Table-2.

Summary of DEE-related GRIN2D variants and patient’s phenotypes

	Patient-1	Patient-2	Patient-3	Patient-4	Patient-5	Patient-6	Patient-7	Patient-8	Patient-9	Patient-10	Patient-11	Patient-12	Patient-13
GRIN2D variants (NM_000836)	c.1345G>A:p.(Asp449Asn)	c.1718C>T: p.(Ser573Phe)	c.1999G>A: p.(Val667Ile)	c.1999G>A:p.(Val667Ile)	c.1999G>A:p.(Val667Ile)	c.2008C>T: p.(Leu670Phe)	c.2008C>T: p.(Leu670Phe)	c.2023G>A: p.(Ala675Thr)	c.2033C>A: p.(Ala678Asp)	c.2043G>C:p.(Met681Ile)	c.2080A>C:p.(Ser694Arg)	c.3812C>T: p.(Ser1271Leu)	c.3937C>T: p.(Arg1313Trp)
Variant location	ABD	pre-M1	M3	M3	M3	M3	M3	M3	M3	M3	ABD	CTD	CTD
Gender	male	female	male	female	female	male	Female	N/A	Female	male	female	male	female
Age at onset	3 days	2mo	9mo	4mo	2mo	< 1yo	4mo	N/A	3y, 5mo	2yo	2yo	2mo	<1yo
Seizure types and EEG	startling seizure; EEG: intermittent multifocal discharges at 15 mon old	focal motor to GTCS; EEG: slow background, multifocal spikes	atypical absence; EEG: bilateral central spikes; hypsarrhythmia	complex partial seizure; EEG: frequent spikes and waves during awake and hypsarrhythmia during sleep	generalized seizure; EEG: sharp and spike wave discharges	epileptic spasms; EEG: diffuse paroxysmal abnormalities	focal motor to GTCS; EEG: continuous hypsarrhythmia with bilateral synchrony	epileptic spasms; EEG: N/A	focal motor → GTCS; EEG: frequent multifocal spikes; runs of faster alpha activity, multifocal spikes	febrile convulsion, afebrile generalized or unilateral convulsions, myoclonic seizure; EEG: Frequent multifocal spikes and diffuse spwc and sharp waves	tonic seizures, atonic seizures, atypical absence; EEG: Diffuse spwc. Focal spikes. Continuous diffuse spwc during sleep	epileptic spasms, myoclonic jerks; EEG: modified hypsarrhythmia; sporadic focal epileptic activity, runs of faster beta activity	GTCS, focal clonic, myoclonic, epileptic spasms; EEG: frequent/almost continuous sharp-waves with high amplitude
Developmental delay and other neurological features	no head control, no rolling over, no speech; hypotonia, hyperreflexia; Disturbed sleep pattern	walked at 2yo; poor eye contact, autistic behaviors	severe DD; mild hypotonia, dyskinetic and choreiform movements; cerebral visual impairment, oculomotor apraxia, changing tone, periodic breathing pattern	sitting alone at 3.5yo, walking with support at 3.5yo, speaking single words at 6.5yo; axial hypotonia, mild appendicular hypertonia; facial dysmorphisms, bilateral mild fifth finger clinodactyly, mild pes planus; poor sleep	rolling over at 9 mon old, unable to sit alone; truncal and orofacial hypotonia, appendicular hypertonia, athetoid limb movements, autistic features; microcephaly, severe pes planus	severe DD; severe hypotonia; cerebral visual impairment, feeding difficulties	severe DD; hypotonia, dyskinetic and choreiform movements; visual impairment with inconstant fixation	DD	walked at 2yo; single words at 2.5yo; hypotonia; poor eye contact, autistic behaviors	sitting alone at 18 mon old, DQ < 10 at 7 yo; myoclonus, ballismus, autism	Walking alone at 14 mon old, speaking two-word sentences at 36 mon old, IQ 64 at 7yo, full-scale IQ 58 at 11yo; ADHD	Severe DD; severe axial hypotonia, continuous movements; cerebral visual impairment, pyramidal signs with abnormal plantars (2yo), failure to thrive	severe; severe hypotonia, tetraplegia; wheelchair user, scoliosis, cerebral visual impairment, amaurosis, feeding difficulties
Brain MRI	loss of white matter, thin corpus callosum at 7.5 mon old	Normal	mild cerebral atrophy	N/A	normal	cortical atrophy	mild cerebral atrophy	N/A	Normal	normal at 6yo	normal at 3yr	normal	mild cerebral atrophy
Response to AEDs	PB, CZP, VPA: partially effective. CLB, Vit. B6: not effective	no formal therapy	seizure free on memantine, IVIG, oral steroids and Mg	Intractable, ACTH, LEV, Memantine, Mg, ketamine, pentobarbital, MDZ	intractable; seizure free on memantine, sultiame, lamotrigine, and valproic acid	no response	mild amelioration of EEG on steroids – no clinical overt seizures	no response	seizure free on VPA, LEV, and clonazepam	Intractable, VPA, CLB, LTG, LEV, LCM	ESM: effective for atonic seizures and atypical absence. CBZ, VPA, CZP: not effective	relatively controlled by VPA, TPM and ELF (in combination with VNS)	no response
Functional consequences	N/A	↑glu/D-serine potency, ↑Mg inhibition, ↓pH inhibition, ↓Popen, ↓current amplitude, ↓receptor cell surface expression	↑glu/gly potency, ↓Mg/pH/zinc inhibition, ↑Popen, ↑deactivation tau, causes neuronal cell death, dendritic swelling	↑glu/gly potency, ↓Mg/pH/zinc inhibition, ↑Popen, ↑deactivation tau, causes neuronal cell death, dendritic swelling	↑glu/gly potency, ↓Mg/pH/zinc inhibition, ↑Popen, ↑deactivation tau, causes neuronal cell death, dendritic swelling	↑glu/gly/D-serine potency, ↓pH inhibition, ↑Popen, ↑deactivation tau, ↑charge transfer, ↓receptor cell surface expression	↑glu/gly/D-serine potency, ↓pH inhibition, ↑Popen, ↑deactivation tau, ↑charge transfer, ↓receptor cell surface expression	↑glu/gly/D-serine potency, ↓pH inhibition, ↓current amplitude, ↓receptor cell surface expression	↑glu/gly/D-serine potency, ↑Popen, ↓current amplitude, ↓receptor cell surface expression; a significant ↓ in neuronal viability	N/A	N/A	↓gly potency, No effects on Mg/pH inhibition, no effects on Popen and current amplitude, ↓receptor cell surface expression	↓gly potency, No effects on Mg/pH inhibition, no effects on Popen and current amplitude, ↓receptor cell surface expression
Source	Tsuchida et a., 2018	XiangWei et al., 2019	XiangWei et al., 2019; Li et al., 2016	Li et al., 2016	Li et al., 2016; XiangWei et al., 2019	XiangWei et al., 2019	XiangWei et al., 2019	XiangWei et al., 2019	XiangWei et al., 2019	Tsuchida et a., 2018	Tsuchida et a., 2018	XiangWei et al., 2019	XiangWei et al., 2019

AED, anti-epileptic drug; DD, developmental delay; GTCS, generalized tonic clonic seizures; LEV, levetiracetam; NA, not available; TPM, topiramate; VGB, vigabatrin; VNS, vagal nerve stimulator; ELF, ethylloflazepate; VPA, valproate.