Effectiveness of add‐on acetazolamide in children with drug‐resistant CHD2‐related epilepsy and in a zebrafish CHD2 model

CHD2‐related epilepsy is characterized by early‐onset photosensitive myoclonic epilepsy with developmental delay and a high rate of pharmacoresistance. We sought to evaluate the efficacy of acetazolamide (ACZ) in CHD2‐related epilepsy, due to ACZ's unexpected efficacy in our first patient harbo...

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Bibliographic Details
Published in:	Epilepsia open Vol. 9; no. 5; pp. 1972 - 1980
Main Authors:	Melikishvili, Gia, Striano, Pasquale, Shojeinia, Elham, Gachechiladze, Tamar, Kurua, Ekaterine, Tabatadze, Nazhi, Melikishvili, Mariam, Koniashvili, Otar, Khachiashvili, Gvantsa, Epitashvili, Nino, Rimma, Gamirova, Belyaev, Oleg, Tomenko, Tatyana, Kharytonov, Volodymyr, Guliyeva, Ulviyya, Esguerra, Camila V., Crawford, Alexander D., Dulac, Olivier
Format:	Journal Article
Language:	English
Published:	United States John Wiley & Sons, Inc 01-10-2024 John Wiley and Sons Inc Wiley
Subjects:	Acetazolamide - pharmacology Acetazolamide - therapeutic use Acids Adolescent Age Animals Anticonvulsants - pharmacology Anticonvulsants - therapeutic use Ataxia Child Child development Child, Preschool Clinical medicine Convulsions & seizures developmental epileptic encephalopathy Disease Models, Animal DNA-Binding Proteins - genetics Drug dosages Drug Resistant Epilepsy - drug therapy Drug Therapy, Combination Electroencephalography Epilepsy Female Genotype & phenotype Humans Male Microcephaly Mutation myoclonic seizures Parents & parenting Patients photosensitivity Short tonic–clonic seizures Treatment Outcome Zebrafish developmental epileptic encephalopathy zebrafish photosensitivity myoclonic seizures tonic–clonic seizures
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Summary:	CHD2‐related epilepsy is characterized by early‐onset photosensitive myoclonic epilepsy with developmental delay and a high rate of pharmacoresistance. We sought to evaluate the efficacy of acetazolamide (ACZ) in CHD2‐related epilepsy, due to ACZ's unexpected efficacy in our first patient harboring a pathogenic CHD2 variant. We collected patients from different Eastern European countries with drug‐resistant CHD2‐related epilepsy who were then treated with ACZ. Patients underwent video EEG before and during ACZ treatment. In a zebrafish model of CHD2‐related epilepsy, ictal‐like events were recorded 5 days post‐fertilization after overnight ACZ exposure. Developmental delay preceded the onset of seizures in 10 of the 12 patients. Four had ataxia, and 6 exhibited autistic features. Seizures, primarily myoclonic, began at an average age of 3.4 years and were photosensitive in all 12 patients. Add‐on ACZ treatment controlled photosensitive seizures in all patients: 6 became seizure‐free, and in the remaining 6, seizure frequency decreased by over 75%. Four patients transitioned to ACZ monotherapy. The median follow‐up was 13 months. In the zebrafish model, ACZ exposure reduced ictal‐like events by 72%. ACZ, a well‐tolerated and cost‐effective medication, could be a good option for CHD2‐related epilepsy, predominantly manifesting with myoclonic seizures and photosensitivity. Plain Language Summary Epilepsy associated with CHD2 mutations is often pharmacoresistant and associated with developmental delay and eventually ataxia. There are several generalized seizure types, including generalized tonic–clonic seizures, but the most characteristic are jerks triggered by light stimulation. We collected 12 patients who received acetazolamide, a drug usually given as a diuretic and registered as a mild antiseizure medication. All jerks triggered by light disappeared while the frequency of spontaneous seizures decreased by over 75%. Further studies are needed to confirm this promising finding and identify the mechanism by which an old compound seems to have such a specific antiseizure effect.
Bibliography:	Elham Shojeinia, Tamar Gachechiladze and Ekaterine Kurua are equally contributing authors. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2470-9239 2470-9239
DOI:	10.1002/epi4.13034