Kumi Kato-Nishimura

Severe mandibuloacral dysplasia caused by novel compound heterozygous ZMPSTE24 mutations in two Japanese siblings

Mandibuloacral dysplasia (MAD) is a rare autosomal recessive progeroid syndrome, characterized by mandibular hypoplasia, acroosteolysis affecting distal phalanges and clavicles, delayed closure of the cranial sutures, atrophic skin, and lipodystrophy. Recently, mutations in lamin A/C (LMNA) and zinc metalloprotease (ZMPSTE24), involved in post‐translational processing of prelamin A to mature lamin A, have been identified in MAD kindreds. We now report novel compound heterozygous mutations in exon 1 (c.121C>T; p.Q41X) and exon 6 (c.743C>T; p.P248L) in ZMPSTE24 in two Japanese sisters, 7‐ and 3‐year old, with severe MAD and characteristic facies and atrophic skin. The older sister had lipodystrophy affecting the chest and thighs but sparing abdomen. Their parents and a brother, who were healthy, had heterozygous mutations. The missense mutation, P248L, was not found in 100 normal subjects of Japanese origin. The mutant Q41X was inactive in a yeast halo assay; however, the mutant P248L retained near normal ZMPSTE24 activity. Immunoblots demonstrated accumulation of prelamin A in the patients’ cell lysates from lymphoblasts. The lymphoblasts from the patients also revealed less intense staining for lamin A/C on immunofluorescence. We conclude that ZMPSTE24 deficiency results in accumulation of farnesylated prelamin A, which may be responsible for cellular toxicity and the MAD phenotype.

Sleep problems are more frequent and associated with problematic behaviors in preschoolers with autism spectrum disorder

BACKGROUND Children with autism spectrum disorder (ASD) often suffer from sleep problems that in turn correlate with behavioral problems. However, in Japan, there have been few studies of sleep problems in children with ASD. AIMS This study compared sleep problems in preschoolers from the community and preschoolers with ASD in Japan, and examined whether sleep problems were related to problematic behaviors in ASD preschoolers. METHODS AND PROCEDURES Sleep problems were assessed in 965 community and 193 ASD preschoolers using the Japanese Sleep Questionnaire for Preschoolers, which was developed to assess sleep problems in Japanese preschoolers. Behavioral problems were assessed in 107 ASD preschoolers using the Child Behavior Checklist. OUTCOMES AND RESULTS Compared with community preschoolers, ASD preschoolers experienced significantly more sleep problems, including obstructive sleep apnea and parasomnias. ASD preschoolers with sleep problems exhibited more behavioral problems than those without sleep problems. The severity of sleep problems, especially insomnia, was significantly correlated with behavioral problems in ASD preschoolers. CONCLUSIONS AND IMPLICATIONS The present study suggests that sleep problems, especially obstructive sleep apnea, are more common in ASD preschoolers than in community preschoolers. The study also shows that sleep problems, especially insomnia, are related to problematic behavior in ASD preschoolers.

Evaluation of oral iron treatment in pediatric restless legs syndrome (RLS).

OBJECTIVE We conducted a retrospective chart review of children with restless legs syndrome (RLS) to evaluate the efficacy of oral iron treatment, which was administered open-label during the course of clinical care. In addition, we provided detailed clinical information about RLS in this pediatric cohort. PATIENTS AND METHODS The study included 30 consecutive Japanese children with RLS who visited the Pediatric Sleep Clinic at Osaka University Hospital, and consisted of 17 boys and 13 girls, aged 2-14 years (mean ± SD, 6.5 ± 2.8). All-night polysomnography was performed in 18 patients and serum ferritin levels were measured in all the patients. After the diagnosis of RLS, iron was administered at doses between 1.6 and 7.8 mg/kg/day (3.2 ± 1.3). Serum ferritin was re-evaluated 3-6 months after iron treatment, or when RLS symptoms had disappeared. RESULTS The patient age at onset of RLS symptoms ranged from six months to 13 years (4.3 ± 3.6). A positive family history was recognized in 19 children (63.3%). Serum ferritin levels before therapy were 9-62 ng/ml (26.6 ± 12.8) and oral iron supplementation was reported to be highly effective in 17 children, effective in 10, and ineffective in three. The serum ferritin level at follow-up was 23-182 ng/ml (83.5 ± 49.8). The onset of treatment effect was within approximately three months. CONCLUSIONS Iron treatment could be effective in Japanese pediatric RLS.

Examination of non-restrictive and non-invasive sleep evaluation technique for children using difference images

In recent years, the inappropriate sleep style for children has become known as one of the important causes of behavioral disorders, for example inattentiveness during waking hours or hyperactivity. Consequently, screening for the children having sleep disorders is needed to treat in the early stage of the behavioral disorders. From the point of view of evaluation for childrens sleep, there are three problems. First, the conventional polysomnogram (PSG) requires great investment in facility and high personnel cost so that hospitals equipped with the PSG examination are rare. Next, the sleep-check examination system such as PSG and so on requires many sensors to be attached to the clients face and body. So the client feels suffering severe stress and the wires of sensors trigger some accidents. At last, it is very difficult to get ordinary sleep style in the sleep examination room because of above factors. It is strongly desirable to develop a new method of sleep evaluation system in place of conventional PSG that is non-restrictive and non-contact. Taking these problems into account, we devised a technique with these characteristics that is completely separated from sensors. It determines the sleep condition from body movement information by measuring movements using difference processing of video image. Our study of using this technique on pediatric patients indicated that this non-restrictive technique could be effective for evaluating body movement during sleep. It was looked for a relationship between movements information and sleep conditions.

Sleep disordered breathing in childhood-onset acid maltase deficiency.

OBJECTIVES To clarify the feature of sleep disordered breathing (SDB) associated with childhood-onset acid maltase deficiency (AMD): the progressive nature of SDB and the stage of AMD. STUDY DESIGN We retrospectively studied 4 patients with childhood-onset AMD by analyzing the results of neurological examinations for muscle wasting and muscle strength and the data on venous gas and from a pulmonary function test and nocturnal polysomnography (PSG). RESULTS Three out of the 4 patients showed muscular symptoms including myalgia, lordoscoliosis, muscle wasting and muscle weakness. They also complained of sleep-related symptoms such as tiredness in the morning and daytime sleepiness. All of them showed SDB by PSG, even in a patient in the earliest stage who exhibited no signs or symptoms of muscle weakness. In 3 patients, noninvasive intermittent positive pressure ventilation during sleep was introduced; and thereafter sleep-related symptoms were resolved and no lower respiratory infection reoccurred. Although their quality of life was improved, no improvement of respiratory function was shown by spirometry over a 2-year follow-up period. CONCLUSIONS SDB seems to be common in childhood-onset AMD, which is not always accompanied by daytime muscular symptoms, especially in mild patients. PSG should be utilized for detecting SDB, which could be one of the earliest signs of respiratory muscle involvement in childhood-onset AMD.

Psychometric properties and population-based score distributions of the Japanese Sleep Questionnaire for Preschoolers

OBJECTIVE We aimed to present psychometric properties and describe the score distributions of the Japanese Sleep Questionnaire for Preschoolers (JSQ-P), a guardian-reported survey questionnaire for assessing sleep disturbances and problematic sleep habits among preschool children. METHODS Guardians of 2998 toddlers in three communities and guardians of 102 patients diagnosed with sleep disorders in two clinics completed the JSQ-P. RESULTS Exploratory factor analysis (EFA) revealed the 10 domains of the JSQ-P to be similar to our previous small-scale study and confirmed the robustness of the JSQ-P. The JSQ-P showed acceptable internal consistency; α coefficients ranged from 0.622 (insufficient sleep) to 0.912 (restless legs syndrome [RLS], motor) for the community sample and 0.696 (insufficient sleep) to 0.959 (RLS, motor) for the clinical sample. The score differentiations between the community and clinical samples associated with RLS, obstructive sleep apnea syndrome (OSAS), morning symptoms, parasomnias, excessive daytime sleepiness, and daytime behaviors were demonstrated in our study. The distributions of percentile T scores for each subscale and age and gender differentiation of scores also were evaluated. CONCLUSIONS We confirmed that the JSQ-P is a valid and reliable instrument to evaluate Japanese sleep habits using a large population-based sample. The JSQ-P may be useful in both clinical and academic settings.

Long-term observation of absence of REM sleep caused by pontine cavernous hemangioma

mia, diplopia, right fixed mydriasis, left hemianopsia, left neglect, sporadic myoclonic jerks, primitive reflexes, and a BMI of 26.84 kg/m. Laboratory and cardiovascular reflex tests were normal, whereas thermoregulatory sweat test disclosed a central anhidrosis. We documented long postprandial naps (1.5–3 h) with SOREMPs, prolonged nocturnal total sleep time (8–10 h) with SOREMPs, and increased recurrence of REM sleep cycles (13 and 8) across the night. The MSLT showed a reduced sleep latency (4.5 min) with two SOREMPs. A significant 24-hour BcT rhythm (p < 0.001) with a normal mesor (36.36 C) and amplitude (0.94 C) showed an inversion of the physiological circadian profile with a nadir of 35.1 C at 3 pm and a maximum of 37.6 C at 7:20 am. Skin, BcT, and heart rate rhythms showed parallel trends across the 24 h (Fig. 1). Post-traumatic cerebral damage involving the right fronto-temporal region and the hypothalamus in our patient resulted in a peculiar clinical picture with narcoleptic-like hypersomnia and inversion of the BcT rhythm that was uncoupled from sleep/wake and light/dark cycles. Polysomnographic evidence of secondary narcolepsy demonstrated the damage of the hypocretinergic system [1], as confirmed by the asymmetric hypothalamic damage at brain MRI, whereas the impairment of central thermoregulatory mechanisms suggested a possible poikilothermic condition [3]. Conversely, the preserved BcT rhythm implied a normal functioning of the suprachiasmatic nucleus (SCN), the master circadian clock of endogenous rhythms, and of the subparaventricular zone, the output branch of the SCN for temperature rhythm [4]. Therefore, the uncoupling between the temperature rhythm and the sleep–wake cycle may reflect a complex imbalance at the highest (i.e., forebrain) level of organization of the central autonomic network modulating BcT rhythm [5]. In conclusion, the damage of the right fronto-temporal region and hypothalamus in our patient may be the cause of the uncoupling between the BcT rhythm and the sleep/wake cycle that in turn may facilitate the instability of sleep with increased recurrence of REM sleep.

Japanese Sleep Questionnaire for Elementary Schoolers (JSQ-ES): validation and population-based score distribution

OBJECTIVE The Japanese Sleep Questionnaire for Elementary Schoolers (JSQ-ES) was developed to measure the sleep habits and disturbances of Japanese children. The current study aimed to present psychometric properties and describe the score distribution of the JSQ-ES. In addition, it examined correlations between the sleep and daytime behavior of school-aged children. METHOD Guardians of 4369 elementary school children and 100 children diagnosed with sleep disorders in two clinics completed the JSQ-ES. RESULTS Exploratory factor analysis and confirmatory factor analysis suggested a nine-factor structure. The JSQ-ES internal consistency was 0.876 and 0.907 for the community and clinical groups, respectively. Score distribution differences were observed between the two groups. A cut-off point of 80 was identified for the total JSQ-ES score. CONCLUSIONS Exploratory factor analysis and confirmatory factor analysis suggested a nine-factor structure: (1) restless legs syndrome; (2) sleep-disordered breathing; (3) morning symptoms; (4) nighttime awakenings; (5) insomnia; (6) excessive daytime sleepiness; (7) daytime behavior; (8) sleep habits; and (9) irregular/delayed sleep phase. The study verified that the JSQ-ES is a valid and reliable instrument with which to evaluate Japanese sleep habits using a large population-based sample. The JSQ-ES may be useful in both clinical and academic settings.

Evaluation of behavioral change after adenotonsillectomy for obstructive sleep apnea in children with autism spectrum disorder

BACKGROUND AND OBJECTIVE Obstructive sleep apnea (OSA) may affect daily cognitive functioning in children. The aims of our study were two-fold. The first aim was to detect, using the Child Behavior Checklist (CBCL), whether adenotonsillectomy (AT) for the treatment of OSA improved the behavior of children with autism spectrum disorder (ASD). The second aim was to identify characteristics for behavioral improvement following the treatment of OSA in these children with ASD. METHODS The behaviors of ASD children aged 5-14 years diagnosed as having OSA (n=30) were evaluated using CBCL before and after AT. CBCL evaluation of ASD children without OSA at two time points with the same interval served as a control (n=24). We statistically examined the two groups. In addition, we conducted a paired t-test to assess changes in CBCL Tscores between the improved group and unchanged/deteriorated group to identify characteristics that may affect behavioral changes following OSA treatment. RESULTS After AT, T-scores of the CBCL scales were significantly improved in the OSA group, but no change was observed in the control. A paired t-test revealed that the improved group had significantly higher scores on the CBCL pre-AT than the unchanged/deteriorated group in ASD children with OSA after OSA treatment. CONCLUSIONS Behavioral problems were significantly improved following AT in ASD children with OSA. Early detection and treatment of children with OSA is essential to prevent behavioral problems and to support mental development.

nCPAP Improves the Quality of Life of Siblings with Mandibuloacral Dysplasia

Mandibuloacral dysplasia (MAD; MIM 248370, 608612) is a rare progeroid syndrome with autosomal reces- sive inheritance. It is characterized by mandibular hypoplasia, acroosteolysis, delayed closure of the cranial sutures, skin atrophy with mottled hyperpigmentation, stiff joints, and growth retardation. We here report Japanese female siblings with a severe MAD phenotype. Because of extreme micrognathia and small mouth and nostril, obstructive sleep apnea syn- drome (OSAS) was observed in both sisters and was especially life-threatening in the younger sister. Nasal continuous positive airway pressure (nCPAP), which seemed to be only one therapeutic choice for these sisters since impaired bone healing made oral surgical approach including maxillomandibular advancement surgery inapplicable to these sisters, suc- cessfully alleviated OSAS in both sisters. Since the initiation of nCPAP, the younger sister has gained weight constantly and her developmental milestones have been steadily achieved. We conclude that possible life threatening sleep- disordered breathing in the patients with progeroid syndromes should be properly managed.