Novel LIAS variants in a patient with epilepsy and profound developmental disabilities.

Multiple mitochondrial enzymes employ lipoic acid as a coenzyme. Pathogenic variants in LIAS, encoding lipoic acid synthase (LIAS), are associated with autosomal recessive LIAS-related disorder (OMIM# 614462). This disorder is characterized by infantile-onset hypotonia, profound psychomotor delay, epileptic encephalopathy, nonketotic hyperglycinemia, and lactic acidosis. We present the case of a 20-year-old female who experienced developmental deficits at the age of 6 months and began to have seizures at 3 years of age. Exome sequencing revealed compound heterozygous novel variants in LIAS, designated c.277delC (p.Leu93Ter) and c.542A > T (p.Asp181Val). The p.Leu93Ter variant is predicted to cause loss of function due to the severe truncation of the encoded protein. To examine the p.Asp181Val variant, functional analysis was performed using Baker's yeast (Saccharomyces cerevisiae) lacking LIP5, the homologue of human LIAS. Wild-type LIAS promoted oxidative growth of the lip5∆ yeast strain. In contrast, lip5∆ yeast expressing p.Asp181Val exhibited poor growth, similar to known pathogenic variants, p.Asp215Glu and p.Met310Thr. Our work has expanded the phenotypic and genotypic spectrum of LIAS-related disorder and established the use of the yeast model as a system for functional study of novel missense variants in LIAS.

Dose-dependent seizure control with MEK inhibitor therapy for progressive glioma in a child with neurofibromatosis type 1.

BACKGROUND: Low-grade gliomas (LGGs) occurring in children can result in many different neurologic complications, including seizures. MEK inhibitors are increasingly being used to treat LGG, but their effect on associated neurologic symptoms has not been established. RESULTS: Here, we report a patient with neurofibromatosis type 1 (NF1), medically refractory epilepsy (MRE), and an extensive optic pathway glioma (OPG) who developed dose-dependent seizure control while being treated with selumetinib. Seizure frequency rebounded after dose reduction for cardiac toxicity, then improved, and finally ceased after restarting full dosing, allowing confidence in the cause of improvement. CONCLUSION: Selumetinib may have promise in epilepsy management in other children with NF1 or LGG.

Gain-of-function HCN2 variants in genetic epilepsy.

Genetic generalized epilepsy (GGE) is a common epilepsy syndrome that encompasses seizure disorders characterized by spike-and-wave discharges (SWDs). Pacemaker hyperpolarization-activated cyclic nucleotide-gated channels (HCN) are considered integral to SWD genesis, making them an ideal gene candidate for GGE. We identified HCN2 missense variants from a large cohort of 585 GGE patients, recruited by the Epilepsy Phenome-Genome Project (EPGP), and performed functional analysis using two-electrode voltage clamp recordings from Xenopus oocytes. The p.S632W variant was identified in a patient with idiopathic photosensitive occipital epilepsy and segregated in the family. This variant was also independently identified in an unrelated patient with childhood absence seizures from a European cohort of 238 familial GGE cases. The p.V246M variant was identified in a patient with photo-sensitive GGE and his father diagnosed with juvenile myoclonic epilepsy. Functional studies revealed that both p.S632W and p.V246M had an identical functional impact including a depolarizing shift in the voltage dependence of activation that is consistent with a gain-of-function. In contrast, no biophysical changes resulted from the introduction of common population variants, p.E280K and p.A705T, and the p.R756C variant from EPGP that did not segregate with disease. Our data suggest that HCN2 variants can confer susceptibility to GGE via a gain-of-function mechanism.

Epilepsy in individuals with neurofibromatosis type 1.

PURPOSE: To describe the clinical characteristics and outcomes of individuals with neurofibromatosis type 1 (NF1) and seizures in the largest cohort reported to date. METHODS: A retrospective cross-sectional review of 536 individuals with NF1 was performed, and clinical data from 51 individuals with a history of at least one seizure were analyzed. KEY FINDINGS: In individuals with NF1, 9.5% had a history of at least one unprovoked seizure, and 6.5% had documented epilepsy. Individuals with seizures were more likely to have inherited NF1 from their mother (p = 0.001). Focal seizures were the most common type, occurring in 57% of individuals, although generalized seizures, specific electroclinical syndromes, and the presence of multiple seizure types were also noted. Moreover, in 21% of individuals with a previously unremarkable magnetic resonance imaging (MRI) study, neuroimaging at seizure onset revealed a new structural abnormality. In this population, 77% of individuals required multiple antiepileptic drugs (AEDs), and some required epilepsy surgery, with the best results following temporal lobe glioma resection. SIGNIFICANCE: Compared to the general population, seizures are more common in individuals with NF1, where they are often focal and related to an intracranial neoplasm. These observations suggest that all individuals with NF1 and a new seizure should undergo MRI despite previous normal neuroimaging. Individuals with seizures and NF1 typically require more aggressive therapy than those without NF1 and should be considered for epilepsy surgery when appropriate.

The Heart of Rett Syndrome: A Quantitative Analysis of Cardiac Repolarization.

Background: Rett syndrome (RTT) is a developmental encephalopathy disorder that is associated with a high incidence of sudden death presumably from cardiorespiratory etiologies. Electrocardiogram (ECG) abnormalities, such as prolonged heart-rate corrected QT (QTc) interval, are markers of cardiac repolarization and are associated with potentially lethal ventricular arrhythmias. This study investigates the cardiac repolarization characteristics of RTT patients, including QTc and T-wave morphology characteristics. Methods: A retrospective quantitative analysis on 110 RTT patients and 124 age and sex-matched healthy controls was conducted. Results: RTT patients had longer QTc, more abnormal T-wave morphology, and greater heterogeneity of cardiac repolarization parameters compared to controls. Even RTT patients without prolonged QTc had more abnormal ECG and T-wave characteristics than controls. Among RTT patients, MECP2 patients had prolonged QTc compared to CDKL5 and FOXG1 patients. A subset of five RTT patients who died had normal QTc, but more abnormal T-wave morphology than the remaining RTT patients. Conclusions: Cardiac repolarization abnormalities are present in RTT patients, even without long QTc. T-wave morphology is related to RTT genotype and may be predictive of mortality. These findings could be used to help the management and monitoring of RTT patients.

Impact of epilepsy surgery on seizure control and quality of life: a 26-year follow-up study.

PURPOSE: The short-term efficacy and safety of epilepsy surgery relative to medical therapy has been established, but it remains underutilized. There is a lack of data regarding the long-term seizure-control rates and quality of life outcomes after epilepsy surgery. This study represents the longest follow-up study to date, with a mean follow-up duration of 26 years. METHODS: We studied the seizure and health-related quality of life outcomes of patients who underwent epilepsy surgery by Dr. Sidney Goldring from 1967 to 1990. Retrospective clinical chart reviews gathered perioperative data and surveys obtained follow-up data. Seizure outcome was evaluated using the Engel classification system. KEY FINDINGS: Of 361 patients, 117 (32.4%) completed follow-up interviews. Fifty-six patients (48%) were Engel class I. Mean overall Quality of Life in Epilepsy (QOLIE-31) questionnaire score for the cohort was 68.2 ± 16. Eighty percent of patients reported their overall quality of life now as being better than before surgery. Seizure freedom was associated with better quality of life. We did not observe a statistically significant association between postoperative complications and long-term outcome. Patients who underwent temporal lobe resection achieved better seizure outcomes than those who underwent other types of procedures. Astatic seizures and bilateral surgery were associated with a worse Engel class outcome. SIGNIFICANCE: Our study demonstrates that the beneficial effects of epilepsy surgery are sustained over decades, and that these beneficial effects are correlated with an improved quality of life. The confirmation of its durability makes us optimistic that the outcomes from modern epilepsy surgery will be even better and that our present enthusiasm for this treatment modality is not misplaced.

CDKL5 Deficiency Disorder-Related Epilepsy: A Review of Current and Emerging Treatment.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental and epileptic encephalopathy with infantile-onset epilepsy. Most individuals with CDD develop refractory epilepsy with multiple seizure types. Management of seizures in CDD remains challenging for clinicians given the highly refractory nature of seizures and the limited number of disease-specific studies that offer a high level of evidence. Epileptic spasms are the most common seizure type in CDD and are more often refractory to standard first-line treatment than are spasms of other etiologies. In other seizure types, the effectiveness of antiseizure medications is limited and wanes over time. Ketogenic diet and palliative surgical treatments have both had mixed results in observational studies. When treating refractory seizures in CDD, we recommend carefully balancing seizure control and treatment-related side effects to optimize each individual's overall quality of life. Clinical trials of medications targeting epilepsy in CDD have been conducted, and additional investigational small molecules, gene therapy, and other disease-modifying therapies are in development for CDD.

Current neurologic treatment and emerging therapies in CDKL5 deficiency disorder.

BACKGROUND: CDKL5 deficiency disorder (CDD) is associated with refractory infantile onset epilepsy, global developmental delay, and variable features that include sleep, behavioral disturbances, and movement disorders. Current treatment is primarily symptom-based and informed by experience in caring for this population. METHODS: We describe medication and non-medication approaches to treatment of epilepsy and additional key neurologic symptoms (sleep disturbances, behavioral issues, movement disorders, and swallowing dysfunction) in a cohort of 177 individuals meeting criteria for CDD, 154 evaluated at 4 CDKL5 Centers of Excellence in the USA and 40 identified through the NIH Natural History Study of Rett and Related Disorders. RESULTS: The four most frequently prescribed anti-seizure medications were broad spectrum, prescribed in over 50% of individuals. While the goal was not to ascertain efficacy, we obtained data from 86 individuals regarding response to treatment, with 2-week response achieved in 14-48% and sustained 3-month response in 5-36%, of those with known response. Additional treatments for seizures included cannabis derivatives, tried in over one-third of individuals, and clinical trial medications. In combination with pharmacological treatment, 50% of individuals were treated with ketogenic diet for attempted seizure control. Surgical approaches included vagus nerve stimulators, functional hemispherectomy, and corpus callosotomy, but numbers were too limited to assess response. Nearly one-third of individuals received pharmacologic treatment for sleep disturbances, 13% for behavioral dysregulation and movement disorders, and 43% had gastrostomy tubes. CONCLUSIONS: Treatment for neurologic features of CDD is currently symptom-based and empiric rather than CDD-specific, though clinical trials for CDD are emerging. Epilepsy in this population is highly refractory, and no specific anti-seizure medication was associated with improved seizure control. Ketogenic diet is commonly used in patients with CDD. While behavioral interventions are commonly instituted, information on the use of medications for sleep, behavioral management, and movement disorders is sparse and would benefit from further characterization and optimization of treatment approaches. The heterogeneity in treatment approaches highlights the need for systematic review and guidelines for CDD. Additional disease-specific and disease-modifying treatments are in development.

Familial aggregation of status epilepticus in generalized and focal epilepsies.

OBJECTIVE: To determine whether familial aggregation of status epilepticus (SE) occurs in a large cohort of familial common epilepsies. METHODS: We used the Epilepsy Phenome/Genome Project dataset, which consisted of 2,197 participants in 1,043 family units with ≥2 members having a common generalized or nonacquired focal epilepsy (NAFE). We identified participants with a history of traditionally defined SE (TSE) (seizures ≥30 minutes) and operationally defined SE (OSE) (seizures ≥10 minutes) by chart review. We assessed familial aggregation of TSE and OSE using χ2 analysis and generalized estimating equations (GEE). RESULTS: One hundred fifty-five (7%) participants in 1,043 families had ≥1 episodes of TSE. Two hundred fifty (11%) had ≥1 episodes of OSE. In a χ2 analysis, the number of family units with ≥2 members having TSE (odds ratio [OR] 4.79, 95% confidence interval [CI] 2.56-8.97) or OSE (OR 4.23, 95% CI 2.67-6.70) was greater than expected by chance. In GEE models adjusted for sex, broad epilepsy class (GE or NAFE), age at onset, and duration of epilepsy, TSE in a proband predicted TSE in a first-degree relative (OR 2.79, 95% CI 1.24-6.22), and OSE in a proband predicted OSE in a first-degree relative (OR 2.91, 95% CI 1.65-5.15). The results remained significant in models addressing epilepsy severity by incorporating the number of antiseizure medications used or epilepsy surgery. CONCLUSIONS: TSE and OSE showed robust familial aggregation in a cohort of familial epilepsy independently of epilepsy severity or class, suggesting that genetic factors contribute to SE independently of the genetic cause of these epilepsies. CLINICALTRIALSGOV IDENTIFIER: NCT00552045.

Successful Treatment of Electrographic Status Epilepticus of Sleep With Felbamate in a Patient With SLC9A6 Mutation.

BACKGROUND: Mutations of SLC9A6 may cause an X-linked clinical syndrome first described by Christianson in 1999 in which affected males exhibited profound intellectual disability, autism, drug-resistant epilepsy, ophthalmoplegia, mild craniofacial dysmorphism, microcephaly, and ataxia. METHODS: We describe a child with an SLC9A6 mutation and an electroencephalographic pattern consistent with electrographic status epilepticus of sleep. RESULTS: Our patient's electrographic status epilepticus of sleep resolved after treatment with felbamate. Following treatment, he remained seizure-free but did not make significant or lasting gains in language. CONCLUSION: Our report extends the clinical epilepsy phenotype in children with SLC9A6 mutations to include electrographic status epilepticus of sleep. In addition, felbamate was an effective treatment for electrographic status epilepticus of sleep in our patient.

Clinical neurogenetics: recent advances in the genetics of epilepsy.

Epilepsy represents a diverse group of disorders with primary and secondary genetic etiologies, as well as non-genetic causes. As more causative genes are identified, genetic testing is becoming increasingly important in the evaluation and management of epilepsy. This article outlines the clinical approach to epilepsy patients, with emphasis on genetic testing. Specific targeted tests are available for numerous individual genetic causes of epilepsy. Broader screening tests, such as chromosome microarray analysis and whole exome sequencing, have also been developed. As a standardized protocol for genetic testing has not been established, individualized diagnostic approaches to epilepsy patients should be used.