Toyojiro Matsuishi

Aicardi syndrome with holoprosencephaly and cleft lip and palate.

This 14-day-old Japanese girl demonstrated the classic features of Aicardi syndrome, including infantile spasms, agenesis of the corpus callosum, chorioretinopathy, microphthalmia, vertebral anomalies, electroencephalographic abnormalities, and severe mental retardation. Furthermore, she had a cleft lip and palate and a severe brain malformation due to semilobar-type holoprosencephaly. This patient is the second reported with Aicardi syndrome and associated cleft lip and posterior palate; she is the first patient with an additional severe brain malformation due to semilobar-type holoprosencephaly.

Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder

Recent studies have established important roles of de novo mutations (DNMs) in autism spectrum disorders (ASDs). Here, we analyze DNMs in 262 ASD probands of Japanese origin and confirm the de novo paradigm of ASDs across ethnicities. Based on this consistency, we combine the lists of damaging DNMs in our and published ASD cohorts (total number of trios, 4,244) and perform integrative bioinformatics analyses. Besides replicating the findings of previous studies, our analyses highlight ATP-binding genes and fetal cerebellar/striatal circuits. Analysis of individual genes identified 61 genes enriched for damaging DNMs, including ten genes for which our dataset now contributes to statistical significance. Screening of compounds altering the expression of genes hit by damaging DNMs reveals a global downregulating effect of valproic acid, a known risk factor for ASDs, whereas cardiac glycosides upregulate these genes. Collectively, our integrative approach provides deeper biological and potential medical insights into ASDs.

De novo HDAC8 mutation causes Rett-related disorder with distinctive facial features and multiple congenital anomalies

We present a unique 11-year-old girl showing clinical features of Rett-related disorder with distinctive facial features and multiple congenital anomalies including ocular hypertelorism, arched eyebrows, a broad nose, dental anomalies, congenital heart disease, truncal obesity, and epilepsy. A novel de novo mutation in histone deacetylase 8 (HDAC8) (c.652Gu202f>u202fT, p.Gly218Cys) was confirmed by whole exome sequencing and Sanger sequencing. X-chromosome inactivation analysis on DNA isolated from peripheral blood lymphocytes revealed a completely skewed pattern associated with an inactive maternal allele. Late clinical loss of acquired purposeful hand movements and psychomotor deterioration may be a feature of Rett-related disorder, while distinctive facial features and multiple congenital anomalies are reminiscent of Cornelia de Lange syndrome.

A novel STXBP1 mutation causes typical Rett syndrome in a Japanese girl

Rett syndrome (RTT) is a neurodevelopmental disorder mostly caused by mutations in Methyl-CpG-binding protein 2 (MECP2); however, mutations in various other genes may lead to RTT-like phenotypes. Here, we report the first case of a Japanese girl with RTT caused by a novel syntaxin-binding protein 1 (STXBP1) frameshift mutation (c.60delG, p.Lys21Argfs*16). She showed epilepsy at one year of age, regression of acquired psychomotor abilities thereafter, and exhibited stereotypic hand and limb movements at 3u202fyears of age. Her epilepsy onset was earlier than is typical for RTT patients. However, she fully met the 2010 diagnostic criteria of typical RTT. STXBP1 mutations cause early infantile epileptic encephalopathy (EIEE), various intractable epilepsies, and neurodevelopmental disorders. However, the case described here presented a unique clinical presentation of typical RTT without EIEE and a novel STXBP1 mutation.

Pathogenesis of Lethal Aspiration Pneumonia in Mecp2 -null Mouse Model for Rett Syndrome

Rett syndrome (RTT) is a neurodevelopmental disorder mainly caused by mutations in the gene encoding the transcriptional regulator Methyl-CpG-binding protein 2 (MeCP2), located on the X chromosome. Many RTT patients have breathing abnormalities, such as apnea and breathing irregularity, and respiratory infection is the most common cause of death in these individuals. Previous studies showed that MeCP2 is highly expressed in the lung, but its role in pulmonary function remains unknown. In this study, we found that MeCP2 deficiency affects pulmonary gene expression and structures. We also found that Mecp2-null mice, which also have breathing problems, often exhibit inflammatory lung injury. These injuries occurred in specific sites in the lung lobes. In addition, polarizable foreign materials were identified in the injured lungs of Mecp2-null mice. These results indicated that aspiration might be a cause of inflammatory lung injury in Mecp2-null mice. On the other hand, MeCP2 deficiency affected the expression of several neuromodulator genes in the lower brainstem. Among them, neuropeptide substance P (SP) immunostaining was reduced in Mecp2-null brainstem. These findings suggest that alteration of SP expression in brainstem may be involved in autonomic dysregulation, and may be one of the causes of aspiration in Mecp2-null mice.

Ghrelin improves dystonia and tremor in patients with Rett syndrome: A pilot study

BACKGROUNDnDystonia occurs in approximately 60% of patients with Rett syndrome (RTT) and severely impairs their quality of life. However, an effective standard therapy has not been established. In a previous study, ghrelin levels were significantly decreased in patients with RTT, in particular, among patients over 10years old. This prompted speculation that ghrelin may play an important role in RTT.nnnOBJECTIVESnFour patients, including two adults, with severe dystonia and tremor, were recruited.nnnMETHODSnGhrelin was intravenously administered at a dose of 3μg/kg, once-daily for 3days, followed by once every 3weeks. Objective evaluation was performed, including scoring for different clinical features (SDCF), the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and the Visual Analog Scale (VAS).nnnRESULTSnThe SDCF, BFMDRS, autonomic dysfunction and VAS scores were markedly improved in two patients with severe dystonia and head tremor.nnnCONCLUSIONnGhrelin may improve extrapyramidal symptoms in patients with RTT.

Increased cortisol awakening response after completing the summer treatment program in children with ADHD

OBJECTIVEnLittle is known about the cortisol awakening response (CAR) in children with attention deficit hyperactivity disorder (ADHD). Here, we examined the CAR in children with ADHD and their mothers before, immediately after, and 4months after an intensive summer treatment program (STP).nnnMETHODSnParticipants were 37 children aged 7-12years who completed the STP in 2009 and 2010, and their mothers. Daily saliva samples for cortisol measurement were collected twice daily at awakening and 30min afterwards at pre-STP, post-STP, and during a follow-up measurement period. ADHD symptom scores were evaluated by parents, and participants completed the Kid-KINDLR QOL questionnaire.nnnRESULTSnCAR was low in children with ADHD before the STP, and increased to the control range 4months after STP. Maternal CAR also tended to increase after STP. Changes in the CAR in children tended to correlate with an improved ADHD inattention scores (p=0.091), physical health (p=0.070), and school life subscales scores in the Kid-KINDLR (p=0.079).nnnCONCLUSIONnWe demonstrated that STP improved the behavior and QOL of children with ADHD. Our results indicate that STP could lead to improvements in HPA axis function, as reflected by increased CAR after STP.

Acute encephalopathy with biphasic seizures and late reduced diffusion associated with staphylococcal toxic shock syndrome caused by burns

We report a case of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) associated with toxic shock syndrome caused by burns. A one-year-old girl was admitted to our hospital for treatment of severe burns. On day 3, she exhibited a fever, generalized rash and multiple organ failure. She was diagnosed with toxic shock syndrome after burns. She had seizures with fever twice on the same day, followed by secondary seizures on day 8 and transient deterioration of the gross motor functions involved in sitting alone and rolling over. On day 9, MRI diffusion-weighted images showed bright tree appearance (BTA). We conclude that she developed AESD.