Research conference summary from the 2014 International Task Force on

OBJECTIVE: METHODS: In 2014, the Alternating Hemiplegia of Childhood Foundation hosted a multidisciplinary workshop intended to address fundamental challenges surrounding the diagnosis and management of individuals with RESULTS: Workshop attendees were charged with the following: (1) to achieve consensus on expanded diagnostic criteria to facilitate the identification of additional patients, intended to supplement existing syndrome-specific diagnostic paradigms; (2) to standardize definitions for the broad range of paroxysmal manifestations associated with AHC to disseminate to families; (3) to create clinical recommendations for common recurrent issues facing families and medical care providers; (4) to review data related to the death of individuals in the Alternating Hemiplegia of Childhood Foundation database to guide future efforts in identifying at-risk subjects and potential preventative measures; and (5) to identify critical gaps where we most need to focus national and international research efforts. CONCLUSIONS: This report summarizes recommendations of the workshop committee, highlighting the key phenotypic features to facilitate the diagnosis of possibl

Genetic Testing to Inform Epilepsy Treatment Management From an International Study of Clinical Practice

IMPORTANCE: It is currently unknown how often and in which ways a genetic diagnosis given to a patient with epilepsy is associated with clinical management and outcomes. OBJECTIVE: To evaluate how genetic diagnoses in patients with epilepsy are associated with clinical management and outcomes. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cross-sectional study of patients referred for multigene panel testing between March 18, 2016, and August 3, 2020, with outcomes reported between May and November 2020. The study setting included a commercial genetic testing laboratory and multicenter clinical practices. Patients with epilepsy, regardless of sociodemographic features, who received a pathogenic/likely pathogenic (P/LP) variant were included in the study. Case report forms were completed by all health care professionals. EXPOSURES: Genetic test results. MAIN OUTCOMES AND MEASURES: Clinical management changes after a genetic diagnosis (ie, 1 P/LP variant in autosomal dominant and X-linked diseases; 2 P/LP variants in autosomal recessive diseases) and subsequent patient outcomes as reported by health care professionals on case report forms. RESULTS: Among 418 patients, median (IQR) age at the time of testing was 4 (1-10) years, with an age range of 0 to 52 years, and 53.8% (n = 225) were female individuals. The mean (SD) time from a genetic test order to case report form completion was 595 (368) days (range, 27-1673 days). A genetic diagnosis was associated with changes in clinical management for 208 patients (49.8%) and usually (81.7% of the time) within 3 months of receiving the result. The most common clinical management changes were the addition of a new medication (78 [21.7%]), the initiation of medication (51 [14.2%]), the referral of a patient to a specialist (48 [13.4%]), vigilance for subclinical or extraneurological disease features (46 [12.8%]), and the cessation of a medication (42 [11.7%]). Among 167 patients with follow-up clinical information available (mean [SD] time, 584 [365] days), 125 (74.9%) reported positive outcomes, 108 (64.7%) reported reduction or elimination of seizures, 37 (22.2%) had decreases in the severity of other clinical signs, and 11 (6.6%) had reduced medication adverse effects. A few patients reported worsening of outcomes, including a decline in their condition (20 [12.0%]), increased seizure frequency (6 [3.6%]), and adverse medication effects (3 [1.8%]). No clinical management changes were reported for 178 patients (42.6%). CONCLUSIONS AND RELEVANCE: Results of this cross-sectional study suggest that genetic testing of individuals with epilepsy may be materially associated with clinical decision-making and improved patient outcomes

Mobile Software as a Medical Device (SaMD) for the Treatment of Epilepsy: Development of Digital Therapeutics Comprising Behavioral and Music-Based Interventions for Neurological Disorders

Digital health technologies for people with epilepsy (PWE) include internet-based resources and mobile apps for seizure management. Since non-pharmacological interventions, such as listening to specific Mozart's compositions, cognitive therapy, psychosocial and educational interventions were shown to reduce epileptic seizures, these modalities can be integrated into mobile software and delivered by mobile medical apps as digital therapeutics. Herein, we describe: (1) a survey study among PWE about preferences to use mobile software for seizure control, (2) a rationale for developing digital therapies for epilepsy, (3) creation of proof-of-concept mobile software intended for use as an adjunct digital therapeutic to reduce seizures, and (4) broader applications of digital therapeutics for the treatment of epilepsy and other chronic disorders. A questionnaire was used to survey PWE with respect to preferred features in a mobile app for seizure control. Results from the survey suggested that over 90% of responders would be interested in using a mobile app to manage their seizures, while 75% were interested in listening to specific music that can reduce seizures. To define digital therapeutic for the treatment of epilepsy, we designed and created a proof-of-concept mobile software providing digital content intended to reduce seizures. The rationale for all components of such digital therapeutic is described. The resulting web-based app delivered a combination of epilepsy self-care, behavioral interventions, medication reminders and the antiseizure music, such as the Mozart's sonata K.448. To improve long-term patient engagement, integration of mobile medical app with music and multimedia streaming via smartphones, tablets and computers is also discussed. This work aims toward development and regulatory clearance of software as medical device (SaMD) for seizure control, yielding the adjunct digital therapeutic for epilepsy, and subsequently a drug-device combination product together with specific antiseizure medications. Mobile medical apps, music, therapeutic video games and their combinations with prescription medications present new opportunities to integrate pharmacological and non-pharmacological interventions for PWE, as well as those living with other chronic disorders, including depression and pain

Alternating Hemiplegia of Childhood: Retrospective Genetic Study and Genotype-Phenotype Correlations in 187 Subjects from the US AHCF Registry

Mutations in ATP1A3 cause Alternating Hemiplegia of Childhood (AHC) by disrupting function of the neuronal Na+/K+ ATPase. Published studies to date indicate 2 recurrent mutations, D801N and E815K, and a more severe phenotype in the E815K cohort. We performed mutation analysis and retrospective genotype-phenotype correlations in all eligible patients with AHC enrolled in the US AHC Foundation registry from 1997-2012. Clinical data were abstracted from standardized caregivers’ questionnaires and medical records and confirmed by expert clinicians. We identified ATP1A3 mutations by Sanger and whole genome sequencing, and compared phenotypes within and between 4 groups of subjects, those with D801N, E815K, other ATP1A3 or no ATP1A3 mutations. We identified heterozygous ATP1A3 mutations in 154 of 187 (82%) AHC patients. Of 34 unique mutations, 31 (91%) are missense, and 16 (47%) had not been previously reported. Concordant with prior studies, more than 2/3 of all mutations are clustered in exons 17 and 18. Of 143 simplex occurrences, 58 had D801N (40%), 38 had E815K (26%) and 11 had G937R (8%) mutations. Patients with an E815K mutation demonstrate an earlier age of onset, more severe motor impairment and a higher prevalence of status epilepticus. This study further expands the number and spectrum of ATP1A3 mutations associated with AHC and confirms a more deleterious effect of the E815K mutation on selected neurologic outcomes. However, the complexity of the disorder and the extensive phenotypic variability among subgroups merits caution and emphasizes the need for further studies

Research conference summary from the 2014 International Task Force on ATP1A3-Related Disorders

Objective: ATP1A3-related neurologic disorders encompass a broad range of phenotypes that extend well beyond initial phenotypic criteria associated with alternating hemiplegia of childhood (AHC) and rapid-onset dystonia parkinsonism. Methods: In 2014, the Alternating Hemiplegia of Childhood Foundation hosted a multidisciplinary workshop intended to address fundamental challenges surrounding the diagnosis and management of individuals with ATP1A3-related disorders. Results: Workshop attendees were charged with the following: (1) to achieve consensus on expanded diagnostic criteria to facilitate the identification of additional patients, intended to supplement existing syndrome-specific diagnostic paradigms; (2) to standardize definitions for the broad range of paroxysmal manifestations associated with AHC to disseminate to families; (3) to create clinical recommendations for common recurrent issues facing families and medical care providers; (4) to review data related to the death of individuals in the Alternating Hemiplegia of Childhood Foundation database to guide future efforts in identifying at-risk subjects and potential preventative measures; and (5) to identify critical gaps where we most need to focus national and international research efforts. Conclusions: This report summarizes recommendations of the workshop committee, highlighting the key phenotypic features to facilitate the diagnosis of possible ATP1A3 mutations, providing recommendations for genetic testing, and outlining initial acute management for common recurrent clinical conditions, including epilepsy