[Treatment for self-injurious behavior in mentally handicapped populations--a report from our practice].

OBJECTIVE: Self-injurious behavior (SIB) is a common problem in individuals with intellectual disabilities, yet its clinical management remains to be established. We aimed to clarify the background factors and profiles of SIB in mentally and physically handicapped subjects and subsequently examined the efficacy of treatments attempted in our practice in order to achieve a better understanding of SIB and appro- priate interventions in these populations. METHODS: We surveyed 92 mentally handicapped subjects with SIB (including 25 females and 67 males, most of whom also had physical disabilities) as outpatients or inpatients of our institution using a retrospective questionnaire com- pleted by the corresponding doctors. RESULTS: Regarding psychobehavioral complications, impulsive mood swings (such as sudden rage) were more frequent than other behaviors. As to probable triggers of SIB, the patient's physical condition (17 cases) and noise or the temperature of the surrounding environment (38 cases) were identified. A total of 81 of 92 patients were given a prescription for SIB. Risperidone was the most commonly prescribed drug (75 cases), found to be effective in 38 (50.6%) cases, whereas phenothiazine antipsychotics were often more effective in patients with profound SIB. SSRIs (selective serotonin reuptake inhibitors) were applied in 20 cases, being effective in only five (25%) patients and discontinued in 11 (55%) patients due to the onset of several side effects, including overexcitement. As an additional agent for mood control, the antiepileptic topiramate was effective in 10 (76.9%) of 13 cases. Aside from medication, equipment for elbow extension was beneficial in some of the patients with profound SIB. CONCLUSIONS: Pharmacological intervention is sometimes beneficial, albeit only partly. Clinicians must therefore also consider triggers and factors in the surrounding environment for the development of SIB in mentally handicapped individuals.

Silent exonic mutation in the acid-alpha-glycosidase gene that causes glycogen storage disease type II by affecting mRNA splicing.

Glycogen-storage disease type II (GSDII) is an autosomal recessive disorder caused by a deficiency of acid alpha-glucosidase (GAA). The residual GAA activity is largely related to the severity of the clinical course. Most patients with infantile-onset GSDII do not show any enzyme activity, whereas patients with the late-onset forms of GSDII show various degrees of GAA activity. We performed a molecular genetic study on a Japanese boy with childhood-onset GSDII. The patient was a compound heterozygote for a newly discovered splice-site c.546G>T mutation and a recurrent missense p.R600C mutation, which usually causes the fatal infantile form in a homozygous state. The c.546G>T mutation, which did not alter the amino-acid sequence, was positioned at the last base of exon 2. cDNA-sequencing analysis revealed that c.546G>T was a leaky splice mutation, leading to the production of a normally spliced transcript, which was responsible for the low-level (approximately 10%) expression of the active enzyme in the patient's fibroblasts.

Molecular analysis and anticonvulsant therapy in two patients with glucose transporter 1 deficiency syndrome: a successful use of zonisamide for controlling the seizures.

Glucose transporter 1 (GLUT1) deficiency syndrome is caused by a deficit in glucose transport to the brain during the pre- and postnatal periods. Here, we report two cases of GLUT1 deficiency syndrome diagnosed on the basis of clinical features, reduced GLUT1 activities, and mutations in the GLUT1 gene. Patient 1 had a novel heterozygous 1bp insertion in exon 7 that resulted in a shift of the reading frame and the introduction of a premature stop codon at amino acid position 380. His clinical phenotype appeared to be more severe than that of Patient 2 who had a missense mutation in exon 8 resulting in an arginine-to-tryptophan substitution at amino acid position 333. Patient 1 had no meaningful words and could not walk unassisted, while Patient 2 could speak and walk unassisted. Both the patients developed seizures of various types that have been successfully treated with zonisamide. Although several antiepileptic drugs, including barbiturates, diazepam, chloralhydrate, and valproic acid, have been shown to inhibit GLUT1 function, the present study demonstrated no inhibitory effect of zonisamide on GLUT1-mediated glucose transport. Our data suggested that zonisamide might be preferable if add-on anticonvulsant therapy is required to control the seizures in patients with this disorder.

Modified Atkins diet therapy for a case with glucose transporter type 1 deficiency syndrome.

Glucose transporter type 1 deficiency syndrome (GLUT-1 DS), giving rise to impaired glucose transport across the blood-brain barrier, is characterized by infantile seizures, complex motor disorders, global developmental delay, acquired microcephaly, and hypoglycorrhachia. GLUT-1 DS can be treated effectively with a ketogenic diet because it can provide an alternative fuel for brain metabolism; however, the excessive restriction of food intake involved frequently makes it difficult for patients to initiate or continue the diet. Recently, the modified Atkins diet, which is much less restrictive in terms of the total calorie and protein intake than the classical ketogenic diet, has been shown to be effective and well tolerated in children with intractable epilepsy. We successfully introduced the modified Atkins diet to a 7-year-old boy with GLUT-1 DS, whose caregivers refused ketogenic diet treatment because of strong concerns over restricting the diet. The modified Atkins diet should be considered for patients with GLUT-1 DS as an alternative to the traditional ketogenic diet.

Actigraphic assessment of sleep disorders in children with chronic fatigue syndrome.

UNLABELLED: Children with chronic fatigue syndrome (CFS) often suffer from sleep disorders, which cause many physiological and psychological problems. Understanding sleep characteristics in children with CFS is important for establishing a therapeutic strategy. We conducted an actigraphic study to clarify the problems in sleep/wake rhythm and physical activity in children with CFS. METHODS: Actigraphic recordings were performed for 1-2 weeks in 12 CFS children. The obtained data were compared with those of healthy age-matched children used as the control. RESULTS: Sleep patterns were divided into two groups based on subjects' sleep logs: irregular sleep type and delayed sleep phase type. Compared to the control group, total sleep time was longer and physical activity was lower in both groups of CFS. Continuous sleep for more than 10h was not uncommon in CFS. In the irregular sleep type, impaired daily sleep/wake rhythms and disrupted sleep were observed. CONCLUSION: Using actigraphy, we could identify several characteristics of the sleep patterns in CFS children. Actigraphic analysis proved to be useful in detecting sleep/wake problems in children with CFS.

[Questionnaire survey on sleep habit of 3-year-old children in Asahikawa City].

The present study surveyed the sleep habits of 3-year-old children in Asahikawa city using questionnaires completed by a parent during children's medical check-ups. Questionnaires were collected from the parents of 404 children (209 males, 195 females; mean age, 3.1 years) enrolled in this survey. Among these children, the mean bedtime was 9.6 PM with 145 children (36%) going to bed after 10 PM. On the other hand, the mean wake-up time was 7.5 AM, with 123 children (30%) waking up after 8 AM. The mean nocturnal sleep duration was 10.1 hours. Nocturnal sleep durations in children that went to bed after 10 PM were significantly shorter than in children who went to bed earlier (p < 0.01). Seventy-three percent of the children had a daily afternoon nap. Twelve percent of these children usually awoke from their nap after 5 PM, and the mean bedtime for these children was 10.1 PM. A late bedtime was significantly correlated with parental complaints such as short-temper and poor appetite (p < 0.05). Although parents were concerned about night-time sleep conditions, they were not concerned about the daytime conditions which regulate children's sleep-wake rhythm, such as daylight exposure, daytime activity, and naps. While 24% of parents had complains regarding their children's sleep, only 3% had consulted with a doctor. Similar to the previous reports, the present findings demonstrate that children in Asahikawa city go to bed late and have decreased sleep duration. Since the establishment of a normal sleep-wake rhythm is essential for both physical and mental development in children, it is necessary to educate parents regarding the importance of children's sleep.

Postnatal development of brainstem serotonin-containing neurons projecting to lumbar spinal cord in rats.

We quantified postnatal changes in brainstem serotonin (5-hydroxytryptamine, 5-HT)-containing neurons projecting to lumbar spinal cord. The medulla-spinal cord descending neurons were identified by a retrograde neurotracer, choleratoxin B subunit (CTb), and 5-HT neurons were stained by immunohistochemistry. Double-labeled neurons were assumed to be 5-HT neurons projecting to the lumbar spinal cord, and were quantitatively analyzed in each raphe nucleus in the medulla. The following results were obtained: (1) At PND 3, numerous CTb-labeled neurons (CTLN) were already present in the raphe pallidus (B1), while few CTLN were seen in raphe obscurus (B2) and raphe magnus (B3). CTLN then rapidly increased in number and were separately distributed after PND 7 in B3 and after PND 14 in B2. (2) At PND 3, numerous 5-HT-containing neurons were already present in B1-B3, with 23.4% and 14.0% of them labeled with CTb in B1 and B2, respectively, while there were few double-labeled neurons in B3. From PND 3 to 28, although the proportion of double-labeled to 5-HT neurons remained unchanged in B1 and B2, that in B3 rapidly increased from 5.8% at PND 7 to 28.8% at PND 14. Previous studies have shown that the 5-HT neurons in B3 send fibers mainly to the dorsal horn, while those in B1 and B2 send fibers mainly to the ventral horn at all spinal cord levels. Taken together, the present findings suggest that the brainstem 5-HT systems influence the ventral horn of the spinal cord, where spinal motoneurons exist earlier than in the dorsal horn. The functional significance of these early 5-HT systems in motor development and/or disabilities is discussed.

[A case of childhood onset myoclonus epilepsy with ragged-red fibers--with special reference to various clinical manifestations].

There are few descriptions about the clinical course of children with myoclonus epilepsy with ragged-red fibers (MERRF). We reported a girl who was diagnosed as having MERRF at 10 years of age and developed various clinical manifestations including chronic respiratory failure, paralytic ileus and pancytopenia at 18 years of age. Administration of cytochrome c worsened lactic acidosis and muscle weakness, while intravenous hyperalimentation with copper supplementation gradually improved these findings as well as pancytopenia. Cytochrome c oxidase is a copper dependent enzyme. Its activity is extremely low in MERRF patients. It was suspected that deficiency of serum copper and supplementation of cytochrome c worsened the clinical symptoms of our patient.

Effect of neonatal hypoxia on the development of intraspinal serotonergic fibers in relation to spinal motoneurons.

Serotonin (5-hydroxytryptamine; 5-HT)-containing neurons trophically affect target neurons and modulate central nervous system neuronal activity. We studied effects of neonatal hypoxia on postnatal development of intraspinal 5-HT fibers in spinal motoneuron pools. Postnatal day (PND) 0 Sprague-Dawley rats received a hypoxic load and survivors were used for histological analyzes on PNDs 1, 7, and 14. Spinal motoneurons were labeled using choleratoxin B subunit as a retrograde neurotracer, and 5-HT fibers were detected immunohistochemically. On PND 1, 5-HT fibers were present in the lateral portion of the ventral horn at the cervical level, but were sparsely distributed at the lumbar level. On PND 14, cervical and lumbar level distributions were nearly identical. The 5-HT fibers and varicosities in close apposition to motoneurons increased from PNDs 1-14, however, the close apposition of cervical motoneurons was significantly different from lumbar motoneurons only on PND 1. Density of 5-HT fibers in control and hypoxic rats was not different on PND 1, while those in hypoxic rats were significantly reduced on PND 14. Close appositions of lumbar motoneurons were reduced more than cervical MNs after neonatal hypoxia. Neurodevelopmental deficit after neonatal hypoxia with a rostro-caudal gradient is associated with significant changes in the 5-HT system.