Clinical manifestations and epilepsy treatment in Japanese patients with pathogenic CDKL5 variants.

OBJECTIVE: Patients with pathogenic cyclin-dependent kinase-like-5 gene (CDKL5) variants are designated CDKL5 deficiency disorder (CDD). This study aimed to delineate the clinical characteristics of Japanese patients with CDD and elucidate possible appropriate treatments. METHODS: We recruited patients with pathogenic or likely pathogenic CDKL5 variants from a cohort of approximately 1,100 Japanese patients with developmental and epileptic encephalopathies, who underwent genetic analysis. We retrospectively reviewed clinical, electroencephalogram, neuroimaging, and genetic information. RESULTS: We identified 29 patients (21 females, eight males). All patients showed severe developmental delay, especially in males. Involuntary movements were observed in 15 patients. No antiepileptic drugs (AEDs) achieved seizure freedom by monotherapy. AEDs achieving ≥ 50% reduction in seizure frequency were sodium valproate in two patients, vigabatrin in one, and lamotrigine in one. Seizure aggravation was observed during the use of lamotrigine, potassium bromide, and levetiracetam. Adrenocorticotrophic hormone (ACTH) was the most effective treatment. The ketogenic diet (KD), corpus callosotomy and vagus nerve stimulation did not improve seizure frequency in most patients, but KD was remarkably effective in one. The degree of brain atrophy on magnetic resonance imaging (MRI) reflected disease severity. Compared with females, males had lower levels of attained motor development and more severe cerebral atrophy on MRI. CONCLUSION: Our patients showed more severe global developmental delay than those in previous studies and had intractable epilepsy, likely because previous studies had lower numbers of males. Further studies are needed to investigate appropriate therapy for CDD, such as AED polytherapy or combination treatment involving ACTH, KD, and AEDs.

Remitted epilepsy with dysembryoplastic neuroepithelial tumor involving the thalamus.

Dysembryoplastic neuroepithelial tumors (DNT) are benign hamartomatous tumors characterized by intractable epilepsy and common localization in the supratentorial cortex, but thalamic involvement in DNT is extremely rare. A 2-year 4-month-old boy presented with intractable epilepsy due to a tumorous lesion in the frontal lobe expanding to the thalamus. Under chronic intracranial electrocorticography guidance, partial lesionectomy with adjacent cortical resection was performed, and the lesion was pathologically diagnosed as DNT, complex form. Subsequently, the seizures completely disappeared without any neurological deficits despite the presence of full residual thalamic lesions. The epileptogenicity of DNT is closely associated with various clinicopathological factors, and the thalamic contribution to the seizure activity remains unclear. Due to the essential epileptogenic characteristics of DNT, the residual thalamic lesions and associated clinical features should be strictly observed in the future in the present case.

White matter abnormalities in an adult patient with l-2-hydroxyglutaric aciduria.

l-2-Hydroxyglutaric aciduria (l-2-HGA) is a rare inborn error of metabolism. Mainly, patients with this disorder exhibit neurological symptoms and characteristic neuroradiological findings, such as subcortical white matter abnormalities, which are believed to be caused by the toxicity of the accumulation of l-2-hydroxyglutaric acid. A genotype-first approach of the whole exome sequence was used to identify compound heterozygous mutations, c.584A>G (p.Y195C) and c.772T>C (p.C258R), in L2HGDH, the gene responsible for this disorder, in an adult patient with intellectual disability and intractable epilepsy. A retrospective assay confirmed the increased concentrations of 2-hydroxyglutaric acid in the urine. These results suggested that neuroradiological findings of subcortical white matter abnormalities are characteristic of l-2-HGA and that clinical exome sequencing has sufficient power to compensate for insufficient clinical evaluations.

[Electroencephalographic characteristics in patients with febrile status epilepticus].

OBJECTIVE: This study was undertaken to investigate the electroencephalographic (EEG) characteristics in patients with febrile status epilepticus. METHODS: Medical records and EEG findings were retrospectively examined in 14 patients with febrile status epilepticus, who were transferred to the Shiga University Hospital between November, 2009 and March, 2012. RESULTS: Mean time to the initial EEG examination from the cessation of febrile status epilepticus was 3.4 hours. δ waves were seen in 9 of 11 patients during awake or forced awake state, and these slow waves disappeared on or after the 2nd day. Slow waves were predominantly detected in the occipital and frontal leads in 4 and 2 patients, respectively, while diffuse slowing was seen in 4 patients. Spindle/hump waves were observed in 10 of 11 patients, but not detected in the 3 patients because only awake recordings were available. CONCLUSIONS: EEGs in the postictal state of febrile status epilepticus show slow waves, but improve early, then normal EEG sleep pattern such spindle/hump waves are commonly recognized thereafter.

[A case of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episode/Leigh overlap syndrome].

We experienced a case in which mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) was identified as complications following the onset of Leigh syndrome along with a 10191 T>C mutation of the mitochondrial gene. The case pertains to a 26-year-old woman. The disease appeared when she was 11 years old due to divergent strabismus, at which point a diagnosis of juvenile Leigh syndrome was made. Many infraction images not conforming to the vessel region were observed upon a brain MRI which was performed at 26 years of age, thus leading to her being diagnosed with MELAS as a complication. Upoon bibliographical consideration, it was speculated that the clinical features of MELAS/Leigh overlap syndrome clearly differ from Leigh syndrome in terms of age of onset, symptoms, and prognosis. Pleiotropic genetic factors including heteroplasmy were presumed to be involved in the diverse phenotype of overlap syndrome.

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.

A pediatric case of reversible cerebral vasoconstriction syndrome with cortical subarachnoid hemorrhage.

Reversible cerebral vasoconstriction syndrome (RCVS) is a rare disorder characterized by acute onset, severe headache, with reversible vasoconstriction of cerebral arteries often accompanied by additional neurological symptoms. This syndrome is seen mainly in middle-aged adults, predominantly women. Herein, we report on a pediatric case of RCVS with cortical subarachnoid hemorrhage (SAH). A 12-year-old boy developed acute, severe headache with paralysis of lower extremities causing gait disturbance after administration of eletriptan. Brain magnetic resonance angiography (MRA) revealed multifocal narrowing of the cerebral arteries, whereas magnetic resonance imaging (MRI) demonstrated sulcal hyperintensity on fluid-attenuated inversion recovery, consistent with cortical SAH. The patient's clinical symptoms resolved spontaneously after a few days and the MRI and MRA findings disappeared 3 months later, suggesting a diagnosis of RCVS. Eletriptan might cause vasoconstriction of cerebral arteries. Although most patients with RCVS are adults and pediatric cases are rare, RCVS should be considered in a child complaining of severe headache.

Sweet's syndrome in a neonate with non-B54 types of human leukocyte antigen.

BACKGROUND: Sweet's syndrome (acute febrile neutrophilic dermatosis) is characterized by fever, polymorphonuclear leukocytosis of blood, painful plaques on the limbs, face and neck, and histologically a dense dermal infiltration with mature neutrophils. Sweet's syndrome is often a complication of hematologic malignant disease or drug-induced sensitivity reactions and has a significant susceptibility correlated with certain human leukocyte antigen (HLA). METHODS: A 5-week-old Japanese girl with Sweet's syndrome confirmed by skin biopsy was successfully treated and HLA analysis was performed. RESULTS: The patient was one of the youngest patients reported with Sweet's syndrome, suggesting the importance of the genetic background. Although the HLA types of the patient did not have B54, which was reported as a significant susceptibility correlation, structural analysis of the patient's HLAs suggested a similar possible motif for the bound peptides. CONCLUSION: Studies on the HLA bound peptides and HLA structural analysis for patients with Sweet's syndrome would be valuable for understanding the molecular mechanism of the pathogenesis.

A Japanese patient with Kabuki syndrome and unilateral perisylvian cortical dysplasia.

Kabuki syndrome is a rare multiple anomaly syndrome characterized by a peculiar face, skeletal and dermatoglyphic anomalies, postnatal growth retardation and mental retardation. We report a case of Kabuki syndrome with unilateral perisylvian cortical dysplasia. This two-year old boy was referred to our hospital at 3-months of age for his growth retardation and muscle hypotonia. Because of his peculiar face, brachydactyly V and fingertip pad, we diagnosed him as having Kabuki syndrome. His MRI revealed cortical dysplasia along the left sylvian fissure. However, neither epileptic seizures nor epileptiform discharges on electroencephalogram were observed. Cortical dysplasia is a relatively rare brain malformation among the central nervous system anomalies accompanying with this syndrome. We have to take into consideration the likely onset of epilepsy in this patient because it is one of the most frequent neurological consequences of cortical dysplasia.

[A case of myoclonic astatic epilepsy with autoantibody for glutamate receptor epsilon 2].

A 3-year-old boy was admitted to our hospital with repetitive drop attacks and generalized tonic-clonic seizures. Brain MRI, SPECT and blood laboratory tests did not show any abnormalities, while antibody to glutamate receptor epsilon 2 (GluR epsilon 2) in spinal fluid was positive. Interictal EEG showed generalized 6 to approximately 7 Hz slow, wave and ictal EEG showed 1 to approximately 2 Hz high amplitude generalized spike and slow wave burst. We made a diagnosis as myoclonic astatic epilepsy (MAE). However, his seizures were refractory to almost all antiepileptic drugs, steroid pulse therapy and gamma-globulin therapy. Eight months after the first attack, administration of ACTH therapy was effective. Seizures disappeared and EEG findings improved. To our knowledge, there have been no previous reports of MAE in which autoantibody to GluR epsilon 2 was positive. It is suggested that autoimmunity in this case was associated with the pathogenesis of MAE.

[A case of hemimegalencephaly with slowly progressive expansion].

We report a case of a male infant with refractory epilepsy, demonstrating hemimegalencephaly with slowly progressive expansion. The patient experienced his first seizure at 4 months of age. Subsequently, tonic seizures occurred very frequently despite extensive antiepileptic medications, and his development deteriorated. Cranial magnetic resonance imaging (MRI) at 4 months of age showed focal cortical dysplasia in the right opercular area. This focal lesion gradually expanded, and became thickened. Five years later, the dysplastic lesion occupied most of the right cerebral hemisphere and the volume of the right hemisphere increased, indicating hemimegalencephaly. He had profound motor and intellectual retardation. In the abnormal cerebral hemisphere, fluorodeoxyglucose-positron emission tomography (FDG-PET) showed marked hypometabolism, and ictal single photon emission computed tomography (SPECT) showed hyperperfusion, more pronounced in the right frontal area. These findings are consistent with a hemimegalencephaly. Hemimegalencephaly with such a progressive expansion has never been described previously. These findings are consistent with a hemimegalencephaly showing progressive expansion, which has never been described previously.