Table S2.
Clinical and EEG data
| RR | Sex | Genotype | Onset myoclonic seizures | Onset GTCS | Clinical photosensitivity | Neurologic examination | Brain imaging | CSF | Neurometabolic screen | Ictal EEG findings | Interictal EEG findings | EEG with ILS | Outcome (observation time) |
| Case 1 | F | dd | 18 mo | — | No | Spinal pain | T1 and T2 hypointensity in the transition area of the frontal lobe and the olfactory bulb (MRI) | WNL | WNL | No myoclonic jerks during recording* | WNL | — | Alive |
| Case 2 | F | dd | 17 mo | 1 y 11 mo | No | PL proprioceptive deficits, mild lumbosacral pain | WNL (MRI) | WNL† | Serum alanine elevated | Generalized 4–5 Hz SWC, at times epileptogenic discharges precede the myoclonic jerks | Generalized 4–5 Hz SWC | — | Dead (killed because of poor seizure control; nercropsy WNL) (7 mo) |
| Case 3 | M | — | 7 mo | — | — | WNL | WNL (CT) | WNL | Results not available, reported WNL | —‡ | — | — | Dead (unknown reason) (3 mo) |
| Case 4 | M | dd | 10 wk | — | No | Abraded claws of all limbs | Asymmetric lateral ventricles§ (CT) | WNL | WNL | Generalized 4 Hz SWC with anterior maximum, at times preceded by 5 Hz slowing, at times polyspikes | Generalized 4 Hz SWC with anterior maximum | — | Alive (6 y 11 mo) |
| Case 5 | M | — | 3 mo | 1 y 5 mo | No | Inconsistent menace OS | Asymmetric lateral ventricles§ (CT, MRI) | WNL | — | —‡ | — | — | Dead (ana-plasmosis, AIHA, ARF) (2 y 5 mo) |
| Case 6 | M | dd | 5 mo | 8 mo | No | WNL | — | WNL | WNL | Myoclonic jerks without clear EEG correlate¶ | WNL | — | Dead (ruptured splenic tumor) (4 y) |
| Case 7 | F | — | 11 mo | 1 y 5 mo | No | WNL | WNL (MRI) | WNL | — | —‡ | — | — | Dead (foreign body, renal tumor) (5 y 5 mo) |
| Case 8 | F | — | 10 wk | — | Yes | WNL | WNL (MRI) | WNL | WNL | —‡ | — | — | Dead (killed due to poor seizure control) (5 y) |
| Case 9 | F | dd | 10 wk | — | Yes | WNL | — | — | — | Right side dominant (C4, T4, F8, Cz, C3) 5–6 Hz biphasic spikes that approach a 4–5 Hz SWC morphology at points; events generalize, occasionally with a time lag, and often with independent spikes occurring at different channels | Right side dominant spikes and 4–5 Hz SWC (C4, T4, F8, Cz, C3), at times spikes in C4/T4 and C3 do not generalize | — | Alive (8 y 9 mo) |
| Case 10 | M | dd | 10 wk | — | Yes | WNL | — | — | — | Single spikes or polyspikes | Single spikes with anterior maximum | — | Alive (8 y 9 mo) |
| Case 11 | F | dd | 14 mo | — | Yes | WNL | — | — | WNL | 4–5 Hz (occasionally 3 Hz) generalized SWC with anterior maximum, at times preceded by 4 Hz slowing, bursts of 7–8 Hz polyspikes | Generalized 4 Hz SWC with anterior maximum | — | Alive (4 y 4 mo) |
| Case 12 | M | dd | 9 wk | 2 y 7 m | No | WNL | — | — | Smear in urinary organic acids (qualitative analysis) | Singlet or douplet SW | WNL | — | Alive (5 y 11 mo) |
| Case 13 | M | dd | 3 mo | 4.5 m | Yes | WNL | Lateral ventricle asymmetry§ and mild meningeal contrast enhancement (MRI) | WNL | WNL | Generalized 4–5 Hz SWC with anterior maximum, at times SW or slowing precede the myoclonic jerks | Generalized 4 Hz SWC with anterior maximum | Photoconvulsive responses with 4 Hz generalized SWC (stimulation frequencies 8–14 Hz) | Alive (1 y 8 mo) |
| Case 14 | M | — | 6 mo | — | No | WNL | WNL (CT) | WNL | — | —‡ | — | — | Dead (killed because of poor seizure control) (3 mo) |
| Case 15 | M | dd | 8 mo | — | No | WNL | WNL (MRI) | WNL | — | Generalized 4 Hz SWC or single spikes, central maximum, at times switching side, at times jerks are preceded by a crescendo of epileptogenic discharges, occasionally myoclonic jerks without clear EEG correlated | Generalized 4 Hz SWC or single spikes, central maximum, at times switching side | — | Alive (1 y 4 mo) |
| Case 16 | M | dd | 11 mo | — | No | WNL | WNL (CT) | WNL | — | —‡ | — | — | Alive (9 y 2 mo) |
| Case 17 | M | dd | 6 mo | — | No | WNL | WNL (MRI) | WNL | — | Single spikes, occasionally myoclonic jerks without clear EEG correlate‖ | Single spikes | — | Alive (1 y 2 mo) |
| Case 18 | F | dd | 6 mo | 8 mo | no | WNL | Slight reduction of brain volume (MRI)** | WNL | WNL†† | —‡‡ | — | — | Alive (1 y 4 mo) |
| Case 19 | M | dd | 6 wk | 7 mo | No | WNL | WNL (MRI) | WNL | — | Irregular generalized 4 Hz SWC, generalized 4 Hz slowing with anterior maximum switching between different leads, at times emerging into SWC, occasionally myoclonic jerks without clear EEG correlated | Irregular generalized 4 Hz SWC with anterior maximum switching between different leads, generalized 4 Hz slowing, at times emerging into SWC | — | Alive (1 y 2 mo) |
| Case 20 | M | dd | 8 wk | 8 mo | Yes | WNL | — | — | — | Single spikes and SW | Single spikes and SW | Photoconvulsive responses with 4 Hz generalized SWC with occipital maximum (stimulation frequencies 6–17 Hz) | Alive (6 mo) |
| Case 21 | F | dd | 4 mo | — | No | WNL | — | — | — | Single spikes | WNL | No PPR | Alive (4 mo) |
| Case 22 | F | dd | 10 wk | — | No | WNL | — | — | — | No myoclonic jerks during recordingi | WNL | No PPR | Alive (5 mo) |
| Case 23 | M | dd | 10 wk | — | Yes | WNL | WNL (CT, MRI) | WNL | — | Polyspikes and SW | WNL | Photoconvulsive responses with 4 Hz generalized SWC with occipital maximum (stimulation frequencies 3–4 Hz) | Alive (5 mo) |
| Case 24 | M | dd | 8 wk | — | Yes | WNL | WNL (CT, MRI) | WNL | — | No myoclonic jerks during recording without activation procedures* | No epilepto-genic discharges during recording without activation procedures | Photoconvulsive responses with 4 Hz generalized SWC with occipital maximum (stimulation frequencies 6–10 Hz) | Alive (10 mo) |
| Control 1 | F | DD | — | — | — | WNL | — | — | — | — | WNL | — | Alive (5 y 1 mo) |
| Control 2 | M | Dd | — | — | — | WNL | — | — | WNL | — | WNL | — | Alive (9 y 2 mo) |
| Control 3 | M | DD | — | — | — | WNL | — | — | — | — | WNL | — | Alive (5 y) |
| Control 4 | M | DD | — | — | — | WNL | — | — | — | — | WNL | — | Alive (9 y 9 mo) |
| Control 5 | F | DD | — | — | — | WNL | — | — | — | — | WNL | — | Alive (7 y 3 mo) |
| Control 6 | F | — | — | — | — | WNL | — | — | — | — | WNL | — | Alive (8 y 10 mo) |
| Control 7 | M | — | — | — | — | WNL | — | — | — | — | WNL | No PPR | Alive (4 y 4 mo) |
| Control 8 | F | Dd | — | — | — | WNL | — | — | — | — | WNL | No PPR | Alive (3 y 10 mo) |
| Control 9 | F | Dd | — | — | — | WNL | — | — | — | — | WNL | No PPR | Alive (3 y 10 mo) |
| Control 10 | F | Dd | — | — | — | WNL | — | — | — | — | WNL | No PPR | Alive (2 y 1 mo) |
| Control 11 | M | DD | — | 1 y 10 m | No | WNL | WNL (MRI) | WNL | — | — | WNL | — | Alive (2 y 10 mo) |
Summary of all clinical and EEG data of generalized myoclonic epilepsy in 24 RR dogs (cohort used for clinical characterization). AIHA, autoimmune hemolytic anemia; ARF, acute renal failure; CT, computed tomographic imaging; DD, wild-type genotype; Dd, heterozygous DIRAS1 mutation (carrier); dd, homozygous DIRAS1 mutation; GTCS, generalized tonic-clonic seizures; ILS, intermittent light stimulation; OS, left eye; PPR, photoparoxysmal response; SW, spike-and-wave; SWC, spike-and-wave complexes; WNL, within normal limits.
*
Treated with AED.
†
Mild increase in monocytes and banded neutrophils in cytospin preparations, normal total nucleated cell count, normal protein.
‡
Unavailable for EEG.
§
May be clinically irrelevant as ventricle asymmetry is seen in 38% of healthy dogs and 44% of dogs with idiopathic epilepsy (15).
¶
EEG correlate was obscured by muscle artifact.
‖
EEG correlate was occasionally obscured by muscle artifact.
**
Unremarkable on repeat 3T MRI.
††
Mild elevation in amino acids cystathionine and homocysteine; organic acids WNL.
‡‡
Nondiagnostic EEG (panting).