Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders.

Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatment regimen and the course of the epilepsy in 66 patients for which well-documented medical information was available. We find that the use of sodium channel blockers was often associated with clinically relevant seizure reduction or seizure freedom in children with early infantile epilepsies (<3 months), whereas other antiepileptic drugs were less effective. In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (≥3 months) and sometimes induced seizure worsening. Regarding the genetic findings, truncating mutations were exclusively seen in patients with late onset epilepsies and lack of response to sodium channel blockers. Functional characterization of four selected missense mutations using whole cell patch-clamping in tsA201 cells-together with data from the literature-suggest that mutations associated with early infantile epilepsy result in increased sodium channel activity with gain-of-function, characterized by slowing of fast inactivation, acceleration of its recovery or increased persistent sodium current. Further, a good response to sodium channel blockers clinically was found to be associated with a relatively small gain-of-function. In contrast, mutations in patients with late-onset forms and an insufficient response to sodium channel blockers were associated with loss-of-function effects, including a depolarizing shift of voltage-dependent activation or a hyperpolarizing shift of channel availability (steady-state inactivation). Our clinical and experimental data suggest a correlation between age at disease onset, response to sodium channel blockers and the functional properties of mutations in children with SCN2A-related epilepsy.

Obstructive sleep apnea in children with cerebral palsy and epilepsy.

AIM: To examine the risk of obstructive sleep apnea (OSA) in children with cerebral palsy (CP) and/or epilepsy. METHOD: This cross-sectional study employs the Pediatric Sleep Questionnaire (PSQ), the Gross Motor Function Classification System (GMFCS), and chart review to identify symptoms of OSA in children presenting to a multi-specialty pediatric healthcare institution. RESULTS: Two-hundred and fifteen patients were grouped into those with epilepsy (n=54), CP (n=18), both (n=55), and neither (comparison group, n=88). The comparison group comprised children with developmental disabilities but not children with typical development. Significantly increased PSQ scores (indicating increased risk of OSA) were found among children with CP (58%) and CP with epilepsy (67%) than among the comparison group (27%; p<0.001 and p<0.0001 respectively). Children with both CP and epilepsy had a greater number of increased PSQ scores compared with CP alone (p<0.05). Increased PSQ scores were observed with increasing CP severity as measured using the GMFCS. The PSQ identified more children at risk of OSA (46%) than did the medical record review for symptoms of OSA (8.2%, p<0.001). INTERPRETATION: Children with CP of greater severity or comorbid epilepsy are at increased risk of OSA. This study supports the routine questionnaire-based assessment for OSA as a regular part of the care of all children with CP, especially in those with more severe CP and those with epilepsy.

Dravet syndrome and parent associations: the IDEA League experience with comorbid conditions, mortality, management, adaptation, and grief.

The advent of social networking via the Internet and the commercial availability of tests for SCN1A mutations permitted the rapid development and growth of parent-led associations that provide advocacy and support, as well as promote education and research regarding Dravet syndrome (DS) in the last 10 years. The International Dravet syndrome Epilepsy Action League (IDEA League) is a partnership of parents and professionals united in the purpose of creating greater awareness and understanding of DS. In 2004, parents in the IDEA League support network began to collect data from families about their children with DS in order to investigate observations that, in addition to epilepsy, many of the children seemed to share similar problems. The information gained suggests comorbid conditions and raises many hypotheses for further research. The process has led to more rigorous formal studies and an increased understanding of the clinical spectrum of DS. There is an urgent need for collaborative research, comprehensive care, and professional and family education. Mortality appears high, primarily due to sudden unexplained death in epilepsy (SUDEP) and status epilepticus (SE). Most parents wish direct discussions with their child's physician about mortality. The high risk of death and the many other stresses related to DS result in recurrent grief and loss for patients and families and highlights their need for additional advocacy and support.

Molecular and clinical genetics of mitochondrial diseases due to POLG mutations.

Mutations in the POLG gene have emerged as one of the most common causes of inherited mitochondrial disease in children and adults. They are responsible for a heterogeneous group of at least 6 major phenotypes of neurodegenerative disease that include: 1) childhood Myocerebrohepatopathy Spectrum disorders (MCHS), 2) Alpers syndrome, 3) Ataxia Neuropathy Spectrum (ANS) disorders, 4) Myoclonus Epilepsy Myopathy Sensory Ataxia (MEMSA), 5) autosomal recessive Progressive External Ophthalmoplegia (arPEO), and 6) autosomal dominant Progressive External Ophthalmoplegia (adPEO). Due to the clinical heterogeneity, time-dependent evolution of symptoms, overlapping phenotypes, and inconsistencies in muscle pathology findings, definitive diagnosis relies on the molecular finding of deleterious mutations. We sequenced the exons and flanking intron region from approximately 350 patients displaying a phenotype consistent with POLG related mitochondrial disease and found informative mutations in 61 (17%). Two mutant alleles were identified in 31 unrelated index patients with autosomal recessive POLG-related disorders. Among them, 20 (67%) had Alpers syndrome, 4 (13%) had arPEO, and 3 (10%) had ANS. In addition, 30 patients carrying one altered POLG allele were found. A total of 25 novel alterations were identified, including 6 null mutations. We describe the predicted structural/functional and clinical importance of the previously unreported missense variants and discuss their likelihood of being pathogenic. In conclusion, sequence analysis allows the identification of mutations responsible for POLG-related disorders and, in most of the autosomal recessive cases where two mutant alleles are found in trans, finding deleterious mutations can provide an unequivocal diagnosis of the disease.

Whole-Exome Sequencing in the Clinic: Lessons from Six Consecutive Cases from the Clinician's Perspective.

Whole-exome sequencing (WES) is being used clinically to diagnose rare Mendelian disorders, especially when standard tests have failed. The diagnostic yield from WES is reported to be ∼15-30%; however, data regarding the clinical utility and interpretative challenges from the clinician's perspective are lacking. Here, we present a series of the first 6 unselected consecutive cases seen over a period of 6 months where WES was employed in clinical labs via trio-based testing (proband and parents). While we do not discount the value of WES in the clinical setting, our cases and experience illustrate the significant clinical challenges of WES, even when a diagnosis may be achieved.

Rapid infusion of sodium valproate in acutely ill children.

The purpose of this study was to investigate the clinical safety of sodium valproate and total and unbound valproic acid plasma concentrations after rapid infusion in hospitalized, acutely ill children. Four children (5-15 years) completed the study. Sodium valproate doses (8.3-15.4 mg/kg) were administered in

Gabapentin successfully manages chronic unexplained irritability in children with severe neurologic impairment.

Neurologically impaired children have an increased frequency of recurrent pain and irritability that persist in some despite comprehensive evaluation and management of possible pain sources. We hypothesized that visceral hyperalgesia was a source of chronic unexplained irritability and report the outcome of gabapentin treatment in 9 severely neurologically impaired children. Caregivers reported marked improvement after treatment ranging from 3 months to 3 years. Nystagmus in 1 child was the only noted adverse effect. Visceral hyperalgesia may be a source of unexplained irritability in the neurologically impaired child. Symptoms may improve with gabapentin treatment.