The DESSH Clinic: A New Multidisciplinary Clinic to Address the Complex Needs of Individuals with a Rare Genetic Disorder.

DeSanto-Shinawi (DESSH) syndrome is a rare autosomal dominant condition caused by pathogenic variants in the WAC gene. DESSH syndrome was first identified in 2015 in six patients, but has since been diagnosed in more than 200 individuals worldwide. Patients exhibit a variable degree of developmental delay (DD), intellectual disability (ID), hypotonia, gastrointestinal and eye abnormalities, epilepsy, behavioral difficulties, and recognizable facial features.

Deletions in the CDKL5 5' untranslated region lead to CDKL5 deficiency disorder.

Pathogenic variants in the cyclin-dependent kinase-like 5 (CDKL5) gene are associated with CDKL5 deficiency disorder (CDD), a severe X-linked developmental and epileptic encephalopathy. Deletions affecting the 5' untranslated region (UTR) of CDKL5, which involve the noncoding exon 1 and/or alternatively spliced first exons (exons 1a-e), are uncommonly reported. We describe genetic and phenotypic characteristics for 15 individuals with CDKL5 partial gene deletions affecting the 5' UTR.

Psychometric evaluation of clinician- and caregiver-reported clinical severity assessments for individuals with CDKL5 deficiency disorder.

Objective: The CDKL5 Clinical Severity Assessment (CCSA) is a comprehensive, content-validated measurement tool capturing the diverse challenges of cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD), a genetically caused developmental epileptic encephalopathy (DEE). The CCSA is divided into clinician-reported (CCSA-Clinician) and caregiver-reported (CCSA-Caregiver) assessments. The aim of this study was to evaluate the factor structure of these measures through confirmatory factor analysis (CFA) and evaluate their validity and reliability.

Modification of a parent-report sleep scale for individuals with CDKL5 deficiency disorder: a psychometric study.

Study Objectives: Sleep difficulties are common in CDKL5 deficiency disorder, a developmental and epileptic encephalopathy. This study evaluated the factor structure of the Disorders of Initiating and Maintaining Sleep (DIMS), Disorders of Excessive Somnolence (DOES), and Sleep Breathing Disorders domains of the Sleep Disturbance Scale for Children for CDKL5 deficiency disorder.

Methods: A cross-sectional psychometric study design was used.

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.

The development, content and response process validation of a caregiver-reported severity measure for CDKL5 deficiency disorder.

Background: CDKL5 Deficiency Disorder (CDD) is a severe X-linked developmental and epileptic encephalopathy. Existing developmental outcome measures have floor effects and cannot capture incremental changes in symptoms. We modified the caregiver portion of a CDD clinical severity assessment (CCSA) and assessed content and response-process validity.

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.

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.

Content Validation of Clinician-Reported Items for a Severity Measure for CDKL5 Deficiency Disorder.

CDKL5 deficiency disorder (CDD) results in early-onset seizures and severe developmental impairments. A CDD clinical severity assessment (CCSA) was previously developed with clinician and parent-report items to capture information on a range of domains. Consistent with US Food and Drug Administration (FDA) guidelines, content validation is the first step in evaluating the psychometric properties of an outcome measure.

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.

Severity Assessment in CDKL5 Deficiency Disorder.

Background: Pathologic mutations in cyclin-dependent kinase-like 5 cause CDKL5 deficiency disorder, a genetic syndrome associated with severe epilepsy and cognitive, motor, visual, and autonomic disturbances. This disorder is a relatively common genetic cause of early-life epilepsy. A specific severity assessment is lacking, required to monitor the clinical course and needed to define the natural history and for clinical trial readiness.

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.

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.

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.

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.

De novo mutations in epileptic encephalopathies.

Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations.

The epilepsy phenome/genome project.

Background: Epilepsy is a common neurological disorder that affects approximately 50 million people worldwide. Both risk of epilepsy and response to treatment partly depend on genetic factors, and gene identification is a promising approach to target new prediction, treatment, and prevention strategies. However, despite significant progress in the identification of genes causing epilepsy in families with a Mendelian inheritance pattern, there is relatively little known about the genetic factors responsible for common forms of epilepsy and so-called epileptic encephalopathies.

Clinical utility, safety, and tolerability of ezogabine (retigabine) in the treatment of epilepsy.

One-third of patients with epilepsy continue to have seizures despite current treatments, indicating the need for better antiseizure medications with novel mechanisms of action. Ezogabine (retigabine) has recently been approved for adjunctive treatment of partial-onset seizures in adult patients with epilepsy. Ezogabine utilizes a novel mechanism of action, involving activation of specific potassium channels.

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.

Profile of ezogabine (retigabine) and its potential as an adjunctive treatment for patients with partial-onset seizures.

Epilepsy is a common disease with significant morbidity and mortality. Approximately one-third of patients with epilepsy are refractory to available seizure medications, emphasizing the need to develop better drugs with novel mechanisms of action. Ezogabine, also known as retigabine, is a new potential adjunctive treatment for adults with intractable partial seizures.