Advances and Perspectives in Epilepsies of Genetic Origin: A Case Report
Journal: Advances in Medicine and Engineering Interdisciplinary Research DOI: 10.32629/ameir.v3i1.3702
Abstract
Progress in genomics has allowed the identification of multiple genetic variants involved in epilepsies, which facilitates early diagnosis and the development of personalized therapies. This case describes a 15-year-old male patient with a clinical picture since the age of 10 months consisting of generalized tonic-clonic seizures, accompanied by moderate intellectual disability with compromised behavioral and adaptive skills, the product of non-consanguineous parents, with no history related to the patient's clinical presentation. Given the age of presentation, characteristics, progression and the need for multiple anticonvulsants, de novo epilepsy of genetic origin was suspected, so whole exome sequencing and copy number variant (CNV) analysis of 110 genes associated with refractory epilepsy were performed, and the results showed a pathogenic hemizygous variant in the PCDH19 gene. Variants of this gene (PCDH19) are associated in databases such as ClinVar with sporadic infantile epileptic encephalopathy, female-limited epilepsy (EFMR or PCDH19RE), and Dravet syndrome. The PCDH19 gene was initially identified in 2008 as responsible for epilepsy and mental retardation limited to females. In 2009, the first mosaic deletion of the gene was described in a male patient, revealing a unique X-linked inheritance pattern. Both heterozygous females and males with mosaicism are affected. Dravet syndrome is a rare and severe childhood epilepsy; some variants of the PCDH19 gene, encoding protocadherin 19, are associated with a Dravet syndrome-like phenotype, known as DS-like. Genetic factors are the major contributors to the cause of epilepsy in up to 80% of epileptics. Research to elucidate the genetic landscape of epileptic and developmental encephalopathies contributes to the elucidation of molecular pathogenesis and the development of personalized targeted therapies in these disorders. Since epilepsy and cognitive disorders have advanced in the knowledge of their genetic cause, it is important to have a specific diagnosis, in order to establish targeted and personalized treatments (pharmacogenomics), follow-up, prognosis, genetic counseling and thus get closer and closer to the 7P medicine (Preventive, Proactive, Participatory, Predictive, Personalized, Pleasant).
Keywords
epilepsy; whole-exome sequencing; de novo variant; PCDH19 gene; developmental epileptic encephalopathy 9; Dravet syndrome; precision medicine
Full Text
PDF - Viewed/Downloaded: 0 TimesReferences
[1] Sands T, Gelinas J, Epilepsy and encephalopathy, Neurological Pediatrics, 2024; 150, 24-31. https://doi.org/10.1016/j.pediatrneurol.2023.09.019
[2] Zhang M, Liang X, Wang J, Gao L, Liao H, He Y, et al. China epilepsy gene 1.0 project. Epilepsy-associated genes, European Journal of Epilepsy, 2024; 116, 4-13.
[3] Yalçın Ç, Yapıcı Z, Özbil M, Çağlayan H, Exome data from patients with epileptic and developmental encephalopathy reveal de novo and heritable pathological variants in epilepsy-associated genes. European Journal of Epilepsy. 2024; 116, 51-64.
[4] Lenge M, Balestrini S, Napolitano A, Mei D, Conti V, Baldassarri G, et al. Morphometric network-based abnormalities correlate with psychiatric comorbidities and gene expression in PCDH19 related epileptic and developmental encephalopathy. Psychiatry transl. 2024; 14(1), 35.
[5] HPO. PCDH19 NCBI gene. 2024. [cited 2024 Oct 12]. Available from: https://hpo.jax.org/browse/gene/NCBIGene:57526
[6] Rampazzo A, Santos R, Maluf F, Simm R, Marson F, Ortega M, et al. Dravet syndrome and Dravet syndrome-like phenotype: a systematic review of the SCN1A and PCDH19 variants. Neurogenetics. 2021; 22:105-15.
[7] Online Mendelian Inheritance in Man (OMIM). Epileptic and developmental encephalopathy 9; DEE9. 2024. [cited 2024 Oct 12]. Available from: https://www.omim.org/entry/300088?search=PCDH19&highlight=pcdh19
[8] Moncayo J, Ayala I, Argudo J, Aguirre A, Parwani J, Pachano A, et al. Understanding the protocadherin protein-driven protein-19 (PCDH19) syndrome: a review of the literature on pathophysiology. Cureus. 2022; 14(6).
[9] Kowkabi S, Yavarian M, Kaboodkhani R, Mohammadi M, Shervin R. PCDH19-clustering epilepsy, pathophysiology and clinical significance. Epilepsy & Behavior. 2024; 154.
[10] Dell'Isola G, Mencaroni E, Fattorusso A, Tascini G, Prontera P, Imperatore V, et al. Expanding the genetic and clinical features of Protocadherin 19 gene mutations. BMC Med Genomics. 2022;15(1):181.
[11] Fatumo S, Chikowore T, Choudhury A, Ayub M, Martin A, Kuchenbaecker K. A roadmap to increase diversity in genomic studies. Nat Med. 2022; 28:243-50.
[12] Ellis C, Petrovski S, Berkovic S. Epilepsy genetics: clinical impacts and biological insights. Lancet Neurol. 2020; 19(1):93-100.
[13] Riggs E, Andersen E, Cherry A, Kantarci S, Kearney H, Patel A, et al. Technical standards for the interpretation and reporting of constitutional copy number variants: a joint consensus recommendation from the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020; 22(2):245-57.
[14] Chen Y, Yang X, Chen J, Yang X, Yang Y, Liu A, et al. PCDH19-related epilepsy in mosaic males: the phenotypic implication of genotype and variant allele frequency. Front Neurol. 2022;13.
[15] Online Database franklin genoox, PCDH19 protocadherina 19. Xq22.1, 2024 [cited 2024 Nov 30] Retrieved from https://franklin.genoox.com/clinical-db/gene/hg19/PCDH19.
[16] Online Database GTEX Portal. PCDH19, 2024 [cited 2024 Nov 30] Retrieved from https://gtexportal.org/home/gene/PCDH19
[17] Giansante G, Mazzoleni S, Zippo A, Ponzoni L, Ghilardi A, Maiellano G, et al. Neural network activity and connectivity are altered in a conditional knockout mouse model with mosaic expression of PCDH19. IRIS Institutional Research Information System - AIR Institutional Research Archive. 2023.
[18] Online Mendelian Inheritance in Man (OMIM). (n.d.). PROTACADHERIN 19; PCDH19. 2024 [cited 2024 Oct 20] Retrieved from https://www.omim.org/entry/300460?search=PCDH19&highlight=pcdh19#contributors.
[19] Kozhanova T, Zhilina S, Meshcheryakova T, Abramov A, Ayvasyan S, Zavadenko N, Whole-exome sequencing is the molecular-genetic test of the first-line in developmental and epileptic encephalopathies. Badalyan Neurological Journal. 2024; 5(2):90-98. (In Russ) https://doi.org/10.46563/2686-8997-2024-5-2-90-98.
[20] Dell'Isola G, Vinti V, Fattorusso A, Tascini G, Mencaroni E, Di Cara G, et al. The broad clinical spectrum of epilepsies associated with the protocadherin 19 gene mutation. Front Neurol. 2022; 12.
[2] Zhang M, Liang X, Wang J, Gao L, Liao H, He Y, et al. China epilepsy gene 1.0 project. Epilepsy-associated genes, European Journal of Epilepsy, 2024; 116, 4-13.
[3] Yalçın Ç, Yapıcı Z, Özbil M, Çağlayan H, Exome data from patients with epileptic and developmental encephalopathy reveal de novo and heritable pathological variants in epilepsy-associated genes. European Journal of Epilepsy. 2024; 116, 51-64.
[4] Lenge M, Balestrini S, Napolitano A, Mei D, Conti V, Baldassarri G, et al. Morphometric network-based abnormalities correlate with psychiatric comorbidities and gene expression in PCDH19 related epileptic and developmental encephalopathy. Psychiatry transl. 2024; 14(1), 35.
[5] HPO. PCDH19 NCBI gene. 2024. [cited 2024 Oct 12]. Available from: https://hpo.jax.org/browse/gene/NCBIGene:57526
[6] Rampazzo A, Santos R, Maluf F, Simm R, Marson F, Ortega M, et al. Dravet syndrome and Dravet syndrome-like phenotype: a systematic review of the SCN1A and PCDH19 variants. Neurogenetics. 2021; 22:105-15.
[7] Online Mendelian Inheritance in Man (OMIM). Epileptic and developmental encephalopathy 9; DEE9. 2024. [cited 2024 Oct 12]. Available from: https://www.omim.org/entry/300088?search=PCDH19&highlight=pcdh19
[8] Moncayo J, Ayala I, Argudo J, Aguirre A, Parwani J, Pachano A, et al. Understanding the protocadherin protein-driven protein-19 (PCDH19) syndrome: a review of the literature on pathophysiology. Cureus. 2022; 14(6).
[9] Kowkabi S, Yavarian M, Kaboodkhani R, Mohammadi M, Shervin R. PCDH19-clustering epilepsy, pathophysiology and clinical significance. Epilepsy & Behavior. 2024; 154.
[10] Dell'Isola G, Mencaroni E, Fattorusso A, Tascini G, Prontera P, Imperatore V, et al. Expanding the genetic and clinical features of Protocadherin 19 gene mutations. BMC Med Genomics. 2022;15(1):181.
[11] Fatumo S, Chikowore T, Choudhury A, Ayub M, Martin A, Kuchenbaecker K. A roadmap to increase diversity in genomic studies. Nat Med. 2022; 28:243-50.
[12] Ellis C, Petrovski S, Berkovic S. Epilepsy genetics: clinical impacts and biological insights. Lancet Neurol. 2020; 19(1):93-100.
[13] Riggs E, Andersen E, Cherry A, Kantarci S, Kearney H, Patel A, et al. Technical standards for the interpretation and reporting of constitutional copy number variants: a joint consensus recommendation from the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020; 22(2):245-57.
[14] Chen Y, Yang X, Chen J, Yang X, Yang Y, Liu A, et al. PCDH19-related epilepsy in mosaic males: the phenotypic implication of genotype and variant allele frequency. Front Neurol. 2022;13.
[15] Online Database franklin genoox, PCDH19 protocadherina 19. Xq22.1, 2024 [cited 2024 Nov 30] Retrieved from https://franklin.genoox.com/clinical-db/gene/hg19/PCDH19.
[16] Online Database GTEX Portal. PCDH19, 2024 [cited 2024 Nov 30] Retrieved from https://gtexportal.org/home/gene/PCDH19
[17] Giansante G, Mazzoleni S, Zippo A, Ponzoni L, Ghilardi A, Maiellano G, et al. Neural network activity and connectivity are altered in a conditional knockout mouse model with mosaic expression of PCDH19. IRIS Institutional Research Information System - AIR Institutional Research Archive. 2023.
[18] Online Mendelian Inheritance in Man (OMIM). (n.d.). PROTACADHERIN 19; PCDH19. 2024 [cited 2024 Oct 20] Retrieved from https://www.omim.org/entry/300460?search=PCDH19&highlight=pcdh19#contributors.
[19] Kozhanova T, Zhilina S, Meshcheryakova T, Abramov A, Ayvasyan S, Zavadenko N, Whole-exome sequencing is the molecular-genetic test of the first-line in developmental and epileptic encephalopathies. Badalyan Neurological Journal. 2024; 5(2):90-98. (In Russ) https://doi.org/10.46563/2686-8997-2024-5-2-90-98.
[20] Dell'Isola G, Vinti V, Fattorusso A, Tascini G, Mencaroni E, Di Cara G, et al. The broad clinical spectrum of epilepsies associated with the protocadherin 19 gene mutation. Front Neurol. 2022; 12.
Copyright © 2025 Cindy Leonela Delgado Salcedo, Lina Johanna Moreno Giraldo
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License
