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Background and objectives: multiple sclerosis (MS) is a chronic demyelinating disorder of the CNS with a variable course and disability progression. The latter may be prevented with disease-modifying therapy (DMT). Initial misdiagnosis may postpone the use of DMT. There are no studies to explore whether initial misdiagnosis is indeed associated with a higher rate of reaching disability in MS patients. We aimed to investigate the association between initial misdiagnosis and reaching disability milestones in relapsing-remitting MS (RR-MS) patients. Materials and methods: Data from 128 RR-MS patients were retrospectively reviewed. EDSS 4 and EDSS 6 were chosen as disability milestones as those associated with a significant decrease in ambulation. Survival analysis was used, and Kaplan–Meier curves were generated to investigate how initial misdiagnosis affects reaching the defined milestones. Results: 53 patients (41.4%, 31 females, 22 males) were initially misdiagnosed. Initially misdiagnosed patients had a lesser risk of reaching EDSS 4 up to 11 years and EDSS 6 up to 22 years from the onset than non-misdiagnosed patients (p = 0.22 and p = 0.25 correspondingly). Median time to reaching EDSS 4 and 6 was eight years (95% CI 0.0–17.6) and 10 years (95% CI 4.25–20.75) in misdiagnosed and three years (95% CI 0.0–20.0 years) and five years (95% CI 0.0–13.73 years) in non-misdiagnosed patients correspondingly. Conclusions: Initially misdiagnosed RR-MS patients tended to reach disability milestones later than non-misdiagnosed ones, which might reflect an intrinsically milder disease. Individuals presenting with mild or non-specific symptoms suspicious of MS, must be deliberately managed.

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Mutations in the ATP1A3 gene have been associated with several syndromes, including rapid‐onset dystonia‐parkinsonism, alternating hemiplegia of childhood, and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss. In this clinical commentary, we report a 2‐year‐old female patient with de novo pathogenic variant in the ATP1A3 gene associated with an early‐onset form of epilepsy with eyelid myoclonia. The patient had frequent eyelid myoclonia occurring 20–30 times per day, without loss of awareness or other motor manifestations. EEG showed generalized polyspikes and spike‐and‐wave complexes maximal in the bifrontal regions, with prominent eye closure sensitivity. A sequencing‐based epilepsy gene panel revealed a de novo pathogenic heterozygous variant in ATP1A3. The patient showed some response to flunarizine and clonazepam. This case highlights the importance of considering ATP1A3 mutations in the differential diagnosis of early‐onset epilepsy with eyelid myoclonia and the potential benefit of flunarizine in improving language and coordination development in patients with ATP1A3‐related disorders.

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Background: Understanding disease progression, age-specific comorbidities, medical treatment patterns, and unmet needs can help improve the care pathway of individuals with rare genetic epilepsies. A matched longitudinal cohort study has not been performed for these variables from childhood to adolescence across the whole phenome. Methods: We identified individuals with likely genetic and non-genetic epilepsy syndromes and onset at ages 0-5 years by linkage across the Cleveland Clinic Health System. We used natural language processing to extract medical terms and procedures from longitudinal electronic health records (EHR) and tested for cross-sectional and temporal associations with genetic epilepsies. Findings: We identified 503 individuals with genetic epilepsy syndromes and matched controls with epilepsy that did not receive genetic testing. The median age at the first encounter was 0.1 years, 7.9 years at the last encounter, and the mean duration of follow-up was 8.2 years. We extracted 188,295 Unified Medical Language System (UMLS) annotations for statistical analysis across 9,659 encounters. Individuals with genetic epilepsy syndromes received an earlier epilepsy diagnosis and had more frequent and complex encounters with the healthcare system. Notably, the highest enrichment of encounters compared to the non-genetic groups was found during the transition from paediatric to adult care. Our computational approach could validate established comorbidities of genetic epilepsies, such as behavioural abnormality and intellectual disability. We also revealed novel associations for genitourinary abnormalities (OR 1.91, 95% CI: 1.66-2.19, p = 2.39x10-19) linked to a spectrum of underrecognized genetic syndromes. Interpretation: This study identified novel features associated with the likelihood of a genetic epilepsy syndrome and quantified the healthcare utilization of genetic epilepsies compared to matched controls with epilepsy who did not receive genetic testing. Our results strongly recommend early genetic testing to stratify individuals into specialized care paths, thus improving the clinical management of people with genetic epilepsies. Funding: Not applicable.