Table 1.

Clinical features and genetic characteristic of eight patients with GRIN2D variants

	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5	Patient 6	Patient 7	Patient 8
Gender	Female	Male	Male	Female	N/A	Female	Male	Female
Age	4 y, 5 mo	2 y, 2 mo	9 y, 8 mo	9 mo	Dead before 2 y	7 y, 3 mo	3 y	34 y
Diagnosis	Epilepsy + DD	EOEE	Epilepsy + ID	EOEE	Epilepsy + ID	Epilepsy + ID	Epilepsy + DD	Epilepsy + ID
GRIN2D variants (NM_000836)	c.1718C>T: p.(Ser573Phe)	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.3812C>T: p.(Ser1271Leu)	c.3937C>T: p.(Arg1313Trp)
ACMG Classification	Pathogenic	Pathogenic	Pathogenic	Pathogenic	Likely pathogenic	Pathogenic	Likely pathogenic	Uncertain significance
Family history	Unremarkable	Maternal uncle has ADHD	Unremarkable	Unremarkable	N/A	Unremarkable	Unremarkable	Unremarkable
Perinatal period	Normal	Normal	Normal	Prolonged delivery	N/A	Foetal bradycardia during delivery	Prolonged delivery and foetal distress	N/A
Age at onset	2 mo	9 mo	<1 y	4 mo	N/A	3 y, 5 mo	2 mo	<1 y
Seizure types	Focal motor → GTCS	Atypical absence	Epileptic spasms	Focal motor → GTCS	Epileptic spasms	Focal motor → GTCS	Epileptic spasms (2 mo), myoclonic jerks (3 y 5 mo)	GTCS, focal clonic, myoclonic, epileptic spasms
(V)EEG	Slow background, multifocal spikes	Bilateral central spikes (9 mo); hypsarrhythmia (1 y 9 mo)	Diffuse paroxysmal abnormalities (<1 y)	Continuous hypsarrhythmia with bilateral synchrony	N/A	Frequent multifocal spikes (3 y 11 mo); runs of faster alpha activity, multifocal spikes (6 y)	Modified hypsarrhythmia (5 mo); sporadic focal epileptic activity, runs of faster beta activity (3 y)	Frequent/almost continuous sharp-waves with high amplitude
Response to AEDs	No formal therapy	seizure free on memantine, IVIG, oral steroids and Mg	no response	Mild amelioration of EEG on steroids – no clinical overt seizures	No response	seizure free on VPA, LEV, and clonazepam	relative controlled by VPA, TPM and ELF (in combination with VNS)	No response
Developmental delay	Walked at 2 y	Severe	Severe	Severe	Yes	Walked at 2 y; single words at 2.5 y	Severe	Severe
Hypotonia and movement disorder	No	Mild hypotonia, dyskinetic and choreiform movements	Severe hypotonia	Hypotonia, dyskinetic and choreiform movements	Hypotonia	Hypotonia	Severe axial hypotonia, continuous movements	Severe hypotonia, tetraplegia
MRI	Normal	Mild cerebral atrophy	Cortical atrophy	Mild cerebral atrophy	N/A	Normal	Normal	Mild cerebral atrophy
Blood/urinary metabolic	Normal	Normal	Normal	Normal	N/A	Normal	Normal	Normal
Other neurological features	Poor eye contact, autistic behaviours	Cerebral visual impairment, oculomotor apraxia, changing tone, periodic breathing pattern	Cerebral visual impairment, feeding difficulties	Visual impairment with inconstant fixation,	N/A	Poor eye contact, autistic behaviours	Cerebral visual impairment, pyramidal signs with abnormal plantars (2 y), failure to thrive	Wheelchair user, scoliosis, cerebral visual impairment, amaurosis, feeding difficulties

AED = anti-epileptic drug; DD = developmental delay; ELF = ethylloflazepate; EOEE = early-onset epileptic encephalopathy; GTCS = generalized tonic clonic seizures; LEV = levetiracetam; mo = months; NA = not available; TPM = topiramate; VGB = vigabatrin; VNS = vagal nerve stimulator; VPA = valproate; y = years.