Yusaku Miyamoto

ECHS1 Mutations Cause Combined Respiratory Chain Deficiency Resulting in Leigh Syndrome

The human ECHS1 gene encodes the short‐chain enoyl coenzyme A hydratase, the enzyme that catalyzes the second step of β‐oxidation of fatty acids in the mitochondrial matrix. We report on a boy with ECHS1 deficiency who was diagnosed with Leigh syndrome at 21 months of age. The patient presented with hypotonia, metabolic acidosis, and developmental delay. A combined respiratory chain deficiency was also observed. Targeted exome sequencing of 776 mitochondria‐associated genes encoded by nuclear DNA identified compound heterozygous mutations in ECHS1. ECHS1 protein expression was severely depleted in the patients skeletal muscle and patient‐derived myoblasts; a marked decrease in enzyme activity was also evident in patient‐derived myoblasts. Immortalized patient‐derived myoblasts that expressed exogenous wild‐type ECHS1 exhibited the recovery of the ECHS1 activity, indicating that the gene defect was pathogenic. Mitochondrial respiratory complex activity was also mostly restored in these cells, suggesting that there was an unidentified link between deficiency of ECHS1 and respiratory chain. Here, we describe the patient with ECHS1 deficiency; these findings will advance our understanding not only the pathology of mitochondrial fatty acid β‐oxidation disorders, but also the regulation of mitochondrial metabolism.

The evaluation of oxidative DNA damage in children with brain damage using 8-hydroxydeoxyguanosine levels

Urinary and cerebrospinal fluid (CSF) levels of 8-hydroxydeoxyguanosine (8-OHdG) were examined to estimate the relevance of oxidative stress in children with brain damage. Urinary 8-OHdG levels were measured in 51 children with various forms of central nervous system (CNS) disorders (status epilepticus [SE], hypoxic-ischemic encephalopathy [HIE], CNS infections and chronic epilepsy) and these levels were compared with those in 51 healthy children. CSF 8-OHdG levels were measured in 25 children with brain damage and in 19 control subjects. In addition, urinary and CSF levels of 8-OHdG were compared between the children with brain damage and healthy children. Finally, the relationship between urinary and CSF levels of 8-OHdG was determined in 12 children that provided both urinary and CSF samples. Our results showed that urinary 8-OHdG levels in children with HIE and CNS infections were higher than those of controls (Steel test; p < 0.05 and p < 0.05, respectively) and that CSF 8-OHdG levels were higher in children with SE, HIE, and CNS infections than in control subjects (Steel test; p < 0.01, 0.05 and 0.05, respectively). In addition, a positive correlation between the levels of urinary and CSF 8-OHdG was noted in the 12 children that provided both CSF and urinary samples (Spearmans rank correlation; rho = 0.82, p < 0.01). Further, we observed changes in the urinary 8-OHdG in a patient with HHV-6 encephalopathy, and found that the changes correlated well with the patients clinical condition. These results suggest that oxidative stress is strongly related to acute brain damage in children, and that 8-OHdG is a useful marker of brain damage. Therefore, repeated measurements of urinary 8-OHdG may be helpful in estimating the extent of brain damage.

Studies on cerebrospinal fluid ionized calcium and magnesium concentrations in convulsive children

Abstract Background : The concentrations of ionized calcium (iCa) and ionized magnesium (iMg) were measured in the cerebrospinal fluid (CSF) of convulsive and non‐convulsive children, to investigate the relationship between seizure manifestation and CSF iCa and iMg concentrations. Standard concentrations of CSF iCa and iMg were also established.

A new trial liposteroid (dexamethasone palmitate) therapy for intractable epileptic seizures in infancy

West syndrome (WS) is a severe age-dependent intractable epilepsy in infants that frequently results in mental retardation. ACTH or glucocorticoids are among several effective treatments in WS, but the relative advantages and disadvantages of these two therapies are still unknown. In a previous study, liposteroid (LS; dexamethasone palmitate) was used for the treatment of WS and compared with ACTH therapy in relation to therapeutic effect and adverse reactions. In this study, a new regimen of LS therapy was tried for WS and its related syndrome in an attempt to hasten the onset of the therapeutic effect and reduce the relapse rate. A single intravenous injection of LS (0.25mg/kg) was administered 12 times in 1 month (total dosage 3.0mg/kg) to four patients with WS and with post-WS aged 5-25 months, and one patient with Lennox-Gastaut syndrome (post-WS) aged 84 months. All five patients had daily seizures uncontrolled by conventional antiepileptic drugs, such as VPA, CZP or ZNS. Nodding spasm and hypsarrhythmia on EEG disappeared in one patient with WS within four doses. More than 50% decrease in seizures, and EEG improvement, were found in other two patients. No notable effects were seen in the other two patients. There were no clinically significant adverse reactions throughout the therapy. Efficacy can be determined in this new experimental LS therapy earlier than with conventional LS therapy. In this small study, a new protocol for LS therapy could be completed safely. This regimen may be useful for those susceptible to adverse reactions from conventional treatment or those unresponsive to other treatments.

Spontaneous resolution of intractable epileptic seizures following HHV-7 infection

PURPOSE We report a three-year-old female with intractable epilepsy post West syndrome whose seizures disappeared following an acute viral infection, without changes in anti-epileptic therapy. METHODS The female infant was born at term to a healthy mother after an uneventful pregnancy and delivery. At the age of five months, she developed intractable brief tonic spasms which had a series of infantile spasms, and an electroencephalogram indicated hypsarrhythmia. She was diagnosed with West syndrome. The seizures were uncontrollable with conventional therapy, including ACTH, vigabatrin, sodium valproate, clonazepam, zonisamide, and ketogenic diet. Daily multiple generalized tonic seizures and brief tonic spasms were observed before an episode of viral infection. RESULTS At the age of three years, the intractable seizures disappeared after a febrile rash illness due to human herpesvirus 7 (HHV-7) infection, without changes in anti-epileptic drugs. CONCLUSIONS The disappearance of intractable epileptic seizures following acute viral infections might be related to the inflammatory or immunologic processes associated with viral infections. This is the first documented case of spontaneous remission of intractable epileptic seizures following HHV-7 infection.

Transient swelling in the globus pallidus and substantia nigra in childhood suggests SENDA/BPAN

Static encephalopathy of childhood with neurodegeneration in adulthood (SENDA) or β-propeller protein-associated neurodegeneration (BPAN) is a subtype of neurodegeneration with brain iron accumulation (NBIA), causing abnormal iron accumulation in the globus pallidus and substantia nigra through autophagic dysfunction due to WDR45 mutations.1,2 SENDA/BPAN is often difficult to diagnose because brain MRI does not detect the characteristic findings in childhood. We found transient hyperintensity and swelling in the globus pallidus and substantia nigra due to infections during childhood as characteristic findings.

Structural brain network analysis of children with localization-related epilepsy

INTRODUCTION Epilepsy is considered to arise from dysfunction in neural networks. Recent advances in neuroimaging and its analysis have made it possible to investigate both functional and structural connectivity in the brain. The aim of this study was to elucidate alterations in the structural connectivity in children with localization-related epilepsy using the mathematical method of graph theoretical analysis. METHODOLOGY Fifteen children with localization-related epilepsy (8 female subjects; mean age, 8.5±3.5years) as an epilepsy group and 23 children without a history of seizure (12 female subjects; mean age, 8.9±3.7years) as a control group underwent three-dimensional T1-weighted brain magnetic resonance imaging (MRI). Gray matter images segmented and spatially normalized from the MRIs of both groups were analyzed using statistical parametric mapping with the Graph Analysis Toolbox. We compared global networks (global efficiency, clustering coefficient and network strength) and regional networks (betweenness centrality and clustering) between patients and controls. RESULTS The global efficiency tended to be increased (p=0.081) and the global modularity was significantly increased (p=0.017) in the epilepsy group as compared with the control group. The epilepsy group showed locally decreased betweenness centrality mainly in the bilateral cingulate gyri, right perisylvian area, and bilateral precentral gyri, and locally increased clustering in the bilateral cingulate gyri, right perisylvian area, and medial frontal lobes as compared with the control group. The epilepsy group showed higher network resilience to random attack and targeted attack than the control group. Voxel-based morphometry did not show any difference between the two groups. CONCLUSIONS We observed globally increased structural connectivity along with excessive network robustness in patients with localization-related epilepsy. Local abnormality of connectivity was observed mainly in the cingulate gyrus, perisylvian area, and precentral gyrus. This alteration in the structural connectivity without any morphometric changes may be related to the underlying epileptogenicity.

A Case of Congenital Left Internal Carotid Artery Defect Associated with Partial Epilepsy.

てんかん発作の出現を契機に発見された左内頸動脈欠損症の12歳男児例を報告した。生来健康であったが、6カ月の間にテレビ視聴中のけいれん発作を2回繰り返し来院した。精査目的で施行した頭部MRIにおいて左内頸動脈のflow voidが描出されず、MRA及び骨条件の頭部CTより左内頸動脈欠損症と診断した。脳波上右中側頭及び後頭に鋭波を認めたため、けいれんはてんかんによるものと考えられた。しかし欠損側と脳波上の発作波出現部位は対側であり、明らかな症候性てんかんとは断定できなかった。カルバマゼピンの内服開始後、発作はコントロールされている。