Table 1.
Clinical and Molecular Findings in Individuals with Pathogenic SLC6A1 Mutations
| Individual | Age and Sex | Epilepsy Syndrome | cDNA Change, Protein Change, and Inheritance | GERP, CADD, PolyPhen-2, Grantham, and SIFT scores | Family History | Development prior to Seizure Onset | Age at Seizure Onset | Seizure Type at Onset | Development after Seizure Onset | Other Seizure Types | Age at Seizure Offset | EEG | Neuroimaging | Other Features | Medications |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Original Cohort of 569 Individuals with Epileptic Encephalopathy | |||||||||||||||
| 1 | 8 years, F | MAE | c.131G>A (p.Arg44Gln), de novo | 4.37, 35, 0.99 (damaging), 43, 1 (tolerated) | negative | delayed | 30 months | atonic drop attacks | plateaued, mild ID | atypical absences (onset 32 months) with blinking, myoclonic seizures (onset 2.5 years), | 4 years | posterior predominant 3.5–4 Hz GSW, bilateral occipital spike-wave on eye closure, no PPR, | delayed myelination | Manual stereotypies, autistic features, hypertelorism, broad short nasal tip | CZP and VPA stopped drop attacks, VPA ceased at 5 years of age |
| 2 | 16 years, F | MAE | c.889G>A (p.Gly297Arg), de novo | 4.8, 27.6, 0.37 (benign), 125, 0 (damaging) | father’s first cousin has absence seizures | isolated speech delay | 31 months | atonic drop attacks | regression at 4 years, severe ID | absences with eyelid myoclonias, myoclonic status, nonconvulsive status epilepticus | ongoing | 3 Hz GSW, GPSW, PPR | normal | Autistic features, moderately severe tremor, reluctant to use hands at 14 years, aggression, thoracic scoliosis | ∗VPA, LTG, ∗CLB, LEV, TPM, ∗ETX; 3.5 years seizure free on CLB before seizure recurrence |
| 3 | 10 years, F | MAE | c.1000G>C (p.Ala334Pro), maternally inh (9% mosaic) | 5.37, 34, 1.00 (damaging), 27, 0.04 (damaging) | maternal great aunt with visual auras, paternal great uncle with GTCS, bilateral family history of speech disorders | delayed | 12 months | drop attacks | moderate ID | absences with eyelid myoclonias, atonic drop attacks preceded by eyelid flutter, GTCS (onset 9 years) | ongoing; GTCS | 2.5–3 Hz GSW, no PPR | normal | hyperlaxity, lumbar lordosis | VPA, LTG, ∗LEV, ∗CZP, and ∗ETX stopped drop attacks; KD was effective but did not completely abolish seizures |
| 4 | 10 years, M | MAE at 4 years, evolving to aBECTs | c.1369_1370 delGG (p.Gly457Hisfs∗10), de novo | NA | negative | delayed | 3 years | myoclonic-atonic, atonic seizures | ID | absence, myoclonic seizures | 6 years | 2.5–3 Hz GSW, right centro-temporal region; CSWS on initial EEG, resolved | normal | autistic features, attention deficit hyperactivity | VPA and LEV, since 2012 only ∗LEV |
| Validation Cohort of 75 Individuals with MAE | |||||||||||||||
| 5 | 12 years, F | MAE | c.578G>A (p.Trp193∗), de novo | 4.86, 38, NA, NA, NA | negative | delayed | 38 months | myoclonic-atonic seizures | mild ID | absence, myoclonic seizures | 3 years and 7 months | GSW, GPSW, PPR | normal | autistic features (mild) | VPA, ETX, ∗CLZ |
| 6 | 22 years, F | MAE | c.863C>T (p.Ala288Val), inh from affected mother | 4.98, 29.7, 1.00 (damaging), 64, 0 (damaging) | mother has MAE | delayed | 14 months | myoclonic-atonic drop attacks | regression from 2 years, moderate ID | absences, absences with eyelid myoclonias, GTCS rare | ongoing; catamenial GTCS, daily absences, myoclonic-atonic seizures | .5–4 Hz GSW, PSW, atypical absences on IPS with PPR and on HV; slow background with excessive beta (drug-related) | normal | autistic features, pyramidal signs, ataxia, tremor, dyslalia, dysarthria | VPA, CBZ, LTG, CZP, CLB, LEV, TPM, ETX; benzodiazepines indispensable; CZP and CLB |
| 7 (mother) | 44 years, F | MAE | c.863C>T, (p.Ala288Val), de novo | as above | negative | delayed | 12 months | one febrile seizure, myoclonic-atonic seizures | regression at puberty, moderate ID | absences, absences with eyelid myoclonias, GTCS (increase with age) | ongoing; catamenial GTCS, daily absences, myoclonic-atonic seizures | 2.5–4.5 Hz GSW, PSW, IPS with PPR; HV provoked subclinical paroxysms | normal | oppositional behaviors (mild) | VPA, LTG, LEV, CZP, TPM |
| Novel 3p25.3 Microdeletion | |||||||||||||||
| 3p25.3 deletion | 7 years, F | MAE | deletion includes SLC6A11 and exon 1 of SLC6A1, de novo | NA | negative | delayed | 3 years | atonic drop attacks | moderate ID | absences with eyelid myoclonia | ongoing | GSW, bilateral, posterior high-voltage activity | normal | hypotonia, autistic traits, absent speech | VPA |
| Previously Published Whole-Exome Sequencing Study Cases | |||||||||||||||
| Rauch, 2012 (ZH50743) | 12 years, F | NA (cohort of individuals with ID) | c.452 delT (p.Leu151Argfs∗35), de novo | NA | negative, Italian origin | delayed speech (48 months) and walking (26 months) | 5.5 years | myoclonic-astatic seizures | moderate ID (IQ < 50) | NA | NA | NA | MRI at 5 years showed mild cerebellar atrophy | autistic features, repetitive behavior, aggression, short attention span, flat and long face, large upper incisors, prognathism, | NA |
| Sanders, 2012 (13832.p1) | NA, M | NA (cohort of individuals with autism spectrum disorders) | c. 863C>T (p.Ala288Val), de novo | 4.55, NA, 1.00 (probably damaging), 64, 0.02 (damaging) | NA | NA | 1.5 years | petit mal (absence) | delayed speech, then regression with loss of speech | NA | ongoing | abnormal at 2 years | MRI normal at 3 years | autism, attention deficit disorder | ADD medications, AEDs, mood stabilizers |
Mutation coordinates based on SLC6A1: NM_003042.3 and protein NP_003033.3
Genome evolutionary rate profiling (GERP) scores range from least (−12.3) to most highly (6.17) conserved residues. Combined annotation dependent depletion (CADD) Phred-scaled scores range 0–99. All PolyPhen-2 scores were calculated under the HumVar model for Mendelian disorders and ranged from 0–1, where 1 is most likely to be damaging. Grantham scores ranged from 0–215 where 215 is predicted to be most damaging. Sorting intolerant from tolerant (SIFT) scores ranged from 0–1, where 0 is predicted to be most damaging. Abbreviations are as follows: inh, inherited; F, female; M, male; aBECTS, atypical benign epilepsy with centro-temporal spikes; CSWS, continuous spike-wave discharges during slow sleep; MAE, myoclonic-atonic epilepsy; ID, intellectual disability; IPS, intermittent photic stimulation; ADD, attention deficit disorder; GTCS, generalized tonic-clonic seizures; AED, anti-epileptic drug; GSW, generalized spike wave; PSW, polyspike wave; PPR, photo-paroxysmal response; HV, hyperventilation; NA, not available; VPA, sodium valproate; LTG, lamotrigine; CLB, clobazam; CBZ, carbamazepine; LEV, levetiracetam; TPM, topiramate; ETX, ethosuxamide; KD, ketogenic diet; CZP, clonazepam. ∗current medication