Canavan disease (CD) is a genetic neurodegenerative leukodystrophy that results in the spongy degeneration of white matter in the brain. CD is characterized by mutations in the gene encoding ...aspartoacylase (ASPA), the substrate enzyme that hydrolyzes N‐acetylaspartic acid (NAA) to acetate and aspartate. Elevated NAA and subsequent deficiency in acetate associated with this disease cause progressive neurological symptoms, such as macrocephaly, visuocognitive dysfunction, and psychomotor delay. The prevalence of CD is higher among Ashkenazi Jewish people, and several types of mutations have been reported in the gene coding ASPA. Highly elevated NAA is more specific to CD than other leukodystrophies, and an examination of urinary NAA concentration is useful for diagnosing CD. Many researchers are now examining the mechanisms responsible for white matter degeneration or dysmyelination in CD using mouse models, and several persuasive hypotheses have been suggested for the pathophysiology of CD. One is that NAA serves as a water pump; consequently, a disorder in NAA catabolism leads to astrocytic edema. Another hypothesis is that the hydrolyzation of NAA in oligodendrocytes is essential for myelin synthesis through the supply of acetate. Although there is currently no curative therapy for CD, dietary supplements are candidates that may retard the progression of the symptoms associated with CD. Furthermore, gene therapies using viral vectors have been investigated using rat models. These therapies have been found to be tolerable with no severe long‐term adverse effects, reduce the elevated NAA in the brain, and may be applied to humans in the future.
Abstract A research committee supported by the Japanese government conducted a nationwide survey on the epidemiology of acute encephalopathy in Japan using a questionnaire. A total of 983 cases ...reportedly had acute encephalopathy during the past 3 years, 2007–2010. Among the pathogens of the preceding infection, influenza virus was the most common, followed by human herpesvirus-6 (HHV-6) and rotavirus. Among syndromes of acute encephalopathy, acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) was the most frequent, followed by clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS), acute necrotizing encephalopathy (ANE) and hemorrhagic shock and encephalopathy syndrome (HSES). Influenza virus was strongly associated with ANE and MERS, HHV-6 with AESD, and rotavirus with MERS. Mortality was high in ANE and HSES, but was low in AESD, MERS and HHV-6-associated encephalopathy. Neurologic sequelae were common in AESD and ANE, but were absent in MERS.
Epilepsy and autism spectrum disorder (ASD) are the common neurological manifestations of tuberous sclerosis complex (TSC). EXIST-3 study has recently demonstrated that everolimus reduces seizures in ...patients with TSC and refractory epilepsy. Here we report the efficacy and safety of everolimus for treatment-refractory seizures in Japanese patients of EXIST-3, along with the exploratory analysis evaluating the everolimus effect on comorbid ASD symptoms in these patients.
Primary endpoint was change in seizure frequency from baseline defined as response rate (≥50% reduction) and median percentage reduction in the seizure frequency. Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS) scores were assessed at baseline and at week-18 for ASD symptoms.
Overall, 35 Japanese patients were randomized to everolimus low-exposure (LE; n = 10), everolimus high-exposure (HE; n = 14), or placebo (n = 11). The response rate was 30.0% and 28.6% versus 0% with the everolimus LE and HE versus placebo arm, respectively. Similarly, the median percentage reduction in seizure frequency was 6.88% and 38.06% versus −6.67%. Stomatitis was the most frequently reported adverse event (everolimus LE, 100%; HE, 78.6%; placebo, 9.1%). Four of 11 patients with ASD in the everolimus arms and 1 of 8 patients with ASD in the placebo arm showed ≥5 point decrease in PARS scores.
Adjunctive everolimus treatment improved seizure frequency with a tolerable safety relative to placebo among 35 Japanese patients with TSC-associated refractory seizures, consistent with the results of overall EXIST-3 study involving 366 patients. A favorable trend towards the improvement of ASD symptoms was observed.
This study aimed to reveal how the COVID-19 stay-at-home period has affected the quality of life (QOL) of children with neurodevelopmental disorders and their parents and to identify possible factors ...that enabled them to maintain their QOL. We enrolled 136 school-aged children (intellectual quotient ≥ 50) and their parents and administered QOL questionnaires to assess the maladaptive behavior of the children; depression, anxiety, and stress of the parents; and activities of their daily lives. The relationship between their QOL and clinical features was examined. The decrease in QOL of children and parents was associated with the mother's limited job flexibility. Decreased QOL was also associated with changes in the sleep rhythms of the children. Maladaptive behaviors in children were associated with parental stress. However, maintained QOL of some families who faced these same conditions of job stress and sleep disorders was associated with less parental stress, less parental depression and anxiety, and milder maladaptive behavior in children. Both mothers with limited job flexibility and changes in the sleep rhythm of children were associated with reduced QOL of children and their parents. Low parental stress was associated with decreased maladaptive behavior in children and with maintained QOL of the family.
Diagnosis of functional (psychogenic) movement disorders is challenging, causing concern for many clinicians. Here, we describe a case in which MRCP (movement related cortical potentials) was useful ...for understanding pathophysiology.
The patient was a 16-year-old male with history of glycogenosis and Crohn’s disease. He also had a history of possible autism spectrum disorder and psychogenic gait disturbance at age 12. On admission, persistent abdominal jerk had appeared. Abdominal jerks presented like hiccups, appearing once every few seconds and reducing in amplitude and frequency with distraction. Surface electromyogram with EEG excluded epileptic spasms. MRCP, with rectus abdominis muscle contractions set as a trigger, showed slowly rising negative waves (Bereitschaftspotentials, BP) from 0.6 s prior to the trigger. The presence of BP suggests that the abnormal movement emerges through a voluntary motor pathway.
We comprehensively diagnosed his involuntary jerks as functional abdominal myoclonus.
In a voluntary movement, after the drive to move from frontal and limbic regions, MRCP shows slow negative waves originating from pre-Supplementary Motor Area (SMA) and SMA, as BP, before real muscle contraction. The sense of agency is also simultaneously generated in this process by the collaborative work of the frontal and parietal lobes. Even though this abnormal movement goes through the voluntary motor pathway, the patient may not be aware of voluntariness due to lack of sense of agency.
MRCP is still challenging, but useful for the diagnosis of functional (psychogenic) movement disorders.
Nanocomposite foams based on isotactic polypropylene (iPP) and cellulose nanofibers (CNFs) with a void fraction as high as 80% were fabricated by a core-back foam injection molding (FIM). The ...hydrophobic CNFs were modified using alkenyl succinic anhydride. Different rheological curves such as the complex viscosity and tan δ–ω curves were investigated to distinguish the effects of CNFs on PP’s viscoelastic properties. Fast scanning chip calorimetry (FSC) results revealed that the added CNFs significantly increased the crystallization temperature and accelerated the crystallization process. Consequently, CNFs, especially with a concentration between 1 and 5wt%, could clearly reduce PP’s cell size and increase its cell density. The specific flexural modulus and bending strength were increased when the void fraction was lower than 80%. These findings suggest that CNFs is effective for strengthening PP foams, and such materials exhibit great potential for automotive and construction applications.
Monocarboxylate transporter 8 (MCT8) deficiency is an X-linked recessive developmental disorder characterized by initially marked truncal hypotonia, later athetotic posturing, and severe intellectual ...disability caused by mutations in SLC16A2, which is responsible for the transport of triiodothyronine (T3) into neurons. We conducted a nationwide survey of patients with MCT8 deficiency to clarify their current status.
Primary survey: In 2016–2017, we assessed the number of patients diagnosed with MCT8 deficiency from 1027 hospitals. Secondary survey: in 2017–2018, we sent case surveys to 31 hospitals (45 cases of genetic diagnosis), who responded in the primary survey. We asked for: 1) perinatal history, 2) developmental history, 3) head MRI findings, 4) neurophysiological findings, 5) thyroid function tests, and 5) genetic test findings.
We estimated the prevalence of MCT8 deficiency to be 1 in 1,890,000 and the incidence of MCT8 deficiency per million births to be 2.12 (95 % CI: 0.99–3.25). All patients showed severe psychomotor retardation, and none were able to walk or speak. The significantly higher value of the free T3/free T4 (fT3/fT4) ratio found in our study can be a simple and useful diagnostic biomarker (Our value 11.60 ± 4.14 vs control 3.03 ± 0.38). Initial white matter signal abnormalities on head MRI showed recovery, but somatosensory evoked potentials (SEP) showed no improvement, suggesting that the patient remained dysfunctional.
For early diagnosis, including in mild cases, it might be important to consider the clinical course, early head MRI, SEP, and fT3/fT4 ratio.
The efficacy of antipyretics for preventing febrile seizure recurrence has been reported by a recent study, and the results might overturn previous evidence. We systematically reviewed the efficacy ...of antipyretics in the prevention of febrile seizure recurrence in children focused on the timing of its administration. We searched the Medline, Embase, and Cochrane Central Register of Controlled Trials databases for randomized and quasi-randomized trials and prospective non-randomized studies of aged up to 60 months, diagnosed with febrile seizure, who were treated with antipyretics. Data were extracted from eight studies. Only one study reported that antipyretics prevented the recurrence of febrile seizures within the same fever episode (9.1% in the acetaminophen group vs. 23.5% in the control group,
p
< 0.01). Four studies found no evidence for the efficacy of antipyretics in preventing febrile seizure recurrence in distant fever episodes (odds ratio, 0.92; 95% confidence interval, 0.57–1.48, for two randomized controlled studies).
Conclusion
: This review provides very limited support for the use of antipyretics in preventing febrile seizure recurrence within the same fever episode and no evidence for its use in distant fever episodes. New studies are required to evaluate this topic further and determine whether the effectiveness of antipyretics is based on intervention timing.
What is Known:
• Reviews of prophylactic drug management among febrile seizure children found that antipyretics had no significant benefits.
• Recent data suggest that antipyretics are effective in preventing febrile seizures.
What is New:
• Weak evidence suggests a possible role in preventing febrile seizure recurrence within the same fever episode.
• There is clearly no role for antipyretic prophylaxis in preventing febrile seizures during distant fever episodes.
FXR is a member of the nuclear receptor superfamily and bile acids are endogenous ligands of FXR. FXR activation has recently been reported to inhibit intestinal inflammation and tumour development. ...This study aimed to investigate whether the novel FXR agonist nelumal A, the active compound of the plant Ligularia nelumbifolia, can prevent colitis and colorectal carcinogenesis. In a mouse colitis model, dextran sodium sulfate-induced colonic mucosal ulcer and the inflammation grade in the colon significantly reduced in mice fed diets containing nelumal A. In an azoxymethane/dextran sodium sulfate-induced mouse inflammation-related colorectal carcinogenesis model, the mice showed decreased incidence of colonic mucosal ulcers and adenocarcinomas in nelumal A-treated group. Administration of nelumal A also induced tight junctions, antioxidant enzymes, and FXR target gene expression in the intestine, while it decreased the gene expression of bile acid synthesis in the liver. These findings suggest that nelumal A effectively attenuates colonic inflammation and suppresses colitis-related carcinogenesis, presumably through reduction of bile acid synthesis and oxidative damage. This agent may be potentially useful for treatment of inflammatory bowel diseases as well as their related colorectal cancer chemoprevention.
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