Table 3.
List of the 23 patients where a PM strategy was tried and was not successful (<50% seizure reduction)
| Gene variant and details | Age at clinical diagnosis (years) | Age at genetic diagnosis (years) | No of ASMs tried before genetic diagnosis/other non-medical treatment | Changes of treatment following genetic diagnosis, and details of outcome | Age at last follow-up (years) | Diagnostic assessment following genetic diagnosis | Previous ASMs worsening seizure control |
| Heterozygous CHRNA4 (c.851C>T, p.Ser284Leu), likely pathogenic | 16 | 22 | 7 | Introduction of nicotine patches and zonisamide, both ineffective | 24 | None | None |
| Heterozygous CHRNA4 (c.868C>A, p.Leu290Met), uncertain significance | 24 | 24 | 7 | Introduction of galantamine, ineffective | 33 | None | None |
| Heterozygous KCNA2 (c.894G>T, p.Leu298Phe), likely pathogenic | 2 | 36 | 13 | Introduction of 4-aminopyridine, seizure deterioration | 41 | ECG | None |
| Heterozygous SCN1A (c.264+3 del), uncertain significance | 38 | 38 | 14 plus VNS | Withdrawal of carbamazepine, introduction of cannabidiol and zonisamide, ineffective | 51 | None | None |
| Heterozygous SCN1A (c.603-2A>G, p.(?)), pathogenic | 20 | 20 | 13 plus VNS | Withdrawal of carbamazepine, introduction of cannabidiol and stiripentol, seizure reduction <50% | 31 | None | Lamotrigine |
| Hterozygous SCN1A (c.1754dup), pathogenic | 29 | 25 | 10 | Withdrawal of carbamazepine, seizure control stable, improved cognition | 29 | ECG | None |
| Heterozygous SCN1A (c.2435C>T, p.Thr812Ile), uncertain significance | 15 | 15 | Five plus callosotomy and VNS | Withdrawal of phenytoin, seizure worsening | 20 | Unknown | Unknown |
| Heterozygous SCN1A (c.2834_2847del, p(Phe945Trpfs*47), pathogenic | 31 | 31 | 18 plus VNS | Withdrawal of carbamazepine, seizure reduction <50% | 38 | None | Lamotrigine |
| Heterozygous SCN1A (c.2836C>T, p.Arg946Cys), likely pathogenic | 17 | 17 | Eight plus KD and VNS | Withdrawal of lacosamide and re-introduction of valproate, ineffective | 18 | None | None |
| Heterozygous SCN1A (c.3797A>C, p.Glu1266Ala), likely pathogenic | 16 | 26 | Ten plus KD | Withdrawal of carbamazepine, introduction of valproate and cannabidiol, seizure reduction <50% | 38 | None | Lamotrigine |
| Heterozygous SCN1A (c.4205_4208del, p.Arg1402Metfs*9), pathogenic | 4 | 17 | 14 plus KD | Withdrawal of phenobarbitone, introduction of stiripentol and zonisamide, seizure reduction <50% | 29 | None | Carbamazepine, lamotrigine |
| Heterozygous SCN1A (c.4384T>C; p.Tyr1462His), likely pathogenic | 14 | 18 | 15 plus VNS | Introduction of clobazam, withdrawal of primidone and phenobarbitone, seizure control stable, cognition improvement | 39 | None | Lamotrigine, levetiracetam |
| Heterozygous SCN1A (c.4396_4372dupCTGT; p.Tyr1458Serfs), pathogenic | 27 | 28 | 9 | Withdrawal of oxcarbazepine, initial >50% seizure reduction but not sustained | 37 | None | None |
| Heterozygous SCN1A (c.4568T>C p.I1523T), likely pathogenic | 36 | 40 | 17 | Withdrawal of lamotrigine, introduction of stiripentol, ineffective | 47 | None | None |
| Heterozygous SCN1A (c.5092G>T, p.Glu1698*), likely pathogenic | 1 | 20 | Ten plus KD | Withdrawal of oxcarbazepine, introduction of stiripentol and cannabidiol, seizure reduction <50% | 25 | ECG | None |
| Heterozygous SCN1A (c.5468T>C, p.Met1823Thr), uncertain significance | Unknown | 54 | 12 | Withdrawal of oxcarbazepine, introduction of clobazam, seizure reduction <50% | 61 | None | Carbamazepine, phenytoin |
| Heterozygous SCN2A (c.4037T>A, p.Ile1346Asn), uncertain significance | 0.1 | 17 | Six plus KD | Introduction of carbamazepine, seizure reduction <50% | 23 | ECG | None |
| Heterozygous SCN2A (c.4949T>C, p.Leu1650Pro), likely pathogenic | 1 | 14 | 7 | Introduction of phenytoin, severe seizure deterioration | 19 | Cardiac assessment | None |
| Heterozygous SCN8A (c.2287A>G, p.I763V), likely pathogenic | 0.5 | 20 | 5 | Introduction of phenytoin, increased dose of carbamazepine, ineffective | 25 | None | None |
| Heterozygous SCN8A (c.2921C>G, p.Ala974Gly), pathogenic | 11 | 10 | 12 plus KD | Introduction of phenytoin, ineffective | 12 | Cardiac assessment | None |
| Heterozygous SLC2A1 (c.1437C>T, p.Pro479=), uncertain significance | 8 | 9 | Six plus KD | Introduction of KD, effective but not tolerated | 15 | None | None |
| Heterozygous TSC2 (c.3671_3674del, p.Asn1224Thrfs*100), pathogenic | 0.4 | Unknown | 8 | Introduction of everolimus, clinical deterioration including seizure worsening | 26 | Multidisciplinary assessment including neurological, renal and cardiac surveillance | None |
| Heterozygous TSC2 (c.4639_4642del, p.Val1547Cysfs*28), pathogenic | 1 | 28 | Nine plus cortical resection | Introduction of everolimus, ineffective | 32 | Multidisciplinary assessment including neurological, renal and cardiac surveillance | None |
ASM, antiseizure medication; KD, ketogenic diet; PM, precision medicine; VNS, vagus nerve stimulation.