Clinical and pedigree study on familial cases of West syndrome in Japan.

Nationwide survey on familial cases of West syndrome (WS) in first- and second-degree relatives was conducted by mailing a questionnaire to 64 major university hospitals, children's hospitals, and epilepsy centers in Japan, and by review of the Japanese cases in the literatures. Thirty-four familial cases, 20 males and 14 females, were obtained in 15 families including one with five affected members in two generations and another with three affected male siblings including a half brother by a different father (X-linked WS). A mother and the child or children were involved in three families. Nine families had 21 cryptogenic cases and six families had 13 symptomatic cases, and the etiologies were same among the affected members in each family. Familial cases of WS have characteristic clinical features and genetic mechanisms. Age of onset, seizure types, electroencephalographic abnormalities, early seizure outcome, effective treatment, long-term seizure prognosis, and long-term developmental prognosis were concordant among the affected members in each family. Long-term seizure and developmental prognoses were far better than those in WS in general, with seizure-free rate of 82% and normal mental development rate of 44%. Poor prognosis was limited to specific symptomatic cases. Adrenocorticotropic hormone (ACTH) was a treatment of choice, and even in relapse of WS after ACTH therapy, the patients well responded to antiepileptic drugs. Specific inheritance pattern was difficult to imagine in the majority of the present cases, except for one family with X-linked WS and another family with five patients of maternal inheritance. These results are helpful for the treatment choice and prognostication of clinical course for familial cases of WS.

Effect of temperature on serum protein binding characteristics of phenytoin in monotherapy paediatric patients with epilepsy.

OBJECTIVES: To determine the effects of temperature on binding characteristics of phenytoin to serum proteins in paediatric patients with epilepsy. METHOD: Serum samples examined in the study were obtained from 41 paediatric patients (23 male, 18 female) with epilepsy on phenytoin monotherapy. Their age ranged from 1 to 15 years (mean +/- SD, 10;2 +/- 4;0 years). Protein binding of phenytoin was evaluated by ultrafiltration under current laboratory routine conditions (25 +/- 3 degrees C) or at a temperature of 37 degrees C. The in vivo binding parameters of phenytoin to serum proteins were determined using a binding equation derived from the Scatchard equation for a one-site binding model. RESULTS: Significant differences were observed in serum concentrations of unbound phenytoin at the two temperatures (P < 0;05). The mean association constant L/micromol (K) of phenytoin to serum proteins is 0.016 L/micromol at 25 +/- 3 degrees C and 0;009 L/micromol at 37 degrees C, while mean total concentration of binding sites (n(Pt)) seems to be similar between the two temperatures (682 micromol/L for 25 +/- 3 degrees C and 746 micromol/L for 37 degrees C). Significant differences were observed in binding characteristics of phenytoin to serum proteins for the different temperature conditions of ultrafiltration (P < 0;05). CONCLUSION: Our study confirms that binding affinity for phenytoin-serum protein interaction is approximately 44% lower at 37 degrees C than at 25 +/- 3 degrees C and consequently, binding potential (K.n(Pt)) is approximately 38% lower at 37 degrees C than at 25 +/- 3 degrees C.

Establishment of L-3,4-Dihydroxyphenilalaninde-induced pharmacological dementia model mouse.

L-3,4-Dihydroxyphenilalaninde (L-DOPA), through its decarboxylation to dopamine, has been used as the most effective therapy for treatment of Parkinson's disease (PD). Despite almost 30 years of clinical experience, doubts remain as to whether L-DOPA has an adverse effect of causing neuronal injury. We therefore examined the effects of L-DOPA on the learning ability of mice in a step-through passive avoidance task. Orally administrated L-DOPA (10-1000 mg/kg) induced irrecoverable cognitive impairment in C57BL/6N mice. The effect of L-DOPA had dose and time dependency. In contrast, D-3,4-Dihydroxyphenilalaninde, which does not pass through the blood-brain barrier, had no effect. These experiments suggest that L-DOPA immediately affected the brain and caused memory deficit. The findings indicate that L-DOPA-treated mice are able to act as a new model for human dementia.

Two novel mutations in the adrenoleukodystrophy gene in two unrelated Japanese families and the long-term effect of bone marrow transplantation.

We identified two novel missense mutations in exon 1 of adrenoleukodystrophy (ALD) gene in two unrelated Japanese families. The first, G(874)C transition results in Arg(163)Pro substitution in the cytoplasmic domain of the ALD protein in adrenomyeloneuropathy family. The second, C(679)G results in Ser(98)Trp substitution in the first transmembrane loop in childhood onset cerebral ALD family. Both mutations cause the substitution of polar amino acid (arginine and serine) with non-polar amino acid (proline and tryptophan). Bone marrow transplantation (BMT) from his non-affected his younger sister was performed on a boy with childhood onset cerebral ALD who showed neurological deficit and brain MRI abnormalities. We evaluated the effect of BMT over a 6-year period in terms of neurological deficit, the level of very-long-chain fatty acids (VLCFA) in plasma and fibroblasts, and brain MRI. After BMT, patient's peripheral white blood cells were replaced by donor's XX ones carrying a normal ALD gene confirmed by in situ hybridization using satellite DNA of the centromere of X and Y chromosomes as probes and the level of VLCFA in lymphocytes was within normal limit. However, his neurological state progressively deteriorated. BMT was not beneficial to him.

Bidirectional actions of docosahexaenoic acid on hippocampal neurotransmissions in vivo.

Docosahexaenoic acid (DHA), a 22-carbon fatty acid with six double bonds, is one of the major polyunsaturated fatty acids in fish oils or in the mammalian central nervous system and is believed to be essential for neuronal plasticity and development. In the present study, we evaluated the effect of DHA on hippocampal neurotransmissions using anesthetized rats. Field excitatory postsynaptic potential (fEPSP) evoked by stimulation of the Schaffer collaterals was recorded from the CA1 stratum radiatum. Following intracerebroventricular injection of DHA 25 nmol, the fEPSP slope decreased gradually in 30 min and was eventually suppressed by about 30%. On the other hand, when fEPSP was evoked by stimulation of the perforant path was recorded in the molecular layer of the dentate gyrus, an increase in fEPSP slope occurred over a similar time course after DHA injection. These phenomena were independent of N-methyl-D-aspartate receptor activity. Linoleic acid, one of polyunsaturated fatty acids, was virtually ineffective. Furthermore, we investigated the effect of DHA on hippocampal synaptic plasticity. Although DHA did not alter the profile of paired-pulse facilitation, it inhibited the induction of long-term potentiation in the CA1 area but not in the dentate gyrus. Thus, DHA exerts regionally different effects on hippocampal neurotransmission and may be a good tool for clarifying physiological functions of the hippocampus.

In vivo binding characteristics of phenytoin to serum proteins in monotherapy pediatric patients with epilepsy.

AIM: The aim of the present study was to determine the binding characteristics of phenytoin (PHT) to serum proteins in the pediatric population. Binding parameters of PHT to serum proteins in our study were conducted to compare with in vivo or in vitro binding parameters of PHT to serum proteins in adult subjects reported by other investigators. SUBJECTS AND MATERIALS: Serum samples in the study were obtained from 40 pediatric patients (16 male, 24 female) receiving PHT monotherapy. Their age ranged from 1 to 15 years (9.2 +/- 3.6 years, mean +/- SD). The in vivo population binding parameters of PHT to serum proteins and theoretical minimal unbound serum PHT fraction (fu) were determined using an equation derived from the Scatchard equation. RESULTS: The association constant (Ka) was 0.014 l/micromol, while the total concentration of binding sites (n(Pt)) was 747 micromol/l. The number of binding sites per albumin molecule (n) was 1.13, while binding ability (n x Ka) was 0.0161/micromol. The fu was 0.087. The n x Ka is approximately 1.2 times higher in PHT monotherapy adult patients of Pospisil et al. [1992] (i.e. 0.0191 l/micromol) than in all our patients. The association constant is approximately 1.3 times higher in the in vitro study of Monks et al. [1978] (i.e. 0.0186 l/micromol) than in our study, while n is similar between the two studies. The fu in our pediatric patients is similar to the unbound serum PHT fraction in adult patients receiving PHT therapy reported by Richens [1979] (i.e. 0.1). CONCLUSION: Our results suggest that there may be small differences in the binding characteristics of PHT to serum proteins between Japanese pediatric and non-Japanese adult subjects. The unbound serum fraction of PHT in pediatric patients with epilepsy can be assumed to be relatively constant in the therapeutic concentration range of PHT.

[A case of acute polyradiculoneuritis with multiple cranial nerve palsy and cerebral lesion--possible evidence of encephalo-myelo-radiculo-neuropathy].

We report a case of acute polyradiculoneuritis with multiple cranial nerve palsy and cerebral lesions. A boy, born on July 26, 1987, developed unusual sensation on the extremities, backache and sleep disturbance on June 23, 1996. On July 2, following a complaint of blindness he developed a convulsion and was admitted to our hospital. Neurological examination revealed intact consciousness, severe external ophthalmoplegia, bifacial palsy and generalized areflexia. On the next day, flaccid tetraplegia and respiratory dysfunction developed and progressed without disturbance of consciousness. After tracheal intubation he was under mechanical ventilation. A lumbar puncture examination showed clear CSF with increased protein 166 mg/dl. no cells and normal myelin basic protein. Serum antibodies against gangliosides (GM1, asialo-GM1, GD1b and GQ1b) were not detected. A posterior tibial nerve conduction velocity was mildly delayed with disappearance of F- wave. On the other hand, very slow background activity was shown by EEG, extensive focal hypoperfusion of cerebral blood flow by SPECT and supratentorial multiple high intensity lesions by T2 weighted MRI of the brain. There were no abnormal signals in the brainstem and cerebellum on MRI. His condition dramatically improved after plasmapheresis. The abnormal findings of SPECT and MRI promptly disappeared within 3 weeks, although abnormal signs on EEG persisted. He was successfully weaned off the respirator and recovered strength of the limbs. He was discharged on August 28, 1996, with supported walk and bifacial palsy, then he completely recovered by 7 months. The condition of case was compatible with 'encephalo-myelo-radiculo-neuropathy', a disease entity that had previously been reported in a few patients in whom with Guillain-Barré or Fisher syndrome and cerebral symptoms co-existed.

MS-430, a synthetic pyrimidine derivative, influences the intracellular signal transduction pathway leading to neuronal differentiation of PC12h cells.

Although NGF (nerve growth factor) induces neuronal differentiation of PC12 cells, EGF (epidermal growth factor) acts as a mitogen for these cells. We have studied the effects of a synthetic pyrimidine derivative, MS-430, on the NGF and EGF actions on PC12h cells. We found that MS-430 accelerated NGF-induced neurite extension of PC12h cells and that, in the presence of MS-430, PC12h cells extended neurites in response to EGF. Next, we investigated the tyrosine phosphorylation of NGF receptor TrkA and the EGF receptor (EGFR) as well as mitogen-activated protein kinase (MAPK), which is a key protein in the intracellular signal transduction pathway. It was found that MS-430 prolonged the EGF-induced phosphorylation of EGFR and MAPK compared to that without MS-430. MS-430 also prolonged the NGF-induced phosphorylation of MAPK, but the phosphorylation of TrkA induced by NGF was not affected by MS-430. These results suggest that MS-430 influences the intracellular signal transduction pathway which causes the neuronal differentiation of PC12h cells.

[A case of isolated ACTH deficiency with neuromuscular symptoms].

A female case of isolated ACTH deficiency associated with neuromuscular symptoms was reported. Although her initial development was delayed with perinatal troubles, developmental catch up was seen. The patient complained of general fatigue with weakness and poor school performance at the age of eleven. Muscle weakness predominant to the proximal portion and mental dullness were suspected from neurological examination. Her laboratory data were as follows; mild elevation of CK in serum, subclinical thyroidal dysfunction, abnormal electrocardiogram, slow wave activity on electroencephalogram, delayed nerve conduction velocity, and localized hypoperfusion of cerebral blood flow on single photon emission computed tomogram. Histological examination of muscle biopsy demonstrated only mild fiber size variation. During two years' follow-up, her intelligence quotient fell down, while muscle weakness did not progress significantly. At the age of fourteen, a low level of plasma ACTH was pointed out by chance and a definitive diagnosis was obtained by endocrinological examinations; no response of ACTH and cortisol on insulin stimulation, delayed response of cortisol on continuous ACTH stimulation, and no response of plasma ACTH on corticotropin releasing hormone stimulation. Other signs of adrenocortical insufficiency, such as hypoglycemia and abnormal serum electrolytes, were not observed during the clinical course. This case suggested that isolated ACTH deficiency should be considered for differential diagnosis of neuromuscular disorders.

[Usefulness of rCBF SPECT in patients with encephalitis: comparison study with MRI].

Twenty-nine rCBF SPECT study was done in 17 patients with encephalitis. Five of 6 patients (83.3%) showed regional high uptake in acute phase within a week after onset and 16 of 23 studies (69.6%) showed regional low uptake in subacute and chronic phase. Six of 19 lesions (31.6%) with regional high uptake changed to low uptake and 11 lesions (57.9%) improved to normal uptake on follow up studies. Seventeen of 51 lesions with low uptake (33.3%) improved to normal uptake. On the comparative study with MRI, 8 of 18 (44.4%) high uptake area showed cortical thickness or high intensity on T2 weighted images. Thirty-six of 74 low uptake area (48.6%) showed cortical thickness, brain atrophy or high intensity on T2 weighted images. Forty-eight of 212 regions (22.6%) with normal MRI findings showed abnormal accumulation of cerebral tracer on rCBF SPECT studies. rCBF SPECT was useful tool for diagnosis and follow up management in patients with encephalitis.

[Reye syndrome evaluated by 99mTc-ECD SPECT: a case report].

We report a three-year-old boy with Reye syndrome evaluated by 99mTc-ECD SPECT. On acute stage, 99mTc-ECD brain SPECT disclosed diffuse high uptake in the cerebral cortex in spite of normal findings on brain X-ray CT. These lesions changed to general low uptake on the chronic state and multiple high intensity areas were shown on T2 weighted MRI image. Such a change of cerebral tracer uptake was considered to reflect the neuropathological change of Reye syndrome. 99mTc-ECD SPECT was a useful modality to diagnose Reye syndrome complementary.

[A case with superficial siderosis of the central nervous system accompanied by sensory high tone hearing loss and recurrent headache and vomiting].

A 13-year-old boy with superficial siderosis of the central nervous system was reported. There were many members, including the proband, with sensory high tone hearing loss in his maternal family, but they did not have other neurological symptoms. Paroxysmal and pulsatile severe headache, and vomiting without aura appeared recurrently at the age of 8. His consciousness was alert and no other abnormal sign or symptom was seen during the attacks. The electroencephalogram and cranial computed tomogram revealed no abnormality. The T2 weighted magnetic resonance image of the cranium showed a superficial low intensity zone on the cerebellar vermis, frontal and parietal lobes of the cerebrum, and cervical and upper portion of the thoracic spinal cord at the age of 12, when he had severe headache and vomiting. Cerebrospinal fluid showed xanthochromia with mild elevation of the protein level during an attack, and a light bloody appearance during the asymptomatic state. The diagnosis of superficial siderosis of the central nervous system was made by these findings of magnetic resonance image and cerebrospinal fluid. The bleeding sources to the subarachnoid space could not be detected by cerebral angiography.

[Infantile spasms in monozygotic twins with Smith-Lemli-Opitz syndrome type I].

Monozygotic twins with Smith-Lemli-Opitz syndrome who developed infantile spasms were presented. They were the result of the first full-term pregnancy of non-consanguineous parents. They had following abnormalities: marked growth and developmental retardation, congenital heart disease, light brown hair which is rare in Japanese, small dolichocephaly, hypertelorism, anteverted nostrils, micrognathia, hypospadias and shawl scrotum. The cranial MRI showed the delayed myelination of occipital lobe. As far as we could review published reports, we were unable to find other report on monozygotic twins having the Smith-Lemli-Opitz syndrome.

Partial characterization of an unusual 185 kDa protein synthesized by dermal fibroblasts from patients with Marfan syndrome: identification of the protein as type IV collagen.

Production of an unusual collagenous protein was observed in culture of dermal fibroblasts from four patients with Marfan syndrome. The apparent molecular weight of the protein was about 185 kDa after reduction with 2-mercaptoethanol and 175 kDa after limited pepsin treatment. The 185 kDa protein was susceptible to the bacterial collagenase but resistant to the animal collagenase. Immunoprecipitation revealed the specific interaction of the pepsin-treated 175 kDa collagenous protein with monoclonal and polyclonal antibodies to human type IV collagen. From the patterns of CNBr peptide mapping the 185 kDa band was identified as alpha 1 (IV) chain. Type IV collagen in the skin is generally considered to be of non-fibroblastic origin. However, in "diseased" condition, dermal fibroblasts might produce type IV collagen. The clinical manifestation in relation to production of type IV collagen by cultured skin fibroblasts from Marfan patients is discussed.