Epilepsy Syndromes in the First Year of Life and Usefulness of Genetic Testing for Precision Therapy
Abstract
:1. Introduction
2. Benign and Self-Limited (Familial) Epilepsy Syndromes in Infancy
2.1. Benign (Familial) Neonatal Epilepsy
2.2. Benign (Familial) Neonatal-Infantile Epilepsy
2.3. Benign (Familial) Infantile Epilepsy
2.4. GEFS+ Spectrum (Including Febrile Seizures Plus)
2.5. Myoclonic Epilepsy in Infancy
3. Developmental and Epileptic Encephalopathies (DEEs)
3.1. Ohtahara Syndrome
3.2. Early Myoclonic Encephalopathy
3.3. Epileptic Spasms Syndrome and West Syndrome
3.4. Dravet Syndrome (DS)
3.5. Epilepsy of Infancy with Migrating Focal Seizures (EIMFS)
4. Advantages and Pitfalls in Genetic Testing of Subjects with Onset of Epilepsy Syndromes during the First Year of Life
5. Utility of Early Genetic Testing for Precision Therapy Approaches
6. Genetic Testing in Self-Limiting Epilepsies
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Epilepsy Syndrome | Gene Involved | Protein Product | Mode of Inheritance | |
---|---|---|---|---|
Benign familial epilepsy syndromes | BFNE | KCNQ2 | Subunit of voltage-gated K+ channel | AD |
KCNQ3 | Subunit of voltage-gated K+ channel | AD | ||
BFNIE | SCN2A | Subunit of voltage-gated Na+ channel | AD | |
BFIE | PRRT2 | Protein-rich transmembrane protein 2 | AD | |
SCN2A | Subunit of voltage-gated Na+ channel | AD | ||
SCN8A | Subunit of voltage-gated Na+ channel | AD | ||
GEFS+ | SCN1A | Subunit of voltage-gated Na+ channel | AD | |
SCN1B | Subunit of voltage-gated Na+ channel | AD, AR | ||
GABRG2 | Subunit of GABAa receptor | AD | ||
STX1B | Syntaxin 1B | AD | ||
Myoclonic epilepsy in infancy | Unknown | - | - | |
Developmental and epileptic encephalopathies | Ohtahara syndrome | STXBP1 (in ~30%) | Syntaxin binding protein 1 | AD |
KCNQ2 (in ~20%) | Subunit of voltage-gated K+ channel | AD | ||
SCN2A (in ~10%) | Subunit of voltage-gated Na+ channel | AD | ||
GNAO1 | Guanine nucleotide-binding protein, α-activating activity polypeptide O | AD | ||
KCNT1 | Subunit of voltage-gated K+ channel | AD | ||
SNC8A | Subunit of voltage-gated NA+ channel | AD | ||
SIK1 | Salt-inducable kinase 1 | AD | ||
AARS | Alanyl-tRNA synthetase 1 | AR | ||
BRAT1 | BRACT1-associated atm activator 1 | AR | ||
CACNA2D2 | Calcium channel, voltage-dependent, α-2/delta subunit 2 | AR | ||
NECAP1 | NECAP endocytosis-associated protein 1 | AR | ||
PIGQ | Phosphatidylinositol glycan anchor biosynthesis class Q protein | AR | ||
SLC25A22 | Solute carrier family 25, member 22 | AR | ||
ARX | Aristaless-related homeobox | XR | ||
PIGA | Phosphatidylinositol glycan anchor biosynthesis class A protein | XR | ||
Early myoclonic encephalopathy | SETBP1 | SET-binding protein 1 | AD | |
SIK1 | Salt-inducable kinase 1 | AD | ||
SLC25A22 | Solute carrier family 25, member 22 | AR | ||
PIGA | Phosphatidylinositol glycan anchor biosynthesis class A protein | XR | ||
Infantile spasms syndrome (including WEST syndrome) | STXBP1 (in ~2%) | Syntaxin binding protein 1 | AD | |
CHD2 | Chromodomain helicase DNA-binding protein 2 | AD | ||
DNM1 | Dynamin 1 | AD | ||
FOXG1 (duplications) | Forkhead box G1 | AD | ||
GABRA1 | Subunit of GABAa receptor | AD | ||
GABRB3 | Subunit of GABAa receptor | AD | ||
GABRG2 | Subunit of GABAa receptor | AD | ||
GNAO1 | Guanine nucleotide-binding protein, α-activating activity polypeptide O | AD | ||
GRIN1 | Glutamate receptor, ionotropic, n-methyl-d-aspartate, subunit 1 | AD, AR | ||
GRIN2A, | Glutamate receptor, ionotropic, n-methyl-d-aspartate, subunit 2A | AD | ||
GRIN2B | Glutamate receptor, ionotropic, n-methyl-d-aspartate, subunit 2B | AD | ||
HCN1 | Hyperpolarization activated cyclic nucleotide gated potassium channel 1 | AD | ||
KCNA2 | Subunit of voltage-gated K+ channel | AD | ||
KCNT1 | Subunit of voltage-gated K+ channel | AD | ||
MAGI2 | Membrane-associated guanylate kinase, WW and PDZ domains-containing 2 | AD | ||
MEF2C | MADS BOX transcription enhancer factor 2, polypeptide C | AD | ||
NDP | Norrin cystine knot growth factor NDP | AD | ||
PTEN | Phosphatase and tensin homolog | AD | ||
SCA2 | Spinocerebellar ataxia 2 | AD | ||
SPTAN1 | Spectrin, α, non-erythrocytic 1 | AD | ||
SETBP1 | SET-binding protein 1 | AD | ||
SIK1 | Salt-inducable kinase 1 | AD | ||
SCN1A | Subunit of voltage-gated Na+ channel | AD | ||
SCN1B | Subunit of voltage-gated Na+ channel | AD, AR | ||
SCN2A | Subunit of voltage-gated Na+ channel | AD | ||
SCN8A | Subunit of voltage-gated Na+ channel | AD | ||
SCN9A | Subunit of voltage-gated Na+ channel | AD | ||
STXBP1 | Syntaxin binding protein 1 | AD | ||
TCF4 | Transcription factor 4 | AD | ||
TSC1 | Tuberous sclerosis complex 1 | AD | ||
TSC2 | Tuberous sclerosis complex 2 | AD | ||
DOCK7 | Dedicator of cytokinesis 7 | AR | ||
NRXN1 | Neurexin 1 | AR | ||
PIGN | Phosphatidylinositol glycan anchor biosynthesis class N protein | AR | ||
PIGP | Phosphatidylinositol glycan anchor biosynthesis class P protein | AR | ||
PIGQ | Phosphatidylinositol glycan anchor biosynthesis class Q protein | AR | ||
PIGS | Phosphatidylinositol glycan anchor biosynthesis class S protein | AR | ||
PLCB1 | Phospholipase C, β-1 | AR | ||
SLC25A22 | Solute carrier family 25, member 22 | AR | ||
ST3GAL3 | ST3 β-galactoside α-2,3-sialyltransferase 3 | AR | ||
TBC1D24 | TBC1 domain family, member 24 | AR | ||
WWOX | WW domain-containing oxidoreductase | AR | ||
CDKL5 | Cyclin-dependent kinase-like 5 | XD | ||
ARX | Aristaless-related homeobox | XR | ||
PIGA | Phosphatidylinositol glycan anchor biosynthesis class A protein | XR | ||
ALG13 | ALG13 UDP-N-acetylglucosaminyltransferase subunit | XL | ||
PCDH19 | Protocadherin subclass of the cadherin superfamily | XL | ||
Dravet/dravet-like phenotypes | SCN1A (in ~90%) | Subunit of voltage-gated Na+ channel | AD | |
CHD2 | Chromodomain helicase DNA-binding protein 2 | AD | ||
HCN1 * | Hyperpolarization activated cyclic nucleotide gated potassium channel 1 | AD | ||
GABRA1 | Subunit of GABAa receptor | AD | ||
GABRB3 | Subunit of GABAa receptor | AD | ||
GABRG2 | Subunit of GABAa receptor | AD | ||
KCNA2 | Subunit of voltage-gated K+ channel | AD | ||
SCN1B | Subunit of voltage-gated Na+ channel | AD, AR | ||
SCN2A | Subunit of voltage-gated Na+ channel | AD | ||
SCN8A | Subunit of voltage-gated Na+ channel | AD | ||
SCN9A | Subunit of voltage-gated Na+ channel | AD | ||
STXBP1 | Syntaxin binding protein 1 | AD | ||
PCDH19 * | Protocadherin subclass of the cadherin superfamily | XL | ||
EIMFS | KCNT1 (in ~27%) | Subunit of voltage-gated K+ channel | AD | |
SCN2A (in ~7%) | Subunit of voltage-gated Na+ channel | AD | ||
SCN1A | Subunit of voltage-gated Na+ channel | AD | ||
GABRA1 | Subunit of GABAa receptor | AD | ||
GABRB1 | Subunit of GABAa receptor | AD | ||
GABRB3 | Subunit of GABAa receptor | AD | ||
HCN1 | Hyperpolarization-activated cyclic nucleotide-gated potassium channel 1 | AD | ||
KCNQ2 | Subunit of voltage-gated K+ channel | AD | ||
SCN8A | Subunit of voltage-gated Na+ channel | AD | ||
ATP1A3 | ATPase, Na+/K+ transporting, α-3 polypeptide | AD | ||
AIMP1 | Aminoacyl-tRNA synthetase complex-interacting multifunctional protein 1 | AR | ||
BRAT1 | BRCA1-associated ATM activator 1 | AR | ||
ITPA | Inosine triphosphatase | AR | ||
KARS | Lysyl-tRNA synthetase 1 | AR | ||
PLCB1 | Phospholipase C, β-1 | AR | ||
QARS | Glutaminyl-tRNA synthetase 1 | AR | ||
SLC12A5 | Solute carrier family 12 | AR | ||
SLC25A22 | Solute carrier family 25, member 22 | AR | ||
TBC1D24 | TBC1 domain family, member 24 | AR | ||
WWOX | WW domain-containing oxidoreductase | AR | ||
CDKL5 | Cyclin-dependent kinase-like 5 | XD | ||
SMC1A | Structural maintenance of chromosomes 1A | XD | ||
PIGA | Phosphatidylinositol glycan anchor biosynthesis class A protein | XR |
Gene | Associated Epilepsy Syndromes | Associated with Structural Brain Anomalies/Lesions | Potential Therapeutic Approaches |
---|---|---|---|
ARX | Ohtahara syndrome | Yes | Currently none available |
Epileptic spasms syndrome | |||
Myoclonic epilepsy | |||
Nonsyndromic intellectual disability with or without epilepsy | |||
Developmental and epileptic encephalopathy 1 | |||
CDKL5 | Epileptic spasms syndrome | Yes | Ganaxolone (PMID 33165915) |
Developmental and epileptic encephalopathy 2 | |||
KCNA2 | Developmental and epileptic encephalopathy 32 | Yes | GoF: 4-Aminopyridine Sodium channel blockers (PMID 33515866) |
ESES | |||
KCNB1 | Developmental and epileptic encephalopathy 26 | Yes | Currently none available |
Epileptic spasms syndrome | |||
ESES | |||
KCNQ2 | Benign familial neonatal epilepsy | Yes | LoF: Sodium channel blockers (PMID 24371303 and 25880994) Retigabine (PMID 27602407) |
Ohtahara syndrome | |||
Neonatal epileptic encephalopathy | |||
EIMFS | |||
Developmental and epileptic encephalopathy 7 | |||
KCNQ3 | Benign familial neonatal epilepsy | Yes | LoF: Sodium channel blockers (PMID 27888506) Retigabine (PMID 27602407) |
KCNT1 | Autosomal dominant sleep-related hypermotor epilepsy | Yes | GoF: Quinidine (PMID 31054119) |
EIMFS | |||
Developmental and epileptic encephalopathy 14 | |||
PRRT2 | Benign familial infantile epilepsy | Yes | Carbamazepine (PMID 32413583) |
Infantile convulsion and choreoathetosis syndrome | |||
Paroxysmal kinesigenic dyskinesia | |||
SCN1A | Dravet syndrome | Yes | Lof: Stiripentol (+ valproate + clobazam) Fenfluramine Cannabidiol Avoid sodium channel blockers (PMID 32413583) |
Genetic epilepsy with febrile seizure plus | |||
EIMFS | |||
Developmental and epileptic encephalopathy 6 | |||
SCN2A | Benign familial neonatal infantile epilepsy | Yes | GoF: Sodium channel blockers (PMID 32413583) LoF: Avoid sodium channel blockers (PMID 32413583) |
Genetic epilepsy with febrile seizures plus | |||
Epileptic spasms syndrome | |||
EIMFS | |||
Ohtahara syndrome | |||
Developmental and epileptic encephalopathy 11 | |||
SCN8A | Benign familial neonatal infantile epilepsy | Yes | GoF: Sodium channel blockers (PMID 32413583) LoF: Avoid sodium channel blockers (PMID 32413583) |
Developmental and epileptic encephalopathy 13 | |||
STXBP1 | Ohtahara syndrome. | Yes | Levetiracetam may have superior effect on seizures and movement disorder (PMID 29896790). |
Epileptic spasms syndrome | |||
Nonsyndromic intellectual disability with or without epilepsy | |||
Developmental and epileptic encephalopathy 4 | |||
SLC25A22 | Ohtahara syndrome | Yes | Currently none available |
Early myoclonic epilepsy | |||
EIMFS | |||
Developmental and epileptic encephalopathy 3 | |||
TSC1 | Epileptic spasms syndrome | Yes | Everolimus and other mTOR inhibitors (PMID 27351628) |
TSC2 | Epileptic spasms syndrome | Yes | Everolimus and other mTOR inhibitors (PMID 27351628) |
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Bayat, A.; Bayat, M.; Rubboli, G.; Møller, R.S. Epilepsy Syndromes in the First Year of Life and Usefulness of Genetic Testing for Precision Therapy. Genes 2021, 12, 1051. https://doi.org/10.3390/genes12071051
Bayat A, Bayat M, Rubboli G, Møller RS. Epilepsy Syndromes in the First Year of Life and Usefulness of Genetic Testing for Precision Therapy. Genes. 2021; 12(7):1051. https://doi.org/10.3390/genes12071051
Chicago/Turabian StyleBayat, Allan, Michael Bayat, Guido Rubboli, and Rikke S. Møller. 2021. "Epilepsy Syndromes in the First Year of Life and Usefulness of Genetic Testing for Precision Therapy" Genes 12, no. 7: 1051. https://doi.org/10.3390/genes12071051