Takeshi Okinaga

Ictal high-frequency oscillations on scalp EEG recordings in symptomatic West syndrome.

OBJECTIVES High-frequency oscillations (HFOs) on intracranial electroencephalography (EEG) recordings have been reported to be useful to identify the epileptogenic zone in intractable epilepsy. We investigated whether the ictal HFOs on scalp EEG seen during spasms contributed to identification of the epileptogenic zone in symptomatic West syndrome (S-WS). METHODS In S-WS, ictal scalp EEGs were recorded during a series of spasms. The HFOs associated with spasms were visualized in the temporally expanded EEG traces and subjected to time-frequency analysis. The results on the distribution of HFOs were compared with that of cortical lesions indicated by neuroimaging. RESULTS In the 4 children examined, HFOs at 80-150 Hz preceded the clinical onsets of spasms. The maximum augmentation of these HFOs was larger than that of HFOs at 20-70 Hz. The regions of the maximum augmentation of HFOs at 80-150 Hz were identical to the lesions detected by neuroimaging. Two patients who underwent dissection of the area including the area with HFOs resulted in Engel class I. CONCLUSION Ictal HFOs of spasms on scalp EEG showed a strong association with neuroimaging abnormalities presumed to be the epileptogenic zone in S-WS. Ictal HFOs can thus be a useful marker for exploring lesions for epilepsy surgery.

Epilepsy in Wolf-Hirschhorn syndrome (4p-).

Summary:  Purpose: We investigated the evolution of epilepsy, seizure types, and effective drugs in Wolf‐Hirschhorn syndrome, which is a malformation syndrome often with refractory seizures and status epilepticus.

Localized donor cells in brain of a Hunter disease patient after cord blood stem cell transplantation.

The efficacy of hematopoietic stem cell transplantation (HSCT) for Hunter disease (deficiency of iduronate-2-sulfatase, IDS) remains unclear. We treated a 6-year-old male suffering from a severe type of Hunter disease with cord blood stem cell transplantation (CBSCT); however, he died at 10 months post-therapy due to a laryngeal post-transplantation lymphoproliferative disorder. During the follow-up period after CBSCT, his hyperactivity, estimated mental age, and brain MR findings had not improved. We assessed the efficacy of CBSCT by biochemical and pathological analyses of the autopsied tissues. There were many distended cells with accumulated substrate in the brain, but not in the liver. IDS enzyme activity in the cerebrum remained very low, although that in the liver reached about 40% of the normal control level. However, a variable number of tandem repeats analyses demonstrated a weak donor-derived band not only in the liver but also in the cerebrum. Furthermore, IDS-immunoreactivity in the liver was recognized broadly not only in Kupffer cells but also in hepatocytes. On the other hand, IDS-immunoreactivity was recognized exclusively in CD68-positive microglia/monocytes in the patients brain; whereas that in the normal brain was also detected in neurons and oligodendrocytes. These donor-derived IDS-positive cells were predominantly localized in perivascular spaces and some of them were evidently present in the brain parenchyma. The efficacy of CBSCT was judged to be insufficient for the brain at 10 months post-therapy. However, the pathological detection of donor-derived cells in the brain parenchyma suggests the potential of HSCT for treatment of neurological symptoms in Hunter disease. This is the first neuropathological report documenting the distribution of donor-derived cells in the brain after CBSCT into a Hunter disease patient.

Induction of hematopoietic prostaglandin D synthase in hyalinated necrotic muscle fibers: its implication in grouped necrosis

Abstract. Prostaglandin (PG) D2 exerts pro-inflammatory and anti-inflammatory functions under various pathological conditions. We found that the immunoreactivity of hematopoietic PGD synthase (HPGDS) appeared in necrotic muscle fibers, mainly in foci of grouped necrosis, in Duchennes muscular dystrophy (DMD) and polymyositis (PM), but not in Beckers muscular dystrophy or in Fukuyama-type congenital muscular dystrophy. The HPGDS expression in DMD and PM was observed to be transient in hyalinated fibers at the early necrotic stage but not detected in opaque fibers, in fibers infiltrated by monocytes/lymphocyte, or in regenerating fibers. The immunoreactivities of a cytosolic form of phospholipase A2 and cyclooxygenase-2, the upstream enzymes of the arachnoid acid cascade, were similarly observed in the HPGDS-positive fibers, suggesting that PGD2 was produced in situ in those necrotic muscle fibers.

A girl with 1p36 deletion syndrome and congenital fiber type disproportion myopathy

AbstractChromosome 1p36 deletion syndrome is characterized by hypotonia, moderate to severe developmental and growth retardation, and characteristic craniofacial dysmorphism. Muscle hypotonia and delayed motor development are almost constant features of the syndrome. We report a 4-year-old Japanese girl with 1p36 deletion syndrome whose muscle pathology showed congenital fiber type disproportion (CFTD) myopathy. This is the first case report of 1p36 deletion associated with CFTD. This association may indicate that one of the CFTD loci is located at 1p36. Ski proto-oncogene −/− mice have phenotypes that resemble some of the features observed in patients with 1p36 deletion syndrome. Because fluorescent in situ hybridization analysis revealed that the human SKI gene is deleted in our patient, some genes in 1p36, including SKI proto-oncogene, may be involved in muscle hypotonia and delayed motor development in this syndrome.

14-3-3ε Gene variants in a Japanese patient with left ventricular noncompaction and hypoplasia of the corpus callosum

BACKGROUND Left ventricular noncompaction (LVNC) is a cardiomyopathy characterized by a prominent trabecular meshwork and deep intertrabecular recesses, and is thought to be due to an arrest of normal endomyocardial morphogenesis. However, the genes contributing to this process remain poorly understood. 14-3-3ε, encoded by YWHAE, is an adapter protein belonging to the 14-3-3 protein family which plays important roles in neuronal development and is involved in Miller-Dieker syndrome. We recently showed that mice lacking this gene develop LVNC. Therefore, we hypothesized that variants in YWHAE may contribute to the pathophysiology of LVNC in humans. METHODS AND RESULTS In 77 Japanese patients with LVNC, including the probands of 29 families, mutation analysis of YWHAE by direct DNA sequencing identified 7 novel variants. One of them, c.-458G>T, in the YWHAE promoter, was identified in a familial patient with LVNC and hypoplasia of the corpus callosum. The -458G>T variant is located within a regulatory CCAAT/enhancer binding protein (C/EBP) response element of the YWHAE promoter, and it reduced promoter activity by approximately 50%. Increased binding of an inhibitory C/EBPβ isoform was implicated in decreasing YWHAE promoter activity. Interestingly, we had previously shown that C/EBPβ is a key regulator of YWHAE. CONCLUSIONS These data suggest that the -458G>T YWHAE variant contributes to the abnormal myocardial morphogenesis characteristic of LVNC as well as abnormal brain development, and implicate YWHAE as a novel candidate gene in pediatric cardiomyopathies.

Long-term developmental outcome in patients with West syndrome after epilepsy surgery.

It has been hypothesized that early seizure control may prevent children with intractable epileptic spasms (ES) from developmental regression and may contribute to better developmental outcome. The effectiveness of surgery for ES has been reported. We investigated long-term post-operative outcomes of seizure control and development in patients with symptomatic West syndrome (S-WS) who underwent epilepsy surgery. Six children who underwent surgical intervention for intractable ES were retrospectively investigated. Cortical malformations were observed on pre-operative MRI in all patients, with hemispheric or multilobar involvement in four children and focal lesions in two. Following surgery, we measured motor function, developmental age (DA), language skills, and sociopsychological function for up to 7years (mean, 4.9years). Post-operative seizure outcome was Engel Class I (n=4) or III (n=2). Motor function and DA was increased following surgery in six and five patients, respectively. Two patients started to speak in sentences following focal resection. Autistic features were noted in four of the five examined patients post-operatively. None of the patients showed developmental regression following surgery. Epilepsy surgery for S-WS with ES may result in good seizure control and improvement in motor development. Improvement in cognitive function was modest in this small cohort of children and autistic features were noted post-operatively in a substantial proportion of the children. While seizure control can be obtained by epilepsy surgery, early intervention for sociopsychological comorbidities may be warranted in children with S-WS.

Generation of Induced Pluripotent Stem Cells From Patients With Duchenne Muscular Dystrophy and Their Induction to Cardiomyocytes.

Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene which encodes dystrophin protein. Dystrophin defect affects cardiac muscle as well as skeletal muscle. Cardiac dysfunction is observed in all patients with DMD over 18 years of age, but there is no curative treatment for DMD cardiomyopathy. To establish novel experimental platforms which reproduce the cardiac phenotype of DMD patients, here we established iPS cell lines from T lymphocytes donated from two DMD patients, with a protocol using Sendai virus vectors. We successfully conducted the differentiation of the DMD patient-specific iPS cells into beating cardiomyocytes. DMD patient-specific iPS cells and iPS cell-derived cardiomyocytes would be a useful in vitro experimental system with which to investigate DMD cardiomyopathy.

INTERSTITIAL DELETION OF 14Q, 46, XY, DEL (14) (Q24.3Q32.1) ASSOCIATED WITH STATUS NONEPILEPTIC MYOCLONIA AND DELAYED MYELINATION

A Japanese boy with interstitial deletion of the long arm of chromosome 14, including band 14q31, is described. The characteristic dysmorphic facial features, such as dolichocephaly, bushy eyebrows, horizontal narrow palpebral fissures, long philtrum, etc, and mental and motor developmental delay were observed. Other characteristic clinical manifestations were anuresis and status nonepileptic myoclonia. The finding of delayed myelination of the cerebral white matter was observed on magnetic resonance examination, suggesting that an unknown factor related to myelination in the central nervous system might be localized in band 14q31. (J Child Neurol 1999;14:756-758).

Prognostic factors for acute encephalopathy with bright tree appearance

OBJECTIVE To determine the prognostic factors for encephalopathy with bright tree appearance (BTA) in the acute phase through retrospective case evaluation. METHODS We recruited 10 children with encephalopathy who presented with BTA and classified them into 2 groups. Six patients with evident regression and severe psychomotor developmental delay after encephalopathy were included in the severe group, while the remaining 4 patients with mild mental retardation were included in the mild group. We retrospectively analyzed their clinical symptoms, laboratory data, and magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) findings. RESULTS Patients in the severe group developed subsequent complications such as epilepsy and severe motor impairment. Univariate analysis revealed that higher maximum lactate dehydrogenase (LDH) levels (p=0.055) were a weak predictor of poor outcome. Maximum creatinine levels were significantly higher (p<0.05) and minimal platelet counts were significantly lower (p<0.05) in the severe group than in the mild group. Acute renal failure was not observed in any patient throughout the study. MRS of the BTA lesion during the BTA period showed elevated lactate levels in 5 children in the severe group and 1 child in the mild group. MRI performed during the chronic phase revealed severe brain atrophy in all patients in the severe group. CONCLUSIONS Higher creatinine and LDH levels and lower platelet counts in the acute phase correlated with poor prognosis. Increased lactate levels in the BTA lesion during the BTA period on MRS may predict severe physical and mental disability.