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Dopa-responsive dystonia (DRD), also known as Segawa syndrome, is a phenotypically and genetically heterogeneous group of neurological disorders that typically presents as early-onset lower limb dystonia with diurnal fluctuation, and exhibits a marked, persistent response to levodopa. Heterozygous loss-of-function mutations in the guanosine triphosphate cyclohydrolase 1 (GCH1) are the most common cause of DRD. In addition to the classic form of the disease, there have been a number of studies addressing atypical clinical features of GCH1 related DRD with variable age of onset. This report describes a 37-year-old Japanese male patient with a 10-year history of focal upper limb dystonia that initially emerged as task-specific, guitarist’s cramp. The dystonic symptoms responded very well to levodopa treatment, and genetic analysis identified a novel heterozygous mutation in the C-terminal catalytic domain of GCH1. Insufficient recognition of this treatable condition often leads to misdiagnosis, which causes delays in the patient receiving adequate dopamine replenishing therapy. A diagnostic trial with levodopa should be considered in all patients with relatively young-onset dystonia, whether they have classic features of DRD or not.

Introduction: Post-synaptic dopamine receptor supersensitivity (DARSS) has been extensively researched by Dr. Masaya Segawa, who has investigated the efficacy of very-low-dose levodopa therapy (VLDT; 0.5–1 mg/kg/day). Considerable Japanese research supports the possibility that VLDT could be used to treat pediatric neurological disorders. We conducted an on-line survey in 2014 to collect real-world data on the use of VLDT to treat DARSS.Methods: A two-step survey, including a screening test and questionnaire, was posted on a private internet site that could be accessed via the VLDT Research Group home page, and 1,165 pediatric neurologists across Japan were invited to complete it.Results: A total of 25 respondents reported prescribing VLDT; 19 used VLDT to treat autism spectrum disorder, 14 for tics, 12 for speech delay, 9 for Rett syndrome, 7 for attention-deficit/hyperactivity disorder, intellectual disability, and 6 for sleep problems. Twelve respondents reported prescribing a dose of 0.5 mg/kg. Twenty-two reported that VLDT was effective for treating behavioral problems, and twenty reported a good efficacy for treating motor symptoms. Adverse events had a low incidence. Notably, respondents chose VLDT for its possible action in DARSS and for its safety. VLDT was commonly used for behavioral problems in patients younger than 5 years, and for motor symptoms in aged 5–9 years.Conclusion: VLDT could safely treat behavioral and motor symptoms in pediatric neurological disorders. In contrast, dopamine antagonists are associated with potent efficacy, but with adverse effects such as sleepiness and obesity. Further surveys should be conducted with a broader participants.

Background Healthy sleep is important not only for physical health but also for brain development in children. Several reports have revealed that Japanese adults and children have later bedtimes and shorter sleep durations compared with those in other countries, possibly because of Japanese culture and lifestyles. Therefore, an intervention tool that is suitable to the Japanese sociocultural environment is urgently needed to improve children’s sleep problems in their early years. Objective To provide appropriate sleep health literacy to caregivers and change their parenting behavior, we developed a smartphone app that allows reciprocal interaction between caregivers and pediatric sleep experts. This paper describes a preliminary study to examine the app’s basic design and functions and to establish its acceptability and usability in a small sample. Methods A total of 10 caregivers and 10 infants (aged 18-28 months; 4/10, 40% boys) living in Japan participated in the study. At the start of the trial, the e-learning content regarding sleep health literacy was delivered via a smartphone. Thereafter, caregivers manually inputted recorded data about their own and their infant’s sleep habits for 8 consecutive days per month for 2 months. After pediatric sleep experts retrieved this information from the Osaka University server, they specified the problems and provided multiple sleep habit improvement suggestions to caregivers. Caregivers then selected one of the feasible pieces of advice to practice and reported their child’s sleep-related behaviors via the app. Actigraphy was used to monitor children’s sleep behaviors objectively. The concordance between the information provided by caregivers and the actigraphy data was assessed. The acceptability and usability of the app were evaluated using self-report questionnaires completed by caregivers; qualitative feedback was obtained via semistructured interviews after the intervention. Results There was no significant difference between the information provided by the caregivers and the actigraphy data for bedtimes and wake-up times (P=.13 to P=.97). However, there was a difference between the actigraphy data and the caregivers’ reports of nighttime sleep duration and nighttime awakenings (P Conclusions The present findings suggest that the app can easily be used and is acceptable by Japanese caregivers. Given the user feedback, the app has the potential to improve children’s sleep habits by sending individualized advice that fits families’ backgrounds and home lives. Further studies are needed to confirm the efficacy of the app and facilitate social implementation.

The originally published version of this article contained an error in Fig. 1 and Table 2. The correct figure and table of this article should have read as below. This has now been corrected in the PDF and HTML versions of the article. The authors apologize for any inconvenience caused.

Introduction Tourette syndrome (TS) is a common neurobehavioral disorder starting from childhood characterized by motor and vocal tics. Some suggest primary hypodopaminergic state followed by upward regulation of dopamine receptors for the cause of tics. The visually-guided saccade (VGS) task is a reflexive saccade task triggered by sudden extinction of a fixation spot and appearance of a target, while the memory-guided saccade (MGS) task is a voluntary saccade task to the memorized target. We previously reported slightly prolonged VGS latency and significantly prolonged MGS latency in Parkinson’s disease, presumably due to impaired function of the direct pathway of the basal ganglia (BG) and excessive inhibition of superior colliculus (SC) caused by the increased BG output. We investigated the performance of VGS and MGS to see whether the pathophysiology of TS represented the dopaminergic deficiency. Methods We recruited 62 male drug-naive participants with TS and 49 normal controls (NC) who were 5–16 years old. In VGS, after illumination of a central spot for 2.0–2.8 s, a target was presented at locations 5°, 10° or 20° to the right or left. The subjects moved their gaze from the spot to the target quickly. In MGS, a target stimulus flashed for 50 ms while they fixated the central spot. Once the spot disappeared, they moved their gaze to the remembered location, where the light re-appeared 600 ms later. Each subject performed at least 36 VGS and 36 MGS trials. Eye movements were recorded by electrooculography. The latency of the saccade from the extinction of the central spot and amplitude of the first saccade were measured in each trial. Age-matched analysis on 29 pairs was performed by Student’s t-test. Results [VGS] The median of latencies in TS was comparable at 5° (202.0 vs 203.3 ms), whereas it was longer at 20° (251.2 vs 236.0 ms). The difference between latencies towards peripheral (20°) and central (5°) targets was larger (49.1 vs 32.6 ms∗, 16.6 ± 15.5 ms). The median of amplitudes was smaller in TS (4.9 vs 5.4°∗ at 5°, 18.3 vs 19.0°∗ at 20°). [MGS] The median of latencies in TS was shorter at 5° (324.1 vs 338.5 ms), whereas it was longer at 20° (308.4 vs 290.3 ms). The difference between latencies towards central and peripheral targets was smaller (15.8 vs 48.1 ms, −32.4 ± 48.4 ms). The median of amplitudes was comparable (5.0 vs 4.6° at 5°, 16.2 vs 15.4° at 20°). Success rate of MGS was lower (61.5 vs 83.1%†). The occurrence of saccades to cue was comparable (30.2 vs 36.6%). ∗ p Conclusion In TS, latencies to peripheral targets in VGS and MGS were longer than in normal subjects. Dopaminergic deficiency may explain the prolonged MGS latency. The resultant excessive tonic inhibition of SC by the increased BG input may decrease the activity of fixation neurons, which may shorten the VGS latency to central targets, while leading to the prolonged latency to peripheral targets through the suppressed activity of saccade neurons.

Severe myoclonic epilepsy in infancy (SMEI) is an age-dependent epileptic encephalopathy occurring in the first year of life and is one of the intractable epilepsies. Heterozygous mutations in the voltage-gated sodium channel α subunit type1 gene (SCN1A) are frequently identified in patients with SMEI; two-thirds of these mutations are truncation mutations (non-sense and frameshift), and one-third are missense mutations. Although most reported SMEI cases arise as sporadic mutations, close relatives of SMEI patients have also been shown to manifest other types of epilepsies at a higher rate than that in the general population. Here, we report a familial case of SMEI, in which two brothers were affected with SMEI while their father had previously experienced simple febrile seizures. A gene-based analysis identified a novel missense mutation in the SCN1A gene (c.5138G>A, S1713N) in both brothers and in their father. Clinically, both siblings showed failure in locomotion, an impairment of the sleep–wake cycle after late infancy, and the subsequent appearance of frontal foci. The similarity in clinical manifestations in both brothers suggests that the impairment of elements of the brainstem, particularly aminergic neurons, develops after late infancy in SMEI. However, the siblings differed in age at onset of SMEI and of myoclonic seizures, as well as in the severity of speech delay. Our molecular and clinical findings suggest that different genetic backgrounds and/or environmental factors may critically affect the clinical features of patients with SCN1A mutations, consistent with the heterogeneity prevalent in this disorder.

Acute encephalopathy with biphasic seizures and reduced diffusion (AESD) encompasses a group of encephalopathy characterized by biphasic seizures and disturbance of consciousness in the acute stage followed in the subacute stage by reduced diffusion in the subcortical white matter on magnetic resonance imaging. The etiology of AESD is viral infection and associated pathological changes. Here we report the first case of AESD caused by bacterial infection (Streptococcus pneumoniae meningitis) in a 1-year-old boy.

A small-for-gestational-age infant with cyanosis due to double outlet right ventricle with severe pulmonary stenosis and patent ductus arteriosus was treated with oral prostaglandin E1 derivative (OP-1206). The constricting ductus arteriosus dilated and the ductus-dependent pulmonary blood flow increased. The recommended dosage was 1.5-2.0 micrograms/kg/day which was lower than that of intravenous PGE1 or of oral PGE2. The administration interval was 6 hours, which was longer than that of oral PGE2. The patient was treated as an out-patient because continuous intravenous infusion was not necessary. Treatment was continued for 2 months without complication, at which time a Blalock-Taussig shunt operation was performed. Orally administered PGE1 derivative (OP-1206) was found to be equally effective to intravenous infusion of PGE1 for both short and long-term management of cyanotic heart disease in which the pulmonary blood flow is mostly dependent on the patency of the ductus arteriosus. Oral PGE1 derivative (OP-1206) may be a possible substitute for intravenous PGE1 infusion therapy.

The minimal sets of degrees of freedom to persist the multidimensional topographical feature are investigated for the funnel, and frustrated energy landscapes of proteins. The robustness of local energy topographies near the global energy minimum structures against a perturbation is also discussed.

Dystonia is characterized by particular abnormalities in posture and movements, which are based on the simultaneous occurrence of muscle contraction in both agonistic and antagonistic muscles and overflow of the contraction to the muscles which are not related to maintaining posture or execution of movements. However, in these abnormal muscle contractions, there are two types, that is, postural and action dystonia, the characteristics of which are shown in Table 1. The former appears as static phenomena of abnormal posturing and the latter as abnormal, often rigorous and ballistic movements. However, the pathophysiology of either type of dystonia has not been clarified. Table 1 Dominantly Inherited Dystonia have two phenotypes Postural Dystonia: Sustained dystonic posture induced by certain posture or movement Hypertonic and hypokinetic state Action Dystonia: Violent ballistic movement induced by certain posture or movement Hyperkinetic state without hypotonia

We describe two adolescent girls with a congenital portosystemic shunt who exhibited hyperandrogenism in addition to insulin resistant hyperinsulinaemia. Case 1 was referred to our clinic to undergo a routine clinical work-up prior to tonsillectomy at 14 years of age. Mild liver dysfunction was identified and hypogenesis of the portal vein with a congenital portosystemic shunt diagnosed. Primary amenorrhoea and virilization were evident and an endocrinological evaluation revealed hyperandrogenism and insulin resistant hyperinsulinaemia. Case 2 was referred at 15 years of age because of cardiomegaly. Mild liver dysfunction and hyperbilirubinaemia led to a diagnosis of agenesis of the portal vein with a congenital portosystemic shunt. Virilization was evident and an endocrinological evaluation revealed hyperandrogenism and insulin resistant hyperinsulinaemia. The haemodynamics of these patients were similar to those of secondary portosystemic shunt due to liver cirrhosis, which is often associated with hyperinsulinaemia and/or non-insulin dependent diabetes mellitus. On the other hand, hyperandrogenism is associated with certain insulin-resistant conditions with hyperinsulinaemia, including the polycystic ovary syndrome (PCO). Hyperinsulinaemia is believed to cause hyperandrogenism in patients with PCO by stimulating androgen production in both the ovary and adrenal gland. Therefore, in congenital portosystemic shunts, hyperinsulinaemia is also thought to cause hyperandrogenism due to the same mechanism. Conclusion A certain percentage of female patients with hyperandrogenism, likely including those with polycystic ovary syndrome may also have congenital portosystemic shunts. Our results indicate that serum levels of total bile acids and ammonia are prognostic indicators of this hepatic vascular anomaly.