L-serine treatment in patients with GRIN-related encephalopathy: a phase 2A, non-randomized study.

GRIN-related disorders are rare developmental encephalopathies with variable manifestations and limited therapeutic options. Here, we present the first non-randomized, open-label, single-arm trial (NCT04646447) designed to evaluate the tolerability and efficacy of L-serine in children with GRIN genetic variants leading to loss-of-function. In this phase 2A trial, patients aged 2-18 years with GRIN loss-of-function pathogenic variants received L-serine for 52 weeks. Primary end points included safety and efficacy by measuring changes in the Vineland Adaptive Behavior Scales, Bayley Scales, age-appropriate Wechsler Scales, Gross Motor Function-88, Sleep Disturbance Scale for Children, Pediatric Quality of Life Inventory, Child Behavior Checklist and the Caregiver-Teacher Report Form following 12 months of treatment. Secondary outcomes included seizure frequency and intensity reduction and EEG improvement. Assessments were performed 3 months and 1 day before starting treatment and 1, 3, 6 and 12 months after beginning the supplement. Twenty-four participants were enrolled (13 males/11 females, mean age 9.8 years, SD 4.8), 23 of whom completed the study. Patients had GRIN2B, GRIN1 and GRIN2A variants (12, 6 and 5 cases, respectively). Their clinical phenotypes showed 91% had intellectual disability (61% severe), 83% had behavioural problems, 78% had movement disorders and 58% had epilepsy. Based on the Vineland Adaptive Behavior Composite standard scores, nine children were classified as mildly impaired (cut-off score > 55), whereas 14 were assigned to the clinically severe group. An improvement was detected in the Daily Living Skills domain (P = 0035) from the Vineland Scales within the mild group. Expressive (P = 0.005), Personal (P = 0.003), Community (P = 0.009), Interpersonal (P = 0.005) and Fine Motor (P = 0.031) subdomains improved for the whole cohort, although improvement was mostly found in the mild group. The Growth Scale Values in the Cognitive subdomain of the Bayley-III Scale showed a significant improvement in the severe group (P = 0.016), with a mean increase of 21.6 points. L-serine treatment was associated with significant improvement in the median Gross Motor Function-88 total score (P = 0.002) and the mean Pediatric Quality of Life total score (P = 0.00068), regardless of severity. L-serine normalized the EEG pattern in five children and the frequency of seizures in one clinically affected child. One patient discontinued treatment due to irritability and insomnia. The trial provides evidence that L-serine is a safe treatment for children with GRIN loss-of-function variants, having the potential to improve adaptive behaviour, motor function and quality of life, with a better response to the treatment in mild phenotypes.

Oxidative Stress and Indicators of Brain Damage Following Pediatric Heart Surgery.

Pediatric cardiac surgery induces an increased oxidative stress (OS) response. Increased OS is associated with poor neurologic outcomes in neonatal populations with similar patterns of brain injury. We investigated OS and brain injury in infants undergoing heart surgery. Patients 6 months or younger, undergoing cardiac surgery with or without cardiopulmonary bypass (CPB), were included in this prospective, observational study. Patients were divided into infant (30 days−6 months) and neonatal (<30 days) groups for analysis. Urine OS biomarker 8-iso-prostaglandin F2α (8-iso-PGF2α) was quantified pre-surgery and at 0 and 24 h post-surgery. A serum brain damage biomarker S100B protein was also measured pre-surgery and at 0 and 72 h post-surgery. Amplitude-integrated electroencephalography during surgery was analyzed. Neuropsychological evaluation using the Bayley III or Vineland test was performed in all patients at 24 months of age. Sixty-two patients were included, 44 of whom underwent follow-up neurologic evaluation. 8-iso-PGF2α and S100B levels were increased after surgery. Postoperative levels of S100B were positively correlated with 8-iso-PGF2α levels 24 h after surgery (rho = 0.5224; p = 0.0261). There was also a correlation between immediate post-surgery levels of 8-iso-PGF2α and intra-surgery seizure burden (rho = 0.4285, p = 0.0205). Patients with an abnormal neurological evaluation had increased levels of S100B 72 h after surgery (p = 0.048). 8-iso-PGF2α levels 24 h after surgery were also related to abnormal neurologic outcomes. Levels of 8-iso-PGF2α following pediatric cardiac surgery are associated with several indicators of brain injury including brain damage biomarkers, intra-operative seizures, and abnormal neurological evaluation at follow-up, suggesting the importance of oxidative stress response in the origin of brain damage in this population.

Early-onset severe spinocerebellar ataxia 42 with neurodevelopmental deficits (SCA42ND): Case report, pharmacological trial, and literature review.

Early-onset severe spinocerebellar ataxia 42 with neurodevelopmental deficits (SCA42ND, MIM#604065) is an ultrarare autosomal dominant syndrome related to de novo CACNA1G gain-of-function pathogenic variants. All patients with SCA42ND show cerebellar atrophy and/or hypoplasia on neuroimaging and share common features such as dysmorphic features, global developmental delay, and axial hypotonia, all manifesting within the first year of life. To date, only 10 patients with SCA42ND have been reported with functionally confirmed gain-of-function variants, bearing either of two recurrent pathogenic variants. We describe a girl with congenital ataxia, without epilepsy, and a de novo p.Ala961Thr pathogenic variant in CACNA1G. We review the published subjects with the aim of better characterizing the dysmorphic features that may be crucial for clinical recognition of SCA42ND. Cerebellar atrophy, together with digital anomalies, particularly broad thumbs and/or halluces, should lead to clinical suspicion of this disease. We describe the first pharmacological attempt to treat a patient with SCA42ND using zonisamide, an antiepileptic drug with T-type channel blocker activity, in an off-label indication using an itemized study protocol. No efficacy was observed at the dose tested. However, without pharmacological treatment, she showed a positive evolution in neurodevelopment during the follow-up.