A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy.

OBJECTIVE: To identify the mutation responsible for autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) in a nonwhite family. BACKGROUND: ADNFLE is newly recognized as an entity of idiopathic partial epilepsy. Recently, two different mutations of the neuronal nicotinic acetylcholine receptor alpha4 subunit (CHRNA4) gene were identified in a white family as a cause of ADNFLE. METHODS: Four affected and three unaffected individuals in three generations of a Japanese family with ADNFLE, and 100 unrelated healthy Japanese volunteers were studied. Clinical features and EEG findings in affected individuals were consistent with those of ADNFLE reported in white families with ADNFLE. Mutations within the CHRNA4 gene were screened for using single-strand conformation polymorphism analysis (SSCA) and were determined by direct sequencing. The mutation identified was sought in volunteers by the amplification refractory mutation system. RESULTS: A C-to-T exchange (C755T) was found in exon 5 of the CHRNA4 gene on one allele of affected individuals. C755T segregated in affected individuals and was not found in 200 alleles obtained from the volunteers. C755T replaced serine 252 (Ser252) in the second membrane-spanning domain (M2) of CHRNA4 with a leucine. Ser252 is conserved characteristically in the alpha-subunit of acetylcholine receptor and is considered to play an important role in channel function. CONCLUSION: C755T is a novel missense mutation of the CHRNA4 gene causing autosomal dominant nocturnal frontal lobe epilepsy in this Japanese family.

Field distribution of antidromically activated digital nerve potentials: model for far-field recording.

In 20 median nerves, the shift in mean latency of the referentially recorded antidromic sensory potential was 0.22 to 0.38 msec per 1.5 cm across the palm and only 0.03 to 0.05 msec per 1.5 cm along the third digit. In five radial nerves, referential recording from the tip of the second digit detected a stationary positive potential that was coincident with the entry of the sensory impulse into the nerve terminal near the base of the digit. These findings are consistent with the view that, in far-field recording of a traveling impulse, a time peak could result from an abrupt change in current flow that is based on the geometry of the volume conductor without fixed neural discharges.

Electronmicroscopy of conjunctival biopsy in mannosidosis.

Electronmicroscopic examination was performed on conjunctival biopsies from two adolescent siblings with mannosidosis. Fibroblasts and endothelial cells contained membrane-bound vacuoles and vesicles that contained homogeneous osmiophilic globules. These vesicles seem to be pathognomonic of mannosidosis. Plasma cells also contained membrane-bound vacuoles, suggesting inhibition of the immunoglobulin production.

Nav1.1 mutations cause febrile seizures associated with afebrile partial seizures.

Recent evidence has suggested that the neuronal voltage-gated sodium channel alpha(1)-subunit gene (Na(v)1.1: SCN1A) is responsible for generalized epilepsy with febrile seizures plus (GEFS+2). Here the authors report two novel disease mutations of Na(v)1.1 in patients with febrile seizures associated with afebrile partial seizures. One is a Val1428Ala substitution in the pore-forming region, and the other is Ala1685Val in the transmembrane helix. These results support the previous findings and contribute to the reliable diagnosis of epilepsy.

A severe muscular dystrophy patient with an internally deleted very short (110 kD) dystrophin: presence of the binding site for dystrophin-associated glycoprotein (DAG) may not be enough for physiological function of dystrophin.

We report a 4-yr and 5-month-old boy with severe clinical features of an early-onset Duchenne muscular dystrophy, who had a very short (110 kDa) dystrophin at the sarcolemma. The patient had a large deletion (exons 2-44) of the dystrophin gene which was predicted to cause a reading frame shift. Sequence analysis of dystrophin mRNA in muscle revealed an alternatively spliced gene product from exons 1 to 51 that caused restoration of the reading frame, in addition to an mRNA corresponding to the DNA deletion. A consistent result was obtained by immunocytochemical analysis of muscle; i.e. positive staining for dystrophin at the sarcolemma using antibodies against the C-terminus, cysteine-rich region and last three of 24 repeat units of the central rod-domain, but not for the remaining antibodies for dystrophin that recognize the N-terminal and proximal rod-domains. Immunostaining for dystrophin-associated glycoproteins (DAGs: 43 and 50 K) and merosin were preserved. Utrophin staining was positive but fainter than other DMD muscles. These results suggest that an extremely short dystrophin lacking the entire actin-binding site in the N-terminus cannot function properly even if the protein possesses the putative DAG-binding cysteine-rich and the C-terminal domains, and still has an ability to associate with sarcolemmal membrane.

Visual evoked potentials in school children: a comparative study of transient and steady-state methods with pattern reversal and flash stimulation.

OBJECTIVE: Flash visual evoked potentials (VEPs) are commonly used in pediatrics, because children are sometimes uncooperative. We performed a comparative study of transient and steady-state VEPs with pattern reversal (PR) and flash (light-emitting diode, LED) stimulation. METHODS: We recorded VEPs in 15 boys and 17 girls (aged 6-12 years) using 4 different stimulus conditions. The latency and amplitude of transient VEPs (T-VEPs) were measured. Steady-state VEPs (S-VEPs) were Fourier analyzed, and both the phase and amplitude of the major components were obtained. RESULTS: The mean P100 latency of LED T-VEPs was longer and had a greater variability than that of PR T-VEPs. The LED T-VEPs had an amplitude of about double that of PR T-VEPs. The first harmonic response in the LED and second harmonic in PR were the major components of S-VEPs. The phases of PR and LED S-VEPs had narrow angular dispersions and amplitudes showed marked intersubject variability. Sex and age had no significant effect on both T-VEPs and S-VEPs. CONCLUSIONS: Reproducible VEPs with 4 stimulus conditions can be obtained in school children. T-VEPs and S-VEPs are clinically useful because these methods provide complementary information.

Development of the temporal lobe in infants and children: analysis by MR-based volumetry.

BACKGROUND AND PURPOSE: Recent advances in data-processing techniques have allowed more accurate MR-based volumetric measurement than was possible in the past. The purpose of this study was to use this technique to evaluate the development of the temporal lobes in childhood. METHODS: The study group consisted of 42 subjects aged 3 weeks to 14 years (mean age, 5 years), all with normal findings on a routine MR study and none with a history of epilepsy. MR images were acquired on a 1.0-T system using a T1-weighted 3D ultrafast gradient-echo sequence. The volumes of the hippocampal formations and temporal lobes were measured by using a workstation, and the percentage of hippocampal formations in the temporal lobes was calculated. Myelination in the limbic system and related structures was also evaluated. RESULTS: The volume of the hippocampal formations increased sharply until the age of 2 years, and continued to increase slowly thereafter. However, the percentage of hippocampal formations in the temporal lobes showed a negative correlation with age. The hippocampal formations on the right side were larger than those on the left in 38 cases (91%), and the anterior temporal lobes on the right were larger than those on the left in 32 cases (76%). This right-left asymmetry of the hippocampal formations and anterior temporal lobes was observed from early infancy, and these differences were statistically significant. A longitudinal fasciculus of high signal intensity was seen in the white matter beneath the subiculum by about 3 months of age. CONCLUSION: MR-based volumetry established developmental characteristics of the temporal lobe, such as a hippocampal growth spurt, a growth difference between the hippocampal formation and the rest of the temporal lobe, and right-left asymmetry. Knowledge of these characteristics may aid in the understanding of hippocampal and temporal lobe abnormalities in children.

A case of hemiplegic migraine in childhood: transient unilateral hyperperfusion revealed by perfusion MR imaging and MR angiography.

We report on an 8-year-old girl with a typical attack of hemiplegic migraine, in whom MR angiography and perfusion MR imaging revealed unilateral dilation of branches of both the middle and posterior cerebral arteries and hyperperfusion of the ipsilateral hemisphere, respectively. The findings resolved spontaneously after the attack. These imaging techniques should be indicated for patients with migraine attacks and may play a role in assessing the vascular events in migraine headache.

Are some idiopathic epilepsies disorders of ion channels?: A working hypothesis.

Epilepsy is a common neurological disease and encompasses a variety of disorders with paroxysms. Although there is a genetic component in the pathogenesis of epilepsy, the molecular mechanisms of this syndrome remains poorly understood. Linkage analysis and positional cloning have not been sufficient tools for determining the pathogenic mechanisms of common idiopathic epilepsies, and hence, novel approaches, based on the etiology of epilepsy, are necessary. Recently, many paroxysmal disorders, including, epilepsy, have been considered to be due to ion channel abnormalities or channelopathies. Results of recent studies employing gene analysis in animal models of epilepsy and human familial epilepsies support the hypothesis that at least some of the so called idiopathic epilepsies, i.e. epilepsies currently, classified as idiopathic could be considered as a channelopathy. This hypothesis is consistent with the putative prerequisites for genes responsible for the majority of idiopathic epilepsies that can adequately explain the following characteristics of epilepsy. Neuronal hyperexcitability, dominant inheritance with various penetrance, pharmacological role of some conventional antiepileptic drugs, age dependency in the onset of epilepsy, and the involvement of genetic factors in the pathogenesis of post-traumatic epilepsy. Search for mutations in ion channels expressed in the central nervous system may help in finding defects underlying some of idiopathic epilepsies, thereby enhancing, our understanding of the molecular pathogenesis of epilepsy. A working hypothesis to view certain idiopathic epilepsies as disorders of ion channels should provide a new insight to our understanding of epilepsy and allow the design of novel therapies.

Autosomal dominant epilepsy with febrile seizures plus with missense mutations of the (Na+)-channel alpha 1 subunit gene, SCN1A.

Evidence that febrile seizures have a strong genetic predisposition has been well documented. In families of probands with multiple febrile convulsions, an autosomal dominant inheritance with reduced penetrance is suspected. Four candidate loci for febrile seizures have been suggested to date; FEB1 on 8q13-q21, FEB2 on 19p, FEB3 on 2q23-q24, and FEB4 on 5q14-15. A missense mutation was identified in the voltage-gated sodium (Na(+))-channel beta 1 subunit gene, SCN1B at chromosome 19p13.1 in generalized epilepsy with the febrile seizures plus type 1 (GEFS+1) family. Several missense mutations of the (Na(+))-channel alpha 1 subunit (Nav1.1) gene, SCN1A were also identified in GEFS+2 families at chromosome 2q23-q24.3. The aim of this report is precisely to describe the phenotypes of Japanese patients with novel SCN1A mutations and to reevaluate the entity of GEFS+. Four family members over three generations and one isolated (phenotypically sporadic) case with SCN1A mutations were clinically investigated. The common seizure type in these patients was febrile and afebrile generalized tonic-clonic seizures (FS+). In addition to FS+, partial epilepsy phenotypes were suspected in all affected family members and electroencephalographically confirmed in three patients of two families. GEFS+ is genetically and clinically heterogeneous, and associated with generalized epilepsy and partial epilepsy as well. The spectrum of GEFS+ should be expanded to include partial epilepsies and better to be termed autosomal dominant epilepsy with febrile seizures plus (ADEFS+).

Effect of growth hormone on high plasma levels of glucagon-like peptide-1 (GLP-1) in hypophysectomized rats.

Fasting plasma GLP-1 levels were significantly higher in hypophysectomized (hypox) rats (n = 6) than in intact (normal) rats (n = 7) (54.3 +/- 5.2 vs. 33.3 +/- 2.4 pmol/L, p < 0.001). To examine the influence of pituitary hormones on plasma GLP-1 levels, concentrations of plasma glucose, insulin and GLP-1 after an oral glucose load to hypox rats that were given either rat growth hormone (rGH) (n = 7), cortisol and thyroxine (n = 7) or no substitution (n = 6) were compared with those of normal rats (n = 7). Plasma glucose levels in the fasting state and after the glucose ingestion were significantly lower in hypox rats, but the hormonal replacements to hypox rats increased their total glucose levels to those of normal rats, although the increasing patterns were different from those in normal rats. Insulin levels both in the fasting state and after the glucose ingestion were significantly decreased in hypox rats and the fasting and total GLP-1 levels were significantly increased in those rats. rGH substitution significantly increased the total insulin levels in hypox rats and decreased the fasting and total GLP-1 levels closely to levels in normal rats, while substitution with cortisol and thyroxine failed to introduce such a significant effect. These results suggested that secretion of GLP-1 might be influenced by the function of GH.

Hydrocephalus due to acute aqueductal stenosis following mumps infection: report of a case and review of the literature.

An acquired form of hydrocephalus due to aqueductal stenosis developing as a sequela of mumps virus infection of the central nervous system is presented. Percutaneous third ventriculostomy and interventriculostomy (aqueduct cannulation) were performed using a flexible fiberoptic ventriculoscope. The aqueduct was blocked with amorphous material but was cleared with the scope. This is the first case of a fulminant phase of mumps ventriculitis leading to aqueductal stenosis, which has been treated using a ventriculoscope for the first time.

Japanese monozygotic twins with Rett syndrome.

We present a study of 28-year-old Japanese monozygotic female twins with Rett syndrome (RS). To our knowledge, this is the first report of monozygotic twins with RS from Japanese family. There are some differences between twins about seizures, scoliosis and stereotypical hand movements during adolescence. Monozygosity was confirmed by both blood typing and HLA titers.

A case of myasthenia gravis complicated with hyperthyroidism and thymic hyperplasia in childhood.

We report here a case of myasthenia gravis complicated with hyperthyroidism and thymic hyperplasia. The patient was a 13-year-old girl with struma and hyperthyroidism which began at age 12. Two weeks following the initiation of treatment against hyperthyroidism she developed left blepharoptosis, diplopia, and dysphagia, which responded promptly to edrophonium administration. An increase of the anti-acetylcholine receptor antibody was found in the serum. A chest CT showed a large soft tissue mass in front of the ascending aorta, which was proven histopathologically as thymic hyperplasia. The patient underwent an extensive thymectomy and was placed on combination therapy with an anti-thyroid drug, glucocorticosteroid, and an anti-cholinesterase drug. Her symptoms and signs have been well controlled by this treatment. Coexistence of myasthenia gravis, hyperthyroidism, and thymic hyperplasia in childhood have never been documented in literature.

Electrophysiological study of four patients with Fisher syndrome: a mechanism of areflexia.

Electrophysiological studies were performed on four patients with the Fisher syndrome (two 4-year-old boys, a 5-year-old boy and a 9-year-old girl). Motor nerve conduction velocity (MNCV), nerve action potential, F wave, H reflex and T reflex were measured at the stage when areflexia was present but ataxia and ophthalmoplegia had recovered. MNCV and SNCV by compound mixed nerve potential were normal in all our patients. The amplitude of the muscle responses (M-responses) and compound mixed nerve action potentials were also within normal limits. The latencies of the F waves and F wave conduction velocities were normal. However, H-reflexes and T-reflexes were absent in all four cases. Our results suggested that areflexia in the Fisher syndrome is attributed to the desynchronization of the impulses or the partial conduction block of GIa fibers.

Application of rapid random stimulation (RRS) to visual evoked potentials in children.

The present study was performed to examine the effects of regular (1 Hz) and modified rapid random stimulation (RRS) (6 and 12 Hz) on visual evoked potentials (VEPs), by simultaneously recording negative waves around 100 ms, wave IV-latency, positive waves around 60 ms, wave III-latency, and amplitudes calculated from peak to peak, without causing impairment of visual acuity, in 44 patients aged 5-17 years. The wave IV-latencies of VEPs obtained by 6 and 12 Hz RRS were easily determined, and the latencies were not significantly changed compared to those obtained by previous 1 Hz regular stimulation. On the other hand, the amplitudes decreased in a frequency-dependent manner (1 < 6 < 12 Hz). These results were found to be similar in both preschool and school children. The examination time of VEPs determined by RRS is one-tenth shorter than that of 1 Hz regular stimulation. Thus, this method has the benefit of shortening the examination time, which decreases fatigue and inattention of the subjects, suggesting that modified RRS is a practically useful method for children.

The effectiveness of clonazepam on the Rolandic discharges.

Rolandic discharge (RD), noted in the electroencephalography (EEG) of patients with benign epilepsy in childhood with centrotemporal spikes (BECCT) has several unique features. One feature is that the amount or frequency of RDs does not correlate well with the incidence of seizures in BECCT although it is a key finding in the diagnosis of this epileptic syndrome. In this study, we examined the efficacy of antiepileptic drugs focusing on the disappearance of RDs in relationship with seizure control. Forty patients with BECCT who were not medically treated prior to this study were randomly sorted into three groups. Twenty patients were assigned for clonazepam (CZP) treatment, 10 patients for valproate (VPA) and the remaining 10 patients for carbamazepine (CBZ). Each drug was administered for 4 consecutive weeks. EEGs were recorded twice during the study, before and 4 weeks after the medication trial. The effects of each treatment on RDs were assessed. RDs disappeared in 15 of the 20 cases treated with CZP (75%) within 4 weeks while the same was observed in only one of the 10 cases treated with VPA (10%). CBZ failed to demonstrate any effect on RD. In the group treated with CZP, there were no differences in seizure incidence, seizure type and blood concentration of CZP between the patients whose RDs disappeared and those whose RDs remained.

Rhythmic slow activity in benign childhood epilepsy with centrotemporal spikes.

In benign childhood epilepsy with centrotemporal spikes (BCECT), focal rhythmic slow EEG activity is occasionally observed in the same region where the centrotemporal spikes or Rolandic Discharges (RD) are seen. This slowing appears especially when RDs are frequent. Holmes therefore hypothesized that these slow waves in BCECT were not the manifestations of structural lesion of the brain but secondary slowing accompanying RD. In order to clarify the origin of the slow activity, clonazepam was administered to four BCECT patients who had the focal slow waves. Clonazepam has recently been found by us to selectively diminish RD in BCECT. After the administration of clonazepam for 4 consecutive weeks, not only RDs but also the slow activity disappeared completely. This finding strongly suggests that these focal rhythmic slow waves in the same region of the RD are a part of the morphology of RD.

Symptomatic Chiari malformation and associated pathophysiology in pediatric and adult patients without myelodysplasia.

The clinical characteristics of eight pediatric and five adult patients with Chiari malformation were evaluated. Six pediatric and five adult patients had associated syringomyelia. All patients initially underwent a suboccipital craniectomy with upper cervical (C-1 and/or C-2) laminectomy and duraplasty, and/or shunting procedures. The clinical characteristics of the pediatric and adult groups were compared. The mean interval between onset of symptoms and operation was shorter in the pediatric group (3 yrs 6 mos) than in the adult group (7 yrs 1 mo). Pediatric patients without syringomyelia had the shortest mean interval of 1 year 8 months. Preoperatively, the clinical features were more severe in the adult patients than in the pediatric patients. Postoperatively, seven of eight pediatric patients improved and one stabilized, while two of five adult patients improved, one stabilized, and in two the disease continued to progress despite multiple corrective procedures. Cine magnetic resonance imaging revealed correction of the abnormal cerebrospinal fluid (CSF) flow at the craniovertebral junction and decreased to-and-fro movement in the syrinx after posterior fossa decompression, which were closely correlated with the improvement of clinical features in pediatric patients. However, adult patients required further procedures because of the multifactorial nature of the disease. Evaluation of abnormal CSF pathways at the craniovertebral junction is important for investigating the pathogenesis of Chiari malformation and associated syringomyelia.

[A case of encephalitis due to Mycoplasma pneumoniae: detection of specific DNA from cerebrospinal fluid and elevation of interleukin-6].

A 9-year-old female was admitted to our hospital due to a generalized seizure and consciousness disturbance. The patient had a fever and rash four days before admission, but she had no respiratory symptoms. The seizure and consciousness disturbance was prolonged and intractable. We diagnosed the patient as having encephalitis because of the increase in the cell count in the cerebrospinal fluid (CSF) and a diffuse slow EEG wave. The computed tomography of the head was normal. The causative agent was identified as Mycoplasma pneumoniae because of the increase of antibodies, and the detection of a specific DNA with a polymerase chain reaction. The interleukin (IL)-6 level of CSF was high (384 pg/ml). In spite of intensive treatment she had severe neurological sequelae. The invasion of Mycoplasma pneumoniae to the central nervous system appeared to have a role in the development of encephalitis in the patient. We speculated that there is a possible relationship between the IL-6 levels of CSF and clinical severity of encephalitis.