Neuropediatrics最新文献

In patients with neurodevelopmental disorders (NDDs), exome sequencing (ES), the diagnostic gold standard, reveals an underlying monogenic condition in only approximately 40% of cases. We report the case of a female patient with profound NDD who died 30 years ago at the age of 3 years and for whom genome sequencing (GS) now identified a single-exon deletion in TBCK previously missed by ExomeDepth, the copy number variation (CNV) detection algorithm in ES.Deoxyribonucleic acid (DNA) was extracted from frozen muscle tissue of the index patient and the parents' blood. Genome data were analyzed for structural variants and single nucleotide variants (SUVs)/indels as part of the Bavarian Genomes consortium project.Biallelic variants in TBCK, which are linked to the autosomal recessive disorder TBCK syndrome, were detected in the affected individual: a novel frameshift variant and a deletion of exon 23, previously established as common but underrecognized pathogenic variant in individuals with TBCK syndrome. While in the foregoing ES analysis, calling algorithms for (SNVs)/indels were able to identify the frameshift variant, ExomeDepth failed to call the intragenic deletion.Our case illustrates the added value of GS for the detection of single-exon deletions for which calling from ES data remains challenging and confirms that the deletion of exon 23 in TBCK may be underdiagnosed in patients with NDDs. Furthermore, it shows the importance of "molecular or genetic autopsy" allowing genetic risk counseling for family members as well as the end of a diagnostic odyssey of 30 years.

Introduction: Severe traumatic brain injury (TBI) increases the risk of early posttraumatic seizures (EPTS). Guidelines suggest the use of prophylactic antiseizure agents, including levetiracetam. This study aims to evaluate the feasibility of using levetiracetam dosing based on Glasgow Comas Scale (GCS) scores with higher doses used for more severe TBI.

Methods: Patients 6 months to 18 years old admitted to Penn State Hershey Children's Hospital (PSHCH) with a TBI who received levetiracetam for EPTS prophylaxis with at least one documented GCS score were included. Patients were divided into two cohorts: before and after implementation of the pediatric TBI Cerner PowerPlan at PSHCH which standardized levetiracetam dosing based on GCS scores. Primary outcome was appropriate dosing of levetiracetam based on GCS. Secondary outcomes included seizure occurrence and adverse effects.

Results: Eighty-five patients were included: 42 in the pre-PowerPlan group and 43 in the post-PowerPlan group. Overall, 46 (54%) patients received the appropriate levetiracetam dose based on GCS (pre-PowerPlan, n = 19 [45%] vs. post-PowerPlan n = 27 [63%], p = 0.104). Sixty-four percent of severe TBI patients received appropriate levetiracetam dosing after implantation of the PowerPlan compared with 28% prior to the PowerPlan (p = 0.039). Three patients in each group experienced a seizure while on levetiracetam. Two patients experienced agitation and somnolence attributed to levetiracetam.

Conclusion: Levetiracetam dosing based on GCS scores in pediatric TBI patients is a novel approach, and dosing accuracy may be increased with use of a PowerPlan. Additional large-scale studies are needed to evaluate efficacy and safety of this approach prior to widespread implementation.

Pathogenic variants in COL4A1, encoding the α chain of type IV collagen, have been associated with cerebrovascular pathology as well as malformations of cortical development, thereby causing structural epilepsy. This case illustrates successful resective epilepsy surgery in a 12-month-old girl with left occipital focal cortical dysplasia (FCD) associated with a heterozygous splice-donor variant in COL4A1. She presented with drug-resistant focal epilepsy with daily seizures from the age of 2 months, refractory to several combinations of antiseizure medications, as well as mild right-sided hemiparesis and developmental delay. All presurgical diagnostic modalities, including ictal and interictal electroencephalography, magnetic resonance imaging, and ictal fluorodeoxyglucose positron emission tomography, showed congruent findings, pointing toward one single left occipital epileptogenic zone (EZ). We performed a left occipital lobectomy, using intraoperative electrocorticography to confirm the boundaries of the EZ. After surgery, the patient has remained seizure free, and both cognitive and motor developments have improved. Histopathology of the resected brain tissue showed FCD type Ia. Resective epilepsy surgery can have a very good outcome, also in patients with genetic mutations in COL4A1, constituting a less invasive option than the previously used more radical surgical procedures such as hemispherectomy.

Background: Magnetic resonance imaging in fetal alcohol spectrum disorder (FASD) children showed altered connectivity, suggesting underlying deficits in networks, which may be related to cognitive outcome. Functional connectivity has been of interest in neurophysiological research with quantitative electroencephalography (QEEG) as useful tool for measuring pathology, not detectable by normal EEG. The aim of this study was to investigate differences in the EEG interhemispheric coherence (ICoh) in children diagnosed with FASD compared with healthy controls and to relate the results to cognitive scores.

Method: Analysis of ICoh in 81 FASD children (4-Digit Code) compared with 31 controls. The children underwent cognitive assessment, and EEG was performed and used for analysis. Group comparisons and analysis of covariance interaction models were used to test for differences between FASD and controls but also to look for differences between FASD subgroups. Significant findings were correlated to cognitive scores.

Results: Lower ICoh was found in the frontal and temporal derivations in the FASD group. When comparing FASD subgroups, children with fetal alcohol syndrome had lower ICoh occipital. Reduced ICoh in the temporal alpha band was correlated with lower performance IQ in the FASD group.

Conclusion: Our findings could imply hypoconnectivity between the hemispheres with impact on cognition. We suggest that EEG coherence analysis could be a sensitive parameter in the detection of electrophysiological abnormalities in FASD with possible clinical relevance. These results may indicate that QEEG could be used as biomarker for FASD. However, further research is needed to determine the role of QEEG analysis in the diagnosis of FASD.

Cyclic nucleotide phosphodiesterase (PDE) enzymes catalyze the breakdown of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which act as intracellular second messengers for signal transduction pathways and modulate various processes in the central nervous system. Recent discoveries that mutations in genes encoding different PDEs, including PDE10A, are responsible for rare forms of chorea in children led to the recognition of an emerging role of PDEs in the field of pediatric movement disorders. A comprehensive literature review of all reported cases of PDE10A mutations in PubMed and Web of Science was performed in English. We included eight studies, describing 31 patients harboring a PDE10A mutation and exhibiting a hyperkinetic movement disorder with onset in infancy or childhood. Mutations in both GAF-A, GAF-B regulatory domains and outside the GAF domains of the PDE10A gene have been reported to cause hyperkinetic movement disorders. In general, patients with homozygous mutations in either GAF-A domain of PDE10A present with a more severe phenotype and at an earlier age but without any extensive abnormalities of the striata compared with patients with dominant variants in GAF-B domain, indicating that dominant and recessive mutations have different pathogenic mechanisms. PDE10A plays a key role in regulating control of striato-cortical movement. Comprehension of the molecular mechanisms within the cAMP and cGMP signaling systems caused by PDE10A mutations may inform novel therapeutic strategies that could alleviate symptoms in young patients affected by these rare movement disorders.

The association between dystonia and early-onset epileptic encephalopathy (EOEE) may have a genetic basis. Phosphatidylinositol glycan biosynthesis class A protein (PIGA) germline mutations have been described in the last decade and associated with refractory EOEEs. Dysmorphisms and visceral abnormalities have also been reported. Here, we present the case of a now 8-month-old child who was evaluated for dystonia, visual impairment, and developmental delay at 2 months of age, followed by refractory focal seizures when he was 4 months old. The remaining examination was normal, besides an accelerated linear growth. His brain magnetic resonance and an extensive metabolic investigation failed to show any abnormalities. At 7 months of age, the exome sequencing found a hemizygous PIGA pathogenic variant-c.1352T > C (p.(Ile451Thr). Seizures improved after the association of carbamazepine with levetiracetam and the beginning of the ketogenic diet. To our knowledge, this is the first time the phenotype associated with this specific mutation is described. Our patient had the singularity of manifesting with remarkable dystonia, over 2 months before the onset of seizures. We also point to the utility of the gene sequencing approach in the diagnosis of patients with dystonia and EOEEs, since identification of the genetic cause may help in patient's management and families' empowerment.

Background: Teenagers with epilepsy require special attention to ensure a successful treatment journey. Our objective was to delineate the clinical characteristics of adolescent-onset epilepsy (AOE) and investigate the predictive factors influencing first-year seizure freedom.

Methods: We retrospectively analyzed the medical records of patients whose first seizure occurred between the ages of 10 and 19 years and who received antiseizure medication (ASM) treatment for at least 12 months.

Results: A total of 67 patients were included, with an average age of 13.5 ± 2.3 years at the onset of their first seizure. The average follow-up period was 45.2 ± 16.9 months, and comorbid conditions were present in 23 patients (34.3%). The majority of the patient population (83.6%) was affected by generalized epilepsy. The most common epilepsy syndrome was epilepsy with generalized tonic-clonic seizures alone at 70.1% (juvenile myoclonic epilepsy 11.9%, juvenile absence epilepsy 1.5%). Regarding ASM treatment, 31 patients (46.3%) received monotherapy, and 28 (41.8%) received dual therapy. Five patients (7.5%) encountered issues related to medication adherence. First-year seizure freedom was observed in 42 patients (62.7%). In multivariate analysis, a negative family history of epilepsy (odds ratio 12.1, 95% confidence interval 1.27-115.44, p = 0.030) was identified as a strong predictive factor of first-year seizure freedom, along with ASM monotherapy (odds ratio 3.99, 95% confidence interval 1.05-15.21, p = 0.043).

Conclusion: These findings suggest that AOE typically exhibits effective control of seizures. A negative family history of epilepsy and ASM monotherapy emerges as robust predictor of achieving favorable outcomes within the early stage of treatment.