We collected the data of 33 affected individuals carrying 18 different novel HCN1 missense variants classified as pathogenic or likely pathogenic using the ACMG criteria, all absent from the GnomAD database (Fig. 1 and Supplementary Table 1). Overall, 14 different variants occurred de novo in 19 sporadic patients (Table 1). Four variants segregated with epilepsy in at least two affected family members of four families (Table 2). All 18 variants led to missense substitutions altering amino acids highly conserved in orthologues and/or paralogues (Supplementary Fig. 1). Five amino acid substitutions (Met153Ile, Met243Arg, Met305Leu, Gly391Ser and Gly391Asp) were each observed twice, Met305Leu and Met153Ile resulting from different nucleotides substitutions. Three different base changes altering glycine 391 (Gly391Ser, Gly391Cys and Gly391Asp) were observed in five patients.
Clinical and genetic summary of the 19 sporadic patients with de novo HCN1 variants
| Patient number . | Gender . | Age at the study . | Seizure onset . | Seizure type at onset . | Seizure type at follow-up . | Sensitivity to fever . | Seizure frequency . | Resistance to AEDs . | Development . | Epilepsy type/ syndromes . | Mutation . |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | F | 12 y 6 m | 12 m | TCS | TCS, At | No | Daily | Yes | Severe ID | EIEE | p.Phe143Tyr |
| 2 | F | 7 y 3 m | 5 m | FS | Fc, TCS | Yes | Weekly to daily | Yes | Mild ID | EIEE | p.Met153Ile |
| 3 | M | 2 y 8 m | 9 m | TCS | TCS, Fc | No | Weekly | Yes | Mild language delay | Uncl epilepsy infantile onset | p.Met153Ile |
| 4 | F | 42 y | 7 m | FS | FS, afebrile TC, Tn and absence | Yes | Last seizure at 20 y | No | Mild ID + autistic traits | GGE-TCS | p.Thr172Pro |
| 5 | F | 17 y | 13 m | FS | FS, afebrile TCS, absence | Yes | R | No | Moderate ID | FS+ | p.Met243Arg |
| 6 | F | 2 y 6 m | 10 m | FS (Tn) | FS | Yes | With fever | No | Normal | FS | p.Met243Arg |
| 7 | F | 2 y | 8 m | FS (Cl) | Cl Gen | Yes | Monthly | No | Normal | FS+ | p.Thr260Ile |
| 8 | M | 5 y 10 m | 9 m | Fc (Cl) | TCS | No | R | No | Normal, mild language delay | Uncl epilepsy infantile onset | p. Ser264Cys |
| 9 | F | 9 y | 42 m | Fc | Fc > TCS; My | No | Daily | Yes | Moderate ID | Childhood focal epilepsy | p.Ile275Thr |
| 10 | F | 12 m | 3 m | TCS | TCS | Yes | 4 m seizure-free | Yes | Mild DD | Uncl epilepsy infantile onset | p.Met305Leu |
| 11 | F | 14 y | 2 m | TCS | TCS, Tn, Fc, Cl | Yes | Monthly | Yes | Severe ID, microcephaly | EIEE | p.Met305Leu |
| 12 | M | Died at 14 m | 30 h | Tn asymmetric, prolonged | Tn asymmetric ± Cl, prolonged apnoea and cyanosis | No | Daily | Yes | Severe ID, microcephaly | NOEE (MMPSI) | p.Gly391Asp |
| 13 | M | Died at 15 m | 48 h | Tn asymmetric, prolonged | Similar but with cyanosis | No | Daily | Yes | Severe ID | NOEE | p.Gly391Asp |
| 14 | F | 6 y 3 m | 5 m | Prolonged FS (20 min) | FS; afebrile TCS: Fc (LOC, hypotonia, cyanosis, vomit) | Yes | Yearly | No | Normal | FS+ | p.Gly391Ser |
| 15 | M | 2 y 5 m | 7 m | HemiCl | Fc, TCS | Yes | Yearly | No | Mild ID | GEFS+ | p.Gly391Ser |
| 16 | F | 29 y | Infancy | Eyelid My | TCS, Fc, absence, My | NA | Monthly to weekly | Yes | Moderate ID, autistic traits | Gen epilepsy with eyelid My | p.Gly391Cys |
| 17 | M | 15 y | 5 m | Hypotonia and cyanosis few h after vaccination | MA; Fc (hypomotor with psychomotor arrest) TCS | Yes | Daily | Yes | Severe ID, autistic traits | EIEE | p.Ile397Leu |
| 18 | M | 7 y | 4 m | Prolonged FS | TCS, with apnoea | Yes | Daily | Yes | Severe ID | EIEE | p.Ser399Pro |
| 19 | M | 15 y | 72 m | Absence | absence + single TCS | No | Daily | Yes | Normal | CAE | p.Arg590Gln |
| Patient number . | Gender . | Age at the study . | Seizure onset . | Seizure type at onset . | Seizure type at follow-up . | Sensitivity to fever . | Seizure frequency . | Resistance to AEDs . | Development . | Epilepsy type/ syndromes . | Mutation . |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | F | 12 y 6 m | 12 m | TCS | TCS, At | No | Daily | Yes | Severe ID | EIEE | p.Phe143Tyr |
| 2 | F | 7 y 3 m | 5 m | FS | Fc, TCS | Yes | Weekly to daily | Yes | Mild ID | EIEE | p.Met153Ile |
| 3 | M | 2 y 8 m | 9 m | TCS | TCS, Fc | No | Weekly | Yes | Mild language delay | Uncl epilepsy infantile onset | p.Met153Ile |
| 4 | F | 42 y | 7 m | FS | FS, afebrile TC, Tn and absence | Yes | Last seizure at 20 y | No | Mild ID + autistic traits | GGE-TCS | p.Thr172Pro |
| 5 | F | 17 y | 13 m | FS | FS, afebrile TCS, absence | Yes | R | No | Moderate ID | FS+ | p.Met243Arg |
| 6 | F | 2 y 6 m | 10 m | FS (Tn) | FS | Yes | With fever | No | Normal | FS | p.Met243Arg |
| 7 | F | 2 y | 8 m | FS (Cl) | Cl Gen | Yes | Monthly | No | Normal | FS+ | p.Thr260Ile |
| 8 | M | 5 y 10 m | 9 m | Fc (Cl) | TCS | No | R | No | Normal, mild language delay | Uncl epilepsy infantile onset | p. Ser264Cys |
| 9 | F | 9 y | 42 m | Fc | Fc > TCS; My | No | Daily | Yes | Moderate ID | Childhood focal epilepsy | p.Ile275Thr |
| 10 | F | 12 m | 3 m | TCS | TCS | Yes | 4 m seizure-free | Yes | Mild DD | Uncl epilepsy infantile onset | p.Met305Leu |
| 11 | F | 14 y | 2 m | TCS | TCS, Tn, Fc, Cl | Yes | Monthly | Yes | Severe ID, microcephaly | EIEE | p.Met305Leu |
| 12 | M | Died at 14 m | 30 h | Tn asymmetric, prolonged | Tn asymmetric ± Cl, prolonged apnoea and cyanosis | No | Daily | Yes | Severe ID, microcephaly | NOEE (MMPSI) | p.Gly391Asp |
| 13 | M | Died at 15 m | 48 h | Tn asymmetric, prolonged | Similar but with cyanosis | No | Daily | Yes | Severe ID | NOEE | p.Gly391Asp |
| 14 | F | 6 y 3 m | 5 m | Prolonged FS (20 min) | FS; afebrile TCS: Fc (LOC, hypotonia, cyanosis, vomit) | Yes | Yearly | No | Normal | FS+ | p.Gly391Ser |
| 15 | M | 2 y 5 m | 7 m | HemiCl | Fc, TCS | Yes | Yearly | No | Mild ID | GEFS+ | p.Gly391Ser |
| 16 | F | 29 y | Infancy | Eyelid My | TCS, Fc, absence, My | NA | Monthly to weekly | Yes | Moderate ID, autistic traits | Gen epilepsy with eyelid My | p.Gly391Cys |
| 17 | M | 15 y | 5 m | Hypotonia and cyanosis few h after vaccination | MA; Fc (hypomotor with psychomotor arrest) TCS | Yes | Daily | Yes | Severe ID, autistic traits | EIEE | p.Ile397Leu |
| 18 | M | 7 y | 4 m | Prolonged FS | TCS, with apnoea | Yes | Daily | Yes | Severe ID | EIEE | p.Ser399Pro |
| 19 | M | 15 y | 72 m | Absence | absence + single TCS | No | Daily | Yes | Normal | CAE | p.Arg590Gln |
At = atonic; CAE = childhood absence epilepsy; Cl = clonic; DD = developmental delay; F = female; Fc = focal; FS = febrile seizures; FS+ febrile seizure plus; Gen = generalized; ID = intellectual disability; LOC = loss of consciousness; M = male; MA = myoclonic-atonic; My = myoclonic; NA = unavailable; NOEE = neonatal-onset epileptic encephalopathy; Tn = tonic; TCS = tonic-clonic seizure(s); Uncl = unclassified. Detailed clinical information, including Brain MRI, EEG findings and antiepileptic treatment is provided for Patients 1–19 in Supplementary Table 2.
Clinical and genetic summary of the 19 sporadic patients with de novo HCN1 variants
| Patient number . | Gender . | Age at the study . | Seizure onset . | Seizure type at onset . | Seizure type at follow-up . | Sensitivity to fever . | Seizure frequency . | Resistance to AEDs . | Development . | Epilepsy type/ syndromes . | Mutation . |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | F | 12 y 6 m | 12 m | TCS | TCS, At | No | Daily | Yes | Severe ID | EIEE | p.Phe143Tyr |
| 2 | F | 7 y 3 m | 5 m | FS | Fc, TCS | Yes | Weekly to daily | Yes | Mild ID | EIEE | p.Met153Ile |
| 3 | M | 2 y 8 m | 9 m | TCS | TCS, Fc | No | Weekly | Yes | Mild language delay | Uncl epilepsy infantile onset | p.Met153Ile |
| 4 | F | 42 y | 7 m | FS | FS, afebrile TC, Tn and absence | Yes | Last seizure at 20 y | No | Mild ID + autistic traits | GGE-TCS | p.Thr172Pro |
| 5 | F | 17 y | 13 m | FS | FS, afebrile TCS, absence | Yes | R | No | Moderate ID | FS+ | p.Met243Arg |
| 6 | F | 2 y 6 m | 10 m | FS (Tn) | FS | Yes | With fever | No | Normal | FS | p.Met243Arg |
| 7 | F | 2 y | 8 m | FS (Cl) | Cl Gen | Yes | Monthly | No | Normal | FS+ | p.Thr260Ile |
| 8 | M | 5 y 10 m | 9 m | Fc (Cl) | TCS | No | R | No | Normal, mild language delay | Uncl epilepsy infantile onset | p. Ser264Cys |
| 9 | F | 9 y | 42 m | Fc | Fc > TCS; My | No | Daily | Yes | Moderate ID | Childhood focal epilepsy | p.Ile275Thr |
| 10 | F | 12 m | 3 m | TCS | TCS | Yes | 4 m seizure-free | Yes | Mild DD | Uncl epilepsy infantile onset | p.Met305Leu |
| 11 | F | 14 y | 2 m | TCS | TCS, Tn, Fc, Cl | Yes | Monthly | Yes | Severe ID, microcephaly | EIEE | p.Met305Leu |
| 12 | M | Died at 14 m | 30 h | Tn asymmetric, prolonged | Tn asymmetric ± Cl, prolonged apnoea and cyanosis | No | Daily | Yes | Severe ID, microcephaly | NOEE (MMPSI) | p.Gly391Asp |
| 13 | M | Died at 15 m | 48 h | Tn asymmetric, prolonged | Similar but with cyanosis | No | Daily | Yes | Severe ID | NOEE | p.Gly391Asp |
| 14 | F | 6 y 3 m | 5 m | Prolonged FS (20 min) | FS; afebrile TCS: Fc (LOC, hypotonia, cyanosis, vomit) | Yes | Yearly | No | Normal | FS+ | p.Gly391Ser |
| 15 | M | 2 y 5 m | 7 m | HemiCl | Fc, TCS | Yes | Yearly | No | Mild ID | GEFS+ | p.Gly391Ser |
| 16 | F | 29 y | Infancy | Eyelid My | TCS, Fc, absence, My | NA | Monthly to weekly | Yes | Moderate ID, autistic traits | Gen epilepsy with eyelid My | p.Gly391Cys |
| 17 | M | 15 y | 5 m | Hypotonia and cyanosis few h after vaccination | MA; Fc (hypomotor with psychomotor arrest) TCS | Yes | Daily | Yes | Severe ID, autistic traits | EIEE | p.Ile397Leu |
| 18 | M | 7 y | 4 m | Prolonged FS | TCS, with apnoea | Yes | Daily | Yes | Severe ID | EIEE | p.Ser399Pro |
| 19 | M | 15 y | 72 m | Absence | absence + single TCS | No | Daily | Yes | Normal | CAE | p.Arg590Gln |
| Patient number . | Gender . | Age at the study . | Seizure onset . | Seizure type at onset . | Seizure type at follow-up . | Sensitivity to fever . | Seizure frequency . | Resistance to AEDs . | Development . | Epilepsy type/ syndromes . | Mutation . |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | F | 12 y 6 m | 12 m | TCS | TCS, At | No | Daily | Yes | Severe ID | EIEE | p.Phe143Tyr |
| 2 | F | 7 y 3 m | 5 m | FS | Fc, TCS | Yes | Weekly to daily | Yes | Mild ID | EIEE | p.Met153Ile |
| 3 | M | 2 y 8 m | 9 m | TCS | TCS, Fc | No | Weekly | Yes | Mild language delay | Uncl epilepsy infantile onset | p.Met153Ile |
| 4 | F | 42 y | 7 m | FS | FS, afebrile TC, Tn and absence | Yes | Last seizure at 20 y | No | Mild ID + autistic traits | GGE-TCS | p.Thr172Pro |
| 5 | F | 17 y | 13 m | FS | FS, afebrile TCS, absence | Yes | R | No | Moderate ID | FS+ | p.Met243Arg |
| 6 | F | 2 y 6 m | 10 m | FS (Tn) | FS | Yes | With fever | No | Normal | FS | p.Met243Arg |
| 7 | F | 2 y | 8 m | FS (Cl) | Cl Gen | Yes | Monthly | No | Normal | FS+ | p.Thr260Ile |
| 8 | M | 5 y 10 m | 9 m | Fc (Cl) | TCS | No | R | No | Normal, mild language delay | Uncl epilepsy infantile onset | p. Ser264Cys |
| 9 | F | 9 y | 42 m | Fc | Fc > TCS; My | No | Daily | Yes | Moderate ID | Childhood focal epilepsy | p.Ile275Thr |
| 10 | F | 12 m | 3 m | TCS | TCS | Yes | 4 m seizure-free | Yes | Mild DD | Uncl epilepsy infantile onset | p.Met305Leu |
| 11 | F | 14 y | 2 m | TCS | TCS, Tn, Fc, Cl | Yes | Monthly | Yes | Severe ID, microcephaly | EIEE | p.Met305Leu |
| 12 | M | Died at 14 m | 30 h | Tn asymmetric, prolonged | Tn asymmetric ± Cl, prolonged apnoea and cyanosis | No | Daily | Yes | Severe ID, microcephaly | NOEE (MMPSI) | p.Gly391Asp |
| 13 | M | Died at 15 m | 48 h | Tn asymmetric, prolonged | Similar but with cyanosis | No | Daily | Yes | Severe ID | NOEE | p.Gly391Asp |
| 14 | F | 6 y 3 m | 5 m | Prolonged FS (20 min) | FS; afebrile TCS: Fc (LOC, hypotonia, cyanosis, vomit) | Yes | Yearly | No | Normal | FS+ | p.Gly391Ser |
| 15 | M | 2 y 5 m | 7 m | HemiCl | Fc, TCS | Yes | Yearly | No | Mild ID | GEFS+ | p.Gly391Ser |
| 16 | F | 29 y | Infancy | Eyelid My | TCS, Fc, absence, My | NA | Monthly to weekly | Yes | Moderate ID, autistic traits | Gen epilepsy with eyelid My | p.Gly391Cys |
| 17 | M | 15 y | 5 m | Hypotonia and cyanosis few h after vaccination | MA; Fc (hypomotor with psychomotor arrest) TCS | Yes | Daily | Yes | Severe ID, autistic traits | EIEE | p.Ile397Leu |
| 18 | M | 7 y | 4 m | Prolonged FS | TCS, with apnoea | Yes | Daily | Yes | Severe ID | EIEE | p.Ser399Pro |
| 19 | M | 15 y | 72 m | Absence | absence + single TCS | No | Daily | Yes | Normal | CAE | p.Arg590Gln |
At = atonic; CAE = childhood absence epilepsy; Cl = clonic; DD = developmental delay; F = female; Fc = focal; FS = febrile seizures; FS+ febrile seizure plus; Gen = generalized; ID = intellectual disability; LOC = loss of consciousness; M = male; MA = myoclonic-atonic; My = myoclonic; NA = unavailable; NOEE = neonatal-onset epileptic encephalopathy; Tn = tonic; TCS = tonic-clonic seizure(s); Uncl = unclassified. Detailed clinical information, including Brain MRI, EEG findings and antiepileptic treatment is provided for Patients 1–19 in Supplementary Table 2.
Clinical and genetic summary of affected members of families with HCN1 variants
| Family/ patient number . | Gender . | Age at study . | Seizure onsset . | Seizure type . | Seizure at follow-up . | AEDs . | EEG . | Brain MRI . | Development . | Epilepsy type/ syndromes . | Mutation . |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Family T | |||||||||||
| 20 | M | 66 y | 8 m | FS and afebrile TCS | Seizure until age 6 y then single TCS in adult age | PB, currently no AEDs | Normal | NA | NA | GEFS+ | p.Thr171Arg |
| 21 | M | 32 y | 8 m | FS; TCS, possible focal onset >TCS | Seizure-free from age 12 y | PB + GVG + VPA currently no AEDs | Normal | Normal | Borderline | GEFS+ | |
| 22 | F | 21 y | 10 m | FS | FS and afebrile TCS, seizure-free for >3 y | VPA, ESM, currently no AEDs | GSW | Normal | Mild ID (TIQ = 50) | GEFS+ | |
| 23 | F | 21 y | 11 m | FS | FS and afebrile TCS, seizure-free for from 10 to 18 y | VPA | Normal | Normal | Mild ID (TIQ = 66) | GEFS+ | |
| Family M1 | |||||||||||
| 24 | F | 49 y | 3 m | FS, febrile, afebrile TCS | Seizure-free from age 12 y after CBZ | CBZ | NA | NA | Normal | GEFS+ | p.Cys329Ser |
| 25 | F | 29 y | 1 y | FS | Seizure-free after VPA | VPA | NA | NA | Normal | FS | |
| 26 | F | 6 y | 18 m | TCS without fever | Status epilepticus episode treated by PHT then seizure-free on VPA | VPA | Normal | Normal | Normal | GGE | |
| 27 | M | 23 y | 8 m | Febrile TCS | FS and afebrile seizure and absence from age 4 y; non-progressive action myoclonus from age 8 y; seizure-free after VPA | VPA | Normal | Normal | Mild ID (TIQ = 52; VIQ = 46; PIQ = 70) | GGE | |
| 28 | F | 20 y | 13 m | FS | Seizure-free with CBZ until 13 y; CBZ was suspended: seizure recurrence. Seizure-free after CBZ reintroduction | CBZ | Normal | Normal CT scan | Normal | GEFS+ | |
| Family M2 | |||||||||||
| 29 | F | 8 y | 18 m | FS, febrile and afebrile TCS | Seizure-free after VPA | VPA | Fast activity | Normal | Borderline (WIPPSI: IQ = 77) | GEFS+ | p.Val414Met |
| 30 | F | 5 y | 18 m | FS | Seizure-free | No AEDs | Rare focal PA, fast activity | Normal | Borderline (DQ Griffith scale = 70) | GEFS+ | |
| 31 | M | 59 y | 12 m | FS | Seizure-free | No AEDs | NA | NA | Normal | FS | |
| Family O | |||||||||||
| 32 | F | 7 y | 7 y | TCS | Seizure-free | VPA | GSW during IPS | Normal | Normal | GGE | p.Ser680Tyr |
| 33 | F | Unknown | Childhood | Absence | Absence and single TCS in childhood, then seizure-free | No AEDs | GSW | Normal | Normal | CAE |
| Family/ patient number . | Gender . | Age at study . | Seizure onsset . | Seizure type . | Seizure at follow-up . | AEDs . | EEG . | Brain MRI . | Development . | Epilepsy type/ syndromes . | Mutation . |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Family T | |||||||||||
| 20 | M | 66 y | 8 m | FS and afebrile TCS | Seizure until age 6 y then single TCS in adult age | PB, currently no AEDs | Normal | NA | NA | GEFS+ | p.Thr171Arg |
| 21 | M | 32 y | 8 m | FS; TCS, possible focal onset >TCS | Seizure-free from age 12 y | PB + GVG + VPA currently no AEDs | Normal | Normal | Borderline | GEFS+ | |
| 22 | F | 21 y | 10 m | FS | FS and afebrile TCS, seizure-free for >3 y | VPA, ESM, currently no AEDs | GSW | Normal | Mild ID (TIQ = 50) | GEFS+ | |
| 23 | F | 21 y | 11 m | FS | FS and afebrile TCS, seizure-free for from 10 to 18 y | VPA | Normal | Normal | Mild ID (TIQ = 66) | GEFS+ | |
| Family M1 | |||||||||||
| 24 | F | 49 y | 3 m | FS, febrile, afebrile TCS | Seizure-free from age 12 y after CBZ | CBZ | NA | NA | Normal | GEFS+ | p.Cys329Ser |
| 25 | F | 29 y | 1 y | FS | Seizure-free after VPA | VPA | NA | NA | Normal | FS | |
| 26 | F | 6 y | 18 m | TCS without fever | Status epilepticus episode treated by PHT then seizure-free on VPA | VPA | Normal | Normal | Normal | GGE | |
| 27 | M | 23 y | 8 m | Febrile TCS | FS and afebrile seizure and absence from age 4 y; non-progressive action myoclonus from age 8 y; seizure-free after VPA | VPA | Normal | Normal | Mild ID (TIQ = 52; VIQ = 46; PIQ = 70) | GGE | |
| 28 | F | 20 y | 13 m | FS | Seizure-free with CBZ until 13 y; CBZ was suspended: seizure recurrence. Seizure-free after CBZ reintroduction | CBZ | Normal | Normal CT scan | Normal | GEFS+ | |
| Family M2 | |||||||||||
| 29 | F | 8 y | 18 m | FS, febrile and afebrile TCS | Seizure-free after VPA | VPA | Fast activity | Normal | Borderline (WIPPSI: IQ = 77) | GEFS+ | p.Val414Met |
| 30 | F | 5 y | 18 m | FS | Seizure-free | No AEDs | Rare focal PA, fast activity | Normal | Borderline (DQ Griffith scale = 70) | GEFS+ | |
| 31 | M | 59 y | 12 m | FS | Seizure-free | No AEDs | NA | NA | Normal | FS | |
| Family O | |||||||||||
| 32 | F | 7 y | 7 y | TCS | Seizure-free | VPA | GSW during IPS | Normal | Normal | GGE | p.Ser680Tyr |
| 33 | F | Unknown | Childhood | Absence | Absence and single TCS in childhood, then seizure-free | No AEDs | GSW | Normal | Normal | CAE |
AED = anti-epileptic drug; CBZ = carbamazepine; DQ = developmental quotient; ESM = ethosuximide; F = female; FS = febrile seizure; FS+ = febrile seizure plus; GSW = generalized spike and wave; GVG = vigabatrin; ID = intellectual disability; IPS = intermittent photic stimulation; IQ = intellectual quotient; M = male; NA = unavailable; PA = paroxysmal activity; PB = phenobarbital; PHT = phenytoin; PIQ = performance intellectual quotient; TCS = tonic-clonic seizure(s); TIQ = full-scale intellectual quotient; WIPPSI = Wechsler preschool and primary scale of intelligence; VIQ = verbal intellectual quotient; VPA = sodium valproate.
Clinical and genetic summary of affected members of families with HCN1 variants
| Family/ patient number . | Gender . | Age at study . | Seizure onsset . | Seizure type . | Seizure at follow-up . | AEDs . | EEG . | Brain MRI . | Development . | Epilepsy type/ syndromes . | Mutation . |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Family T | |||||||||||
| 20 | M | 66 y | 8 m | FS and afebrile TCS | Seizure until age 6 y then single TCS in adult age | PB, currently no AEDs | Normal | NA | NA | GEFS+ | p.Thr171Arg |
| 21 | M | 32 y | 8 m | FS; TCS, possible focal onset >TCS | Seizure-free from age 12 y | PB + GVG + VPA currently no AEDs | Normal | Normal | Borderline | GEFS+ | |
| 22 | F | 21 y | 10 m | FS | FS and afebrile TCS, seizure-free for >3 y | VPA, ESM, currently no AEDs | GSW | Normal | Mild ID (TIQ = 50) | GEFS+ | |
| 23 | F | 21 y | 11 m | FS | FS and afebrile TCS, seizure-free for from 10 to 18 y | VPA | Normal | Normal | Mild ID (TIQ = 66) | GEFS+ | |
| Family M1 | |||||||||||
| 24 | F | 49 y | 3 m | FS, febrile, afebrile TCS | Seizure-free from age 12 y after CBZ | CBZ | NA | NA | Normal | GEFS+ | p.Cys329Ser |
| 25 | F | 29 y | 1 y | FS | Seizure-free after VPA | VPA | NA | NA | Normal | FS | |
| 26 | F | 6 y | 18 m | TCS without fever | Status epilepticus episode treated by PHT then seizure-free on VPA | VPA | Normal | Normal | Normal | GGE | |
| 27 | M | 23 y | 8 m | Febrile TCS | FS and afebrile seizure and absence from age 4 y; non-progressive action myoclonus from age 8 y; seizure-free after VPA | VPA | Normal | Normal | Mild ID (TIQ = 52; VIQ = 46; PIQ = 70) | GGE | |
| 28 | F | 20 y | 13 m | FS | Seizure-free with CBZ until 13 y; CBZ was suspended: seizure recurrence. Seizure-free after CBZ reintroduction | CBZ | Normal | Normal CT scan | Normal | GEFS+ | |
| Family M2 | |||||||||||
| 29 | F | 8 y | 18 m | FS, febrile and afebrile TCS | Seizure-free after VPA | VPA | Fast activity | Normal | Borderline (WIPPSI: IQ = 77) | GEFS+ | p.Val414Met |
| 30 | F | 5 y | 18 m | FS | Seizure-free | No AEDs | Rare focal PA, fast activity | Normal | Borderline (DQ Griffith scale = 70) | GEFS+ | |
| 31 | M | 59 y | 12 m | FS | Seizure-free | No AEDs | NA | NA | Normal | FS | |
| Family O | |||||||||||
| 32 | F | 7 y | 7 y | TCS | Seizure-free | VPA | GSW during IPS | Normal | Normal | GGE | p.Ser680Tyr |
| 33 | F | Unknown | Childhood | Absence | Absence and single TCS in childhood, then seizure-free | No AEDs | GSW | Normal | Normal | CAE |
| Family/ patient number . | Gender . | Age at study . | Seizure onsset . | Seizure type . | Seizure at follow-up . | AEDs . | EEG . | Brain MRI . | Development . | Epilepsy type/ syndromes . | Mutation . |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Family T | |||||||||||
| 20 | M | 66 y | 8 m | FS and afebrile TCS | Seizure until age 6 y then single TCS in adult age | PB, currently no AEDs | Normal | NA | NA | GEFS+ | p.Thr171Arg |
| 21 | M | 32 y | 8 m | FS; TCS, possible focal onset >TCS | Seizure-free from age 12 y | PB + GVG + VPA currently no AEDs | Normal | Normal | Borderline | GEFS+ | |
| 22 | F | 21 y | 10 m | FS | FS and afebrile TCS, seizure-free for >3 y | VPA, ESM, currently no AEDs | GSW | Normal | Mild ID (TIQ = 50) | GEFS+ | |
| 23 | F | 21 y | 11 m | FS | FS and afebrile TCS, seizure-free for from 10 to 18 y | VPA | Normal | Normal | Mild ID (TIQ = 66) | GEFS+ | |
| Family M1 | |||||||||||
| 24 | F | 49 y | 3 m | FS, febrile, afebrile TCS | Seizure-free from age 12 y after CBZ | CBZ | NA | NA | Normal | GEFS+ | p.Cys329Ser |
| 25 | F | 29 y | 1 y | FS | Seizure-free after VPA | VPA | NA | NA | Normal | FS | |
| 26 | F | 6 y | 18 m | TCS without fever | Status epilepticus episode treated by PHT then seizure-free on VPA | VPA | Normal | Normal | Normal | GGE | |
| 27 | M | 23 y | 8 m | Febrile TCS | FS and afebrile seizure and absence from age 4 y; non-progressive action myoclonus from age 8 y; seizure-free after VPA | VPA | Normal | Normal | Mild ID (TIQ = 52; VIQ = 46; PIQ = 70) | GGE | |
| 28 | F | 20 y | 13 m | FS | Seizure-free with CBZ until 13 y; CBZ was suspended: seizure recurrence. Seizure-free after CBZ reintroduction | CBZ | Normal | Normal CT scan | Normal | GEFS+ | |
| Family M2 | |||||||||||
| 29 | F | 8 y | 18 m | FS, febrile and afebrile TCS | Seizure-free after VPA | VPA | Fast activity | Normal | Borderline (WIPPSI: IQ = 77) | GEFS+ | p.Val414Met |
| 30 | F | 5 y | 18 m | FS | Seizure-free | No AEDs | Rare focal PA, fast activity | Normal | Borderline (DQ Griffith scale = 70) | GEFS+ | |
| 31 | M | 59 y | 12 m | FS | Seizure-free | No AEDs | NA | NA | Normal | FS | |
| Family O | |||||||||||
| 32 | F | 7 y | 7 y | TCS | Seizure-free | VPA | GSW during IPS | Normal | Normal | GGE | p.Ser680Tyr |
| 33 | F | Unknown | Childhood | Absence | Absence and single TCS in childhood, then seizure-free | No AEDs | GSW | Normal | Normal | CAE |
AED = anti-epileptic drug; CBZ = carbamazepine; DQ = developmental quotient; ESM = ethosuximide; F = female; FS = febrile seizure; FS+ = febrile seizure plus; GSW = generalized spike and wave; GVG = vigabatrin; ID = intellectual disability; IPS = intermittent photic stimulation; IQ = intellectual quotient; M = male; NA = unavailable; PA = paroxysmal activity; PB = phenobarbital; PHT = phenytoin; PIQ = performance intellectual quotient; TCS = tonic-clonic seizure(s); TIQ = full-scale intellectual quotient; WIPPSI = Wechsler preschool and primary scale of intelligence; VIQ = verbal intellectual quotient; VPA = sodium valproate.
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