Wilson's disease and Menkes disease are inherited genetic disorders of copper metabolism. Each disease results from the absence or dysfunction of homologous copper-transporting ATPases present in the trans-Golgi network of cells. The Wilson ATPase transports copper into the hepatocyte secretory pathway for incorporation into ceruloplasmin and excretion into the bile. Thus, patients with Wilson's disease of the autosomal recessive trait present with signs and symptoms arising from impaired biliary copper excretion. The Menkes ATPase transports copper across the placenta, gastrointestinal tract, and blood-brain barrier, and the clinical features of this X-linked disease arise from copper deficiency. Despite striking differences in the clinical presentation of these two diseases, the respective ATPases function in precisely the same fashion within the cell. The different clinical features of each disease are the results of the tissue specific expression of these ATPases.
In Wilson's disease, impaired biliary copper excretion leads to accumulation of this metal in the liver. When the capacity for hepatic storage is exceeded, cell death ensues, with copper release into the plasma resulting in hemolysis and deposition of copper in extrahepatic tissues. Affected patients usually present in the first or second decade of life with chronic hepatitis and cirrhosis or acute liver failure. Copper accumulation in the cornea results in Kayser-Fleischer rings. Neuropsychiatric symptoms are more common in adults and include dystonia, tremor, personality changes, and cognitive impairment as a results of copper accumulation in the basal ganglia and other brain regions.
The diagnosis of Wilson's disease is confirmed by decreased serum ceruloplasmin, increased urinary copper, and elevated hepatic copper concentration. A large number of different mutations occur in the genes of patients with Wilson disease. Copper chelation drugs and zinc are effective in most cases. New treatment guidelines now advise physicians to start patients on zinc.

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The bylaws of Japanese Society of Child Neurology (JSCN) declare that the purpose of this Society is to promote research activity, educational programs for child neurologists, and cooperation with other related organizations. It also has a large role to provide the results of research to the wider community. As for promotion of research, acquisition of research funding is quite important. It is necessary to increase applications for grants and to be well known by other researchers, and especially by the relevant authorities. One way to do this is to send reprints to the authorities in various research fields. Participating to the congress party to let lots of people notice his/her activity may also be effective. To promote the Impact Factor of the official journal of JSCN, Brain & Development (B & D), members should cite as many articles from B & D as possible when they submit a manuscript. The members of JSCN must respond to the demands of patients and family members as specially trained child neurologists. I am pleased that the newly founded Social Activity and Public Relations Committee has acted vigorously. I want to ask all the young members to participate positively in our activities and support the Society.

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Congenital muscular dystrophy (CMD) is a group of heterogeneous disorders characterized clinically by delayed milestones due to generalized muscle weakness and dystrophic muscle pathology. The discovery of fukutin, responsible gene for Fukuyama CMD (FCMD) and defective glycosylation in its muscle biopsy has lead significant advances in CMD researches, especially disorders with glycosylation defects to α dystroglycan (α DG). The highly glycosylated α DG is one of the major dystrophin-associated proteins anchored a basement membrane protein, laminin 2 to the dystrophin molecule. The disorders with the defective glycosylation are now categorized as α dystroglycanopathies which include FCMD, muscle-eye-brain (MEB) disease, Walker-Warburg syndrome (WWS) and diseases with mutations in fukutin-related protein (FKRP) and LARGE genes. Among them, MEB and WWS were proven to have mutations in the glycosyltransferase genes, POMGnT1 (protein O-mannose β 1, 2-Nacetylglucosaminyl/transferase 1) and POMT1 (protein O-mannosyltransferase 1), respectively, though others are still unknown how the glycosylation defect is induced. Although the disease with FKRP mutation has variable phenotypes from CMD to limb-girdle muscular dystrophy, others with defective to decreased α DG show CMD, central nervous system involvement with migration disorder (polymicrogyria) and ocular abnormalities.

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Developmental disorders such as mental retardation, language disorders, autistic disorders, learning disorders, attention deficit/hyperactivity syndrome and conduct disorders are an important part of our daily practice in child neurology. Early diagnosis and early or timely intervention in these kinds of developmental disorders were stressed and family support in child-rearing was emphasized in this symposium. In addition to the above, sleep disorders in developmental disorders were discussed.

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Autism is a syndrome that consists of disturbances in social interactions, communication and imagination, and its first-choice of therapy is education. Of special interest is the period of the onset and early diagnosis of autism, and its relation to the period of intervention. In retrospective studies from questionnaire and home videotape analysis, it has been reported that autistic children display significantly less social interaction, joint attention behavior and communicative behavior compared to typical children, before 12 to 18 months of age. Although there is less evidence of a marked reduction in autistic symptomatology, early intervention studies have been found to have positive effects with significant improvements being reported in social behavior, self care, and academic skill. However, early interventions are controversial. We discuss early diagnosis and interventions in children with autism in this paper.

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In the diagnosis of speech retardation, not only speech production and comprehension, but the assessment of interpersonal relationships is important as an indicator of non-language development. The newly revised K method developmental examination (“Shinban K-shiki Kensahou”) is widely used as an assessment for preschool children. I think the Enjouji method analytical developmental examination for infant and preschool children (“Enjouji-shiki Bunsekiteki Kensahou”) is a simple and useful examination scale of developmentaldelay because it includes the category of interpersonal relationship.
Developmental language disorder (DLD) is the most frequently noted (4.3%) in the general population as seen in our research of speech retardation of 1 year-6 month examination in Ota-ku district. Some academic societies of children warn that TV watching for a long time causes speech retardation or psychiatric disorders, but it seems to me that this influence is of limited significance. To assess autism adequately we made a checklist that includes concrete behavioral abnormalities based on the criteria of DSM-1V. The criteria of DLD are diverse and are not currently standardized now. I proposed, therefore, a criterion by unifying them.

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Patients with mental retardation (MR) cannot always be diagnosed accurately by physicians who are specialized in child neurology and/or developmental disorders at their first visit to the clinic. Precise examination such as psychological tests and chromosomal analysis are often necessary to diagnose them. Some patients with autistic disorders without MR often are misdiagnosed as having MR. Patients with mild to moderate MR are sometimes diagnosed late in their late teens or twenties. Timely diagnosis and timely/continuous intervention is more important than early diagnosis and early intervention for the mentally retarded.

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I described a novel system of health examination of five-year-olds in Tottori prefecture. This health examination was aimed at effective detection of children with attention deficit/hyperactivity disorders (AD/HD), learning disorders (LD), higher functioning pervasive disorders (HFPDD) and so on. It is difficult for these developmental disorders to be detected adequately at three years old because hyperactivity, short attention span, lower social interaction and cognitive deficits are not able to be confirmed as specific symptoms in three-year-olds. As a result of our health examination of five-year-olds, there are many children with these developmental disorders who were overlooked at the health examination at three years old.
Health examination for babies/infants and consultation with their guardians should be performed as one package to detect children with AD/HD, LD, HFPDD effectively, and this package must have an important relation to school enrollment.

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Many patients with developmental disabilities exhibit various types of sleep disturbance. However, we have no idea of a specific approach to relieve the symptoms on sleep disturbance, although recent basic neuroscience has provided many novel findings on the neuronal mechanisms of the sleep-wakefulness cycle. In this brief review, a flip-flop circuit was introduced to explain neuronal mechanisms of the abrupt change between sleep and wakefulness. The rate of atonia during non-REM sleep was also introduced, as this index may useful for assessing the cholinoaminergic balance of the central nervous system. Sleep hygiene was also based on basic sleep-wakefulness mechanisms. To maintein sleep hygiene is a fundamental approach caring for patients with sleep disturbance, and specific approaches such as medication and treatment of sleep disordered breathing should also be based on the basic mechanisms of the sleep-wakefulness cycle. It was emphasized that effective intervention should only occur after the careful assessment of neuronal background of each patient.

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Conduct disorder (CD) is a serious psychiatric disorder of children and adolescents. A common association is the presence of attention-deficit hyperactivity disorder. The present paper reviews empirical findings on CD. The correlative factors were analyzed according to their bio-psycho-social aspects. To be effective, early detection and intervention on CD must be multimodal.
We should address treatments on multiple foci, and continue them over an extensive period of time.

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[in Japanese]

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