EFMR Syndrome: Epilepsy and Mental Retardation Restricted to Females in Childhood
Stefan Bittmann *
Department of Pediatrics, Ped Mind Institute (PMI), Hindenburgring 4, D-48599 Gronau, Germany.
Elisabeth Luchter
Department of Pediatrics, Ped Mind Institute (PMI), Hindenburgring 4, D-48599 Gronau, Germany.
Elena Moschüring-Alieva
Department of Pediatrics, Ped Mind Institute (PMI), Hindenburgring 4, D-48599 Gronau, Germany.
Lara Bittmann
Department of Pediatrics, Ped Mind Institute (PMI), Hindenburgring 4, D-48599 Gronau, Germany.
Aysel Shirinova
Department of Pediatrics, Ped Mind Institute (PMI), Hindenburgring 4, D-48599 Gronau, Germany.
*Author to whom correspondence should be addressed.
Abstract
Epilepsy with intelligence impairment, restricted to the female sex, is a rare X-linked epilepsy syndrome. It is characterized by febrile or afebrile seizures, mainly tonic-clonic, but also absence, myoclonic, and atonic beginning in the first years of life. In most cases, developmental delay and intelligence impairment of varying severity is present. Behavioral disorders, autistic traits, hyperactivity, and aggressiveness are commonly associated. This disease exclusively affects females. Male carriers are not affected despite an X-linked inheritance.
Keywords: EFMR, PCDH19, children, mutation, epilepsy
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Yang C, Shi Y, Li X, Guan L, Li H, Lin J. Cadherins and the pathogenesis of epilepsy. Cell Biochem Funct. 2022 Jun; 40(4):336-348. DOI: 10.1002/cbf.3699 Epub 2022 Apr 8. PMID: 35393670.
Biswas S, Emond MR, Jontes JD. Protocadherin-19 and N-cadherin interact to control cell movements during anterior neurulation. J Cell Biol. 2010 Nov 29; 191(5):1029-41. DOI: 10.1083/jcb.201007008 PMID: 21115806; PMCID: PMC2995167.
Yokota S, Hirayama T, Hirano K, Kaneko R, Toyoda S, Kawamura Y, et al. Identification of the cluster control region for the protocadherin-beta genes located beyond the protocadherin-gamma cluster. J Biol Chem. 2011 Sep 9;286(36):31885-95. DOI: 10.1074/jbc.M111.24560 Epub 2011 Jul 19. PMID: 21771796; PMCID: PMC3173131.
Duszyc K, Terczynska I, Hoffman-Zacharska D. Epilepsy and mental retardation restricted to females: X-linked epileptic infantile encephalopathy of unusual inheritance. J Appl Genet. 2015 Feb;56(1):49-56. DOI: 10.1007/s13353-014-0243-8 Epub 2014 Sep 10. PMID: 25204757.
Hoshina N, Johnson-Venkatesh EM, Hoshina M, Umemori H. Female-specific synaptic dysfunction and cognitive impairment in a mouse model of PCDH19 disorder. Science. 2021 Apr 16;372(6539):eaaz3893.
DOI: 10.1126/science.aaz3893 PMID: 33859005; PMCID: PMC9873198.
Moncayo JA, Vargas MN, Castillo I, Granda PV, Duque AM, Argudo JM, et al. Adjuvant Treatment for Protocadherin 19 (PCDH19) Syndrome. Cureus. 2022 Jul 22;14(7):e27154. DOI: 10.7759/cureus.27154
PMID: 36004035; PMCID: PMC9392850.
Iqbal M, Maroofian R, Çavdarlı B, Riccardi F, Field M, Banka S, et al. Biallelic variants in PCDHGC4 cause a novel neurodevelopmental syndrome with progressive microcephaly, seizures, and joint anomalies. Genet Med. 2021 Nov; 23(11):2138-2149. DOI: 10.1038/s41436-021-01260-4 Epub 2021 Jul 9. PMID: 34244665; PMCID: PMC8553613.
Antelmi E, Mastrangelo M, Bisulli F, Spaccini L, Stipa C, Mostacci B, Mei D, Guerrini R, Tinuper P. Semiological study of ictal affective behaviour in epilepsy and mental retardation limited to females (EFMR). Epileptic Disord. 2012 Sep;14(3): 304-9. DOI: 10.1684/epd.2012.0526 PMID: 22932693.
Breuillard D, Leunen D, Chemaly N, Auclair L, Pinard JM, Kaminska A, Desguerre I, Ouss L, Nabbout R. Autism spectrum disorder phenotype and intellectual disability in females with epilepsy and PCDH-19 mutations. Epilepsy Behav. 2016 Jul;60:75-80. DOI: 10.1016/j.yebeh.2016.04.009 Epub 2016 May 12. PMID: 27179713.
Smith L, Singhal N, El Achkar CM, Truglio G, Rosen Sheidley B, Sullivan J, Poduri A. PCDH19-related epilepsy is associated with a broad neurodevelopmental spectrum. Epilepsia. 2018 Mar;59(3):679-689. DOI: 10.1111/epi.14003
Epub 2018 Jan 28. Erratum in: Epilepsia. 2018 Jun;59(6): 1272. PMID: 29377098; PMCID: PMC6264912.
Nagarajan L, Ghosh S, Dyke J, Lee S, Silberstein J, Azmanov D, Richard W. Epilepsy surgery in PCDH 19 related developmental and epileptic encephalopathy: A case report. Epilepsy Behav Rep. 2022 Jul 6;19: 100560.
DOI: 10.1016/j.ebr.2022.100560 PMID: 35856042; PMCID: PMC9287778.
Liu YH, Cheng YT, Tsai MH, Chou IJ, Hung PC, Hsieh MY, et al. Genetics and clinical correlation of Dravet syndrome and its mimics - experience of a tertiary center in Taiwan. Pediatr Neonatol. 2021 Sep; 62(5):550-558.
DOI: 10.1016/j.pedneo.2021.05.022 Epub 2021 Jun 23. PMID: 34226156.
Lim J, Ryu J, Kang S, Noh HJ, Kim CH. Autism-like behaviors in male mice with a Pcdh19 deletion. Mol Brain. 2019 Nov 20;12(1):95. DOI: 10.1186/s13041-019-0519-3 PMID: 31747920; PMCID: PMC6864969.
Dell'Isola GB, Vinti V, Fattorusso A, Tascini G, Mencaroni E, Di Cara G, Striano P, Verrotti A. The Broad Clinical Spectrum of Epilepsies Associated With Protocadherin 19 Gene Mutation. Front Neurol. 2022 Jan 17;12:780053.
DOI: 10.3389/fneur.2021.780053 PMID: 35111125; PMCID: PMC8801579.
Yang L, Arafat A, Peng J, Chen C, Ma Y, Yin F. [PCDH19 gene mutations lead to epilepsy with mental retardation limited to females in 2 cases and literature review]. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2017 Jun 28;42(6):730-736. Chinese. DOI: 10.11817/j.issn.1672-7347.2017.06.021 PMID: 28690234.
Scheffer IE, Turner SJ, Dibbens LM, Bayly MA, Friend K, Hodgson B, et al. Epilepsy and mental retardation limited to females: An under-recognized disorder. Brain. 2008 Apr;131(Pt 4):918-27. DOI: 10.1093/brain/awm338 Epub 2008 Jan 29. PMID: 18234694.
Kolc KL, Sadleir LG, Scheffer IE, Ivancevic A, Roberts R, Pham DH, Gecz J. A systematic review and meta-analysis of 271 PCDH19-variant individuals identifies psychiatric comorbidities, and association of seizure onset and disease severity. Mol Psychiatry. 2019 Feb;24(2):241-251. DOI: 10.1038/s41380-018-0066-9
Epub 2018 Jun 11. PMID: 29892053; PMCID: PMC6344372.
Zhao X, Wang Y, Mei S, Kong X. A novel PCDH19 missense mutation, c.812G>A (p.Gly271Asp), identified using whole-exome sequencing in a Chinese family with epilepsy female restricted mental retardation syndrome. Mol Genet Genomic Med. 2020 Jun;8(6):e1234. DOI: 10.1002/mgg3.1234 Epub 2020 Apr 21. PMID: 32314541; PMCID: PMC7284031.
Hudson JD, Tamilselvan E, Sotomayor M, Cooper SR. A complete Protocadherin-19 ectodomain model for evaluating epilepsy-causing mutations and potential protein interaction sites. Structure. 2021 Oct 7;29(10):1128-1143.e4. DOI: 10.1016/j.str.2021.07.006 Epub 2021 Sep 13. PMID: 34520737.
Chemaly N, Losito E, Pinard JM, Gautier A, Villeneuve N, Arbues AS, et al. Early and long-term electroclinical features of patients with epilepsy and PCDH19 mutation. Epileptic Disord. 2018 Dec 1;20(6):457-467.
DOI: 10.1684/epd.2018.1009 PMID: 30530412.
Kozina AA, Okuneva EG, Baryshnikova NV, Fedonyuk ID, Kholin AA, Il'ina ES, et al. Two novel PCDH19 mutations in Russian patients with epilepsy with intellectual disability limited to females: a case report. BMC Med Genet. 2020 Oct 21;21(1):209. DOI: 10.1186/s12881-020-01119-6 PMID: 33087045; PMCID: PMC7579871.
Brown A, Arpone M, Schneider AL, Micallef S, Anderson VA, Scheffer IE. Cognitive, behavioral, and social functioning in children and adults with Dravet syndrome. Epilepsy Behav. 2020 Nov;112:107319.
DOI: 10.1016/j.yebeh.2020.107319
Epub 2020 Aug 25. PMID: 32858363.
Chen ZS, Hsieh A, Sun G, Bergey GK, Berkovic SF, Perucca P, et al. MS-BioS Study Group. Interictal EEG and ECG for SUDEP Risk Assessment: A Retrospective Multicenter Cohort Study. Front Neurol. 2022 Mar 18;13: 858333.
DOI: 10.3389/fneur.2022.858333
PMID: 35370908; PMCID: PMC8973318.
Krüger J, Schubert J, Kegele J, Labalme A, Mao M, Heighway J, Seebohm G, Yan P, Koko M, Aslan-Kara K, et al. Loss-of-function variants in the KCNQ5 gene are implicated in genetic generalized epilepsies. EBioMedicine. 2022 Oct;84: 104244. DOI: 10.1016/j.ebiom.2022.104244 Epub 2022 Sep 9. PMID: 36088682; PMCID: PMC9471468.
Chouery E, Makhlouf J, Daoud Khatoun W, Mehawej C, Megarbane A. PCDH19 in Males: Are Hemizygous Variants Linked to Autism? Genes (Basel). 2023 Feb 27; 14(3):598.
DOI: 10.3390/genes14030598 PMID: 36980870; PMCID: PMC10048232.
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 Nov 3;13: 1041509.
DOI: 10.3389/fneur.2022.1041509 PMID: 36408521; PMCID: PMC9669318.
Pancho A, Mitsogiannis MD, Aerts T, Dalla Vecchia M, Ebert LK, Geenen L, et al. Modifying PCDH19 levels affects cortical interneuron migration. Front Neurosci. 2022 Oct 25;16:887478.
DOI: 10.3389/fnins.2022.887478 PMID: 36389226; PMCID: PMC9642031.
Gecz J, Thomas PQ. Disentangling the paradox of the PCDH19 clustering epilepsy, a disorder of cellular mosaics. Curr Opin Genet Dev. 2020 Dec;65:169-175. DOI: 10.1016/j.gde.2020.06.012 Epub 2020 Jul 26. PMID: 32726744.
Sadleir LG, Kolc KL, King C, Mefford HC, Dale RC, Gecz J, Scheffer IE. Levetiracetam efficacy in PCDH19 Girls Clustering Epilepsy. Eur J Paediatr Neurol. 2020 Jan;24:142-147. DOI: 10.1016/j.ejpn.2019.12.020
Epub 2020 Jan 3. PMID: 31928905.
Gerosa L, Mazzoleni S, Rusconi F, Longaretti A, Lewerissa E, Pelucchi S, et al. The epilepsy-associated protein PCDH19 undergoes NMDA receptor-dependent proteolytic cleavage and regulates the expression of immediate-early genes. Cell Rep. 2022 May 24;39(8): 110857. DOI: 10.1016/j.celrep.2022.110857 PMID: 35613587; PMCID: PMC9152703.