RESUMO
Although the treatment strategy for febrile infection-related epilepsy syndrome (FIRES) is improving, current research focuses on acute management. Evidence for the management of the chronic phase is limited. We present the case of a 19-year-old woman with FIRES who showed excellent response to a ketogenic diet (KD) administered in the chronic phase. At the age of four years, she presented with new-onset super-refractory status epilepticus after a febrile episode. She was diagnosed with FIRES and had profound motor and cognitive deterioration and drug-resistant epilepsy. From the age of 17, she experienced numerous seizures that often led to status epilepticus with respiratory failure, necessitating laryngotracheal separation and nocturnal mechanical ventilation. To improve seizure control, we planned a KD for the first time 15 years after the onset of FIRES. We introduced a classic KD (ketogenic ratio, 3:1) using blended meals through gastrotomy. Two months after starting the KD, she experienced a decrease in seizure frequency and duration. Moreover, as unexpected stabilization of respiration was achieved, mechanical ventilation was stopped. Our case implies that KD may be a promising treatment option for patients with FIRES in the chronic phase, as is believed to be the case in the acute phase.
RESUMO
Heterozygous transmembrane protein 63A (TMEM63A) variants cause transient infantile hypomyelinating leukodystrophy-19, which features remarkable natural resolution of clinical and imaging findings during childhood. Previous reports have mainly described de novo variants lacking detailed familial cases. Herein, we describe the clinical course of familial cases with a TMEM63A variant. A 5-month-old girl presented with nystagmus, global hypotonia, and difficulty swallowing since birth. Brain magnetic resonance imaging at 1.5 and 5 months revealed diffuse hypomyelination. Her mother, maternal aunt, and grandfather had nystagmus and motor developmental delays in infancy, which resolved spontaneously during childhood. Compared with these cases, the proband's motor developmental delay was profound, and she was the only one with feeding difficulties, necessitating nasogastric tube feeding. Genetic testing revealed a heterozygous TMEM63A variant (NM_014698.3:c.1658G>A, p.(Gly553Asp)) in the proband and her family. This is the first three-generation familial report of a TMEM63A variant that provides insight into its history and heterogeneity.
RESUMO
Pneumatosis cystoides intestinalis (PCI) is a rare disease wherein air accumulates in the intestinal subserosa and submucosa, causing multiple gaseous cysts within the gastrointestinal wall. While PCI has various known risk factors, reports identifying muscular diseases as a factor are scarce. The aim of this study is to elucidate the clinical characteristics of PCI in muscle disease. We present a case series of five cases, including two cases of Duchenne muscular dystrophy (DMD) and three cases of rare congenital myopathies. All cases are of male patients, with poor intestinal peristalsis and constipation, who underwent tube feeding and mechanical ventilation via tracheostomy. They had no signs of severe complications, such as intestinal necrosis, and all of them improved with conservative treatment. Case 1 is a 23-year-old man with DMD who developed cardiopulmonary arrest at the age of 20 years. Pulmonary hemorrhage occurred three months before the incidental detection of PCI in the ascending colon, which resolved with conservative oxygen treatment. Case 2 is a 25-year-old man with DMD who progressed to immobility necessitating tracheostomy at the age of 20 years. He experienced persistent abdominal pain and nausea, and PCI was detected in the cecum and ascending colon. He showed near-complete resolution of PCI after three months of conservative treatment. Case 3 is a six-year-old boy with reducing body myopathy. Constipation was diagnosed at four years of age. He experienced intermittent bloody stools, leading to the incidental detection of PCI at six years of age. After two months of conservative treatment, the PCI resolved with no subsequent recurrence. Case 4 is a 33-year-old man with infantile severe myotubular myopathy. He required mechanical ventilation immediately after birth and later underwent tracheostomy and tube feeding due to complications. At the age of 27 years, PCI was incidentally detected on abdominal CT. He had episodes of remission and worsening for a few years; however, PCI completely resolved after three years. Case 5 is a 27-year-old man with nemaline myopathy. At the age of 14 years, he had persistent bloody stools. After lower gastrointestinal endoscopy, he was diagnosed with PCI with numerous rectal cysts. PCI required no specific therapeutic intervention. There was spontaneous resolution of PCI and bloody stools. Given that PCI lacks specific symptoms and cases with muscular diseases often experience abdominal issues, many cases are liable to be overlooked or misdiagnosed. Cases with muscular diseases complaining of persistent abdominal symptoms should undergo radiographic imaging to rule out PCI.
RESUMO
Febrile infection-related epilepsy syndrome (FIRES) is a rare epileptic encephalopathy that occurs in children or adolescents. To date, evidence for the management of the post-acute phase of FIRES is focused on drug-resistant epilepsy that continues from the acute phase. Information on involuntary movements, which are newly developed in the chronic phase, is limited. We report a 13-year-old boy, who had a history of FIRES at nine years of age and experienced worsening seizure control that was accompanied by unremitting involuntaryãmovements after two years of a fairly controlled period. The involuntary movements resulted in motor deterioration and forced him to be bedridden. Although no neuronal autoantibodies were detected, we hypothesized that the boy's neurological deterioration was triggered by an autoimmune response based on the elevation of serum anti-glutamic acid decarboxylase and serum anti-thyroid peroxidase antibodies and hypermetabolism of bilateral lenticular nuclei on 18-fluorodeoxyglucose positron emission tomography that resembled those reported in patients with other types of autoimmune encephalitis. Serial methylprednisolone pulse therapy and intravenous immunoglobulin therapy ameliorated involuntary movements and improved his activities of daily living. Late-onset involuntary movements, along with seizure exacerbation, may appear in the chronic phase of FIRES. Immunotherapy could be effective in treating these symptoms.
RESUMO
OBJECTIVE: This study aimed to investigate the clinical characteristics of pediatric-onset dystonia in Japan, addressing the diagnostic challenges arising from symptom variations and etiological diversity. METHODS: From 2020 to 2022, questionnaires were distributed to 1218 board certified child neurologists (BCCNs) by Japanese Society of Child Neurology. In the primary survey, participants were asked to report the number of patients with pediatric-onset dystonia under their care. Subsequently, the follow-up secondary survey sought additional information on the clinical characteristics of these patients. RESULTS: The primary survey obtained 550 responses (response rate: 45 %) from BCCNs for their 736 patients with dystonia. The predominant etiologies included inherited cases (with DYT10
Assuntos
Idade de Início , Humanos , Japão/epidemiologia , Criança , Feminino , Masculino , Inquéritos e Questionários , Adolescente , Pré-Escolar , Distonia/epidemiologia , Lactente , Distúrbios Distônicos/epidemiologia , Distúrbios Distônicos/diagnóstico , Estudos EpidemiológicosRESUMO
BACKGROUND: Little is known about the social difficulties and health care needs of adult Duchenne muscular dystrophy (DMD) patients in Japan, as well as the financial and physical stress experienced by their caregivers. This study aimed to clarify the social circumstances surrounding adult DMD patients and assess the degree of involvement of family members in their care and the associated economic burden of the disorder in Japan. METHODS: Adult DMD patients were identified through the Registry of Muscular Dystrophy (Remudy) in Japan and invited to complete a questionnaire together with a caregiver. Data on health care use, quality of life, work status, informal care, and household expenses were collected to estimate the costs associated with DMD from social and caregiver household perspectives. RESULTS: In total, 234 (63.7%) of 367 adult DMD patients (mean age, 27.4 ± 6.0; range, 20-48 years) completed the questionnaire. Of these, 38 (21%) had developmental disorders (mental retardation, autism, and learning disorders), 57 (33%) experienced bullying in school, and 44 (77%) indicated the reason for bullying to be their physical handicap. Employment histories were noted by 72 (31%), although 23 (10%) lost their jobs mainly due to physical difficulties. Of the 234 patients, 164 (74%) lived with their relatives, and 78% of care time was supplied by family members, in particular, their mothers. The mean rate of care work provided by family members was 81%. Household income of families with an adult DMD patient was lower, whereas the rate of living with parent(s) and grandparent(s) was higher, in comparison with the general Japanese population. CONCLUSIONS: Adult DMD patients in Japan experience many social difficulties from childhood up to adulthood. As adults, many DMD patients experience bullying and workplace difficulties. Families were found to provide most of the care and financial support for DMD patients. Our results suggest the need to improve public patient care systems, including financial support, to address the physical and economic burdens of care for adult DMD patients in Japan.
Assuntos
Cuidadores , Distrofia Muscular de Duchenne , Humanos , Distrofia Muscular de Duchenne/economia , Distrofia Muscular de Duchenne/terapia , Distrofia Muscular de Duchenne/psicologia , Adulto , Inquéritos e Questionários , Japão , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Feminino , Cuidadores/psicologia , Qualidade de Vida , Sistema de Registros , Efeitos Psicossociais da Doença , População do Leste AsiáticoRESUMO
BACKGROUND: Two preclinical studies using mouse models of Pelizeaus-Merzbacher disease (PMD) have revealed the potential therapeutic effects of curcumin. In this study, we examined the effects of curcumin in patients with PMD. METHODS: We conducted a study administering an open-label oral bioavailable form of curcumin in nine patients genetically confirmed to have PMD (five to 20 years; mean 11 years) for 12 months (low doses for two months followed by high doses for 10 months). We evaluated changes in clinical symptoms as the primary end point using two scales, Gross Motor Function Measure (GMFM) and the PMD Functional Disability Score (PMD-FDS). The level of myelination by brain magnetic resonance imaging (MRI) and the electrophysiological state by auditory brainstem response (ABR) were evaluated as secondary end points. The safety and tolerability of oral curcumin were also examined. RESULTS: Increase in GMFM and PMD-FDS were noted in five and three patients, respectively, but overall, no statistically significant improvement was demonstrated. We found no clear improvement in their brain MRI or ABR. No adverse events associated with oral administration of curcumin were observed. CONCLUSIONS: Although we failed to demonstrate any significant therapeutic effects of curcumin after 12 months, its tolerability and safety were confirmed. This study does not exclude the possibility of therapeutic effects of curcumin, and a trial of longer duration should be considered to compare the natural history of the disease with the effects of curcumin.
Assuntos
Curcumina , Doença de Pelizaeus-Merzbacher , Animais , Camundongos , Humanos , Doença de Pelizaeus-Merzbacher/diagnóstico por imagem , Doença de Pelizaeus-Merzbacher/tratamento farmacológico , Doença de Pelizaeus-Merzbacher/genética , Curcumina/farmacologia , Curcumina/uso terapêutico , Encéfalo/patologia , Imageamento por Ressonância Magnética , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Proteína Proteolipídica de MielinaRESUMO
BACKGROUND AND PURPOSE: Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental disease caused by ATP1A3 mutations. Using voxel-based morphometry (VBM) analysis, we compared an AHC patient cohort with controls. Additionally, with single-case VBM analysis, we assessed the associations between clinical severity and brain volume in patients with AHC. MATERIALS AND METHODS: To investigate structural brain changes in gray matter (GM) and white matter (WM) volumes between 9 patients with AHC and 20 age-matched controls, VBM analysis was performed using three-dimensional T1-weighted magnetic resonance imaging. Single-case VBM analysis was also performed on nine patients with AHC to investigate the associations between the respective volumes of GM/WM differences and the motor level, cognitive level, and status epilepticus severity in patients with AHC. RESULTS: Compared with controls, patients with AHC showed significant GM volume reductions in both hippocampi and diffuse cerebellum, and there were WM reductions in both cerebral hemispheres. In patients with AHC, cases with more motor dysfunction, the less GM/WM volume of cerebellum was shown. Three of the six cases with cognitive dysfunction showed a clear GM volume reduction in the insulae. Five of the six cases with status epilepticus showed the GM volume reduction in hippocampi. One case had severe status epilepticus without motor dysfunction and showed no cerebellar atrophy. CONCLUSION: With single-case VBM analysis, we could show the association between region-specific changes in brain volume and the severity of various clinical symptoms even in a small sample of subjects.
Assuntos
Imageamento por Ressonância Magnética , Estado Epiléptico , Humanos , Imageamento por Ressonância Magnética/métodos , Encéfalo/patologia , Substância Cinzenta/patologia , Estado Epiléptico/patologia , ATPase Trocadora de Sódio-PotássioRESUMO
Background: Health insurance claims data are used in various research fields; however, an overview on how they are used in healthcare research is scarce in Japan. Therefore, we conducted a scoping review to systematically map the relevant studies using Japanese claims data. Methods: MEDLINE, EMBASE, and Ichushi-Web were searched up to April 2021 for studies using Japanese healthcare claims data. We abstracted the data on study characteristics and summarized target diseases and research themes by the types of claims database. Moreover, we described the results of studies that aimed to compare health insurance claims data with other data sources narratively. Results: A total of 1,493 studies were included. Overall, the most common disease classifications were "Diseases of the circulatory system" (18.8%, n = 281), "Endocrine, nutritional, and metabolic diseases" (11.5%, n = 171; mostly diabetes), and "Neoplasms" (10.9%, n = 162), and the most common research themes were "medical treatment status" (30.0%, n = 448), "intervention effect" (29.9%, n = 447), and "clinical epidemiology, course of diseases" (27.9%, n = 417). Frequent diseases and themes varied by type of claims databases. A total of 19 studies aimed to assess the validity of the claims-based definition, and 21 aimed to compare the results of claims data with other data sources. Most studies that assessed the validity of claims data compared to medical records were hospital-based, with a small number of institutions. Conclusions: Claims data are used in various research areas and will increasingly provide important evidence for healthcare policy in Japan. It is important to use previous claims database studies and share information on methodology among researchers, including validation studies, while informing policymakers about the applicability of claims data for healthcare planning and management.
RESUMO
AIM: The purpose of this study is to evaluate the safety and pharmacokinetics of the novel morpholino oligomer NS-089/NCNP-02 which can induce exon 44 skipping, in patients with DMD. Additionally, we aimed to identify markers predictive of therapeutic efficacy and determine the optimal dosing for future studies. METHODS: This is an open-label, dose-escalation, two-center phase I/II trial in ambulant patients with DMD, presence of an out-of-frame deletion, and a mutation amenable to exon 44 skipping. Part 1 is a stepwise dose-finding stage (4 weeks) during which NS-089/NCNP-02 will be administered intravenously at four dose levels once weekly (1.62, 10, 40, and 80 mg/kg); Part 2 is a 24-week evaluation period based on the dosages determined during Part 1. The primary (safety) endpoints are the results of physical examinations, vital signs, 12-lead electrocardiogram and echocardiography tests, and adverse event reporting. Secondary endpoints include expression of dystrophin protein, motor function assessment, exon 44 skipping efficiency, plasma and urinary NS-089/NCNP-02 concentrations, and changes in blood creatine kinase levels. DISCUSSION: Exon-skipping therapy using ASOs shows promise in selected patients, and this first-in-human study is expected to provide critical information for subsequent clinical development of NS-089/NCNP-02.
Assuntos
Distrofia Muscular de Duchenne , Humanos , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/metabolismo , Oligonucleotídeos Antissenso/efeitos adversos , Morfolinos/efeitos adversos , Éxons , Mutação , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase I como AssuntoRESUMO
BACKGROUND: Heterozygous KCNQ2 variants cause benign familial neonatal seizures and early-onset epileptic encephalopathy in an autosomal dominant manner; the latter is called KCNQ2 encephalopathy. No case of KCNQ2 encephalopathy with arthrogryposis multiplex congenita has been reported. Furthermore, early-onset scoliosis and opisthotonus have not been documented as characteristics of KCNQ2 encephalopathy. CASE REPORT: A male infant born with scoliosis and arthrogryposis multiplex congenita developed intractable epilepsy on the second day of life. At 4 months of age, he developed opisthotonus. The opisthotonus was refractory to medication in the beginning, and it spontaneously disappeared at 8 months of age. Whole-exome sequencing revealed a novel de novo heterozygous variant in KCNQ2, NM_172107.4:c.839A > C, p.(Tyr280Ser). CONCLUSIONS: Early-onset scoliosis, arthrogryposis multiplex congenita, and opisthotonus may be related to KCNQ2 encephalopathy.
Assuntos
Artrogripose , Encefalopatias , Distonia , Escoliose , Lactente , Recém-Nascido , Humanos , Masculino , Artrogripose/complicações , Artrogripose/genética , Escoliose/complicações , Escoliose/genética , Mutação/genética , Canal de Potássio KCNQ2/genética , Encefalopatias/complicações , Encefalopatias/genéticaRESUMO
BACKGROUND: Real-world data have shown variability in treatment responses to nusinersen in spinal muscular atrophy (SMA). We investigated whether the magnitude of muscle impairment assessed by magnetic resonance imaging (MRI) at baseline can predict the treatment response. METHODS: We retrospectively assessed the clinical data in relevance to the thigh and pelvic MRI taken before the nusinersen treatment. A total of 16 patients with SMA types 2 and 3 (age = mean [SD]; 9.2 [4.6] year) receiving nusinersen treatment were enrolled. The T1-weighted MRI images of the pelvis and thigh were scored for muscle fatty infiltration and atrophy. The minimally clinically important difference (MCID) was considered as gaining at least 3 points of Hammersmith Functional Motor Scale-Expanded (HFMSE) from baseline. RESULTS: Of these 16 individuals, 14 had been treated for at least 15 months with baseline data. At 15 months, seven individuals obtained MCID in HFMSE. Baseline muscle MRI score could not differentiate the two groups; however, individuals who obtained MCID had significantly less severe scoliosis. In addition, there was a significant and negative relationship between baseline MRI score and the change of score in HFMSE after 15 months of treatment. Further, baseline Cobb angle along with MRI score also indicated the correlation to the degree of change in motor function. CONCLUSION: The degree of muscle damage may confer the variability in response to nusinersen in SMA types 2 and 3. Muscle MRI score along with the severity of scoliosis assessed at baseline may help to predict the motor function change.
Assuntos
Atrofia Muscular Espinal , Escoliose , Atrofias Musculares Espinais da Infância , Humanos , Estudos Retrospectivos , Atrofia Muscular Espinal/diagnóstico por imagem , Atrofia Muscular Espinal/tratamento farmacológico , Músculos , Imageamento por Ressonância MagnéticaRESUMO
PURPOSE: Cerebellar hypoplasia and atrophy (CBHA) in children is an extremely heterogeneous group of disorders, but few comprehensive genetic studies have been reported. Comprehensive genetic analysis of CBHA patients may help differentiating atrophy and hypoplasia and potentially improve their prognostic aspects. METHODS: Patients with CBHA in 176 families were genetically examined using exome sequencing. Patients with disease-causing variants were clinically evaluated. RESULTS: Disease-causing variants were identified in 96 of the 176 families (54.5%). After excluding 6 families, 48 patients from 42 families were categorized as having syndromic associations with CBHA, whereas the remaining 51 patients from 48 families had isolated CBHA. In 51 patients, 26 aberrant genes were identified, of which, 20 (76.9%) caused disease in 1 family each. The most prevalent genes were CACNA1A, ITPR1, and KIF1A. Of the 26 aberrant genes, 21 and 1 were functionally annotated to atrophy and hypoplasia, respectively. CBHA+S was more clinically severe than CBHA-S. Notably, ARG1 and FOLR1 variants were identified in 2 families, leading to medical treatments. CONCLUSION: A wide genetic and clinical diversity of CBHA was revealed through exome sequencing in this cohort, which highlights the importance of comprehensive genetic analyses. Furthermore, molecular-based treatment was available for 2 families.
Assuntos
Exoma , Malformações do Sistema Nervoso , Criança , Humanos , Exoma/genética , Mutação , Malformações do Sistema Nervoso/genética , Atrofia/genética , Receptor 1 de Folato/genética , CinesinasRESUMO
BACKGROUND: Stereotactic ablation surgeries including radiofrequency thermocoagulation (RFTC) and laser interstitial thermal therapy are recent less invasive treatment methods for insular epilepsy. Volume-based RFTC after stereoelectroencephalography was first proposed by a French group as a more effective method for seizure relief in insular epilepsy patients than stereoelectroencephalography-guided RFTC. OBJECTIVE: To describe the feasibility and technical details about volume-based RFTC in patients with insulo-opercular epilepsy. METHODS: We successfully treated 3- and 6-year-old patients with medically refractory insulo-opercular epilepsy with volume-based RFTC, in which the target volume of coagulation was flexibly designed by combining multiple spherical models of 5-mm diameter which is smaller than reported previously. RESULTS: The insula was targeted by oblique trajectory from the frontoparietal area in one case, and the opercular cortex was targeted by perpendicular trajectories from the perisylvian cortex in the other case. The use of the small sphere model required more trajectories and manipulations but enabled more exhaustive coagulation of the epileptogenic zone, with 70% to 78% of the planned target volume coagulated without complications, and daily seizures disappeared after RFTC in both patients. CONCLUSION: Volume-based RFTC planned with small multiple sphere models may improve the completeness of lesioning for patients with insulo-opercular epilepsy. Careful planning is necessary to reduce the risks of vascular injuries.
Assuntos
Epilepsia do Lobo Frontal , Criança , Pré-Escolar , Eletrocoagulação/métodos , Eletroencefalografia/métodos , Epilepsia do Lobo Frontal/cirurgia , Estudos de Viabilidade , Humanos , Técnicas EstereotáxicasRESUMO
INTRODUCTION: Pathogenic truncating variants in SMC1A, which is located on chromosome Xp11.2, are known to cause infantile-onset epilepsy and severe intellectual disability in girls. Several studies have reported a correlation between SMC1A truncations and seizure clustering; however, the associated electroencephalogram (EEG) patterns remain largely unknown. CASE PRESENTATION: We investigated an 12-year-old girl who had developed epilepsy at the age of 4 months. The patient experienced unknown onset, tonic-clonic seizures that occurred in clusters several times a week. Her interictal EEG at the age of 2 years showed paroxysmal, generalized, high-amplitude slow waves, whereas epileptiform discharges were scarce. The patient's interictal EEG gradually deteriorated; at the age of 11 years, diffuse continuous spike-and-wave discharges were predominantly observed in the left temporal region and were particularly obvious in the awake state. Although the unknown onset, tonic seizures occurring weekly persisted under multiple antiepileptic medications, the patient did not experience seizure clustering since the age of 9 years. Whole-genome sequencing revealed a de novo known nonsense variant in SMC1A (c.2923C > T, p.R975*). CONCLUSION: Our patient presented with a mild abnormality in the interictal EEG during infancy and early childhood despite frequent seizure clustering. Notably, the patient's EEG findings gradually deteriorated over time, which was inconsistent with the amelioration of seizure clustering.
Assuntos
Epilepsia , Convulsões , Anticonvulsivantes/uso terapêutico , Criança , Pré-Escolar , Eletroencefalografia , Epilepsia/tratamento farmacológico , Epilepsia/genética , Feminino , Humanos , Lactente , Convulsões/tratamento farmacológico , Convulsões/genética , VigíliaRESUMO
PURPOSE: To clarify brain abnormalities on magnetic resonance imaging (MRI) and its clinical implications in lissencephaly/subcortical band heterotopia (LIS/SBH) spectrum patients. METHODS: The clinical severity and classification according to Di Donato were retrospectively reviewed in 23 LIS/SBH spectrum patients. The morphological and signal abnormalities of the brainstem, corpus callosum, and basal ganglia were also assessed. The brainstem distribution pattern of the corticospinal tract (CST) was analyzed by diffusion tensor imaging (DTI) and categorized into two types: normal pattern, in which the CST and medial lemniscus (ML) are separated by the dorsal portion of the transverse pontine fiber, and the abnormal pattern, in which the CST and ML are juxtaposed on the dorsal portion of a single transverse pontine fiber. Correlations between MR grading score and potential additional malformative findings of the brain and clinical symptoms were investigated. RESULTS: All patients with grade 3 (n = 5) showed brainstem deformities, signal abnormalities of pontine surface and had a tendency of basal ganglia deformity and callosal hypoplasia whereas those abnormalities were rarely seen in patients with grade 1 and 2 (n = 18). For DTI analysis, the patients with grade 3 LIS/SBH had typically abnormal CST, whereas the patients with grade 1 and 2 LIS/SBH had normal CST. The classification was well correlated with CST and brainstem abnormalities and clinical severity. CONCLUSION: MR assessment including DTI analysis may be useful in assessing the clinical severity in LIS/BH spectrum and may provide insight into its developmental pathology.
Assuntos
Lissencefalias Clássicas e Heterotopias Subcorticais em Banda , Imagem de Tensor de Difusão , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/diagnóstico por imagem , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/patologia , Imagem de Tensor de Difusão/métodos , Humanos , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Tratos Piramidais/diagnóstico por imagem , Tratos Piramidais/patologia , Estudos RetrospectivosRESUMO
Exon skipping using short antisense oligonucleotides (AONs) is a promising treatment for Duchenne muscular dystrophy (DMD). Several exon-skipping drugs, including viltolarsen (NS-065/NCNP-01), have been approved worldwide. Immortalized human skeletal muscle cell lines, such as rhabdomyosarcoma cells, are frequently used to screen efficient oligonucleotide sequences. However, rhabdomyosarcoma cells do not recapitulate DMD pathophysiology as they express endogenous dystrophin. To overcome this limitation, we recently established a direct human somatic cell reprogramming technology and successfully developed a cellular skeletal muscle DMD model by using myogenic differentiation 1 (MYOD1)-transduced urine-derived cells (MYOD1-UDCs). Here, we compared in vitro drug screening systems in MYOD1-UDCs and rhabdomyosarcoma cells. We collected UDCs from patients with DMD amenable to exon 51 skipping, and obtained MYOD1-UDCs. We then compared the efficiency of exon 51 skipping induced by various morpholino-based AONs, including eteplirsen in differentiated MYOD1-UDCs (UDC-myotubes) and rhabdomyosarcoma cells. Exon skipping was induced more efficiently in UDC-myotubes than in rhabdomyosarcoma cells even at a low AON concentration (1 µM). Furthermore, exon 51 skipping efficiency was higher in UDC-myotubes with a deletion of exons 49-50 than in those with a deletion of exons 48-50, suggesting that the skipping efficiency may vary depending on the DMD mutation pattern. An essential finding of this study is that the sequence of eteplirsen consistently leads to much lower efficiency than other sequences. These findings underscore the importance of AON sequence optimization by our cellular system, which enables highly sensitive screening of exon skipping drugs that target different types of DMD mutations.
Assuntos
Distrofia Muscular de Duchenne , Splicing de RNA , Distrofina/genética , Humanos , Distrofia Muscular de Duchenne/genética , Mutação/genética , OligonucleotídeosRESUMO
A heterogeneous spectrum of clinical manifestations caused by mutations in ATP1A3 have been previously described. Here we report two cases of infantile-onset cerebellar ataxia, due to two different ATP1A3 variants. Both patients showed slowly progressive cerebellar ataxia without paroxysmal or episodic symptoms. Brain magnetic resonance imaging revealed mild cerebellar cortical atrophy in both patients. Whole exome sequencing revealed a de novo heterozygous variant in ATP1A3 in both patients. One patient had the c.460A>G (p.Met154Val) variant, while the other carried the c.1050C>A (p.Asp350Lys) variant. This phenotype was characterized by a slowly progressive cerebellar ataxia since the infantile period, which has not been previously described in association with ATP1A3 variants or in ATP1A3-related clinical conditions. Our report contributes to extend the phenotypic spectrum of ATP1A3 mutations, showing paediatric slowly progressive cerebellar ataxia with mild cerebellar atrophy alone as an additional clinical presentation of ATP1A3-related neurological disorders.
Assuntos
Ataxia Cerebelar/genética , ATPase Trocadora de Sódio-Potássio/genética , Adolescente , Atrofia/patologia , Ataxia Cerebelar/patologia , Ataxia Cerebelar/fisiopatologia , Córtex Cerebelar/diagnóstico por imagem , Córtex Cerebelar/patologia , Criança , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Fenótipo , Sequenciamento do ExomaRESUMO
INTRODUCTION: An alteration in postoperative cognitive function varies according to the patients' background characteristics, such as etiology, focus, and seizure duration. Accurate prediction and assessment of postoperative cognitive function is difficult in each patient. Adaptive behavior could describe the typical performance of daily activities and represents the ability to translate cognitive potential into real-world skills. We examined the relationship between alterations of executive function (EF) and adaptive behavior in school children undergoing surgery for intractable epilepsy. METHODOLOGY: We enrolled 31 children with focal resection or corpus callosotomy for intractable epilepsy [mean age at surgery, 12.5 years; 16 boys; mean intellectual quotient, 73.3]. We surveyed answered questionnaires on attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and adaptive behavior using the Vineland Adaptive Behavior Scale, 2nd edition (VABS-II), and performed continuous performance tests (CPTs) on children pre- and postoperatively. RESULT: ADHD and ASD symptoms improved after epilepsy surgery. The omission error (OE) in the CPT variable improved after epilepsy surgery, especially in children with a shorter preoperative period. Improved ASD symptoms led to an increased score of the coping skills subdomain. The reduced OE observed after surgery also increased the score of the community skills subdomain. CONCLUSION: Improvement in EF and ASD symptoms resulted in better adaptive behavior postoperatively. These results were important for the pre- and postoperative evaluation and re-evaluation of children with epilepsy requiring special education and related services.