TABLE 1.
Clinical characteristics of SLC6A1 variant carriers
| Patient no. | Gender/ age at inclusion |
Family history |
Cognition before epilepsy onset |
Age at epilepsy onset |
Seizure type | EEG | Epilepsy syn- drome at diagnosis |
Cognition after seizure onset |
Behavioral problems |
Neurological findings |
Effective AED | Mutation |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | F/6 y | None | NA | 5 mo | Atypical absences atonic, eyelid myoclonia | BG slowing bilat. occipital +/− generalized epileptic discharges | EOAE (atypical form) | Moderate ID | NA | Hypotonia | Sz free on VPA + CLZ | c.104dupA p.Lys36GluFsTer171 de novo |
| 2 | M/13 y | Father has spastic paraparesis (SP) | Mild ID | 4 y | Absences (up to 100/day) | Generalized atypical SW | Unclassified generalized | Mild ID | None | Mild walking difficulties related to the SP inherited from his father | VPA (partially effective), sz free with VPA + LTG | c.223G>A p.Gly75Arg de novo |
| 3 | F/17 y | None | Speech delay | 2 y | Myoclonic atonic, myoclonic, absences, nonconvulsive status | Generalized epileptiform activity | MAE | Mild to moderate ID | None | Normal | Sz free | c.419A>G p.Tyr140Cys de novo |
| 4 | F/28 mo | None | — | — | None | NA (referred as normal) | — | Mild ID | Autism, irritability | Mild hypotonia, ataxia, chorea | — | c.434C>T p.Ser145Phe de novo |
| 5 Prev.publ. in Carvill et al.9 | F/12 y | None | Mild ID | 3 y, 2 mo | Absences, myoclonic atonic | BG slowing generalized SW (3 y, 6 mo) –> normal (4 y) | MAE- | Mild ID | Mild autistic traits | Normal | ESM, CBZ (partially effective), sz free with VPA | c.578G>A p.Thp193Ter de novo |
| 6 | M/10 y | None | Mild ID | 2 y | Atypical absences (at onset) | Centrotemporal spikes (at evolution) Extreme activation during NREM sleep (7 y) |
MAE evolving to aBECTS with an ESES-like pattem | Mild ID | None | Normal | NA | c.695G>T, p.Gly232Val de novo |
| 7 Family 1, proband | M/17 y | Yes | NA | 1 y | Absences, atonic | BG slowing Generalized SW (3 Hz) |
MAE | Moderate ID | None | Mild ataxia | VPA, ESM, LTG (partially effective) | c.695G>T p.Gly232Val maternal |
| 8 Family 1, brother | F/10 y | Yes | Normal | 13 mo | Absences, atonic | BG slowing Generalized SW/poly-SW |
MAE | Mild ID | None | Normal | Sz free with ESM | c.695G>T p.Gly232Val maternal |
| 9 Family 1, mother | F/NA | NA | — | — | None | NA | — | Learning disabilities | None | NA | — | c.695G>T p.Gly232Val |
| 10 | M/7 y | None | Speech delay | 18 mo | Atypical absences | Occipital notched rhythmic delta SW (2–2.5 Hz) |
Unclassified generalized | Mild ID | ADHD, irritability | Normal | TPM, VPA (partially effective) | c.809T>C p.Phe270Ser de novo |
| 11 | M/8 y | None | Mild ID | 22 mo | Absences, atonic, myoclonic | generalized SW (3 Hz) | MAE | Mild ID | None | Normal | Sz free with VPA, LTG | C.863C>T p.Ala288Val de novo |
| 12 | F/7 y | Psychiatric disease | NA | 5 y | Focal (at onset), absences (at evolution) | Initially centrotemporal spikes → generalized SW | Initially BECTs-like → unclassified generalized | Moderate to severe ID | Autistic features, aggressive behaviors, stereotypies | Normal | LTG (partially effective) | C.863C>T p.Ala288Val unknown |
| 13 | M/12 y | None | Mild ID | 18 mo | Atypical absences atonic, Myoclonic | BG slowing Generalized SW |
MAE | Moderate ID | Attention deficit | Mild ataxia | Sz free with LTG + ESM | c.881_883del p.Phe294del de novo |
| 14 | F/11 y | None | Mild ID | 5.5 y | Falls (seizure type not specified) | BG slowing Generalized slow waves and SW |
MAE | Mild ID | Hyperkinetic, aggressive behaviors, excess, smiling | Normal | Sz free with VPA | С.987C>А p.Cys329Ter de novo |
| 15 Family 2, proband | M/19 y | Yes | Normal | 2 y | Atypical absences Atonic, GTCS | BG slowing Generalized SW Multifocal spikes |
MAE | Severe ID | Attention deficit | Tremor | VPA + ESM (partially effective) | c.1024G>A p.Val342Met paternal |
| 16 Family 2, brother | M/12 y | Yes | Mild ID | 15 mo | Atypical absences, atonic, myoclonic atonic | BG slowing Generalized SW Multifocal spikes |
MAE | Moderate ID | Autistic features, aggressive behaviors | Mild hypotonia | Sz free with ESM+ZSM | c.1024G>A p.Val342Met paternal |
| 17 Family 2, brother | M/28 y | Yes- | Normal | childhood | Absences, GTCS | Generalized SW (3 Hz) | CAE | Normal | NA | Normal | VPA (partially effective) | c,1024G>A p.Val342Met paternal |
| 18 Family 2, sister | F/NA | Yes | — | — | None | NA | — | Mild ID | None | Normal | — | c.1024G>A p.Val342Met paternal |
| 19 Family 2, father | M/NA | None | NA | 3 y | Absences | NA | Unclassified generalized | Learning disability | NA | NA | Treated with ESM till age of 17 y, now sz free | c,1024G>A p.Val342Met de novo |
| 20 | M/8 y | None | Moderate ID | 5 y | Atypical absences | Generalized SW (3 Hz) | Unclassified generalized | Moderate ID | Rigidness, autism, stereotypies | NA | Sz free with VPA | c.1024G>A p.Val342Met de novo |
| 21 | F/5 y | None | Moderate ID | 2 y | Absences, atonic, myoclonic | Generalized SW and poly-SW (2.5–3.5 Hz) | MAE | Moderate ID | Mood swings, ADHD | Verbal dyspraxia, weak fine motor skills | NA | c,1024G>A p.Val342Met de novo |
| 22 | F/10 | Autism, mother’s side | Mild ID | 13 mo | Eyelid myoclonia, absences | GSW and 3 Hz runs with occipital spikes; high voltage notched delta esp occipital. | Eyelid myoclonia with absences | Moderate ID | Autism spectrum | Ataxia | Sz free with VPA | c.l024G>A p.Val342Met de novo |
| 23 | F/9 y | None | Moderate ID | 11 mo | Atypical absences, atonic | Generalized delta activity and SW SW left occipital Spikes/SW left centrotemporal |
MAE | Mild ID | Hand stereotypies | Microcephaly Unsteady gait | Sz free with LEV + LTG | C.1070C>T p.Ala357Val de novo |
| 24 | F/21 y | NA | Mild ID | 7 y | Focal, GTCS | Spikes left frontotemporal Generalized SW and generalized 3–4 Hz activity on HV |
TLE | Moderate ID | None | NA | NA | c.1084g>a p.Gly362Arg unknown |
| 25 Prev.publ. in Hal vors en et al.8 | M/NA | None | NA | 1 y | Atypical absences, Atonic, GTCS | Mild BG slowing 2 Hz generalized poly-SW | Lennox-Gastaut syndrome | Moderate ID | None | NA | None effective, VNS not effective | c.1084G>A p.Gly362Arg from mosaic mother |
| 26 | M/10 y | None | Normal | 15 mo | Myoclonic atonic, myoclonic | 3–4 second spike and wave complexes over posterior third of head provoked by eye closure and complete darkness | MAE | Mild ID | Autistic spectrum disorder | Broad based gait | Sz free with LEV | C.1155C>G p.Phe385Leu de novo |
| 27 | F/10 y | None | Moderate ID | 3 y | Atonic, myoclonic, tonic/myoclonic | Generalized and lateralized (L or R) delta activity and SW | MAE | Moderate ID (nonverbal) | Autism, self-stim behavior, bruxism, rep. night waking | Brisk reflexes, unsteady gait (walked at 3.75 y) | Sz free with CLZ | c.1342A>T p.Lys448Ter de novo |
| 28 Prev.publ. in Carvill et al.9 | M/12 y | NA | Mild ID | 3 y | Absences, atonic, myoclonic atonic → perioral myoclonia mainly during sleep, rare GTCS | Generalized poly-SW (at onset) Centrotemporal spikes (at evolution) Extreme activation during NREM sleep Now normal |
MAE → aBECTs + ESES-like | Mild ID | None | Unsteady gait/balance problems | Sz free with LEV | c.1369_1370 delGG Gly457HisFsTer10 de novo |
| 29 | F/13 y | None | Severe ID | 5 y | Absences | Generalized spikes/poly spikes | Unclassified generalized | Severe ID (almost nonverbal) | Aggressive behaviors, stereotypies | Normal (walked at 2 y) | Sz free with VPA | C.1377C>G p.Ser459Arg de novo |
| 30 | M/5 y | None | Normal | 1 y | Atypical absences | BG slowing Bursts of irregular, diffuse spike and wave activity followed by diffuse delta Stereotyped focal spikes |
Unclassified generalized | Mild ID (verbal) | ADHD | Normal | Sz improved with VPA/LTG | C.1531G>A p.Val511Met de novo |
| 31 | F/5 y | None | Mild ID | 2 y | Atypical absences, atonic, myoclonic, eyelid myoclonia | BG slowing Bi occipital delta activity Generalized SW |
MAE | Mild ID | ADD | Mild ataxia, dyskinesia | Sz free with ESM, LTG | C.1600C>T p.Gln534Ter de novo |
| 32 | F/4 y | NA | Normal | 16 mo | Absences, atonic, myoclonic atonic | Generalized delta activity and SW (posterior prev.) | MAE | Mild ID | NA | Mild fine motor delay | Sz free with LEV + VPA | c.850-2A>G de novo |
| 33 | F/12 y | Sister with a 22ql3 deletion | NA | 6 y | Absences | SW (3 Hz) Rare bifrontal spikes |
CAE | Mild ID | NA | Action tremor | Sz free with VPA | c.6,1528-1G>C de novo |
| 34 Prev.publ. in Carvill et al.9 | F/7 y | None | NA | 3 y | Absences, myoclonic atonic | BG slowing Generalized delta activity and SW |
MAE | Mild/moderate ID | None | Normal | Sz free with VPA, LEV | 3p25.3 del. including SLC6A11 and SLC6A1 (exon 1) de novo |
Prev.publ., previously published; aBECTs, atypical benign childhood epilepsy with centrotemporal spikes; Ab, absence seizures; A, atonic seizures; AA, atypical absence seizures; ADD, attention deficit disorder; ADHD, attention-deficit/hyperactivity disorder; BG, background; CAE, childhood absence epilepsy; CLZ, clonazepam; ESES, electrical status epilepticus during sleep; rep., repeated; ESM, ethosuximide; EOAE, early onset absence epilepsy; F, female; GTC, generalized tonic–clonic; ID, intellectual disability; LEV, levetiracetam; LTG, lamotrigine; MAE, myoclonic atonic epilepsy; M, Male; m, months; NA, not available; NREM, non–rapid eye movement; Sz, seizure; SW, spike wave; TPM, topiramate; VPA, valproic acid; VNS, vagus nerve stimulation; y, years; ZSM, zonisamide; del., deletion.