Many patients with developmental and epileptic encephalopathies present with variants in genes coding for GABA_A receptors. These variants are presumed to cause loss-of-function receptors leading to reduced neuronal GABAergic activity. Yet, patients with GABA_A receptor variants have diverse clinical phenotypes and many are refractory to treatment despite the availability of drugs that enhance GABAergic activity. Here we show that 44 pathogenic GABRB3 missense variants segregate into gain-of-function and loss-of-function groups and respective patients display distinct clinical phenotypes. The gain-of-function cohort (n = 27 patients) presented with a younger age of seizure onset, higher risk of severe intellectual disability, focal seizures at onset, hypotonia, and lower likelihood of seizure freedom in response to treatment. Febrile seizures at onset are exclusive to the loss-of-function cohort (n = 47 patients). Overall, patients with GABRB3 variants that increase GABAergic activity have more severe developmental and epileptic encephalopathies. This paradoxical finding challenges our current understanding of the GABAergic system in epilepsy and how patients should be treated.

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting following repeated muscle damage and inadequate regeneration. Impaired myogenesis and differentiation play a major role in DMD as well as intracellular calcium (Ca²⁺) mishandling. Ca²⁺ release from the sarcoplasmic reticulum is mostly mediated by the type 1 ryanodine receptor (RYR1) that is required for skeletal muscle differentiation in animals. The study objective was to determine whether altered RYR1-mediated Ca²⁺ release contributes to myogenic differentiation impairment in DMD patients. The comparison of primary cultured myoblasts from six boys with DMD and five healthy controls highlighted delayed myoblast differentiation in DMD. Silencing RYR1 expression using specific si-RNA in a healthy control induced a similar delayed differentiation. In DMD myotubes, resting intracellular Ca²⁺ concentration was increased, but RYR1-mediated Ca²⁺ release was not changed compared with control myotubes. Incubation with the RYR-calstabin interaction stabilizer S107 decreased resting Ca²⁺ concentration in DMD myotubes to control values and improved calstabin1 binding to the RYR1 complex. S107 also improved myogenic differentiation in DMD. Furthermore, intracellular Ca²⁺ concentration was correlated with endomysial fibrosis, which is the only myopathologic parameter associated with poor motor outcome in patients with DMD. This suggested a potential relationship between RYR1 dysfunction and motor impairment. Our study highlights RYR1-mediated Ca²⁺ leakage in human DMD myotubes and its key role in myogenic differentiation impairment. RYR1 stabilization may be an interesting adjunctive therapeutic strategy in DMD.

Aim: To study long‐term sequelae in children with Guillain–Barré syndrome (GBS).Method: This was a prospective observational study with children from two French tertiary centres. Data were from clinical and several standardized scales or questionnaires.Results: Fifty‐one patients were included with a median follow‐up of 6 years 4 months (range 3–20 years) after the acute phase. The sequelae rate was 67% (95% confidence interval [CI] 53–78) and did not vary with time. Most children had minor sequelae (Guillain–Barré Syndrome Disability Score [GBSDS] = 1); only one was unable to run (GBSDS = 2). The most frequent complaints were paraesthesia (43%), pain (35%), and fatigue (31%). The neurological examination was abnormal in 18% of children, autonomy was compromised in 14%, and symptoms of depression occurred in 34%. The factors associated with late‐onset sequelae were correlated with severity during the initial phase (i.e. initial GBSDS >4, odds ratio 6.6, 95% CI 1.8–33; p = 0.009). The predictive factors of more severe late‐onset conditions were initial severity (p = 0.002) and sex (female patients; p = 0.01).Interpretation: Two‐thirds of children with GBS had late‐onset sequelae following an episode, often minor, but sometimes with continuing effects on their everyday lives. Particularly affected were those who had severe GBS during the acute phase and who lost the ability to walk.What this paper adds: Two‐thirds of children with Guillain–Barré syndrome (GBS) had persistent sequelae. Sequelae were often minor, but daily repercussions of them were sometimes serious. Sequelae were significantly associated with severe GBS during the acute phase.

Fine motor skills (FMS) allow for the control and coordination of the distal musculature of hands and fingers, a skill required to brush teeth. The objective of this study was to investigate the association between FMS and toothbrushing efficacy. This cross-sectional study included 42 low-income Latino children aged 5 to 9 years from Pasto, Colombia. Toothbrushing efficacy was determined by the children's dental plaque Quigley-Hein Index (QH-I) mean-score difference from before and after toothbrushing. FMS were evaluated using the 5-15R parent evaluation, the spiral drawing Archimedes test, and a neurodevelopmental assessment of movements and prehension patterns during toothbrushing. A descriptive analysis was performed to assess the characteristics of FMS and children's toothbrushing, and a generalized linear model was used to determine associations between these skills and toothbrushing efficacy. Eighty-six percent of the children had at least one difficulty with FMS, and in 7%, they interfered with daily activities. Fourteen percent presented a moderate pattern in the Archimedes test, and 43% had inefficient prehension patterns. Toothbrushing reduced the QH-I by a mean of 1.45 (SD = 0.78-2.12) (p < 0.001). Toothbrushing efficacy was only significantly associated with age (mean-difference = -0.315, 95%CI: -0.481 to -0.148, p < 0.001). FMS and toothbrushing efficacy were not significantly associated. Other components of fine motor control should be analyzed to understand the kinetics of toothbrushing.

Acute transverse myelitis (ATM) in children is a rare and often severe disease for which there are few known prognostic factors, particularly the subsequent risk of multiple sclerosis (MS) diagnosis. To determine the clinical course and prognostic factors after a first episode of ATM in children. Thirty children below 16 years of age diagnosed with a first neurological episode of ATM were included retrospectively. Clinical evaluation, treatment, laboratory, and MRI data were collected. Median age at onset was 11 years (range 3–15 years). Follow-up data were available for a median of 4 years (range 0.5–16.7 years). Five patients subsequently had a diagnosis of MS (17%), which was associated with acute partial transverse myelitis (odds ratio 5; 95% confidence interval 2.3–11), with a 60% probability of having a relapse at five years (p < 0.01). The 2011 Verhey criteria correctly identified MS in children with the highest specificity (96%) and sensitivity (80%). Acute partial transverse myelitis and brain MRI abnormalities at initial presentation are significantly predictive of a subsequent diagnosis of MS in children with ATM. These findings suggest that closer brain MRI monitoring after acute partial transverse myelitis might make the earlier introduction of disease-modifying therapies possible.