Neuropsychological profiles of patients with 2q37.3 deletion associated with developmental dyspraxia.

Patients with 2q37 deletions manifest brachydactyly mental retardation syndrome (BDMR). Recent advances in human molecular research have revealed that alterations in the histone deacetylase 4 gene (HDAC4) are responsible for the clinical manifestations of BDMR. Here, we report two male patients with 2q37.3 deletions. One of the patients showed a typical BDMR phenotype, and HDAC4 was included in the deletion region. HDAC4 was preserved in the other patient, and he showed a normal intelligence level with the delayed learning of complex motor skills. Detailed neuropsychological examinations revealed similar neuropsychological profiles in these two patients (visuo-spatial dyspraxia) that suggested developmental dyspraxia. These observations suggested that some other candidate genes for neuronal development exist in the telomeric region of HDAC4.

Clinical and genetic characterization of a 2-year-old boy with complete PLP1 deletion.

We report herein a case of 2-year-old boy diagnosed with a mild form of Pelizaeus-Merzbacher disease due to deletion of the entire proteolipid protein 1 (PLP1) gene. The patient demonstrated spastic quadriplegia, mental retardation, and microcephaly. He exhibited brainstem auditory evoked potentials with prolonged interpeak latencies and magnetic resonance imaging characteristics suggestive of hypomyelination in most areas of the brain with the exception of the brainstem, cerebellar peduncles, corpus callosum, and the posterior limbs of the internal capsules. Proton magnetic resonance spectroscopy revealed a mildly reduced ratio of N-acetyl aspartate to creatine levels in the white matter, suggesting axonal involvement. Additionally, nerve conduction velocity of the lower extremities was mildly decreased. Genetic analysis showed a deletion of PLP1 in this patient. Further genome mapping followed by sequence analysis of the deletion breakpoints revealed that a genomic region, about 73 kb in length, including the entire PLP1 and RAB9B, was deleted. The size of the deletion was the smallest among those previously reported in this region. Except for the 1-base pair microhomology, there were no homologous sequences between the regions around the distal and proximal breakpoints, which suggests that the deletion occurred by nonhomologous end joining.

A randomized, double-blind, placebo-controlled study of atomoxetine in Japanese children and adolescents with attention-deficit/hyperactivity disorder.

OBJECTIVES: Until the recent approval of methylphenidate (MPH), Japan had no approved treatment for attention-deficit/hyperactivity disorder (ADHD). The need still exists for an effective, safe, nonstimulant treatment. This first placebo-controlled Japan study of an ADHD nonstimulant therapy assessed atomoxetine efficacy and safety to determine the optimal dose for controlling ADHD symptoms in children and adolescents. METHODS: A total of 245 Japanese children and adolescents, aged 6-17 years and diagnosed with ADHD, were randomly assigned to receive placebo or one of three atomoxetine doses (0.5, 1.2, and 1.8 mg/kg per day) over 8 weeks. Symptoms were assessed with the Japanese Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator scored and integrated with teacher reports (ADHD RS-IV-J:I/Sch). Adverse events, vital signs, laboratory tests, and electrocardiograms (ECGs) were obtained for safety analysis. RESULTS: In all, 234 patients completed the study. Atomoxetine at 1.8 mg/kg per day was significantly superior to placebo in reducing ADHD symptoms (p = 0.01; one-sided). Decreased appetite and vomiting were significantly greater in the atomoxetine treatment groups; however, no clinically significant differences were observed. Two patients discontinued due to affect lability and headache. A linear dose-response and vital signs similar to those from other atomoxetine studies were observed. CONCLUSION: Atomoxetine provides an effective and safe nonstimulant option for the treatment of Japanese pediatric patients with ADHD.

Live birth prevalence of Down syndrome in Tottori, Japan, 1980-1999.

One hundred sixty-four patients with Down syndrome (DS) were confirmed in Tottori Prefecture, Japan, from 1980 to 1999. The sex ratio of 1.52 (99 males and 65 females) was comparable to that reported in previous studies. The live birth prevalence per 1,000 was 1.52 (95% CI: 1.29-1.75) from 1980 to 1999, with a prevalence of 1.34 (95% CI: 1.05-1.63) recorded between 1980 and 1989, and 1.74 (95% CI: 1.37-2.11) between 1990 and 1999. There was no statistically significant change between these two decades (chi(2)-test). Live birth prevalence in these two decades showed a significant increase (chi(2)-test, P < 0.005) compared with that recorded in 1969-1978 in Tottori Prefecture (0.803, 95% CI: 0.677-0.929). Mean ages of mothers at the birth of a DS patient were 31.0 years in 1980-1989 and 32.4 years in 1990-1999 (t-test, no significant difference). Dispersion analysis on the mean age of mothers at birth for patients born between 1969-1978, 1980-1989, and 1990-1999 showed a significant difference (t-test, P < 0.005), while comparing the mean age of mothers in 1969-1978 to those in 1990-1999 also revealed a significant difference (t-test, P < 0.001). Live birth prevalence has increased due to the rise in fertility rates among older women, although maternal age-specific risk rates remain unchanged. The widespread introduction of induced abortion following prenatal diagnosis decreased live birth prevalence of DS largely in European (and a few Asian) countries after 1990, or kept prevalence steady, despite increasing fertility rates among women aged 30 and over. In contrast, all published studies have reported an increase in live birth prevalence of this syndrome in Japan, probably resulting from the fact that prenatal diagnoses are used only exceptionally in this country (due to the negative attitude toward selection of life in Japanese culture).

Martsolf syndrome in Japanese siblings.

We describe a Japanese brother and sister with Martsolf syndrome. They had short stature, severe mental retardation, cataract, hypogonadism, craniofacial dysmorphism, and bone and joint symptoms including scoliosis, lax finger joints, and talipes valgus. Previously undescribed findings included proximal femoral epiphyseal dysplasia reminiscent of Legg-Calve-Perthes disease in both patients, and Klippel-Feil malformation and osteopathia striata in one patient. Brain MRI showed mild frontal and temporal lobe atrophy, and mild ventricular enlargement. Severe GH deficiency was demonstrated after insulin tolerance and glucagon/propranolol tolerance tests. No responses to serum LH and FSH after a gonadotropin-releasing hormone (GnRH) test suggested secondary hypogonadism, that is, hypogonadotropic hypogonadism, due to hypothalamus-pituitary axis insufficiency in both patients.

Contribution of the interleukin 4 gene to susceptibility to subacute sclerosing panencephalitis.

BACKGROUND: Although the exact pathogenesis of subacute sclerosing panencephalitis (SSPE) remains to be determined, both viral and host factors seem to be involved. OBJECTIVE: To identify host genetic factors involved in the development of SSPE. METHODS: We investigated the association of polymorphisms in the T helper (Th)1 and Th2 cytokine, and related genes (interferon [IFN]-gamma, IFN-gamma receptor 1 [IFN-gamma R1], IFN-gammaR2 [IRF-1], interleukin 12 receptor beta 1 [IL-12Rbeta1], IL-4, IL-4R, and IL-10 genes) with SSPE in Japanese subjects. RESULTS: A significant association (P =.03) was observed between SSPE and the T allele of the biallelic polymorphism at position -589 in the promoter region of the IL-4 gene. The IRF-1 allele 1 tended to interact with the IL-4 promoter -589 T genotype in the development of SSPE (P =.06), as judged on logistic regression analysis. The frequency of the genotype combination of IL-4 promoter -589 T and IRF-1 allele 1 (at least 1 allele) in patients with SSPE was much higher than that in the controls (47.7% vs 22.0%; P =.003, chi2 analysis). However, there was no association between other polymorphisms and SSPE. CONCLUSION: To our knowledge, this study is the first to demonstrate the possibility that the IL-4 promoter gene -589 T gene polymorphism with increased IL-4 synthesis in combination with IRF-1 allele 1 confers host genetic susceptibility to SSPE in Japanese subjects.

Unilateral occlusion of the middle cerebral artery after varicella-zoster virus infection.

We report a 4-year-old child who developed hemiplegia 6 months after varicella-zoster virus (VZV) infection. Cerebral angiography showed complete occlusion of the right middle cerebral artery with basal moyamoya vessels. Elevation of anti-VZV antibody in the cerebrospinal fluid indicated central nervous system involvement. The association between VZV cerebral angitis and unilateral occlusion of right middle cerebral artery is discussed.

[A case of left thalamic infarction with aphasia and dysgraphia in Kanji].

We reported an 11-year-old girl with left thalamic infarction causing aphasia and dysgraphia. The lesion corresponded to the perfusion area of the tuberothalamic and paramedian arteries. Confrontation naming and word finding were impaired, but phonological cuing was very helpful despite the absence of amnesia. Dysgraphia was observed only in Kanji (morphogram) writing, and was also improved by visual cuings. These findings suggested difficulty in memory retrieval, in which the left thalamus might have some role.