RESUMO
OBJECTIVES: To investigate the prevalence and background of children with medical complexity (CMC) and its secular trend in Japan. METHODS: CMC were defined as patients under the age of 20 years requiring medical care and devices. The patients were enrolled using the national health insurance claims data of three hospitals and two rehabilitation centers in Tottori Prefecture. The study period was divided into three periods: Period 1, 2007-2010; Period 2, 2011-2014; and Period 3, 2015-2018. RESULTS: A total of 378 CMC were enrolled. The prevalence of CMC was 1.88 per 1000 population among subjects aged <20 years in 2018, and it increased by approximately 1.9 times during the study period. The number of CMC who presented with severe motor and intellectual disabilities did not change from Period 1 to Period 3. Meanwhile, the number of CMC who had relatively preserved motor and intellectual abilities increased from 58 to 98. The proportion of CMC who required respiratory management and oxygen therapy increased by 1.3 and 1.8 times, respectively. By contrast, the proportion of CMC who need tube feeding decreased significantly between periods 1 and 3 (P < 0.05). CONCLUSIONS: The prevalence of CMC increased almost twice during the 12-year study period; however, the increase in the number of patients with relatively preserved motor and intellectual abilities was pronounced. This study showed that the need for medical care and devices differed based on the underlying disorders and severity of CMC; therefore, individualized medical, welfare, and administrative services and education about the various types of CMC must be provided.
Assuntos
Atenção à Saúde/tendências , Crianças com Deficiência/estatística & dados numéricos , Pessoas com Deficiência Mental/estatística & dados numéricos , Adolescente , Criança , Pré-Escolar , Atenção à Saúde/economia , Atenção à Saúde/métodos , Equipamentos e Provisões/provisão & distribuição , Feminino , Humanos , Japão/epidemiologia , Estudos Longitudinais , Masculino , Prevalência , Adulto JovemRESUMO
OBJECTIVE: To elucidate the genetic background and genotype-phenotype correlations for epilepsy with myoclonic-atonic seizures, also known as myoclonic-astatic epilepsy (MAE) or Doose syndrome. METHODS: We collected clinical information and blood samples from 29 patients with MAE. We performed whole-exome sequencing for all except one MAE case in whom custom capture sequencing identified a variant. RESULTS: We newly identified four variants: SLC6A1 and HNRNPU missense variants and microdeletions at 2q24.2 involving SCN1A and Xp22.31 involving STS. Febrile seizures preceded epileptic or afebrile seizures in four patients, of which two patients had gene variants. Myoclonic-atonic seizures occurred at onset in four patients, of which two had variants, and during the course of disease in three patients. Variants were more commonly identified in patients with a developmental delay or intellectual disability (DD/ID), but genetic status was not associated with the severity of DD/ID. Attention-deficit/hyperactivity disorder and autistic spectrum disorder were less frequently observed in patients with variants than in those with unknown etiology. SIGNIFICANCE: MAE patients had genetic heterogeneity, and HNRNPU and STS emerged as possible candidate causative genes. Febrile seizures prior to epileptic seizures and myoclonic-atonic seizure at onset indicate a genetic predisposition to MAE. Comorbid conditions were not related to genetic predisposition to MAE.
RESUMO
Sudden death in patients with severe motor and intellectual disabilities (SMID) is sometimes caused in part by pulmonary thromboembolism (PTE), and deep venous thrombosis (DVT) has drawn attention as a possible embolic source. Warfarin, which is a conventional therapeutic agent, is not easy to control appropriately, and daily management can be especially difficult in SMID patients. On the other hand, edoxaban tosilate hydrate, which has been newly approved for insurance coverage for the treatment of DVT, is not listed in the Guidelines for the Diagnosis, Treatment and Prevention of Pulmonary Thromboembolism and Deep Vein Thrombosis (DVT-PTE guidelines). The aim of this study is to evaluate the efficacy and safety of anticoagulation therapy (warfarin vs. edoxaban) in DVT treatment in SMID patients by means of an open-label, randomized controlled trial. The primary endpoint is the incidence of hemorrhagic events during 12 months of follow up.
Assuntos
Anticoagulantes/uso terapêutico , Inibidores do Fator Xa/uso terapêutico , Deficiência Intelectual/complicações , Inteligência , Atividade Motora , Transtornos Motores/complicações , Pessoas com Deficiência Mental/psicologia , Piridinas/uso terapêutico , Tiazóis/uso terapêutico , Trombose Venosa/tratamento farmacológico , Varfarina/uso terapêutico , Anticoagulantes/efeitos adversos , Inibidores do Fator Xa/efeitos adversos , Hemorragia/induzido quimicamente , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/fisiopatologia , Deficiência Intelectual/psicologia , Japão , Transtornos Motores/diagnóstico , Transtornos Motores/fisiopatologia , Transtornos Motores/psicologia , Estudos Multicêntricos como Assunto , Piridinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Tiazóis/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Trombose Venosa/complicações , Trombose Venosa/diagnóstico , Varfarina/efeitos adversosRESUMO
Previous studies have reported a high prevalence of polycystic ovary syndrome (PCOS) among women taking sodium valproate (VPA). We report the case of a 28 year-old epileptic female taking VPA, who developed PCOS and later hepatocellular adenoma. She had been taking VPA for intractable epilepsy since the age of 15 months. At the age of 22 years, she suffered spontaneous rupture of a liver tumor that was diagnosed as hepatocellular adenoma. At the age of 24 years, bilateral polycystic ovaries were found by transabdominal ultrasonography, and PCOS was diagnosed. VPA may directly influence steroidogenesis in the ovary and cause hyperandrogenemia with ensuing PCOS. It is known that abnormality in the sex hormones contributes to the onset of hepatocellular adenoma. Therefore, we speculate that hyperandrogenemia due to VPA contributed to the development of hepatocellular adenoma in this case.
Assuntos
Adenoma de Células Hepáticas/induzido quimicamente , Neoplasias Hepáticas/induzido quimicamente , Síndrome do Ovário Policístico/induzido quimicamente , Ácido Valproico/efeitos adversos , Adulto , Epilepsia/tratamento farmacológico , Feminino , Humanos , Hiperandrogenismo/induzido quimicamente , Fatores de TempoRESUMO
BACKGROUND: This study aimed to clarify the characteristics of acute encephalopathic episodes in patients with congenital adrenal hyperplasia (CAH), which we termed "CAH-associated encephalopathy (CAHE)." METHODS: This retrospective study was conducted using a questionnaire as a nationwide survey of patients with CAH with acute encephalopathy and related episodes. RESULTS: Fifteen patients were recruited on the bases of clinical data that supported a diagnosis of CAHE. Fourteen patients displayed seizures at onset, and 12 patients exhibited refractory seizures. Deep coma lasting >24h was noted in 12 patients. Neuroimaging studies revealed some heterogeneous features. Diffuse or focal edematous lesions in the cerebrum, which produce high signal intensity on diffusion-weighted magnetic resonance imaging or low density on computer tomography, were found in the acute period in all 15 patients. In the chronic period, 14 patients survived, 11 of whom had some degree of neurological sequelae. Moreover, various degrees of cerebral shrinkage were observed in 11 of 14 surviving patients. Surprisingly, there were no abnormal neuroimaging findings in the basal ganglia, brainstem, and cerebellum in any patient. CONCLUSION: Our results indicated that patients with CAH have a risk of developing CAHE, and thus, they should be followed closely because not only status epilepticus or deep coma but also minor symptoms, such as fever and nausea, may lead to CAHE. Because CAHE may feature some heterogeneous encephalopathic episodes, further validation is needed to clarify its etiology.
Assuntos
Hiperplasia Suprarrenal Congênita/diagnóstico por imagem , Hiperplasia Suprarrenal Congênita/epidemiologia , Encefalopatias/diagnóstico por imagem , Encefalopatias/epidemiologia , Encéfalo/diagnóstico por imagem , Hiperplasia Suprarrenal Congênita/fisiopatologia , Encéfalo/fisiopatologia , Encefalopatias/fisiopatologia , Criança , Pré-Escolar , Imagem de Difusão por Ressonância Magnética , Eletroencefalografia , Feminino , Humanos , Lactente , Japão/epidemiologia , Masculino , Estudos Retrospectivos , Síndrome , Tomografia Computadorizada por Raios XRESUMO
Succinate semialdehyde dehydrogenase (SSADH; ALDH5A1) deficiency, a rare metabolic disorder that disrupts the normal degradation of GABA, gives rise to a highly heterogeneous neurological phenotype ranging from mild to very severe. The nature of the mutation has so far been reported in patients from six families world wide and eight different mutations were described. Here we report the mutational spectrum in 48 additional unrelated families of different geographic origin. We detected 27 novel mutations at the cDNA level, of which 26 could be attributed to changes at the genomic level. Furthermore, six mutations were detected that did not strongly affect SSADH activity when expressed in HEK 293 cells and are considered nonpathogenic allelic variants. Twenty of the mutations were only found in one family. The spectrum of disease-causing mutations from all patients sequenced thus far consists of 25 point mutations, four small insertions, and five small deletions. Seven of these mutations affect splice junctions, seven are nonsense mutations, and 12 are missense mutations. Although there were no mutational hotspots or prevalent mutations responsible for a significant number of cases, 14 out of 37 (38%) of the missense alleles were present in exon 4 or 5. With one exception, the missense mutations we consider to be causative of SSADH deficiency reduced the SSADH activity to less than 5% of the normal activity in our in vitro expression system. This indicates that residual expression is not likely to be an important factor contributing to the large phenotypic differences observed among different families and even among siblings, suggesting that other modifying factors are of great importance in disease pathology.
Assuntos
Aldeído Oxirredutases/deficiência , Aldeído Oxirredutases/genética , Mutação , Aldeído Oxirredutases/metabolismo , Linhagem Celular , Códon sem Sentido , DNA/química , DNA/genética , Análise Mutacional de DNA , DNA Complementar/química , DNA Complementar/genética , Regulação Enzimológica da Expressão Gênica , Genótipo , Humanos , Hidroxibutiratos/metabolismo , Mutagênese Insercional , Mutação de Sentido Incorreto , Mutação Puntual , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Deleção de Sequência , Succinato-Semialdeído DesidrogenaseRESUMO
We report an 11-year-old girl with Turner syndrome with 45, X/46, X, mar (X) who had mental retardation. EEG showed remarkable provocation of paroxysmal activity by photic stimulation. Diffuse irregular poly-spike and wave bursts were elicited by photic stimuli, without accompanying by clinical seizure.
Assuntos
Encéfalo/patologia , Eletroencefalografia , Estimulação Luminosa , Síndrome de Turner/fisiopatologia , Criança , Cromossomos Humanos X , Feminino , Humanos , Deficiência Intelectual/genética , Imageamento por Ressonância Magnética , Síndrome de Turner/genéticaRESUMO
OBJECTIVE: Congenital white matter disorders are a heterogeneous group of hypomyelination disorders affecting the white matter of the brain. Recently, mutations in the genes encoding the subunits of RNA polymerase III (Pol III), POLR3A and POLR3B, have been identified as new genetic causes for hypomyelinating disorders. METHOD: Whole-exome sequencing was applied to identify responsible gene mutations in a 29-year-old female patient showing hypomyelination of unknown cause. To investigate the pathological mechanism underlying the hypomyelination in this patient, the expression level of 7SL RNA, a transcriptional target of Pol III, was analyzed in cultured skin fibroblasts derived from the patient with POLR3A mutations. RESULTS: Novel compound heterozygous mutations of POLR3A were identified in the patient, who started to show cerebellar signs at 3 years, lost ambulation at 7 years, and became bedridden at 18 years. Brain magnetic resonance imaging showed severe volume loss in the brainstem, the cerebellum, and the white matter associated with hypomyelination. In addition to hypodontia and hypogonadism, she showed many pituitary hormone-related deficiencies. The expression level of 7SL RNA in cultured skin fibroblasts derived from this patient showed no significant abnormality. CONCLUSION: The many pituitary hormone-related deficiencies identified in this patient may be an essential finding for the Pol III-related leukodystrophies spectrum. Further investigation is needed for a better understanding of the disease mechanism.
Assuntos
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , RNA Polimerase III/genética , Adulto , Encéfalo/patologia , Células Cultivadas , Análise Mutacional de DNA/métodos , Exoma/genética , Feminino , Fibroblastos/metabolismo , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/metabolismo , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Humanos , Imageamento por Ressonância Magnética , Mutação , RNA Polimerase III/metabolismo , RNA Citoplasmático Pequeno/metabolismo , Partícula de Reconhecimento de Sinal/metabolismo , Pele/metabolismoRESUMO
We report on a girl with monosomy 1p36.3 and Angelman syndrome due to an unbalanced transmission of a maternal balanced chromosomal translocation. She manifested monosomy 1p36 and Angelman syndrome including generalized hypopigmentation, ataxic movements, intractable seizures with characteristic electroencephalographic (EEG) abnormality compatible with Angelman syndrome, and other minor anomalies, large anterior fontanelle, severe psychomotor retardation, and seizures due to monosomy 1p36. Her karyotype was 45, XX, der(1) t(1;15)(p36.31;q13.1),-15, derived from maternal translocation. Molecular analysis determined a breakpoint of 1p between D1S243 and D1S468, which suggested that most genes contributing to the common phenotype are in the distal region.
Assuntos
Anormalidades Múltiplas/genética , Síndrome de Angelman/patologia , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 1/genética , Monossomia , Translocação Genética , Anormalidades Múltiplas/patologia , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , CariotipagemRESUMO
Mitochondrial NAD(+)-dependent succinic semialdehyde dehydrogenase (ALDH5A1, SSADH) represents the last enzyme in the GABA catabolism and irreversibly oxidizes SSA to succinate. In human, SSADH deficiency results in 4-hydroxybutyric aciduria, an autosomal recessive disorder due to an accumulation of GABA and 4-hydroxybutyric acid in the CNS. We already identified SSADH gene on human chromosome 6p22 and characterized the coding region. Furthermore, we described the first two mutations causing the disease. We report here the complete cDNA and genomic structure of the gene. A single transcription start site was identified by RNase protection 122 bp upstream of the ATG. EST database search and reporter gene constructs of the 3(') genomic region showed that the two major SSADH mRNA isoforms are due to alternative polyadenylation sites. The two mRNAs of 1827 and 5225 nt were analyzed for differential stability and translation efficiency. The analysis of mRNA turnover showed that both SSADH transcripts are equally stable. Similarly, a measurement of polysomal association capability of the two GFP-SSADH reporter mRNAs (containing the 3' UTR regions of the two SSADH mRNAs) did not reveal any difference. However, we cannot exclude the fact that differential properties could be restricted to particular physiological conditions and/or specific tissues. We have also identified an alternatively spliced small exon, which may lead to a novel isoform of the enzyme. Furthermore, we report here on naturally occurring missense variants, which may significantly contribute to inter-individual variation of SSADH activity, possibly influencing GABA and GHB endogenous levels.