NEUROLOGY/2014/577221
Table e-1. Clinical and molecular details for the ten cases with CHD2 epileptic encephalopathy
Case / 1 / 2 / 3 / 4 / 5Sex, age / Female, 31 years / Female, 18 years / Male, 13 years / Male, 6 years / Male, 18 years
Protein change / G491Vfs*13
De novo / R121X
De novo / R1644Kfs*22
De novo / L823P
De novo / E1412Gfs*64
De novo
Age at seizure onset / 12 months / 12 months / 24 months / 30 months / 12 months
Seizure types / 12 months: AA
31 months: MS Always when a camera flashed, once with high frequency photic stimulation.
31 months : TS
31 months: GTCS
6 years: AT associated with GSW seen on EEG.
11 years: NCSE, CSE
Teenage years: TA / 12 months: MS
2 years: TS mostly nocturnal.
2 years: MS: self-induced with TV
8 years: GTCS
10 years: falls, TA.
11 years: NCSE / 2 years: atonic myoclonic absence (video)
2 years: MS
7 years: GTCS, mostly nocturnal
8yr: CSE / 30 months: atonic myoclonic absence
30 months: MS
5 years: TS
5 years: AT
5 years: NCSE / 1 year: EMA(self-induced withtelevision) atonic myoclonic absence
1 year: MS, MA
2 years: TA
2 years: FS
10 years: GTCS
Reflex photic seizures / With camera flash as baby / Self induced with TV / Not reported / Not reported / Self induced with TV
Atonic myoclonic absence seizure captured on video (duration) / 2 years: Sudden eye elevation, single facial myoclonic seizure and head extension with atonic fall to the ground, bilateral upper limb extension followed by myoclonic seizures associated with rhythmic abduction of the upper limbs; occurs while watching television
(7- 8 seconds). / 5 years: Upwards eye elevation, rhythmic neck extension with loss of postural tonefollowed by rhythmic abduction of the upper limbs, which may be left predominant. Occasional oral automatisms while playing computer games
(4 -5 seconds). / 7 years: Self inducing by placing face adjacent to television: Atonic head nod associated with bilateral upper limb jerking with rhythmic abduction of the upper limbs
15 years: Bilateral upper limb jerking
18 years: Bilateral upper limb jerking is more vigorous with subtle neck jerking
(2 -4 seconds).
EEG during atonic myoclonic absence seizure / Generalized epileptiform activity with abrupt onset and offset lasting 2 seconds (ambulatory EEG) / 3-4 Hz GPSW / 3-4 Hz GPSW
Interictal and background / 3 years: Slow background. Frequent polyphasic spike, spike slow waves.
5 years and13 years: diffuse slowing with multifocal and generalized slow waves.
20 years: diffuse slowing of the background, multifocal epileptiform discharges, 2Hz GSW.
No photoparoxysmal response. / 10 years: Normal background for age. Multifocal discharges, generalized discharges activated by sleep. Paroxysmal fast activity and slow GPSW.
No photoparoxysmal response. / 2 years: Diffuse mildly slow background with bursts of 2-3 Hz GSW and GPSW in wake and sleep
4 years: Background slow for age (5-6 Hz theta with admixed 3 Hz delta), bursts of GPSW of up to 5 seconds particularly in sleep
13 years: Slow SW, rapid high amplitude spikes in wake and sleep. / 2.5 years: Diffusely slow background, no interictal abnormalities.
4 years: Frequent bifrontal spike and slow waves, particularly from sleep, background normal for age.
5 years: Background normal for age. Frequent bursts of 2-5Hz GSW and GPSW with left temporal sharp waves (seen in sleep and wake). 95 seizures in 48 hours of monitoring. / 9 years: Diffusely slow background with symmetrical theta and 3 Hz delta.
14 years: Normal background for age –brief bursts of 3-4 Hz regular rhythmic GSW. No photoparoxysmalresponse.
Level of intellectual disability / ASD /ADHD
Early development
Regression
Behavioral issues / Profound / no / no
Delayed
Walked at 12 months
No words at 2 years
Yes
No / Severe / no / no
Delayed
Walked at 10 months
Limited speech development after 12 months
Yes
Aggression / Severe /no, but obsessions /no
Delayed
Walked at 18 months
Limited speech development after 12 months
Yes
No / Severe / ASD /no
Delayed
Walked at 18 months
Single words at 2.5years
Yes
Aggression / Moderate - Severe / ASD /no
Delayed
Walked at 10 months
Single words only at 7 years
Yes
Aggression
HC centile/ Height / Gait / 2 / NK / Needs guidance to walk / <1 / Short stature / Stooped gait. Poor coordination and balance. / 35 / Short stature / Crouch gait; transient ataxia on valproate / 64 / Normal / Crouch gait / 23 / Normal / Crouch gait; transient ataxia on valproate
MRI / 7 years: ‘normal’ (images not available for review) / 10 years: ‘normal’ (images not available for review) / 2 years: Decreased occipital lobe volume and deep sulci
7 years: Marked atrophy, decreased corpus callosum size, decreased white matter volume occipitally / 5 years: limited sequences
7 years: mild volume loss with increase in ventricular size / 2 years and 4 years: no increase in corpus callosum size over time
Case / 6 / 7 / 8 / 9 / 10
Sex, age / Female, 13 years / Male, 12 years / Male, 14 years / Female, 36years / Male, 19 years
Protein change / Gly1575Valfs*
De novo / L1591Xfs
De novo / Q909X
De novo / 15q26 deletion
De novo / W548R
De novo
Age at seizure onset / 30 months / 42 months / 30 months / 34 months / 36 months
Seizure types / 2.5 years: EMA
2.5 years: MS: self-induced with TV
3 years:TA
nocturnal GTCS
5 years: TS
13 years: nocturnal GTCS only / 3.5 years: GTCS
4 years: AA
4.5 years: MS, MA
Good control between 8-9.5 years (rare seizures)
9.5 years: NCSE (myoclonic SE) / 2.5 years: AT
2.5 years: GTCS
2.5 years: MS: self-induced with TV
Good control between 2.5 and 5 years of age.
4 years: EMA
10 years : NCSE
10 years: CSE / 34 months: GTCS
4 years: MS: self-induced withTV or light through trees. Offset at 25 years by avoiding stimuli.
4 years: EMA
33 years: GTCS returned / 3 years: MS
3 years: HS
3 years: GTCS.
5 to 10 years: Seizure free from off medication
10 years: GTCS returned.
10 years: GTCS: Self-induced with TV.
Reflex photic seizures / Self inducedwith TV / Not reported / Self inducedwith TV; photic stimulation / Self inducedwith TV or light through trees / Self induced with TV
Interictal and background / 3 years: slow background for age. Inter-ictal GSW GPSW, bi frontal slow spike wave (2Hz). Eye flickering – bursts of 2 Hz bifrontal spike and wave
4 years: 18 EMAs captured in 30 minutes, GSW, GPSW. Activated by eye closure.
7 years: normal background, irregular GSW with a frontal predominance
10 years; GSW on eye closure and during eyelid myoclonia
No photoparoxysmal response. / 4 years: Diffusely slow background and GPSW runs between 1 and 12 seconds / 32 months: Normal background, frontal predominant GSW, GPSW
5.5 years: normal background, multifocal GSW
11 years: Diffusely slow background. 3-4Hz GSW
multifocalepileptiform activity with 3Hz GSW, bifrontal spikes, activated in sleep. Eye closure brought out 4-5Hz posteriorly dominant GSW.
12 years; continuous slowing in wake and marked generalized epileptiform activity in sleep
14 years: diffuse theta slowing. Active interictal GSW GPSW discharges >3Hz increased by hyperventilation. Grade 4 PPR across a range of frequencies. Five seizure types captured. / 5 years: generalized epileptiform discharges every 1- 2 minutes / 3 years: diffusely slow (L>R). Independent bitemporalslowing. Bursts of irregular spike-wave activity over both hemispheres.
Not photosensitive.
12 years: Fast GSW on eye closure, fragments of GSW on a normal background.
Level of intellectual disability / ASD /ADHD
Early development
Regression
Behavioral issues / Moderate-severe / ASD /ADHD
Delayed
Walked at 12 months
Only single words at 7 years
No
Aggression / Moderate-severe / no / ADHD
Delayed
Yes
Aggression / Mild / no/ ADHD
Walked at 12 months
No delay to speech
Late regression at 9 years from normal intellect
Aggression / Mild / autistic traits/ no
Delayed
Walked at 13 months
Verbal comprehension poor at 2 years
Yes
Aggression / Mild / no /no
Delayed
Walked 14 months
Speech delayed at 2 years
No
Aggression in childhood. Florid psychosis at 19.
HC centile / Height / Gait / 50 / Short stature / Normal / NK / Normal / Mild ataxia / 26 / Short stature /
Mild crouch gait; ataxia. Good runner. / NK / Normal / Mild crouch gait / 80 / Normal / Normal
MRI / 12 years: generalized cerebellar atrophy with large v4 and prominent folia. The posterior corpus callosum is foreshortened and smaller posteriorly. / 11 years: ‘normal’ (images not available for review) / 10 years & 11 years: atrophy between scans, markedly in the cerebellum. The corpus callosum is hypoplastic posteriorly with a small splenium / 35 years: unremarkable / 3 and 13 years: unremarkable
Key: ADHD = attention deficit hyperactivity disorder; ASD = autism spectrum disorder; NK = Not known; GPSW = generalized polyspike wave; GSW = generalized spike wave.
Seizure types: AA = atypical absence; AT = atonic seizures; CSE = convulsive status epilepticus; EMA = absence with eyelid myoclonia; FS = febrile seizures; GTCS = generalized tonic clonic seizures; HS = hemiclonic seizures; MA = myoclonic absence; MS = myoclonic seizures; NCSE = non-convulsive status epilepticus; PPR = photoparoxysmal response; TA = typical absence; TS = tonic seizure.