. Author manuscript; available in PMC: 2023 Dec 27.

Published in final edited form as: Epileptic Disord. 2022 Oct 1;24(5):765–786. doi: 10.1684/epd.2022.1448

Table 5.

Examples of precision therapies based on genetic findings in epilepsy.

Genes	Proteins	Main pathophysiology	Potential precision treatment approaches	Evidence	Reference
ALDH7A1 PNPO PROSC	Aldehydedehydrogenase Pyridoxine phosphate oxidase Pyridoxine phosphate binding protein	Vitamin B6 deficiency	Supplementation with pyridoxine Supplementation with pyridoxal-5-phosphate	⁺	Mills et al., 2014 [69] Darin et al., 2016 [70]
CAD	Trifunctional protein (CPSase, ATCase, DHOase) in pyrimidine biosynthesis	Deficiency in pyrimidine biosynthesis	Supplementation with uridine	⁺	Koch et al., 2017 [71]
CHRNA4 CHRNB2 CHRNA2	Nicotinic acetylcholine receptor (AChR)	Desensitization of the nicotinic AChR	Nicotine	⁺	Fox et al., 2021 [72] Lossius et al., 2020 [73]
GRIN1 GRIN2A GRIN2B GRIN2D	Glutamate receptor (NMDAR)	GoF/LoF	Memantine, dextrometorphane, ketamine for GOF, Serine for LOF	⁺	Pierson et al., 2014 [74] Gale et al., 2021 [75] Amador et al., 2020 [76] Soto et al., 2019 [63] Krey et al., 2022 [64]
KCNA2	Voltage-gated K⁺ channel K_V1.2 (A-type)	Loss or gain of function (or a mixture of both)	4-aminopyridine for GOF or some GOF+LOF variants to reduce channel overactivity	⁺	Syrbe et al., 2015 [77] Hedrich et al., 2021 [78]
KCNQ2 KCNQ3	Voltage-gated K⁺ channels K_V7.2, K_V7.3 (M-type)	Loss or gain of function, depending on variant	Na⁺ channel blockers for LOF variants (indirect effect blocking increased neuronal firing induced by reduced activity of K⁺ channels); K_V7.2/K_V7.3 channel activators, such as ezogabine/retigabine	⁺	Pisano et al., 2015 [79] Sands et al., 2016 [80] Nissenkorn et al., 2021 [81] Orhan et al., 2014 [82] Millichap et al., 2016 [83] Vanoye et al., 2022 [84]
SCN1A SCN2A SCN8A	Voltage-gated Na⁺ channels Na_V1.1, Na_V1.2, Na_V1.6	LOF or GOF of Na⁺ channel function depending on individual variants	Na⁺ channel blockers for GOF (to reduce channel overactivity), avoid such drugs for LOF variants (which may enhance reduced channel activity)	⁺	Guerrini et al., 1998 [85] Wolff et al., 2017 [86] Johannesen et al., 2021 [43]
SLC2A1	Glucose transporter type 1 (GLUT1)	Reduced glucose transport across the blood-brain barrier	Ketogenic diet, providing ketone bodies as alternative fuel instead of glucose	⁺	Klepper et al., 2020 [87]
TSC1 TSC2	Hamartin, Tuberin	mTOR disinhibition	Everolimus, Sirolimus (mTOR inhibitor)	⁺⁺	French et al., 2016 [88]

⁺

: evidence from retrospective case series or clinical experiences from study groups

⁺⁺

: evidence from a controlled clinical trial; GoF: gain of function; LoF: loss of function; AChR: acetylcholine receptor; AMPAR: a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; mTOR : mechanistic target of rapamycin.