Individuals with mutations in forkhead box G1 (
) belong to a distinct clinical entity, termed "
-related encephalopathy". There are two clinical phenotypes/syndromes identified in
-related ...encephalopathy, duplications and deletions/intragenic mutations. In children with deletions or intragenic mutations of
, the recognized clinical features include microcephaly, developmental delay, severe cognitive disabilities, early-onset dyskinesia and hyperkinetic movements, stereotypies, epilepsy, and cerebral malformation. In contrast, children with duplications of
are typically normocephalic and have normal brain magnetic resonance imaging. They also have different clinical characteristics in terms of epilepsy, movement disorders, and neurodevelopment compared with children with deletions or intragenic mutations. FOXG1 is a transcriptional factor. It is expressed mainly in the telencephalon and plays a pleiotropic role in the development of the brain. It is a key player in development and territorial specification of the anterior brain. In addition, it maintains the expansion of the neural proliferating pool, and also regulates the pace of neocortical neuronogenic progression. It also facilitates cortical layer and corpus callosum formation. Furthermore, it promotes dendrite elongation and maintains neural plasticity, including dendritic arborization and spine densities in mature neurons. In this review, we summarize the clinical features, molecular genetics, and possible pathogenesis of
-related syndrome.
Chronic tic disorder and Tourette syndrome are common childhood-onset neurological diseases. However, the pathophysiology underlying these disorders is unclear, and most studies have focused on the ...disinhibition of the corticostriatal-thalamocortical circuit. An autoimmune dysfunction has been proposed in the pathogenetic mechanism of Tourette syndrome and related neuropsychiatric disorders such as obsessive-compulsive disorder, autism, and attention-deficit/hyperactivity disorder. This is based on evidence from animal model studies and clinical findings. Herein, we review and give an update on the clinical characteristics, clinical evidence, and genetic studies in vitro as well as animal studies regarding immune dysfunction in Tourette syndrome.
To demonstrate the feasibility of presymptomatic diagnosis of spinal muscular atrophy (SMA) through newborn screening (NBS).
We performed a screening trial to assess all newborns who underwent ...routine newborn metabolic screening at the National Taiwan University Hospital newborn screening center between November 2014 and September 2016. A real-time polymerase chain reaction (RT-PCR) genotyping assay for the SMN1/SMN2 intron 7 c.888+100A/G polymorphism was performed to detect homozygous SMN1 deletion using dried blood spot (DBS) samples. Then the exon 7 c.840C>T mutation and SMN2 copy number were determined by both droplet digital PCR (ddPCR) using the original screening DBS and multiplex ligation-dependent probe amplification (MLPA) using a whole blood sample.
Of the 120 267 newborns, 15 tested positive according to the RT-PCR assay. The DBS ddPCR assay excluded 8 false-positives, and the other 7 patients were confirmed by the MLPA assay. Inclusion of the second-tier DBS ddPCR screening assay resulted in a positive prediction value of 100%. The incidence of SMA was 1 in 17 181 (95% CI, 1 in 8323 to 1 in 35 468). Two of the 3 patients with 2 copies of SMN2 and all 4 patients with 3 or 4 copies of SMN2 were asymptomatic at the time of diagnosis. Five of the 8 false-positives were caused by intragenic recombination between SMN1 and SMN2.
Newborn screening can detect patients affected by SMA before symptom onset and enable early therapeutic intervention. A combination of a RT-PCR and a second-tier ddPCR can accurately diagnose SMA from DBS samples with no false-positives.
ClinicalTrials.gov NCT02123186.
Background and objective
The epidemiology of pediatric acquired demyelinating disorders remains to be clarified in many parts of Asia. We carry out this study to depict the epidemiology of pediatric ...multiple sclerosis (MS), neuromyelitis optica (NMO), and optic neuritis (ON) in Taiwan.
Methods
We conducted a retrospective nationwide population-based study using data from Taiwan’s National Health Insurance Research Database. Prevalent cases of pediatric MS and NMO during 2001–2015, and incident cases of pediatric MS, NMO, and ON during 2003–2015 were identified. The demographic features and comorbidities were investigated.
Results
We identified 403 MS, 42 NMO, and 1496 ON incident cases under the age of 20 during 2003–2015. The majority of pediatric MS (86.1%) and NMO (90.5%) patients were 10 years old or above. The incidence of MS and ON was relatively steady, while that of NMO increased prominently later during the study period. The average incidence of pediatric MS and NMO during 2011–2015 was 0.52 and 0.11 per 100,000 person-years, respectively. The female preponderance was evident for pediatric MS and NMO, and less so for pediatric ON. The most common autoimmune comorbidities for pediatric MS were thyrotoxicosis (1.0%) and systemic lupus erythematosus (0.7%).
Conclusion
The epidemiology of pediatric MS was largely stationary in Taiwan during 2001–2015, while the prevalence of pediatric NMO rose steeply during this period, probably reflecting better recognition of this clinical entity. Autoimmune comorbidities were uncommon for pediatric MS and NMO in Taiwan.
Coenzyme Q10 (CoQ10) is one of the essential substances for mitochondrial energy synthesis and extra-mitochondrial vital function. Primary CoQ10 deficiency is a rare disease resulting from ...interruption of CoQ10 biosynthetic pathway and biallelic COQ4 variants are one of the genetic etiologies recognized in this hereditary disorder. The clinical heterogenicity is broad with wide onset age from prenatal period to adulthood. The typical manifestations include early pharmacoresistant seizure, severe cognition and/or developmental delay, dystonia, ataxia, and spasticity. Patients may also have multisystemic involvements such as cardiomyopathy, lactic acidosis or gastro-esophageal regurgitation disease. Oral CoQ10 supplement is the major therapeutic medication currently. Among those patients, c.370G > A variant is the most common pathogenic variant detected, especially in Asian population. This phenomenon also suggests that this specific allele may be the founder variants in Asia. In this article, we report two siblings with infantile onset seizures, developmental delay, cardiomyopathy, and diffuse brain atrophy. Genetic analysis of both two cases revealed homozygous COQ4 c.370G > A (p.Gly124Ser) variants. We also review the clinical manifestations of primary CoQ10 deficiency patients and possible treatment categories, which are still under survey. As oral CoQ10 supplement may improve or stabilize disease severity, early precise diagnosis of primary CoQ10 deficiency and early treatment are the most important issues. This review article helps to further understand clinical spectrum and treatment categories of primary CoQ10 deficiency with COQ4 variant.
FOXG1 syndrome is a rare neurodevelopmental disorder associated with severe cognitive dysfunction, autistic behavior, and early-onset hyperkinetic movement disorders. Patients have also been reported ...to experience sleep disturbances. However, these findings are mainly based on subjective caregivers' reports, and limited by small case numbers. Moreover, no studies using objective evaluation tools, such as actigraphy, have been reported. We analyzed the clinical and sleep manifestations of children with FOXG1 syndrome registered in the FOXG1 Research Foundation Patient Registry database. A total of 258 individuals with FOXG1 syndrome were included in this research. 132 (51.16%) had sleep disturbances. The more impaired of language acquisitions (absence of speech, OR: 3.99, 95%CI = 1.69-9.42, p = 0.002), hyperkinetic movement disorders (OR: 2.64, 95%CI = 1.34-5.20 p = 0.005) and feeding difficulties (OR: 2.81, 95% CI = 1.52-5.19, p = 0.001) were significantly associated with an increase in odds of sleep disturbance after adjusting for age, sex, and antiepileptic drugs. We also performed sleep studies on six individuals with FOXG1 syndrome using The Children's Sleep Habits Questionnaire (CSHQ), the Sleep Disturbance Scale for Children (SDSC), and 7-day data from Actiwatch. The Pittsburgh Sleep Quality Index (PSQI) and 7-day data from Actiwatch were also used to evaluate the sleep condition of their parents. The CSHQ scores revealed bedtime resistance, sleep onset delay, sleep duration, sleep anxiety, night-waking, and parasomnia. Sleep-wake transition disorders and disorders of initiating and maintaining sleep were also suggested by the SDSC scores. The children's actigraphy revealed short sleep durations, impaired sleep efficiency, longer wake after sleep onset, and frequent night-waking. All caregivers reported significantly higher PSQI scores, mildly declined sleep efficiency, and shorter total sleep duration. Sleep disturbances, especially in initiating and maintaining sleep, are common in individuals with FOXG1 syndrome and their caregivers. Sleep disorders in patients with FOXG1 syndrome and their caregivers should be investigated.
Increasing animal studies supported the harmful effects of prolonged or frequent neonatal seizures in developing brain, including increased risk of later epilepsy. Various nonlinear analytic measures ...had been applied to investigate the change of brain complexity with age. This study focuses on clarifying the relationship between later epilepsy and the changes of electroencephalogram (EEG) complexity in neonatal seizures.
EEG signals from 19 channels of the whole brain from 32 neonates below 2 months old were acquired. The neonates were classified into 3 groups: 9 were normal controls, 9 were neonatal seizures without later epilepsy, and 14 were neonatal seizures with later epilepsy. Sample entropy (SamEn), multiscale entropy (MSE) and complexity index (CI) were analyzed.
Although there was no significant change in SamEn, the CI values showed significantly decreased over Channels C3, C4, and Cz in patients with neonatal seizures and later epilepsy compared with control group. More multifocal epileptiform discharges in EEG, more abnormal neuroimaging findings, and higher incidence of future developmental delay were noted in the group with later epilepsy.
Decreased MSE and CI values in patients with neonatal seizures and later epilepsy may reflect the mixed effects of acute insults, underlying brain immaturity, and prolonged seizures-related injuries. The analysis of MSE and CI can therefore provide a quantifiable and accurate way to decrypt the mystery of neonatal seizures, and could be a promising predictor.
Sleep disturbances in children with epilepsy are prevalent, and are associated with substantial adverse medical and psychosocial consequences. This study is a 5-year follow-up of a clinic-based sleep ...intervention study that randomized 100 toddlers and preschool-age children with epilepsy to a usual care group or a sleep intervention group. The intervention group received standard paediatric neurology care plus three education sessions during the child's routine clinic visit. The outcomes measured were: (1) child sleep by actigraphy and parental report; and (2) maternal sleep and depression. We aimed to evaluate the long-term benefits of a clinic-based sleep intervention for paediatric epilepsy. In total, 42 families (42.0%) participated. The average child's age at follow-up was 9.55 years. Thirty-eight (90.5%) children were not obtaining sufficient sleep at baseline, and 40 (95.2%) at the 5-year follow-up. The numbers of children with clinically significant sleep disturbances were 40 (95.2%) at baseline and 36 (85.7%) at the 5-year follow-up. Fourteen mothers (33.3%) had poor sleep quality and high depressive symptoms at both assessment time points. There were no differences (P > 0.05) in the child and maternal outcomes between the two trial arms. Overall, there was no evidence that a clinic-based sleep intervention that effectively improved multiple aspects of sleep in toddlers and preschool-age children with epilepsy had long-lasting beneficial effects. Our findings suggest that sleep interventions for families of children with epilepsy require ongoing reinforcement and monitoring during routine paediatric neurology care to prevent sleep problems from persisting or recurring.
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