Neuropediatrics最新文献

The elucidation of the molecular basis of monogenic epilepsies is advancing rapidly. For clinicians, knowing not only the affected gene, but also the patient's exact genetic variant and gaining insight into its effect on RNA, protein, cell, and organism level is becoming increasingly important. As different variants in the same gene can lead to opposing functional effects, an understanding of their nature is crucial for informed treatment choices. Correctly counseling patients, parents, and families regarding the patient's prognosis and the risk to other family members of being affected or having an affected child is only possible with detailed knowledge of the genetic and functional alterations underlying the condition. This review aims to provide a comprehensive overview of genetic variants and their effects, following them from the DNA to the organism level. Protein-level outcomes, such as gain- and loss-of-function mechanisms as well as dominant-negative effects, will be illustrated using examples from monogenic epilepsies. Their downstream impact on cellular function and phenotype will be traced to shed light on the mechanisms by which different variants in the same gene can result in diverging clinical presentations. In doing so, we illustrate key genetic concepts relevant to clinical practice to help inform clinical interpretation of genetic variants and facilitate therapeutic decision-making.

Pyridoxal-5'-phosphate (PLP) is in most patients the effective treatment for pyridox(am)ine-5'-phosphate oxidase (PNPO) deficiency, a rare autosomal recessive cause of neonatal-onset developmental and epileptic encephalopathy. Although generally considered safe, long-term high-dose PLP exposure may have hepatotoxic effects, particularly in the absence of pharmaceutical-grade formulations.We report a series of four pediatric patients with vitamin B6-dependent epilepsy who received long-term PLP therapy. Two had genetically confirmed PNPO deficiency, and two were later diagnosed with ALDH7A1 deficiency. All received high-dose oral PLP, with frequent changes in formulation due to availability issues.Three of the four patients developed hepatocellular carcinoma after several years of PLP treatment; one developed fully reversible severe hepatotoxicity. The shared exposure to prolonged high-dose PLP across all affected patients, despite differing metabolic conditions, suggests a possible role for PLP toxicity independent of the underlying metabolic disorder. Known toxic mechanisms include mitochondrial dysfunction, Schiff base-mediated protein modification, and accumulation of reactive PLP degradation products. In two patients, the total PLP dose was successfully reduced by over 30% through increasing administration frequency, without loss of seizure control.These findings raise significant concerns about the long-term hepatic safety of oral PLP in patients with vitamin B6-dependent epilepsies. As intravenous PLP is unfeasable for lifelong therapy, there is an urgent need for standardized, high-quality PLP preparations and exploration of alternative delivery routes such as intranasal administration. Regular hepatic monitoring should be implemented in all patients receiving chronic PLP therapy.

We report the clinical course of a 13-year-old male patient with a history of focal structural epilepsy starting at the age of 18 months due to focal cortical dysplasia (FCD) IIa and undetected genetic arrhythmia syndrome due to a pathogenic variant in sodium voltage-gated channel alpha subunit 5 (SCN5A) gene at that time.High-resolution MRI detected FCD in the left suprabasal margin matching the EEG focus. At the age of 12 years, epileptological-surgical evaluation led to lesionectomy, which resulted in seizure freedom postoperatively. Months later, the patient experienced an episode of leg pain, increased tone of the upper body, and subsequent cardiac arrest. Resuscitation efforts were successful, leading to survival with hypoxic brain injury. Unexpected cardiac arrest not in line with the previous seizure semiology led to further cardiological examinations including electrophysiology and genetic testing, revealing a pathogenic SCN5A variant associated with arrhythmia syndromes. A two-chamber implantable cardioverter defibrillator (ICD) was implanted. To our knowledge, this combination of diseases has not been reported yet, a causal relationship stays speculatively. Nevertheless, it highlights the complexity of coexisting structural and genetic conditions that can only be detected in alertness to uncommon conditions and via an interdisciplinary approach.

NPRL3 (nitrogen permease regulator-like 3) variants are associated with focal epilepsy syndromes, including sleep-related hypermotor epilepsy (SHE) and familial focal epilepsy with variable foci (FFEVF), with or without focal cortical dysplasia (FCD). The NPRL3 gene encodes a protein that forms the GATOR1 complex, which regulates the mTOR signaling pathway.To characterize the epilepsy phenotype associated with NPRL3, assess treatment strategies, and evaluate patient prognosis.We conducted a multicenter, retrospective study using an online questionnaire to collect clinical data on seizure onset, crisis-like seizure exacerbations, MRI findings, neuropsychological assessment, treatment, and genetic variants. Variants were classified per ACMG guidelines. The study was part of the Network for Therapy in Rare Epilepsies (NETRE).Data from 37 patients with NPRL3-associated epilepsy were analyzed. Mean age at seizure onset was 3.7 years (median with interquartile range [IQR] 1.3-4.9). Over 1 to 45 years of follow-up (mean 13.6, IQR 5.4-18), 21/37 (57%) experienced crisis-like seizure exacerbations. MRI abnormalities were present in 10/36 (28%) cases: 8 FCD, 1 hippocampal sclerosis, and 1 hippocampal asymmetry. Persistent focal epileptiform discharges were present on serial EEGs in 20/37 patients (54%). Highest drug response rates were seen with lacosamide, followed by clobazam, carbamazepine/oxcarbazepine, and lamotrigine. Epilepsy surgery (n = 8) led to seizure freedom in four and significant reduction in one case.Crisis-like seizure exacerbations were common in NPRL3-associated epilepsy. Sodium channel blockers showed notable efficacy. Epilepsy surgery was beneficial even in MRI-negative cases. No distinct genotype-phenotype correlation was identified.

This retrospective, dual-center Italian study assessed the incidence, electroclinical characteristics, and risk factors for post-neonatal epilepsy among neonates with hypoxic-ischemic encephalopathy (HIE) treated with therapeutic hypothermia (TH). The study aims to better define the long-term risk factors for developing epilepsy or neurodevelopmental issues.We included neonates with HIE who underwent TH. Neurological examination and general movements were assessed before and after TH. Amplified-integrated EEGs (aEEG) or polygraphic EEGs (pEEG) were performed within 6 hours of life; a pEEG was performed after TH (72 hours to 10 days) and at 3, 9 to 12, and 24 months, and then yearly. Brain MRI was conducted within 30 days. The 24-month developmental outcome was evaluated using Griffiths Mental Development Scales. The median follow-up duration was 48 months. Epilepsy was classified according to ILAE criteria.We enrolled 159 patients: 15 (9.4%) developed epilepsy. Nine (5.6%) had onset before 24 months; three of them developed infantile epileptic spasm syndrome (IESS). Seizure onset was after 24 months in 6/159 individuals (3.8%). At the last follow-up, all 15 patients had focal epilepsy. Global development was pathological in 11/15 (10/15 <2SD; 1/15 <1SD). Risk factors for post-neonatal epilepsy included: MRI lesions involving the basal ganglia and thalamus (p < 0.0001), severe HIE (p = 0.0008), and severe anomalies on the pEEG recorded pre-TH (p = 0.0032) and post-TH (p = 0.0071).Our study confirms that post-neonatal epilepsy is rare and generally well-controlled. MRI, HIE-3, and early pEEGs are key predictors. High-risk patients should be screened for IESS in the early months, and patients with electroclinical and neuroradiological risk factors should continue long-term neurological follow-up beyond 24 months.

Pompe disease is a rare lysosomal storage disorder with a wide clinical spectrum ranging from infantile-onset Pompe disease (IOPD) with early severe cardiomyopathy to late-onset Pompe disease (LOPD) with progressive muscle weakness. This study aimed to evaluate clinical features, genotype-phenotype correlations, treatment outcomes, and significant events in a real-life pediatric cohort of Pompe patients.We retrospectively analyzed 30 pediatric patients diagnosed with Pompe disease (27 IOPD, 3 LOPD). Demographic, clinical, biochemical, genetic, and radiologic data were collected. Recurrent clinical events were assessed using the Andersen-Gill extension of the Cox model to evaluate the effect of enzyme replacement therapy (ERT).The median age at diagnosis was 5 (range 20 days to 80 months) months, and consanguinity was present in 83% of cases. IOPD cases predominantly showed hypotonia and cardiac involvement, whereas LOPD cases were asymptomatic or mildly symptomatic, with delayed motor development and increased CK levels. Novel GAA mutations were identified in seven patients. ERT was administered to 24 IOPD patients, leading to improved cardiac function and prolonged survival. Event incidence was significantly lower in the ERT group (HR = 0.06, p < 0.005), despite a longer follow-up. However, 56% of patients-all with IOPD-died during follow-up. Non-muscular findings such as neurogenic bladder in 6.6% (2/30), sensorineural hearing loss in 13.3% (4/30), and white matter abnormalities in 40.9% (9/21) were also documented.This real-life evidence reinforces the central role of early, individualized ERT and comprehensive multidisciplinary care in altering the natural course of Pompe disease.