<i>DEPDC5</i> mutations in familial epilepsy syndrome: genetic insights and therapeutic approaches
Background. DEPDC5 (disheveled, Egl-10 and pleckstrin domain-containing protein 5) familial epilepsy syndrome is a group of epilepsy disorders caused by mutations in DEPDC5 gene, which is a part of the gap activity towards rag 1 (GATOR1) complex involved in regulating the mechanism target of rapamyc...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | Russian |
| Published: |
IRBIS LLC
2025-01-01
|
| Series: | Эпилепсия и пароксизмальные состояния |
| Subjects: | |
| Online Access: | https://www.epilepsia.su/jour/article/view/1152 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1839584004627496960 |
|---|---|
| author | M. K.C. Diallo S. Mukesh L. Kapil R. Singla D. Tar S. N. Tammineedi E. Singer H. Chhayani K. Arumaithurai U. K. Patel R. Arora |
| author_facet | M. K.C. Diallo S. Mukesh L. Kapil R. Singla D. Tar S. N. Tammineedi E. Singer H. Chhayani K. Arumaithurai U. K. Patel R. Arora |
| author_sort | M. K.C. Diallo |
| collection | DOAJ |
| description | Background. DEPDC5 (disheveled, Egl-10 and pleckstrin domain-containing protein 5) familial epilepsy syndrome is a group of epilepsy disorders caused by mutations in DEPDC5 gene, which is a part of the gap activity towards rag 1 (GATOR1) complex involved in regulating the mechanism target of rapamycin (mTOR) pathway. These mutations lead to hyperactivation of the mTOR pathway, disrupting the shaping of neurons and resulting in increased excitatory transmission and the development of epilepsy. The incidence and prevalence of DEPDC5 familial epilepsy syndrome are not well established, but studies suggest it may account for up to 10% of familial focal epilepsy cases. Genetic testing, electroencephalography (EEG), and brain magnetic resonance imaging (MRI) are important in diagnosing the disorder, although normal MRI results are common.Objective: to explain the rare sporadic mutation in DEPDC5 gene with p.R389H, a variant of unknown significance.Case report. A 6-year-old South-Asian girl was born at 34-weeks from non-consanguineous marriage without any prenatal events. She had hyperbilirubinemia by week-1, which was successfully treated with phototherapy. Her initial seizure occurred when she was three months old, just 2 days after the fever from the vaccination had subsided. It was considered a simple-febrile seizure and no treatment was given. At 3.5-months, she started having recurrent seizures. Workup including MRI/ infectious/metabolic panel was non-conclusive. EEG during the initial presentation showed epileptiform activity from the left temporal region. Despite being on multiple anti-epileptic drugs, the child was diagnosed with refractory epilepsy. Subsequently, EEG at 2.5-years showed inter-ictal bi-hemispheric epileptiform activity. EEG at 5-years showed inter-ictal spikes and wave discharges from bilateral fronto-temporal region with secondary generalization. By 3-years, MRI showed mildly deformed corpus callosum with inadequate thickening of splenium. DNA analysis confirmed heterozygous missense mutation in exon 16 of DEPDC5 gene, without chromosomal abnormalities. Mother was heterozygous for the same mutation but no mutations in the father was found. The child has grossly delayed milestones. Corrected age is approximately 1-year for fine motor and language, 1.5-years for gross motor, 2.5-years for cognition, social skills. She had developed autistic features as well with significant impaired auditory/visual processing. She had hypotonia (Right>Left), wide-based gait, and extrapyramidal movements.Conclusion. DEPDC5 gene mutation results in amino acid substitution of Histidine for Arginine at codon 389. This mutation has shown to be inherited in familial pattern. This R389H variant is not present in the 1000 genomes database and is predicted to be benign. However, It rather appears to be a sporadic mutation, which is a very rarely observed phenomena. Such patients may respond well to mTOR inhibitors such as rapamycin, making prompt diagnosis and treatment crucial. |
| format | Article |
| id | doaj-art-dbb80a89d60e4e988acd751a1055508a |
| institution | Matheson Library |
| issn | 2077-8333 2311-4088 |
| language | Russian |
| publishDate | 2025-01-01 |
| publisher | IRBIS LLC |
| record_format | Article |
| series | Эпилепсия и пароксизмальные состояния |
| spelling | doaj-art-dbb80a89d60e4e988acd751a1055508a2025-08-03T19:51:23ZrusIRBIS LLCЭпилепсия и пароксизмальные состояния2077-83332311-40882025-01-0116433834810.17749/2077-8333/epi.par.con.2024.193668<i>DEPDC5</i> mutations in familial epilepsy syndrome: genetic insights and therapeutic approachesM. K.C. Diallo0S. Mukesh1L. Kapil2R. Singla3D. Tar4S. N. Tammineedi5E. Singer6H. Chhayani7K. Arumaithurai8U. K. Patel9R. Arora10Carle Foundation HospitalLiaquat University of Medical and Health SciencesCaribbean Medical UniversityMedical University of South Carolina Columbia Downtown CenterTouro University College of Osteopathic MedicineKamineni institute of Medical sciencesThe University of Texas MD Anderson Cancer CenterG.M.E.R.S. Medical CollegeMayo Clinic Health SystemIcahn School of Medicine at Mount SinaiZucker School of Medicine at Hofstra/NorthwellBackground. DEPDC5 (disheveled, Egl-10 and pleckstrin domain-containing protein 5) familial epilepsy syndrome is a group of epilepsy disorders caused by mutations in DEPDC5 gene, which is a part of the gap activity towards rag 1 (GATOR1) complex involved in regulating the mechanism target of rapamycin (mTOR) pathway. These mutations lead to hyperactivation of the mTOR pathway, disrupting the shaping of neurons and resulting in increased excitatory transmission and the development of epilepsy. The incidence and prevalence of DEPDC5 familial epilepsy syndrome are not well established, but studies suggest it may account for up to 10% of familial focal epilepsy cases. Genetic testing, electroencephalography (EEG), and brain magnetic resonance imaging (MRI) are important in diagnosing the disorder, although normal MRI results are common.Objective: to explain the rare sporadic mutation in DEPDC5 gene with p.R389H, a variant of unknown significance.Case report. A 6-year-old South-Asian girl was born at 34-weeks from non-consanguineous marriage without any prenatal events. She had hyperbilirubinemia by week-1, which was successfully treated with phototherapy. Her initial seizure occurred when she was three months old, just 2 days after the fever from the vaccination had subsided. It was considered a simple-febrile seizure and no treatment was given. At 3.5-months, she started having recurrent seizures. Workup including MRI/ infectious/metabolic panel was non-conclusive. EEG during the initial presentation showed epileptiform activity from the left temporal region. Despite being on multiple anti-epileptic drugs, the child was diagnosed with refractory epilepsy. Subsequently, EEG at 2.5-years showed inter-ictal bi-hemispheric epileptiform activity. EEG at 5-years showed inter-ictal spikes and wave discharges from bilateral fronto-temporal region with secondary generalization. By 3-years, MRI showed mildly deformed corpus callosum with inadequate thickening of splenium. DNA analysis confirmed heterozygous missense mutation in exon 16 of DEPDC5 gene, without chromosomal abnormalities. Mother was heterozygous for the same mutation but no mutations in the father was found. The child has grossly delayed milestones. Corrected age is approximately 1-year for fine motor and language, 1.5-years for gross motor, 2.5-years for cognition, social skills. She had developed autistic features as well with significant impaired auditory/visual processing. She had hypotonia (Right>Left), wide-based gait, and extrapyramidal movements.Conclusion. DEPDC5 gene mutation results in amino acid substitution of Histidine for Arginine at codon 389. This mutation has shown to be inherited in familial pattern. This R389H variant is not present in the 1000 genomes database and is predicted to be benign. However, It rather appears to be a sporadic mutation, which is a very rarely observed phenomena. Such patients may respond well to mTOR inhibitors such as rapamycin, making prompt diagnosis and treatment crucial.https://www.epilepsia.su/jour/article/view/1152depdc5mtorgator1familial focal epilepsy with variable fociffevfmagnetic resonance imagerymrisudden unexplained death in epilepsysudepelectroencephalogrameegfocal cortical dysplasiafcd |
| spellingShingle | M. K.C. Diallo S. Mukesh L. Kapil R. Singla D. Tar S. N. Tammineedi E. Singer H. Chhayani K. Arumaithurai U. K. Patel R. Arora <i>DEPDC5</i> mutations in familial epilepsy syndrome: genetic insights and therapeutic approaches Эпилепсия и пароксизмальные состояния depdc5 mtor gator1 familial focal epilepsy with variable foci ffevf magnetic resonance imagery mri sudden unexplained death in epilepsy sudep electroencephalogram eeg focal cortical dysplasia fcd |
| title | <i>DEPDC5</i> mutations in familial epilepsy syndrome: genetic insights and therapeutic approaches |
| title_full | <i>DEPDC5</i> mutations in familial epilepsy syndrome: genetic insights and therapeutic approaches |
| title_fullStr | <i>DEPDC5</i> mutations in familial epilepsy syndrome: genetic insights and therapeutic approaches |
| title_full_unstemmed | <i>DEPDC5</i> mutations in familial epilepsy syndrome: genetic insights and therapeutic approaches |
| title_short | <i>DEPDC5</i> mutations in familial epilepsy syndrome: genetic insights and therapeutic approaches |
| title_sort | i depdc5 i mutations in familial epilepsy syndrome genetic insights and therapeutic approaches |
| topic | depdc5 mtor gator1 familial focal epilepsy with variable foci ffevf magnetic resonance imagery mri sudden unexplained death in epilepsy sudep electroencephalogram eeg focal cortical dysplasia fcd |
| url | https://www.epilepsia.su/jour/article/view/1152 |
| work_keys_str_mv | AT mkcdiallo idepdc5imutationsinfamilialepilepsysyndromegeneticinsightsandtherapeuticapproaches AT smukesh idepdc5imutationsinfamilialepilepsysyndromegeneticinsightsandtherapeuticapproaches AT lkapil idepdc5imutationsinfamilialepilepsysyndromegeneticinsightsandtherapeuticapproaches AT rsingla idepdc5imutationsinfamilialepilepsysyndromegeneticinsightsandtherapeuticapproaches AT dtar idepdc5imutationsinfamilialepilepsysyndromegeneticinsightsandtherapeuticapproaches AT sntammineedi idepdc5imutationsinfamilialepilepsysyndromegeneticinsightsandtherapeuticapproaches AT esinger idepdc5imutationsinfamilialepilepsysyndromegeneticinsightsandtherapeuticapproaches AT hchhayani idepdc5imutationsinfamilialepilepsysyndromegeneticinsightsandtherapeuticapproaches AT karumaithurai idepdc5imutationsinfamilialepilepsysyndromegeneticinsightsandtherapeuticapproaches AT ukpatel idepdc5imutationsinfamilialepilepsysyndromegeneticinsightsandtherapeuticapproaches AT rarora idepdc5imutationsinfamilialepilepsysyndromegeneticinsightsandtherapeuticapproaches |