Table 1.

Summary of Clinical and Molecular Findings in Individuals with Heterozygous De Novo EIF2AK1 and EIF2AK2 Variants

	Proband 1	Proband 2	Proband 3	Proband 4	Proband 5	Proband 6	Proband 7	Proband 8	Proband 9
Molecular Findings
Gene	EIF2AK1	EIF2AK2	EIF2AK2	EIF2AK2	EIF2AK2	EIF2AK2	EIF2AK2	EIF2AK2	EIF2AK2
cDNA	NM_014413.4; c.1342A>G	NM_002759.3; c.31A>C	NM_002759.3; c.398A>T	NM_002759.3; c.973G>A	NM_002759.3; c.1382C>G	NM_002759.3; c.326C>T	NM_002759.3; c.325G>T	NM_002759.3; c.95A>G	NM_002759.3; c.290C>T
Protein	p.Ile448Val	p.Met11Leu	p.Tyr133Phe	p.Gly325Ser	p.Ser461Cys	p.Ala109Val	p.Ala109Ser	p.Asn32Ser	p.Ser97Phe
Inheritance	de novo	de novo	de novo	de novo	de novo	de novo	de novo	de novo	de novo
AOH	no	no	no	no	no	47 Mb on chromosome 17	no	n/a	no
CNV	no	no	no	no	no	no	no	n/a	no
Background
Gender	female	male	male	female	male	male	male	male	male
Age at most recent assessment	6 years	10 years	13 years	3 years	18 months	19 months	3 years	12 years	4 years
Ancestry	Irish, German	German, Mexican, Spanish	Chinese	European	European	Moroccan, Kuwaiti	European	European	German, Irish, Apache, Cherokee
Neurology
Dysarthria or nonverbal	dysarthria	dysarthria	dysarthria	dysarthria	nonverbal	nonverbal	dysarthria	dysarthria	nonverbal
Nonambulatory	no	no	no	no	yes	yes	no	no	yes
Gait ataxia	no	yes	yes	yes	n/a	n/a	yes	no	no
Truncal ataxia	no	yes	no	no	yes	yes	no	no	no
Hypotonia	no	yes	yes	yes	yes	yes	yes	no	yes
Hypertonia	yes, lower extremities	yes	yes	no	yes	yes	yes	yes	yes
Hyperreflexia	yes, lower extremities	no	yes	no	yes	no	yes	yes	yes
Spasticity	yes, lower extremities	no	yes	yes	yes	no	yes	yes	yes
Dystonia	no	yes	yes	no	yes	yes	no	no	yes
Tremor	no	yes	no	yes	yes	no	no	no	no
Myoclonus	no	yes	no	no	no	no	no	no	no
Choreathetosis	no	yes	no	no	no	no	no	no	no
Hemiballismus	no	yes	no	no	no	no	no	no	no
Extrapyramidal signs	bradykinesia	parkinsonism, tremor, dystonia	parkinsonism, bradykinesia, bradyphrenia	tremor	parkinsonism, bradykinesia, rigidity, mask-like facies	no	no	parkisonism, hypomimia, abnormal postural reactions	no
Seizures	no	yes	no	no	yes	yes	no	no	yes
Seizure history	N/A	GTC	N/A	concern for seizure activity, normal EEG	focal complex seizures, focal epileptiform discharges	focal tonic seizures, multifocal epileptiform discharges, seizure onset at 7 months old	N/A	no	focal complex seizures, focal epileptiform discharges, seizure onset at 4 months old
OFC at birth	N/A	31.5 cm (Z = −0.5)	35.5 cm (0.82)	n/a	32 cm (Z = −0.5)	N/A	N/A	34 cm (Z = −0.5)	N/A
OFC at latest assessment	51.5 cm (Z = 1.0)	53.2 cm (Z = −0.05)	52.8 cm (Z score = −0.66)	44.50 (Z = −1.18, 17 months)	43 cm (Z = −3.0)	44.5 cm (Z = −2.42)	48.8 cm (Z = −1.4)	49 cm (Z = −1.0)	49 cm (Z = −1.61)
Neurologic regression with febrile illness	not reported	yes	yes	yes	yes	yes	yes	yes	yes
Features of neurologic regression	n/a	n/a	neurologic decline with febrile illnesses	neurologic decline with febrile illnesses	neurologic decline with febrile illnesses	loss of eye contact, babbling, and motor skills with influenza A illness at 13 months	abruptly nonverbal with neurologic decline following febrile RSV illness at 4 years old	transient but severe worsening of the postural instability during febile illness	loss of crawling and oral skills with human metapneumovirus illness at 4 years old
Additional features	urinary and fecal urgency, slow finger tapping movements	urinary and fecal incontinence, silent aspiration of thin liquids	intellectual disability, dysphagia, poor eye contact	abnormal eye movements concerning for seizure	acquired microcephaly, laryngomalacia, gastroparesis, head titubations	exacerbation of epilepsy with febrile illnesses	progressive contractures, walks in a crouched position with elbows flexed, thumbs adducted, bilateral feet pronation	acquired microcephaly	failure to thrive
MRI Brain
Age at assessment	3 years	7 years	10 years	17 months	6 months	18 months	4 years	8.5 years	4 years
Cerebral volume loss	no	yes	no	yes	yes	yes	yes	yes	yes
T1W signal	isointense	isointense	isointense	isointense	isointense	isointense	isointense	isointense	hyperintensity throughout the supratentorial and infratentorial white matter
T2W signal	hyperintensity, posterior lateral ventricles	hyperintensity, dorsal-most upper cervical cord, dorsal medulla, dorsal pons, periaqueductal gray	hyperintensity, confluent signal in subcortical and periventricular white matter, patchy signal in brainstem	isointense	isointense	isointense	hyperintensity, dorsal medulla and periventricular	hyperintensity, posterior part of putamen, periventricual and deep white matter, inferior cerebellar peduncles	hypointensity throughout the supratentorial and infratentorial white matter
Contrast enhancement	no	no	no	no	no	no	no	no	no
Diffusion restriction	no	no	no	no	no	no	no	no	no
Delayed myelination	N/A, age greater than 2 years	N/A, age greater than 2 years	N/A, age greater than 2 years	N/A, age greater than 2 years	yes	yes	N/A, age greater than 2 years	N/A, age greater than 2 years	N/A, age greater than 2 years
Hypomyelination/abnormal myelination	no	yes	yes	yes	N/A, age less than 2 years	N/A, age less than 2 years	yes	yes	yes
Thinning of the corpus callosum	no	yes	yes	yes	yes	yes	yes	yes	yes
Vermis volume loss	no	yes	yes	no	no	yes	yes	no	yes
Additional features	periventricular gliosis	progressive enlargement of lateral ventricles, mild prominence of supratentorial sulci	prominent cisterna magna, prominent ventricles, widening of the sylvian fissures, diffuse hypomyelination	prominent sulci and enlargement of the ventricles, generalized cerebral atrophy, hypomyelination	pronounced delayed myelination, diffuse hypomyelination, generalized cerebral atrophy, prominent ventricles	pronounced delayed myelination in cerebral hemispheres, brainstem, and cerebellum; inferior vermian hypoplasia	bifrontal lobe polymicrogyria, arachnoid cyst	atrophy of posterior part of putamina, hyperintense T2 signal of periventricular and deep white matter	pronounced delayed myelination, bifrontal lobe polymicrogyria, numerous areas of T1 hyperintensity throughout the supra and infratentorial white matter

Abbreviations: T1W, T1-weighted; T2W, T2-weighted; IUGR, intrauterine growth restriction; SGA, small for gestational age; EEG, electroencephalography; GTC, generalized tonic-clonic; OFC, occipital frontal circumference; AOH, absence of heterozygosity; CNV, copy number variant; N/A, not available.