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PURPOSE: Cerebellar hypoplasia and atrophy (CBHA) in children is an extremely heterogeneous group of disorders, but few comprehensive genetic studies have been reported. Comprehensive genetic analysis of CBHA patients may help differentiating atrophy and hypoplasia and potentially improve their prognostic aspects. METHODS: Patients with CBHA in 176 families were genetically examined using exome sequencing. Patients with disease-causing variants were clinically evaluated. RESULTS: Disease-causing variants were identified in 96 of the 176 families (54.5%). After excluding 6 families, 48 patients from 42 families were categorized as having syndromic associations with CBHA, whereas the remaining 51 patients from 48 families had isolated CBHA. In 51 patients, 26 aberrant genes were identified, of which, 20 (76.9%) caused disease in 1 family each. The most prevalent genes were CACNA1A, ITPR1, and KIF1A. Of the 26 aberrant genes, 21 and 1 were functionally annotated to atrophy and hypoplasia, respectively. CBHA+S was more clinically severe than CBHA-S. Notably, ARG1 and FOLR1 variants were identified in 2 families, leading to medical treatments. CONCLUSION: A wide genetic and clinical diversity of CBHA was revealed through exome sequencing in this cohort, which highlights the importance of comprehensive genetic analyses. Furthermore, molecular-based treatment was available for 2 families.
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Exoma , Malformaciones del Sistema Nervioso , Niño , Humanos , Exoma/genética , Mutación , Malformaciones del Sistema Nervioso/genética , Atrofia/genética , Receptor 1 de Folato/genética , CinesinasRESUMEN
PURPOSE: To investigate walking ability in Japanese patients with Rett syndrome (RTT). METHODS: Walking ability was assessed in 100 female Japanese patients with RTT using univariate and multivariate analysis in all age groups, and in patients over 10 years of age. We analyzed walking ability and confounding factors including prenatal-perinatal histories, developmental milestones, somatic and head growth, anthropometric data, body mass index, age of loss of purposeful hand use, age at onset of stereotypic hand movement, history of autistic behavior, age at regression, presence or absence of seizures, and the results of MECP2 genetic examination from the Japanese Rett syndrome database. RESULTS: Univariate analysis revealed that acquisition of walking in all age groups was significantly correlated with the acquisition of meaningful words, microcephaly, and crawling (P < 0.0001, P = 0.005, P < 0.0001, respectively). Univariate analysis revealed that walking ability over 10 years of age was significantly correlated with acquisition of meaningful words, microcephaly, and body mass index (P < 0,0001, P = 0.005, P = 0.0018, respectively). MECP2 mutations R306C, R133C, and R294X were significantly associated with different acquisition of crawling (P = 0.004) and walking (P = 0.01). Multivariate analysis revealed that only acquisition of meaningful words was significantly correlated with walking ability over 10 years of age. This trend excluded the genetic effects of R306C, R133C, and R294X. CONCLUSIONS: Meaningful word acquisition was robustly associated with walking ability over 10 years. Prognosis of walking ability may be predicted by the acquisition of meaningful words. This information is potentially useful for early intervention and the planning of comprehensive treatment for young children with RTT.
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Síndrome de Rett/psicología , Habla/fisiología , Caminata/fisiología , Adolescente , Adulto , Niño , Preescolar , Femenino , Genotipo , Humanos , Lactante , Japón , Proteína 2 de Unión a Metil-CpG/genética , Proteína 2 de Unión a Metil-CpG/metabolismo , Microcefalia , Mutación , Fenotipo , Proteínas Represoras/genética , Síndrome de Rett/genética , Síndrome de Rett/fisiopatología , Índice de Severidad de la Enfermedad , Vocabulario , Adulto JovenRESUMEN
BACKGROUND: Most cases of Rett syndrome (RTT) are caused by mutations in methyl CpG binding protein 2 (MECP2), and individuals with RTT have somatic growth failure, growth arrest of brain, epilepsy, and intellectual disability (ID). Ghrelin is a peptide hormone which stimulates growth hormone (GH) secretion from the pituitary gland. Ghrelin and GH regulate insulin-like growth factor-1 (IGF-1) synthesis, and this GH/IGF-1 axis is an endocrine axis involved in energy and sleep homeostasis and plays crucial roles in somatic and brain growth. This study aimed to determine whether circulating ghrelin, GH and IGF-1 reflect somatic and brain growth in RTT patients. METHODS: We examined anthropometric data and circulating ghrelin, GH, and IGF-1 in 22 female RTT patients with epilepsy and ID (RTT-Ep/ID) and 14 age-matched females with epilepsy and ID (non-RTT-Ep/ID). RESULTS: Body mass index (BMI) and height/length were significantly lower in RTT-Ep/ID than in non-RTT-Ep/ID in patients less than 20 years old. Plasma ghrelin in RTT-Ep/ID patients showed a significant inverse correlation with weight but had no significant correlations with BMI or height. Head circumference in both groups showed a significant positive correlation with circulating ghrelin and a significant negative correlation with circulating IGF-1. The ratio of octanoyl-ghrelin to total-ghrelin (O/T-ratio) is used as an indicator to estimate the biological activity of ghrelin. Among pre-adolescents, O/T-ratios were significantly higher in the RTT-Ep/ID group than in the non-RTT-Ep/ID group (P < 0.05). CONCLUSIONS: Timing of growth-spurts differed between the RTT-Ep/ID and non-RTT-Ep/ID groups, possibly due to a common (but yet unknown) mechanism of growth failure. Ghrelin/GH/IGF-1 axis function was aberrant in both the RTT-Ep/ID and non-RTT-Ep/ID groups. The initial clinical course of Rett syndrome affects the development of the sleep-wake cycle and locomotion in early infancy, both of which may be based on the dysfunction of the aminergic neurons modulated by ghrelin/GH/IGF-1 axis. Further study with a larger sample size should help clarify the precise mechanisms controlling the somatic growth and hormonal features in Rett syndrome.
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Epilepsia/fisiopatología , Ghrelina/sangre , Hormona del Crecimiento/sangre , Factor I del Crecimiento Similar a la Insulina/metabolismo , Discapacidad Intelectual/fisiopatología , Síndrome de Rett/fisiopatología , Adolescente , Factores de Edad , Estatura , Índice de Masa Corporal , Peso Corporal , Niño , Preescolar , Epilepsia/complicaciones , Femenino , Humanos , Discapacidad Intelectual/complicaciones , Radioinmunoensayo , Síndrome de Rett/complicaciones , Adulto JovenRESUMEN
Most patients with Rett syndrome (RTT) have both gastrointestinal problems and somatic growth failure, including microcephaly. Ghrelin is a peptide hormone involved in growth hormone secretion, interdigestive motility, and feeding behavior. Plasma ghrelin assays have previously been described for other neurodevelopmental disorders. To examine the pathophysiology of RTT, we measured plasma levels of ghrelin in patients with RTT. A case-control study examining plasma levels of ghrelin, serum growth hormone, and insulin-like growth factor-1 (IGF-1) was performed on 27 patients with RTT and 53 controls. Plasma levels of total (T)- and octanoyl (O)-ghrelin were significantly lower in patients with RTT than in controls. Plasma levels of T-ghrelin correlated significantly with serum IGF-1 levels and head circumference. Significantly lower levels of plasma T-ghrelin and O-ghrelin were observed in RTT patients with eating difficulties, while lower levels of plasma T-ghrelin were observed in RTT patients with constipation, in comparison to patients without either of these symptoms. Alterations in plasma ghrelin levels may reflect various clinical symptoms and signs in RTT patients, including growth failure, acquired microcephalus, autonomic nerve dysfunction, and feeding difficulties. We describe the role of ghrelin in RTT and suggest this peptide as a novel biological marker in patients with RTT.
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Trastornos de Alimentación y de la Ingestión de Alimentos/sangre , Trastornos de Alimentación y de la Ingestión de Alimentos/etiología , Ghrelina/sangre , Síndrome de Rett/sangre , Síndrome de Rett/complicaciones , Adolescente , Adulto , Niño , Hormona del Crecimiento/sangre , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Síndrome de Rett/fisiopatología , Adulto JovenRESUMEN
In 2005 we established the first American-style summer treatment program (STP) for children with attention deficit hyperactivity disorder (ADHD) located outside North America. This program was based on methods established by professor Pelham and has been used in a number of studies and at a number of sites in the USA. A total of 137 children diagnosed with ADHD, ranging in age from 6 to 12 years, participated in at least one of five annual summer treatment programs in Kurume city, Japan, during 2005-2009. The duration of the STP was 2 weeks in 2005, 2008, and 2009; 3 weeks in 2006 and 2007. A set of evidence-based behavioral modification techniques comprising the STP behavioral program (e.g., point system, daily report card, positive reinforcement, time out) was used. We also assessed the cognitive function of individual children before and after STP using the CogState(R) batteries. Every year, regardless of the duration of the STP, most children showed positive behavioral changes in multiple domains of functioning, demonstrated by significant improvement in points earned daily, which reflect behavior frequencies. Cognitive functions, particularly the rate of anticipatory errors in executive function, significantly improved after the STP, suggesting that STP has positive effects not only on behavioral aspects but also on some cognitive functions. Further studies are necessary to confirm this finding by studying sequential cognitive function of age-matched children who do not attend STP.
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Trastorno por Déficit de Atención con Hiperactividad/terapia , Adulto , Trastorno por Déficit de Atención con Hiperactividad/psicología , Terapia Conductista , Niño , Conducta Infantil/fisiología , Cognición/fisiología , Interpretación Estadística de Datos , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Femenino , Humanos , Japón , Masculino , Destreza Motora , Pruebas Neuropsicológicas , Padres , Conducta Social , Deportes/psicología , Resultado del TratamientoRESUMEN
We reported the results of the 3-week summer treatment program (STP) for children with attention deficit hyperactivity disorder (ADHD) in 2006. The STP was based on methods established by Professor Pelham in Buffalo, NY and has been used in a number of studies and at a number of sites in the U.S. This is the first STP outside North America. Thirty-six children age 6-12 years with ADHD participated. The collection of evidence-based behavioral modification techniques that comprises the STP's behavioral program (e.g., point system, daily report card, positive reinforcement, time out) was used. Most children showed positive behavioral changes in multiple domains of functioning, demonstrated by significant improvement in points earned daily, which reflect behavior frequencies. Only one child with ADHD co-morbid with pervasive developmental disorder required an individualized program for excessive time outs. The ADHD rating scale, symptoms of oppositional defiant disorder, and hyperactivity/inattention in Strength and Difficulties Questionnaires evaluated by parents significantly improved after STP. Although the 3-week STP was much shorter than most STPs run in the U.S., the program is more intensive than typical outpatient treatment, providing 105h of intervenion in 3 weeks. The short-term effect of the STP was demonstrated for Japanese children with ADHD.
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Asertividad , Trastorno por Déficit de Atención con Hiperactividad/terapia , Terapia Conductista/métodos , Refuerzo en Psicología , Américas , Trastorno por Déficit de Atención con Hiperactividad/psicología , Niño , Femenino , Humanos , Japón , Masculino , Padres/psicología , Esquema de Refuerzo , Conducta Social , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
This reports describes a 12-year-old Japanese female with Noonan syndrome who had antiphospholipid syndrome and moyamoya-like vascular changes. She presented choreic movements in her face and extremities. She manifested phenotypic features of Noonan syndrome with short stature, mental retardation, and a webbed neck. Magnetic resonance angiography revealed occlusion of bilateral internal carotid arteries and moyamoya-like vascular changes around the basal ganglion region. Pimozide completely resolved the patient's choreic movements. Tests for anticardiolipin antibody and lupus anticoagulant were positive. The patient has manifested no symptoms for 2 years with pimozide, aspirin, and growth hormone treatment, without further aggravation of moyamoya-like vascular changes. This article is the first report of Noonan syndrome with antiphospholipid syndrome and moyamoya-like vascular lesions.