Behavioral development of infant holding and its laterality in relation to mothers' handedness and child-care attitude.

The holding of 465 Japanese infants by their mothers was longitudinally observed at 4 and 9 months with several checkups and questionnaires of physical and psychological development and child-care attitude in a larger longitudinal study of mother-child relationships. A left side bias in holding was significant for the 4-month-old infants. The infants' increased autonomy in their ability to adopt a posture at 9 months weakened the holding bias. The mothers' handedness was related to different right/left hand contact patterns, but it was significant only for holding on the left side. The infants' reflexes relating to posture did not correlate with the holding bias at 4 months. The meaning and possible determinants of holding laterality are discussed.

Neuropathological analysis in spinal muscular atrophy type II.

We performed a neuropathological analysis, including in situ nick end labeling (ISEL) and immunohistochemistry, of two cases of clinicogenetically confirmed infantile spinal muscular atrophy (SMA) type II. Both cases showed severe reduction of the motor neurons and gliosis in the spinal cord and brain stem, although the occurrences of central chromatolysis and ballooned neurons were not frequent. Clark's and lateral thalamic nuclei, which are usually altered in SMA type I, were spared, whereas Betz cells in the precentral gyrus and large myelinated fibers in the lateral funiculus were reduced in number. Regarding apoptosis, only the younger case demonstrated a few ISEL-positive nuclei in the dorsal horn, with reduced Bcl-x expression level in the Purkinje cells. Unlike SMA type I, the expression of neurofilaments was not disturbed and the reduction in synaptophysin expression level in the anterior horn was mild. An oxidative stress-related product was deposited in atrophic motor neurons in the spinal cord, and neurons with nuclei immunoreactive for 8-hydroxy-2'-deoxyguanosine were found in the lateral thalamus. In contrast, the expression of glial glutamate transporters was not altered. These data suggest that oxidative stress and, to a lesser extent, apoptotic cell death, but not disturbed neurofilament metabolism or excitotoxicity, may be involved in neurodegeneration in SMA type II.

The gene copy ratios of SMN1/SMN2 in Japanese carriers with type I spinal muscular atrophy.

Spinal muscular atrophy is an autosomal recessive neurodegenerative disorder with progressive weakness and atrophy of voluntary muscles. The survival motor neuron gene (SMN) is present in two highly homologous copies (SMN1 and SMN2) on chromosome 5q13. Homozygous deletion of exons 7 and 8 of SMN1 is responsible for spinal muscular atrophy. In spinal muscular atrophy patients, SMN2 partially compensates for the lack of SMN1. Previously, we reported the relatively high incidence of a large deletion including the SMN1 region in Japanese spinal muscular atrophy type I patients. In order to further establish the genetic background of Japanese spinal muscular atrophy type I patients, we investigated the SMN1/SMN2 ratio in the carriers. In normal individuals, there is one copy of each gene on the chromosome (the SMN1/SMN2 ratio was 1). Among 15 carriers (14 parents and one carrier sibling of Japanese type I spinal muscular atrophy patients with homozygous deletion of exons 7 and 8 of SMN1), we found that the SMN1/SMN2 ratio was 0.5 or 1 in 11 (73.3%) carriers. The remaining four carriers had an SMN1/SMN2 ratio of 1/3. This finding supports the idea that deletion rather than conversion is the main genetic event in type I spinal muscular atrophy. In addition, the ratio of SMN1/SMN2 among Japanese carriers, which was thought to be higher than that of the Western population, was compatible with the results obtained in Western populations. For further insight into the characteristic genetic background of spinal muscular atrophy in Japanese, determination of the gene copy number is essential.

Enhanced expression of a-series gangliosides in fibroblasts of patients with peroxisome biogenesis disorders.

Peroxisome biogenesis disorders (PBD) are classified into Zellweger syndrome (ZS), infantile Refsum disease (IRD) and neonatal adrenoleukodystrophy. Disturbances in the differentiation of neural cells such as migration arrest are characteristic of PBD. So far the pathogenesis of these disturbances is not clearly understood. We describe an altered metabolism of glycosphingolipids in PBD which has not yet been investigated. We observed an increased amount of a-series gangliosides, GM2, GM1 and GD1a, in the fibroblasts of patients with ZS and IRD. Gangliosides GM1 and GD1a were not present in detectable amounts in normal subjects. A key step in the synthesis of a-series gangliosides is a transfer of GalNAc to ganglioside GM3, so we determined the level of ganglioside GM3 by immunohistochemical methods. We found a granular structure, which was positive toward anti-ganglioside GM3 antibody in the cytoplasm of the patients' fibroblasts. In control cells, the cell membrane was slightly positive toward anti-GM3 antibody. These results may help to clarify the pathogenesis of PBD with respect to the functional roles of glycosphingolipids in cell differentiation, proliferation and apoptosis.

Varicella-associated acute necrotizing encephalopathy with a good prognosis.

A patient with acute necrotizing encephalophathy (ANE) following varicella infection with a good prognosis is reported. A somatosensory evoked magnetic field (SEF) study using a 37-channel-magnetoencephalography system demonstrated normal latency and strength of the first component (N20m) elicited by median nerve stimulation, despite bilateral symmetrical thalamic lesions on MRI. The normal SEF findings and the good prognosis suggested a reversible breakdown of the blood-brain barrier, and an edematous process as the brain pathology. Furthermore, our results support the idea of distinct generators for the three earliest cortical SEF components (N20m, P30m, N45m).

Neuronal expression of the fukutin gene.

Fukuyama-type congenital muscular dystrophy (FCMD), a relatively common autosomal recessive disorder in Japan, is characterized by severe congenital muscular dystrophy in combination with cortical dysgenesis (polymicrogyria). The gene responsible for FCMD encodes a novel protein, fukutin, which is likely to be an extracellular protein. Pathological study of brain tissue from FCMD fetuses revealed frequent breaks in the glia limitans and basement membrane complex. Disruption of the basal lamina in FCMD muscle was also seen. Thus, structural alteration of the basal lamina appears to play a key role in the pathophysiology of FCMD. To investigate the role of fukutin in brain anomalies, we examined fukutin mRNA expression in the human brain. Northern blot and RT-PCR analysis revealed that the fukutin gene is expressed at similar levels in fetal and adult brain, whereas its expression is much reduced in FCMD brains. Tissue in situ hybridization analysis revealed fukutin mRNA expression in the migrating neurons, including Cajar-Retzius cells and adult cortical neurons, as well as in hippocampal pyramidal cells and cerebellar Purkinje cells. However, we observed no expression in the glia limitans, the subpial astrocytes (which contribute to basement membrane formation) or other glial cells. In the FCMD brain, neurons in regions with no dysplasia showed fair expression, whereas transcripts were nearly undetectable in the overmigrated dysplastic region. These observations suggest that fukutin function may influence neuronal migration itself rather than formation of the basement membrane. Furthermore, differences in mRNA levels among neurons in early developmental stages may partially differentiate normal and abnormal regions.

Long-term ventilator support in patients with Werdnig-Hoffmann disease.

BACKGROUND: Withholding and withdrawing life-sustaining treatment for patients with Werdnig-Hoffmann disease (WHD) have been accepted as standard medical practice in most Western countries. However, a number of Japanese pediatricians are providing ventilator care for patients with this otherwise fatal disorder. We investigated the attitude of physicians in Japan who are providing ventilator care for patients with WHD. METHODS: A postal questionnaire was sent to 40 hospitals where pediatricians were taking care of 55 ventilator-assisted patients with WHD. Their views were sought on aspects of the care of these patients. RESULTS: Thirty-three pediatricians from 31 hospitals responded to the questionnaire. Mechanical ventilation was initiated as an emergency measure in one-third (12/32) of the patients before obtaining full informed consent from the parents. Two-thirds (19/32) of parents asked the physicians to start ventilator care for the patients, while only three parents asked for the life-sustaining treatment to be withheld. Although 80% (24/30) of the physicians thought that the quality of life of the ventilator-dependent patients with WHD was inadequate, about half (17/30) answered that they would start ventilator assistance if they had a new patient with WHD. DISCUSSION: Strong familial endorsement for the prolongation of a patient's life, the secure national insurance and general pro-life beliefs could have affected physicians' decisions in favor of providing life-sustaining treatments for patients with WHD.

Zonisamide - induced urinary lithiasis in patients with intractable epilepsy.

We report here three patients with intractable epilepsy who developed urinary lithiasis during zonisamide (ZNS) treatment. Abdominal pain due to left-sided hydronephrosis was the initial symptom in the first patient, and it was resolved after the excretion of a stone. The second patient, who had no specific symptoms, was found to have a thick sludge of calcium phosphate in the bladder when he suffered from aspiration pneumonia and dehydration. The third patient, who had a history of recurrent urinary obstruction, was also found to have a thick sludge of calcium oxalate in the bladder. The urinalysis of the three patients revealed alkaline urine and hypercalciuria. Although their urinary lithiasis was resolved by discontinuation of ZNS and supportive therapy, routine examination of urine parameters such as pH and sediments, and daily urine-output checks are thought to be necessary during treatment with ZNS, especially for patients who are bedridden for a long time and receive multiple antiepileptic drugs.

Magnetoencephalographic study of giant somatosensory evoked responses in patients with rolandic epilepsy.

We report five patients with rolandic epilepsy associated with giant somatosensory responses to median nerve stimulation, in whom we analyzed the pathophysiologic relationship between rolandic discharges and the somatosensory responses using magnetoencephalography. Four of the five patients showed giant P30m, the current source of which was localized in the primary somatosensory cortex, while the first cortical response, N20m, was not enhanced, except in one patient. The current source of the giant middle-latency component, N70m, was localized posterior to that of N20m, possibly in the posterior parietal cortex, in all patients. The initial positive peak and large negative peak of rolandic discharges were identical to P30m and N70m with respect to the current source localization, wave form, topographic pattern, and time relationship in the electroencephalogram and magnetoencephalogram, and somatosensory evoked magnetic field and somatosensory evoked potential records, respectively. In addition, the secondary sensory cortex was considered to be the generator of the middle-latency component in one patient. In one patient, the current intensity of the N70m was normalized along with clinical improvement and the disappearance of rolandic discharges, whereas those of other somatosensory evoked magnetic field components remained unchanged. Our data suggest that the rolandic discharge generator mechanism in these patients could be closely related to the developmental alteration of excitability in the primary somatosensory cortex, posterior parietal cortex, and secondary somatosensory cortex, which decreased with age, and it could share a common neuronal pathway, at least in part, with the giant P30m-N70m (N90m) in the somatosensory evoked magnetic field through the sequential and parallel processing of somatosensory information.

[Medical care and support for children with mental retardation in school].

Development of medical knowledge and technology has greatly improved our understanding of mental retardation. However, clinically applicable treatment of mental retardation is still limited. As described in the definition of mental retardation by the American Association of Mental Retardation, functional maladaptations in various aspects of everyday life are the most integral part of disabilities in mental retardation. The role of pediatric neurologist in the medical care for children with mental retardation is not limited in medical treatment. Pediatric neurologists should play an important role as a coordinators in integrated care. Providing of medical care in special schools for children with mental retardation is among the most important issues, since children spend most of their time either at home or in school. The current situation of "medical care" in school, and its problems are discussed.

Ethical attitudes of Japanese physicians regarding life-sustaining treatment for children with severe neurological disabilities.

Ethical attitudes of Japanese physicians regarding life-sustaining treatment for children with severe neurological disabilities (SND) were investigated by mailing a translated questionnaire which the Child Neurology Society (CNS) of the United States used for their survey. The questionnaire was sent to 202 council members of the Japanese Society of Child Neurology (JSCN), and the answers of 147 respondents (72.8%) were analyzed. It was found that the majority (85. 0%) of respondents believed that the same level of care should be provided to children with SND as those without it. However, fewer respondents (15.6%) believed that cardiopulmonary resuscitation was indicated for children with progressive or degenerative brain disorders. With respect to the authoritative role of medical indications and family/guardian's wishes in clinical decision-making for children with SND, about 30% of respondents believed that medical indications should override family/guardian's wishes. However, almost as many respondents (29.9%) chose an ambivalent answer. If compared with the results of the preceding CNS survey, considerably more respondents gave ambivalent answers (average 26. 6%) than in the CNS survey (5.8%). About half of the respondents (49. 0%) acknowledged the need for ethical guidelines to help physicians make ethically difficult decisions. Although statistical comparison was not possible, there were considerable differences between the results of the current study and those of the CNS survey.

New ocular movement detector system as a communication tool in ventilator-assisted Werdnig-Hoffmann disease.

A non-contact communication system was developed for a ventilator-assisted patient with Werdnig-Hoffmann disease who had lost all voluntary movements except for those of the eye. The system detects the extraocular movements and converts them to either a 'yes' signal (produced by one lateral eyeball movement) or a 'no' signal (produced by two successive lateral eyeball movements) using a video camera placed outside the patient's visual field. The patient is thus able to concentrate on performing a task without any intrusion from the detection system. Once the setting conditions of the device have been selected, there is no need for any resetting, as the patient is unable to move his body. In addition to playing television games, the child can use the device to select television channels, compose music, and learn written Japanese and Chinese characters. This seems to broaden the patient's daily world and promote mental development.

Hyperinsulinaemic hypoglycaemia associated with persistent hyperammonaemia.

UNLABELLED: Two cases of hyperinsulinaemic hypoglycaemia associated with persistent hyperammonaemia in unrelated infants of 7 days and 4 months of age are reported. Blood ammonia levels were 100-300 micromol/l (normal values <40 micromol/l). The hyperammonaemia was asymptomatic and not associated with any of the abnormalities of amino acids or organic acids observed in urea cycle enzyme defects. Orotic aciduria was normal. The hyperammonaemia was not influenced by the levels of blood glucose nor by subtotal pancreatectomy. On admission blood glucose was ca. 1.2 mmol/l (21.6 mg/dl) corresponding to blood insulin levels of 35 and 22 mU/l respectively in both infants. Continuous intravenous glucose perfusion was necessary to prevent hypoglycaemia. Furthermore 2-oxoglutaric acid in urine was increased in the second infant to 3.15 mg/mg creatinine (normal 0.41+/-0.12). This may point to mutations in the glutamate dehydrogenase gene. CONCLUSION: 2-Oxoglutaric aciduria may be an important clue to the diagnose in this syndrome.