Diagnostic gap in genetic epilepsies: A matter of age

Aledo‐Serrano, Ángel; García‐Morales, Irene; Toledano, Rafael; Jiménez‐Huete, Adolfo; Parejo, Beatriz; Anciones, Carla; Mingorance, Ana; Ramos, Primitivo; Gil‐Nagel, Antonio

doi:10.1016/j.yebeh.2020.107266

Cited by 11 publications

(6 citation statements)

References 14 publications

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“…16 Clinical evidence supports a reduction in SUDEP risk in patients with DS after fenfluramine treatment. 17 Given that SUDEP has been reported in ~10% of patients with SCN8A epilepsy (although the adult phenotype is not well-documented yet, 3 and these patients have a high burden of GTCS, 1,3,18 and typically have ictal respiratory impairment, with O 2 desaturation with cyanosis 3 ) fenfluramine may have important implications for lowering SUDEP risk in patients with SCN8A-epilepsy.…”

Section: Discussionmentioning

confidence: 99%

Effect of fenfluramine on seizures and comorbidities in SCN8A‐developmental and epileptic encephalopathy: A case series

et al. 2022

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SCN8A‐developmental and epileptic encephalopathy is caused by pathogenic variants in the SCN8A gene encoding the Nav1.6 sodium channel, and is characterized by intractable multivariate seizures and developmental regression. Fenfluramine is a repurposed drug with proven antiseizure efficacy in Dravet syndrome and Lennox–Gastaut syndrome. The effect of fenfluramine treatment was assessed in a retrospective series of three patients with intractable SCN8A epilepsy and severe neurodevelopmental comorbidity (n = 2 females; age 2.8–13 years; 8–16 prior failed antiseizure medications [ASM]; treatment duration: 0.75–4.2 years). In the 6 months prior to receiving fenfluramine, patients experienced multiple seizure types, including generalized tonic–clonic, focal and myoclonic seizures, and status epilepticus. Overall seizure reduction was 60%–90% in the last 3, 6, and 12 months of fenfluramine treatment. Clinically meaningful improvement was noted in ≥1 non‐seizure comorbidity per patient after fenfluramine, as assessed by physician‐ratings of ≥“Much Improved” on the Clinical Global Impression of Improvement scale. Improvements included ambulation in a previously non‐ambulant patient and better attention, sleep, and language. One patient showed mild irritability which resolved; no other treatment‐related adverse events were reported. There were no reports of valvular heart disease or pulmonary arterial hypertension. Fenfluramine may be a promising ASM for randomized clinical trials in SCN8A‐related disorders.

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Section: Discussionmentioning

confidence: 99%

Effect of fenfluramine on seizures and comorbidities in SCN8A‐developmental and epileptic encephalopathy: A case series

et al. 2022

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“…Conversely, we demonstrate the extent to which EMR usage limits EMR-based analyses in these rare diseases: despite a cohort of 658 individuals, only 27 etiologies were amenable to age-specific phenotypic similarity analysis, and at limited ages. This lack of data demonstrates the challenges of investigating the outcomes of genetic epilepsies in adolescence and adulthood [ 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

Phenotypic homogeneity in childhood epilepsies evolves in gene-specific patterns across 3251 patient-years of clinical data

et al. 2021

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While genetic studies of epilepsies can be performed in thousands of individuals, phenotyping remains a manual, non-scalable task. A particular challenge is capturing the evolution of complex phenotypes with age. Here, we present a novel approach, applying phenotypic similarity analysis to a total of 3251 patient-years of longitudinal electronic medical record data from a previously reported cohort of 658 individuals with genetic epilepsies. After mapping clinical data to the Human Phenotype Ontology, we determined the phenotypic similarity of individuals sharing each genetic etiology within each 3-month age interval from birth up to a maximum age of 25 years. 140 of 600 (23%) of all 27 genes and 3-month age intervals with sufficient data for calculation of phenotypic similarity were significantly higher than expect by chance. 11 of 27 genetic etiologies had significant overall phenotypic similarity trajectories. These do not simply reflect strong statistical associations with single phenotypic features but appear to emerge from complex clinical constellations of features that may not be strongly associated individually. As an attempt to reconstruct the cognitive framework of syndrome recognition in clinical practice, longitudinal phenotypic similarity analysis extends the traditional phenotyping approach by utilizing data from electronic medical records at a scale that is far beyond the capabilities of manual phenotyping. Delineation of how the phenotypic homogeneity of genetic epilepsies varies with age could improve the phenotypic classification of these disorders, the accuracy of prognostic counseling, and by providing historical control data, the design and interpretation of precision clinical trials in rare diseases.

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“…Most of these monogenic epilepsies have a pediatric presentation, but as introduced earlier, many patients reach adulthood still suffering a diagnostic gap and there are even adult-onset cases reported in literature ( 87 ). This sort of specific therapeutic approaches may lay upon more or less solid evidence foundation and may have been reported as more or less clinically effective.…”

Section: Clinical Implications Of Diagnosis: Optimization Of Therapy ...mentioning

confidence: 99%

Epilepsy Genetics and Precision Medicine in Adults: A New Landscape for Developmental and Epileptic Encephalopathies

Beltrán‐Corbellini

Aledo‐Serrano

Møller³

et al. 2022

Front. Neurol.

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This review aims to provide an updated perspective of epilepsy genetics and precision medicine in adult patients, with special focus on developmental and epileptic encephalopathies (DEEs), covering relevant and controversial issues, such as defining candidates for genetic testing, which genetic tests to request and how to interpret them. A literature review was conducted, including findings in the discussion and recommendations. DEEs are wide and phenotypically heterogeneous electroclinical syndromes. They generally have a pediatric presentation, but patients frequently reach adulthood still undiagnosed. Identifying the etiology is essential, because there lies the key for precision medicine. Phenotypes modify according to age, and although deep phenotyping has allowed to outline certain entities, genotype-phenotype correlations are still poor, commonly leading to long-lasting diagnostic odysseys and ineffective therapies. Recent adult series show that the target patients to be identified for genetic testing are those with epilepsy and different risk factors. The clinician should take active part in the assessment of the pathogenicity of the variants detected, especially concerning variants of uncertain significance. An accurate diagnosis implies precision medicine, meaning genetic counseling, prognosis, possible future therapies, and a reduction of iatrogeny. Up to date, there are a few tens of gene mutations with additional concrete treatments, including those with restrictive/substitutive therapies, those with therapies modifying signaling pathways, and channelopathies, that are worth to be assessed in adults. Further research is needed regarding phenotyping of adult syndromes, early diagnosis, and the development of targeted therapies.

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Diagnostic gap in genetic epilepsies: A matter of age

Cited by 11 publications

References 14 publications

Effect of fenfluramine on seizures and comorbidities in SCN8A‐developmental and epileptic encephalopathy: A case series

Effect of fenfluramine on seizures and comorbidities in SCN8A‐developmental and epileptic encephalopathy: A case series

Phenotypic homogeneity in childhood epilepsies evolves in gene-specific patterns across 3251 patient-years of clinical data

Epilepsy Genetics and Precision Medicine in Adults: A New Landscape for Developmental and Epileptic Encephalopathies

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