Patrick Lawlor, Lorelei's neurologist in Michigan, described the severity of CACNA1E to local news outlet WXYZ, saying, “The lack of progress is something that really signals how severe her disorder is. Probably one of the most severe children I’ve taken care of. She has clusters of brief seizures. Sometimes 10 or 20 times per day.”
The Michigan mom explained that it's “even harder” because Lorelei has “no head control or upper body control.” Kayleigh added, "Even though we’re desensitized. It breaks my heart to see her like this."
Kayleigh has been documenting Lorelei's health journey on TikTok, inciting an outpouring of love and support, including when she had a G-tube surgery in January.
"She took it like a champ, and I could not be prouder of her," Kayleigh captioned the TikTok video. "I cannot wait to get her home and comfortable in her own bed. But for now, I’m going to enjoy this quiet moment alone in our little hospital room, just the two of us."
Kayleigh told WXYZ that Lorelei, who enjoys bath time, is nonverbal, adding, “For someone who is nonverbal, she is very vocal.”
The mother is hopeful that their family’s story encourages other people to get tested for neurological conditions.
Angela Munaco, one of the family’s close friends set up a GoFundMe to help the family cover Lorelei's medical bills and other costs.
“Shortly after her diagnosis, Kayleigh’s husband [Ryan] suffered a serious back injury at work, leaving him unable to work for several months,” the GoFundMe said. “Between his recovery, endless doctor appointments, and the long wait for state approval of Lorelei’s special needs insurance, Kayleigh had no choice but to step back from full-time work. She now works part-time when she can, balancing her career with being Lorelei’s full-time caregiver.”
Kayleigh told WXYZ, “I just want [Lorelei] to know I tried everything I can to make her better.”
Lexi Lane
https://people.com/michigan-girl-diagnosed-with-rare-genetic-disorder-cacna1e-11940319
Di Micco V, Affronte L, Khinchi MS, Rønde G, Miranda MJ, Hammer TB, Specchio N, Beniczky S, Olofsson K, Møller RS, Gardella E. Seizure and movement disorder in CACNA1E developmental and epileptic encephalopathy: Two sides of the same coin or same side of two different coins? Epileptic Disord. 2024 Aug;26(4):520-526. doi: 10.1002/epd2.20242. Epub 2024 May 23. PMID: 38780451.
Abstract
Pathogenic variants in CACNA1E are associated with early-onset epileptic and developmental encephalopathy (DEE). Severe to profound global developmental delay, early-onset refractory seizures, severe hypotonia, and macrocephaly are the main clinical features. Patients harboring the recurrent CACNA1E variant p.(Gly352Arg) typically present with the combination of early-onset DEE, dystonia/dyskinesia, and contractures. We describe a 2-year-and-11-month-old girl carrying the p.(Gly352Arg) CACNA1E variant. She has a severe DEE with very frequent drug-resistant seizures, profound hypotonia, and episodes of dystonia and dyskinesia. Long-term video-EEG-monitoring documented subsequent tonic asymmetric seizures during wakefulness and mild paroxysmal dyskinesias of the trunk out of sleep which were thought to be a movement disorder and instead turned out to be focal hyperkinetic seizures. This is the first documented description of the EEG findings in this disorder. Our report highlights a possible overlap between cortical and subcortical phenomena in CACNA1E-DEE. We also underline how a careful electro-clinical evaluation might be necessary for a correct discernment between the two disorders, playing a fundamental role in the clinical assessment and proper management of children with CACNA1E-DEE.
Ortiz Cabrera NV, Duat Rodríguez A, Fernández Garoz B, Bernardino Cuesta B, Jiménez Legido M, Cantarín Extremera V, García Peñas JJ. Dystonia and Contractures are Potential Early Signs of CACNA1E-Related Epileptic Encephalopathy. Mol Syndromol. 2021 Mar;12(1):25-32. doi: 10.1159/000511926. Epub 2020 Dec 10. PMID: 33776624; PMCID: PMC7983621.
Abstract
Epileptic encephalopathy related to CACNA1E has been described as a severe neurodevelopmental disorder presenting with early-onset refractory seizures, hypotonia, macrocephaly, hyperkinetic movements, and contractures and is associated with an autosomal dominant inheritance pattern. Most pathogenic variants described to date are missense variants with a gain of function effect, and the role of haploinsufficiency has yet to be clarified. We describe 2 cases of CACNA1E encephalopathy. Notable findings include congenital contractures and movement disorders predating onset of epilepsy, particularly dystonia. We further compared the key phenotypic features depending on variant location. In conclusion, the appearance of congenital contractures, areflexia, and movement disorders before the onset of epilepsy may provide key guidance in the diagnosis of epileptic CACNA1E encephalopathy. A genotype-phenotype correlation was found between the presence of movement disorders and severe intellectual disability and the location of the variant in the CACNA1E gene.
Helbig KL, Lauerer RJ, Bahr JC, Souza IA, Myers CT, Uysal B, Schwarz N, Gandini MA, Huang S, Keren B, Mignot C, Afenjar A, Billette de Villemeur T, Héron D, Nava C, Valence S, Buratti J, Fagerberg CR, Soerensen KP, Kibaek M, Kamsteeg EJ, Koolen DA, Gunning B, Schelhaas HJ, Kruer MC, Fox J, Bakhtiari S, Jarrar R, Padilla-Lopez S, Lindstrom K, Jin SC, Zeng X, Bilguvar K, Papavasileiou A, Xing Q, Zhu C, Boysen K, Vairo F, Lanpher BC, Klee EW, Tillema JM, Payne ET, Cousin MA, Kruisselbrink TM, Wick MJ, Baker J, Haan E, Smith N, Sadeghpour A, Davis EE, Katsanis N; Task Force for Neonatal Genomics; Corbett MA, MacLennan AH, Gecz J, Biskup S, Goldmann E, Rodan LH, Kichula E, Segal E, Jackson KE, Asamoah A, Dimmock D, McCarrier J, Botto LD, Filloux F, Tvrdik T, Cascino GD, Klingerman S, Neumann C, Wang R, Jacobsen JC, Nolan MA, Snell RG, Lehnert K, Sadleir LG, Anderlid BM, Kvarnung M, Guerrini R, Friez MJ, Lyons MJ, Leonhard J, Kringlen G, Casas K, El Achkar CM, Smith LA, Rotenberg A, Poduri A, Sanchis-Juan A, Carss KJ, Rankin J, Zeman A, Raymond FL, Blyth M, Kerr B, Ruiz K, Urquhart J, Hughes I, Banka S; Deciphering Developmental Disorders Study; Hedrich UBS, Scheffer IE, Helbig I, Zamponi GW, Lerche H, Mefford HC. De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias. Am J Hum Genet. 2018 Nov 1;103(5):666-678. doi: 10.1016/j.ajhg.2018.09.006. Epub 2018 Oct 18. Erratum in: Am J Hum Genet. 2019 Mar 7;104(3):562. doi: 10.1016/j.ajhg.2019.02.015. PMID: 30343943; PMCID: PMC6216110.
Abstract
Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.
No comments:
Post a Comment