB, which led to a biochemical diagnosis of SSADH deficiency. Genetic analysis of the ALDH5A1 gene revealed a novel missense mutation c.1586G>A inherited from his father. It also demonstrated three single nucleotide polymorphisms (SNPs) (c.106G>C, c.538C>T, and c.545C>T), all of which were inherited from his mother and are known to reduce SSADH enzyme activity. There were no duplications or deletions in other exons in the patient or his parents. No variants in the upstream, intronic, or downstream regions of the ALDH5A1 gene were found in the patient. Enzymatic assay revealed a marked reduction of SSADH enzyme activity (≈2% of the lower limit of the normal range). CONCLUSION: Although other mechanisms cannot be fully excluded, the clinical manifestation of SSADH deficiency in this patient may be attributed to the combined effect of the mutation and the three enzyme activity-reducing SNPs. Urine metabolome analysis effectively detected his elevated GHB and is thus considered to be a good screening method for this underdiagnosed and potentially manageable metabolic disorder.


Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/genética , Discapacidades del Desarrollo/genética , Polimorfismo de Nucleótido Simple , Succionato-Semialdehído Deshidrogenasa/deficiencia , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Pueblo Asiatico/genética , Discapacidades del Desarrollo/diagnóstico , Diagnóstico Diferencial , Técnicas de Genotipaje , Humanos , Japón , Masculino , Mutación Missense , Succionato-Semialdehído Deshidrogenasa/genética
18.
Brain Dev ; 38(6): 581-4, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26725305

RESUMEN

A patient with an unusually mild form of Pelizaeus-Merzbacher disease was studied. Clinically, mild developmental delay with acquisition of assisted walking at 16months and mild spastic tetraplegia were evident, but no nystagmus, cerebellar, or extra-pyramidal signs were present. PLP1 mutation analysis revealed a nucleotide substitution adjacent to the acceptor site of intron 3, NM_000533.4:c.454-9T>G. Expression analysis using the patient's leukocytes demonstrated an additional abnormal transcript including the last 118bp of intron 3. In silico prediction analysis suggested the reduction of wild-type acceptor activity, which presumably evokes the cryptic splicing variant. Putative cryptic transcript results in premature termination, which may explain the mild clinical phenotype observed in this patient.


Asunto(s)
Mutación , Proteína Proteolipídica de la Mielina/genética , Enfermedad de Pelizaeus-Merzbacher/genética , Encéfalo/diagnóstico por imagen , Niño , Análisis Mutacional de ADN , Humanos , Intrones , Leucocitos/metabolismo , Imagen por Resonancia Magnética , Masculino , Proteína Proteolipídica de la Mielina/metabolismo , Enfermedad de Pelizaeus-Merzbacher/diagnóstico por imagen , Enfermedad de Pelizaeus-Merzbacher/metabolismo , Fenotipo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Índice de Severidad de la Enfermedad
19.
Tohoku J Exp Med ; 236(3): 225-32, 2015 07.
Artículo en Inglés | MEDLINE | ID: mdl-26118651

RESUMEN

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.


Asunto(s)
Adenosina Trifosfato/metabolismo , Supervivencia Celular/efectos de los fármacos , Descubrimiento de Drogas , Fibroblastos/efectos de los fármacos , Ácidos Indolacéticos/química , Ácidos Indolacéticos/farmacología , Enfermedades Mitocondriales/tratamiento farmacológico , Fenilbutiratos/farmacología , Análisis de Varianza , Línea Celular Tumoral , Supervivencia Celular/fisiología , Fibroblastos/fisiología , Humanos , Fosforilación Oxidativa , Fenilbutiratos/química , Bibliotecas de Moléculas Pequeñas
20.
Brain Dev ; 37(4): 442-5, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25123644

RESUMEN

Pyridoxine-dependent epilepsy (PDE) is an autosomal recessive disorder characterized by early onset and recurrent seizures that can be controlled by a high dose of pyridoxine. PDE is caused by mutations in ALDH7A1, which encodes antiquitin. Antiquitin converts α-aminoadipic semialdehyde to α-aminoadipic acid. Seizure recurrence after pyridoxine withdrawal is a criterion for diagnosis, but PDE can be diagnosed conclusively by genetic testing for mutations in the ALDH7A1 gene. In this case study, we report the long-term follow-up of a patient suspected with PDE. She experienced prolonged generalized tonic seizures and was hospitalized in an intensive care unit following pyridoxine withdrawal. Later, we identified a compound heterozygous mutation, c.1216G>A, p.Gly406Arg, and a novel splice donor site mutation, IVS9+5G>A. Confirmation of these mutations would have prevented an unsafe withdrawal test. This case suggests the importance of the genetic determination of PDE to avoid the diagnostic withdrawal of pyridoxine.


Asunto(s)
Anticonvulsivantes/administración & dosificación , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Piridoxina/administración & dosificación , Convulsiones/tratamiento farmacológico , Convulsiones/genética , Aldehído Deshidrogenasa/genética , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Análisis Mutacional de ADN , Diagnóstico Diferencial , Electroencefalografía , Epilepsia/diagnóstico , Epilepsia/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Mutación , Convulsiones/diagnóstico , Convulsiones/fisiopatología , Síndrome de Abstinencia a Sustancias , Adulto Joven
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