Perampanel markedly improved clinical seizures in a patient with a Rett-like phenotype and 960-kb deletion on chromosome 9q34.11 including the STXBP1.

Intractable epilepsy was successfully controlled using perampanel, an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-type glutamate receptor antagonist, in a 27-year-old woman who presented with a Rett syndrome-like phenotype and novel 960-kb deletion involving syntaxin-binding protein 1 on chromosome 9q34.11. Perampanel may be an effective antiepileptic drug for intractable epilepsy associated with STXBP1 mutations.

Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy.

Although there are many known Mendelian genes linked to epileptic or developmental and epileptic encephalopathy (EE/DEE), its genetic architecture is not fully explained. Here, we address this incompleteness by analyzing exomes of 743 EE/DEE cases and 2366 controls. We observe that damaging ultra-rare variants (dURVs) unique to an individual are significantly overrepresented in EE/DEE, both in known EE/DEE genes and the other non-EE/DEE genes. Importantly, enrichment of dURVs in non-EE/DEE genes is significant, even in the subset of cases with diagnostic dURVs (P = 0.000215), suggesting oligogenic contribution of non-EE/DEE gene dURVs. Gene-based analysis identifies exome-wide significant (P = 2.04 × 10-6) enrichment of damaging de novo mutations in NF1, a gene primarily linked to neurofibromatosis, in infantile spasm. Together with accumulating evidence for roles of oligogenic or modifier variants in severe neurodevelopmental disorders, our results highlight genetic complexity in EE/DEE, and indicate that EE/DEE is not an aggregate of simple Mendelian disorders.

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.652G > T, 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.

Three Cases of KCNT1 Mutations: Malignant Migrating Partial Seizures in Infancy with Massive Systemic to Pulmonary Collateral Arteries.

KCNT1 mutations are gain-of-function mutations in potassium channels resulting in severe infantile epilepsy. Herein we describe 3 infants with malignant migrating partial seizures with KCNT1 mutations accompanied by massive systemic to pulmonary collateral arteries with life-threatening hemoptysis and heart failure.

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.

BACKGROUND: Dystonia 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. OBJECTIVES: Four patients, including two adults, with severe dystonia and tremor, were recruited. METHODS: Ghrelin 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). RESULTS: The SDCF, BFMDRS, autonomic dysfunction and VAS scores were markedly improved in two patients with severe dystonia and head tremor. CONCLUSION: Ghrelin may improve extrapyramidal symptoms in patients with RTT.

De novo KCNT1 mutations in early-onset epileptic encephalopathy.

KCNT1 mutations have been found in epilepsy of infancy with migrating focal seizures (EIMFS; also known as migrating partial seizures in infancy), autosomal dominant nocturnal frontal lobe epilepsy, and other types of early onset epileptic encephalopathies (EOEEs). We performed KCNT1-targeted next-generation sequencing (207 samples) and/or whole-exome sequencing (229 samples) in a total of 362 patients with Ohtahara syndrome, West syndrome, EIMFS, or unclassified EOEEs. We identified nine heterozygous KCNT1 mutations in 11 patients: nine of 18 EIMFS cases (50%) in whom migrating foci were observed, one of 180 West syndrome cases (0.56%), and one of 66 unclassified EOEE cases (1.52%). KCNT1 mutations occurred de novo in 10 patients, and one was transmitted from the patient's mother who carried a somatic mosaic mutation. The mutations accumulated in transmembrane segment 5 (2/9, 22.2%) and regulators of K(+) conductance domains (7/9, 77.8%). Five of nine mutations were recurrent. Onset ages ranged from the neonatal period (<1 month) in five patients (5/11, 45.5%) to 1-4 months in six patients (6/11, 54.5%). A generalized attenuation of background activity on electroencephalography was seen in six patients (6/11, 54.5%). Our study demonstrates that the phenotypic spectrum of de novo KCNT1 mutations is largely restricted to EIMFS.

Disturbance of cardiac gene expression and cardiomyocyte structure predisposes Mecp2-null mice to arrhythmias.

Methyl-CpG-binding protein 2 (MeCP2) is an epigenetic regulator of gene expression that is essential for normal brain development. Mutations in MeCP2 lead to disrupted neuronal function and can cause Rett syndrome (RTT), a neurodevelopmental disorder. Previous studies reported cardiac dysfunction, including arrhythmias in both RTT patients and animal models of RTT. In addition, recent studies indicate that MeCP2 may be involved in cardiac development and dysfunction, but its role in the developing and adult heart remains unknown. In this study, we found that Mecp2-null ESCs could differentiate into cardiomyocytes, but the development and further differentiation of cardiovascular progenitors were significantly affected in MeCP2 deficiency. In addition, we revealed that loss of MeCP2 led to dysregulation of endogenous cardiac genes and myocardial structural alterations, although Mecp2-null mice did not exhibit obvious cardiac functional abnormalities. Furthermore, we detected methylation of the CpG islands in the Tbx5 locus, and showed that MeCP2 could target these sequences. Taken together, these results suggest that MeCP2 is an important regulator of the gene-expression program responsible for maintaining normal cardiac development and cardiomyocyte structure.

De novo SHANK3 mutation causes Rett syndrome-like phenotype in a female patient.

Rett syndrome (RTT) is a neurodevelopmental disorder predominantly affecting females. Females with the MECP2 mutations exhibit a broad spectrum of clinical manifestations ranging from classical Rett syndrome to asymptomatic carriers. Mutations of genes encoding cyclin-dependent kinase-like 5 (CDKL5) and forkhead box G1 (FOXG1) are also found in early onset RTT variants. Here, we present the first report of a female patient with RTT-like phenotype caused by SHANK3 (SH3 and multiple ankylin repeat domain 3) mutation, indicating that the clinical spectrum of SHANK3 mutations may extend to RTT-like phenotype in addition to (severe) developmental delay, absence of expressive speech, autistic behaviors and intellectual disability.

Clinically mild encephalitis with a reversible splenial lesion (MERS) after mumps vaccination.

We retrospectively collected three patients with clinically mild encephalitis with a reversible splenial lesion (MERS) after mumps vaccination, and reviewed five patients, including two patients previously reported. The five patients (all males, aged 1 to 9) presented with fever, vomiting, or headache as the initial symptoms (day 0), suggesting meningitis, at 13 to 21 days after mumps vaccination. Consciousness disturbance, delirious behavior, seizures, or dysarthria was observed on days 1 to 3, which had completely resolved before day 11. Hyponatremia was observed in all patients. A cerebrospinal fluid study showed pleocytosis, and confirmed the vaccine strain genome. MRI revealed reduced diffusion in the splenium of the corpus callosum on days 2 to 4, which had completely disappeared on the follow-up studies performed on days 7-15. EEG showed high voltage slow wave in three patients, which later normalized. These findings led to a diagnosis of MERS after mumps vaccination. MERS after mumps vaccination may be more common than previously considered. MERS is suspected when a male patient after mumps vaccination presents with neurological symptoms with hyponatremia, following symptoms of aseptic meningitis, and MRI would be performed to examine the splenium of the corpus callosum.

A serial ¹8FDG-PET study of a patient with SSPE who had good prognosis by combination therapy with interferon alpha and ribavirin.

We describe a 15-year-old girl with subacute sclerosing panencephalitis (SSPE) in stage II who was treated with isoprinosine, intraventricular interferon alpha (IFN-α), and ribavirin for 3 years. She is alive at three years from onset and studies at school with the assistance of a special educational teacher. To assess residual brain function, serial (18)FDG-positron emission tomography (PET) was performed three times to measure cortical metabolism: at onset, a year later, and three years later. At onset, PET study revealed preserved glucose metabolism of the cerebral cortex. In serial PET study, glucose metabolism of the cerebral cortex was also preserved even after three years. Although SSPE is a progressive disease of the neuronal system, and typically leads to death in approximately 2-3 years, the neurological prognosis of our case was good. We consider that combination therapy in the very early stage without hypometabolism in the cerebral cortex may be effective for SSPE.

Relation between circulating levels of GH, IGF-1, ghrelin and somatic growth in Rett syndrome.

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.

An adult patient with mucolipidosis III alpha/beta presenting with parkinsonism.

A 36-year-old man with mucolipidosis type III alpha/beta presented with hypoactivity, mutism, muscle rigidity, and involuntary movement. The involuntary movement was interpreted to be tremor at rest on physical examination and surface electromyography, which revealed mostly asynchronous contractions at 3-4 Hz of the biceps and triceps brachii muscles. All these symptoms were consistent with abnormalities of parkinsonism, which is caused by an insult to the basal ganglia that permeates the entire basal ganglia-thalamocortical circuitry. This report is the first to present a case of mucolipidosis type III alpha/beta in association with parkinsonism.

Eyelid myoclonia with absences occurring during the clinical course of cryptogenic myoclonic epilepsy of early childhood.

We describe a 15-year-old boy with learning difficulties and eyelid myoclonia with absences (EMA). Myoclonic jerks of the extremities and trunk occurred 9 years before the onset of EMA, when the patient was 6. At that time, we diagnosed him with cryptogenic myoclonic epilepsy of early childhood, because he manifested mainly myoclonic jerks with generalized 3- to 6-Hz spike/polyspike-and-slow-wave complexes on EEG, normal neurological examination, good response to antiepileptic drugs, and no evidence of previous brain damage. This is an unusual case showing that myoclonic epilepsy of early childhood can evolve to EMA. Although the question of whether EMA is a seizure type or an epilepsy syndrome remains controversial, our case suggests that EMA is a seizure type during the clinical course of a particular kind of myoclonic epilepsy.

Ghrelin levels are reduced in Rett syndrome patients with eating difficulties.

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.

A case of clinically mild encephalitis with a reversible splenial lesion (MERS) after mumps vaccination.

We describe for the first time an 8-year-old male patient who demonstrated clinically mild encephalitis with a reversible splenial lesion after mumps vaccination. He suffered from transient hallucinations, nuchal rigidity, and inappropriate antidiuretic hormone secretion syndrome. On the 5th day of admission, his head MRI showed symmetrical high-signal-intensity lesions on T2, FLAIR, and diffusion-weighted images in the splenium of the corpus callosum and in the periventricular white matter, while an apparent diffusion coefficient map showed reduced diffusion. The images were not enhanced by gadolinium. Follow-up MRI on the 16th day of admission revealed none of these abnormalities. His serum IgM and IgG antibodies against the mumps virus were positive according to an enzyme immunoassay. Mumps Torii vaccine strain was isolated from the patient's cerebrospinal fluid. Previous reports demonstrated that transient delirious behavior, the syndrome of inappropriate antidiuretic hormone secretion, and good prognosis were the main clinical features of mild encephalitis with a reversible splenial lesion. This case shows that mild encephalitis with a reversible splenial lesion could occur after mumps vaccination.

Prefrontal brain function in children with anorexia nervosa: a near-infrared spectroscopy study.

To investigate the prefrontal hemodynamic response during a cognitive task in childhood anorexia nervosa (AN), we measured regional cerebral blood volume changes in terms of changes in hemoglobin concentrations [Hb], using near-infrared spectroscopy (NIRS). Sixteen females with AN (mean age 14.2 years old) and 12 age-matched healthy female control subjects (mean age 14.3 years old) participated in this study. Waveform patterns for [Hb] during the word fluency task differed between the two groups, although their task performances showed no significant difference. In the control group, the [total-Hb] and [oxy-Hb] immediately increased and the [deoxy-Hb] immediately decreased after the beginning of the task and gradually reached the baseline level after the end of the task. The patients with AN were consistently characterized by an unchanged or less fluctuating response pattern of [total-Hb], [oxy-Hb] and [deoxy-Hb] during the task and rest periods. In the AN group, subjects with higher Eating Attitudes Test (EAT-26) scores showed higher [oxy-Hb] during the task. On the other hand, in the control group, subjects with higher EAT-26 scores showed lower [oxy-Hb] during the task. The grand waveforms of each [Hb] during a motor activation task, which was applied as a control task, did not differ significantly between two groups. The different prefrontal hemodynamic responses might indicate that AN subjects might apply fewer brain circuits or fewer neurons per circuit during cognitive tasks and might use different brain circuits in relation to their preoccupation with eating behaviors.

Comparison of the strengths and difficulties questionnaire (SDQ) scores between children with high-functioning autism spectrum disorder (HFASD) and attention-deficit/hyperactivity disorder (AD/HD).

The aim of this research was to compare the Strengths and Difficulties Questionnaire (SDQ) scores and subscale scores in children with high-functioning autism spectrum disorder (HFASD) and attention-deficit/hyperactivity disorder (AD/HD), and also to clarify the differences between parent- and teacher-assessed SDQ scores/subscores in HFASD and AD/HD children. These patients' total difficulties scores were significantly high compared to the community sample. In the parent rating, HFASD children had significantly higher scores in the subscales of emotional symptoms and peer problems. In the teacher rating, AD/HD children showed significantly higher scores in the subscales of hyperactivity/inattention and conduct problems, whereas peer problems were significantly higher in HFASD. The teacher rating showed significantly greater difficulties than the parent rating on the subscale of prosocial behavior in both the AD/HD and HFASD groups. These results suggest that each subscale may reflect behavioral, emotional, and social characteristics of HFASD and AD/HD.

Scale properties of the Japanese version of the Strengths and Difficulties Questionnaire (SDQ): a study of infant and school children in community samples.

The Strengths and Difficulties Questionnaire (SDQ) is a short screening instrument which addresses the positive and negative behavioral attributes of infants, children and adolescents. The SDQ is widely used to evaluate child developmental disabilities, psychological and psychiatric conditions or disorders in Japan. However, we did not have normative data for the Japanese version until now. To establish the community-based data and properties for the Japanese version, we collected and evaluated parent ratings of a total of 2899 Japanese children aged 4-12 years, including 1463 boys and 1436 girls. Statistical evaluation of psychometric properties included a factor analysis verifying the proposed scale structure, an assessment of scale homogeneities, and the determination of age, gender and relationship of each difficulties scale, or prosocial scale. The total difficulties score in boys (8.70 +/- 5.03) was higher than in girls (7.86 +/- 4.88). Based on the distributions of SDQ scores observed in the Japanese community sample, recommended bandings identifying normal, borderline, and abnormal (clinical ranges) were defined for each scale, and some gender difference was found in some difficulties and prosocial SDQ scores. After evaluating parent ratings obtained in a community-based sample, the Japanese SDQ was shown to possess favorable psychometric properties. Thus, the Japanese translation of this popular and versatile instrument seems to be approximately as reliable and useful as the original English questionnaire.