Kenji Sugai

De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood.

Static encephalopathy of childhood with neurodegeneration in adulthood (SENDA) is a recently established subtype of neurodegeneration with brain iron accumulation (NBIA). By exome sequencing, we found de novo heterozygous mutations in WDR45 at Xp11.23 in two individuals with SENDA, and three additional WDR45 mutations were identified in three other subjects by Sanger sequencing. Using lymphoblastoid cell lines (LCLs) derived from the subjects, aberrant splicing was confirmed in two, and protein expression was observed to be severely impaired in all five. WDR45 encodes WD-repeat domain 45 (WDR45). WDR45 (also known as WIPI4) is one of the four mammalian homologs of yeast Atg18, which has an important role in autophagy. Lower autophagic activity and accumulation of aberrant early autophagic structures were demonstrated in the LCLs of the affected subjects. These findings provide direct evidence that an autophagy defect is indeed associated with a neurodegenerative disorder in humans.

Clinical spectrum of early onset epileptic encephalopathies caused by KCNQ2 mutation.

KCNQ2 mutations have been found in patients with benign familial neonatal seizures, myokymia, or early onset epileptic encephalopathy (EOEE). In this study, we aimed to delineate the clinical spectrum of EOEE associated with KCNQ2 mutation.

Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis

Sakuma H, Awaya Y, Shiomi M, Yamanouchi H, Takahashi Y, Saito Y, Sugai K, Sasaki M. Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis. 
Acta Neurol Scand: 2010: 121: 251–256.
© 2009 The Authors Journal compilation

Cerebro-Oculo-Hepato-Renal Syndrome (Arima's Syndrome): A Distinct Clinocopathological Entity

Three children with Lebers congenital amaurosis, agenesis of the cerebellar vermis, and infantile polycystic kidneys are described. The common clinical findings of three unrelated patients (two boys and one girl) included severe visual impairment from early infancy, profound psychomotor retardation, hypotonia, nystagmus, characteristic facial appearance with blepharoptosis, and progressive chronic renal insufficiency. The two boys died of uremia at ages 13 and 12 years. The common pathological findings in these two patients consisted of minor disproportions of cerebral lobes, almost total aplasia of the cerebellar vermis, micropolygyria of the dentate nuclei, malformations of the brain stem (including pachygyria of the inferior olivary nuclei and partial absence and anomalous position of the pyramidal tracts), and infantile polycystic kidneys; there was fatty liver in one case and hepatic fibrosis in the other. The clinicopathological findings of our two patients were entirely compatible with those of patients previously reported by Arima and other Japanese authors. Therefore, these patients seem to comprise a distinct clinicopathological entity, cerebro-oculo-hepato-renal syndrome (Arimas syndrome), different from other syndromes with retinal, cerebellar, and renal abnormalities. (J Child Neurol 1986;1:338-346)

Tremor and seizures associated with chronic manganese intoxication

Tremor and seizures developed in a 2-year-old girl receiving total parenteral nutrition. T1-weighted images on MRI revealed areas of hyperintensity in the basal ganglia, brainstem and cerebellum. Blood manganese was elevated. The symptoms and MRI abnormalities disappeared after withdrawal of manganese administration. The recommendation of daily parenteral manganese intake was discussed.

Surgical Treatment of a Case of Early Infantile Epileptic Encephalopathy with Suppression-Bursts Associated with Focal Cortical Dysplasia

Summary: We report a surgically treated case of early infantile epileptic encephalopathy (EIEE) with supression‐bursts associated with focal cortical dysplasia. Tonic‐clonic seizures followed by a series of spasms occurred about a hundred times a day at a few days of age. Interictal electroencephalogram (EEG) revealed a suppression‐burst pattern that was predominant in the left hemisphere. Magnetic resonance imaging (MRI) suggested focal cortical dysplasia in the left prefrontal area. Combination therapies with antiepileptic treatments showed only partial efficacy. The patient underwent lesionectomy at age 4 months, after which he gradually showed psychomotor development and a decrease of spasms to 0‐2 series daily. In cases of EIEE with focal cortical dysplasia, surgical treatment may have beneficial effects on both psychomotor development and seizure control.

Characteristic EEG findings in ring 20 syndrome as a diagnostic clue

OBJECTIVE To review the EEG features of ring 20 syndrome in two patients and determine the characteristic pattern of this syndrome. The features of our cases and 24 patients reported in the literature will be discussed. SUBJECTS AND METHODS Report of two patients and review of literature. RESULTS The two patients had intractable epilepsy since childhood. Their clinical seizures were mostly complex partial seizures. Often the patients seizures were of prolonged duration. Ictal EEG revealed characteristic slow waves, and sharp waves. The slow waves were (1) usually synchronous high-voltage slow waves with or without a spike component predominantly in the frontal and frontopolar areas, (2) sometimes showed a change in frequency every several seconds, (3) continued for a long period, and (4) easily spread diffusely. The sharp waves were 5-6 Hz irregular and diffuse discontinuous sharp waves, and sometimes appeared predominantly in the centroparietal area. The clinical seizure pattern and EEG findings were similar in the 24 published cases. CONCLUSIONS These EEG findings may be a characteristic feature of ring 20 syndrome and thus may be useful as a diagnostic clue.

Inflammatory changes in infantile-onset LMNA-associated myopathy.

Mutations in LMNA cause wide variety of disorders including Emery-Dreifuss muscular dystrophy, limb girdle muscular dystrophy, and congenital muscular dystrophy. We recently found a LMNA mutation in a patient who was previously diagnosed as infantile onset inflammatory myopathy. In this study, we screened for LMNA mutations in 20 patients suspected to have inflammatory myopathy with onset at 2years or younger. The diagnosis of inflammatory myopathy was based on muscle pathology with presence of perivascular cuffing and/or endomysial/perimysial lymphocyte infiltration. We identified heterozygous LMNA mutations in 11 patients (55%), who eventually developed joint contractures and/or cardiac involvement after the infantile period. Our findings suggest that LMNA mutation should be considered in myopathy patients with inflammatory changes during infancy, and that this may help avoid life-threatening events associated with laminopathy.

Haplotype structures of EPHX1 and their effects on the metabolism of carbamazepine-10,11-epoxide in Japanese epileptic patients.

ObjectiveMicrosomal epoxide hydrolase (mEH) is an enzyme that detoxifies reactive epoxides and catalyzes the biotransformation of carbamazepine-10,11-epoxide (CBZ-epoxide) to carbamazepine-10,11-diol (CBZ-diol). Utilizing single nucleotide polymorphisms (SNPs) of the EPHX1 gene encoding mEH, we identified the haplotypes of EPHX1 blocks and investigated the association between the block haplotypes and CBZ-epoxide metabolism.Methods SNPs of EPHX1 were analyzed by means of polymerase chain reaction amplification and DNA sequencing using DNA extracted from the blood leukocytes of 96 Japanese epileptic patients, including 58 carbamazepine-administered patients. The plasma concentrations of CBZ and its four metabolites were determined using high-performance liquid chromatography.ResultsFrom sequencing all 9 exons and their surrounding introns, 29 SNPs were found in EPHX1. The SNPs were separated into three blocks on the basis of linkage disequilibrium, and the block haplotype combinations (diplotypes) were assigned. Using plasma CBZ-diol/CBZ-epoxide ratios (diol/epoxide ratios) indicative of the mEH activity, the effects of the diplotypes in each EPHX1 block were analyzed on CBZ-epoxide metabolism. In block 2, the diol/epoxide ratios increased significantly depending on the number of haplotype *2 bearing Y113H (P=0.0241). In block 3, the ratios decreased depending on the number of haplotype *2 bearing H139R (P=0.0351). Also, an increasing effect of a *1 subtype, *1c, was observed on the ratio.ConclusionThese results show that some EPHX1 haplotypes are associated with altered CBZ-epoxide metabolism. This is the first report on the haplotype structures of EPHX1 and their potential in vivo effects.

Clinical Aspects of Hemimegalencephaly by Means of a Nationwide Survey

We surveyed Japanese patients with hemimegalencephaly by means of a questionnaire. Clinical findings, including intellectual and motor function levels and epileptic symptoms, were investigated. All 44 patients (28 males and 16 females) with hemimegalencephaly were sporadic. Sixteen patients had underlying neurocutaneous syndromes. The number of patients with right-sided hemimegalencephaly (n = 29) was almost twice that of patients with left-sided hemimegalencephaly (n = 15). Forty-one patients had mental retardation and hemiparesis and 14 patients were bedridden. All patients had epileptic seizures, which first appeared within a month in 18 cases and within 6 months in 11 cases. In 42 patients, magnetic resonance imaging revealed both cortical and white-matter abnormalities in the affected hemisphere. Antiepileptic drugs were not very effective. Fifteen patients were surgically treated. Eleven patients underwent functional hemispherectomy, which resulted in fairly good seizure control and improved development. There is a correlation between the onset of epilepsy and the degree of clinical severity of motor deficit and intellectual level. Neither underlying disorders nor laterality of the affected side was related to the degree of clinical severity. (J Child Neurol 2005;20:337—341).