Béatrice Desnous

Background and ObjectivesDevelopmental and epileptic encephalopathies (DEEs) with early burst-suppression EEG (EIDEE-BS) are among the most severe neonatal epileptic syndromes, typically presenting...

Introduction: Cardiac complications are well-documented in propionic acidemia (PA), and there are a few reported cases of cardiomyopathies in methylmalonic acidemia (MMA). Left-ventricular global longitudinal strain (LV GLS) measurement is known to be able to detect early ventricular dysfunction, leading potentially to cardiomyopathy. The aim of our study was to evaluate left-ventricular global longitudinal strain (LV GLS) in MMA and PA patients and compare it with the pediatric general population. Methods: In this monocentric retrospective study, 26 patients with organic aciduria (OA) were included. Demographic, clinical, electrocardiographic and echocardiographic data were collected. The mean LV GLS in MMA and PA patients was compared with the GLS in the pediatric general population. Results: The left-ventricular ejection fraction (LVEF) was similar between MMA and PA patients and in the normal range (66.27 ± 6.24% vs. 61.41 ± 11.02%; p = 0.182). LV GLS was significantly lower in PA patients than in MMA patients (−15.8 ± 5.67% vs. −20.6 ± 3.19%; p = 0.011). LV GLS was significantly lower in PA patients when compared with the general pediatric population (p = 0.029). Conclusions: Patients with propionic acidemia may have impaired global longitudinal strain even in the presence of normal LVEF. LV GLS might be a useful tool for cardiac follow-up in pediatric patients with OA.

Background Children with complex congenital heart disease (CCHD) are at high risk for early neurodevelopmental delays across all domains. Neuromotor delay often emerges first and may impact broader development. Identifying early biomarkers of motor function could capture a critical window for intervention. We assessed the prognostic value of neuron-specific enolase (NSE) and S100B in predicting 4-month motor outcomes in newborns undergoing cardiac surgery with cardiopulmonary bypass (CPB). Methods Between December 2021 and October 2024, we conducted a prospective, single-centre study including term neonates with (CCHD) who required cardiac surgery within the first two months of life. NSE and S100B levels were measured at five perioperative time points. Blinded Alberta Infant Motor Scale (AIMS) assessment at four months evaluated motor outcomes. Results Of 35 newborns, 27 completed follow-up. Preoperative NSE levels were significantly higher in infants with AIMS scores below the 10th percentile (32.7 vs. 20.9 ng/mL, p = 0.044) and negatively correlated with AIMS percentiles (ρ = –0.617, p = 0.006. There was no significant association between motor outcomes, MRI findings or S100B levels. Conclusions Higher preoperative NSE levels predict poor early motor outcomes in CCHD and may be a marker for early risk stratification and intervention. Impact Neuron-specific enolase (NSE) may serve as an early biomarker of neuromotor development in newborns with complex congenital heart disease (CCHD). Elevated preoperative NSE levels were associated with poorer motor outcomes at four months. NSE may serve as an additional biomarker within a multimodal risk stratification strategy, complementing clinical, imaging, and electrophysiological assessments to refine prognostic evaluation. These findings highlight the prognostic value of perioperative biomarkers for predicting early motor outcomes and support earlier identification of at-risk newborns, enabling targeted neurodevelopmental interventions. This work adds new evidence to limited literature on biological predictors of motor development after neonatal cardiac surgery.

Objective: Neonatal seizures initiate the onset of epilepsy in less than 20% of cases. Establishing accurate and prompt diagnosis for precision medicine, offering tailored care, and informing families about neurodevelopmental prognosis represents a significant challenge. We aim to describe the natural history of drug‐resistant epilepsy and negative brain MRI with neonatal onset, and to identify predictors of neurodevelopmental outcomes. Methods: We retrospectively analyzed demographic, clinical, electroencephalogram (EEG), and genetic data from neonates with epilepsy onset before 1 month of age, with no provoked cause, and a normal brain MRI, followed at a tertiary center from 2000 to 2020. Neonates with self‐limited epilepsy (SLE) or those responding to phenobarbital without later epilepsy were excluded. Results: Among 56 patients, 60% had a genetic etiology (KCNQ2, STXBP1, KCNT1, others). Most (96%) developed intellectual disability (ID); moderate ID without cerebral palsy (CP) was recorded in 11, and profound intellectual and multiple disabilities (PIMD) in 42. Only two patients had a favorable neurodevelopmental outcome without intellectual disability. An abnormal neurological exam at epilepsy onset was the sole risk factor for future PIMD. Significance: Neonatal‐onset pharmacoresistant epilepsies with a normal brain MRI are predominantly monogenic and lead to poor neurodevelopmental outcomes. An abnormal initial neurodevelopmental assessment predicts future PIMD. Plain Language Summary: Our study found that epilepsy starting in the neonatal period is often linked to a strong genetic component. The prognosis is generally poor, with frequent neurodevelopmental delays. An abnormal neurological examination during the neonatal period is a predictor of worse outcomes.

The fibroblast growth factor 12 (FGF12) gene encodes a protein interacting with voltage‐gated sodium channels. Two variants, p.(Arg52His) and p.(Gly50Ser), have repeatedly been associated with developmental and epileptic encephalopathy‐47 (DEE47; Mendelian Inheritance in Man #617166) with poor outcome. We aim to refine the electroclinical phenotype and outcomes of 10 unpublished patients (2–38 years old) with these recurrent pathogenic variants in the FGF12 gene without DEE (p.[Arg52His], n = 4; p.[Gly50Ser], n = 6). The patients with p.(Gly50Ser) showed later and more explosive epilepsy onset, whereas p.(Arg52His) cases had gradual onset. All developed epilepsy before 5 months, with 70% achieving seizure remission by 6 months with antiseizure medication (ASM), leading to good neurodevelopmental outcomes (median follow‐up = 6.8 years). In contrast, the patients with mild intellectual disability had persistent epilepsy despite ASM. Additionally, patients with favorable neurodevelopmental outcomes and FGF12 pathogenic variants showed no signs of cerebellar atrophy. Moreover, we did not find a clear correlation between treatment with sodium channel blockers, its timing, and neurodevelopmental outcome. Here, we expand the phenotypic spectrum of FGF12 pathogenic variants and underscore cases with favorable neurodevelopmental outcomes.

There is a paucity of data directly comparing the outcome of surgical techniques available for the treatment of hypothalamic hamartomas (HHs). This study aims to evaluate the safety and efficacy of commonly used surgical approaches in the treatment of HH-related epilepsy. A systematic review and individual participant data (IPD) meta-analysis was conducted. The PubMed, Embase, and Scopus online databases were searched without any date restrictions for original studies with more than 1 participant reporting on patients with HH-related epilepsy who underwent surgical treatment. Random-effects modeling was used to calculate the pooled proportions of seizure freedom (Engel I) at the last follow-up. IPD were used to perform mixed-effects logistic regression to identify predictors of seizure freedom and major postoperative complications. Sixty-four studies were included, and IPD on 517 patients were obtained. The overall quality of evidence was low. After the index procedure, the pooled proportion of overall seizure freedom was 50.0% (95% CI 42.7%-57.4%), which increased to 64.5% (95% CI 57.2%-71.5%) after multiple treatments. Magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) and radiofrequency thermocoagulation (RFTC) demonstrated the highest efficacy at the last follow-up, with seizure freedom rates of 74.5% (95% CI 66.8%-81.7%) and 78.5% (95% CI 71.6%-84.8%), respectively. Factors independently associated with a lower likelihood of seizure freedom included multiple seizure types (odds ratio [OR] 0.296, 95% CI 0.140-0.624, p = 0.001) and previous surgery (OR 0.418, 95% CI 0.198-0.884, p = 0.023). Stereotactic radiosurgery (SRS) was the safest approach, with a pooled proportion of major complications of 0.0% (95% CI 0.0%-1.4%). Only surgical technique emerged as an independent predictor of major complications, with SRS (OR 0.024, 95% CI 0.002-0.292, p = 0.004), RFTC (OR 0.133, 95% CI 0.026-0.692, p = 0.017), and MRgLITT (OR 0.234, 95% CI 0.056-0.968, p = 0.045) being associated with a lower likelihood of major complications. MRgLITT and RFTC offer superior efficacy and safety compared with open microsurgery and should be considered as first-line options. Despite its lower efficacy, SRS is associated with few reported long-term complications, making it a viable alternative for select cases, such as small HHs with good baseline functioning. Direct comparisons between techniques are limited by short follow-up durations in RFTC and MRgLITT cohorts. Further large-scale, multicenter studies directly comparing these modalities are warranted.

Hereditary sensory and autonomic neuropathy type 1 is an autosomal dominant neuropathy caused by the SPTLC1 or SPTLC2 variants. These variants modify the preferred substrate of serine palmitoyl transferase, responsible for the first step of de novo sphingolipids synthesis, leading to accumulation of cytotoxic deoxysphingolipids. Diagnosis of HSAN1 is based on clinical symptoms, mainly progressive loss of distal sensory keep, and genetic analysis. Aim: Identifying new SPTLC1 or SPTLC2 “gain-of-function” variants raises the question as to their pathogenicity. This work focused on characterizing six new SPTLC1 variants using in silico prediction tools, new meta-scores, 3D modeling, and functional testing to establish their pathogenicity. Methods: Variants from six patients with HSAN1 were studied. In silico, CADD and REVEL scores and the 3D modeling software MITZLI were used to characterize the pathogenic effect of the variants. Functional tests based on plasma sphingolipids quantification (total deoxysphinganine, ceramides, and dihydroceramides) were performed by tandem mass spectrometry. Results: In silico predictors did not provide very contrasting results when functional tests discriminated the different variants according to their impact on deoxysphinganine level or canonical sphingolipids synthesis. Two SPTLC1 variants were newly described as pathogenic: SPTLC1 NM_006415.4:c.998A>G and NM_006415.4:c.1015G>A. Discussion: The combination of the different tools provides arguments to establish the pathogenicity of these new variants. When available, functional testing remains the best option to establish the in vivo impact of a variant. Moreover, the comprehension of metabolic dysregulation offers opportunities to develop new therapeutic strategies for these genetic disorders.

The clinical effects of a serious game with electromyography feedback (EMGs_SG) and physical therapy (PT) was investigated prospectively in children with unilateral spastic cerebral palsy (USCP). An additional aim was to better understand the influence of muscle shortening on function. Thirty children with USCP (age 7.6 ± 2.1 years) received four weeks of EMGs_SG sessions 2×/week including repetitive, active alternating training of dorsi- and plantar flexors in a seated position. In addition, each child received usual PT treatment ≤ 2×/week, involving plantar flexor stretching and command strengthening on dorsi- and plantar flexors. Five-Step Assessment parameters, including preferred gait velocity (normalized by height); plantar flexor extensibility (XV1); angle of catch (XV3); maximal active ankle dorsiflexion (XA); and derived coefficients of shortening, spasticity, and weakness for both soleus and gastrosoleus complex (GSC) were compared pre and post treatment (t-tests). Correlations were explored between the various coefficients and gait velocities at baseline. After four weeks of EMGs_SG + PT, there was an increase in normalized gait velocity from 0.72 ± 0.13 to 0.77 ± 0.13 m/s (p = 0.025, d = 0.43), a decrease in coefficients of shortening (soleus, 0.10 ± 0.07 pre vs. 0.07 ± 0.08 post, p = 0.004, d = 0.57; GSC 0.16 ± 0.08 vs. 0.13 ± 0.08, p = 0.003, d = 0.58), spasticity (soleus 0.14 ± 0.06 vs. 0.12 ± 0.07, p = 0.02, d = 0.46), and weakness (soleus 0.14 ± 0.07 vs. 0.11 ± 0.07, p = 0.005, d = 0.55). At baseline, normalized gait velocity correlated with the coefficient of GSC shortening (R = −0.43, p = 0.02). Four weeks of EMGs_SG and PT were associated with improved gait velocity and decreased plantar flexor shortening. A randomized controlled trial comparing EMGs_SG and conventional PT is needed.