Two patients with a GRIN2A mutation and childhood-onset epilepsy

Original research article by S.P. DeVries and A.D. Patel et al. (2013)

Read the abstract here.

Neurotransmitters are chemicals that aid in signaling between nerve cells in the brain. Genetic changes in GRIN2A can have an impact on neurotransmitter function and have been linked to childhood-onset epilepsy of varying degrees of severity, as well as to autism and other neurological disorders. The authors of this paper describe the clinical features of two people with changes in GRIN2A.

Patient #1 was a 3-year-old boy with global developmental delay. It was reported that he experienced his first seizure at the age of two. An EEG revealed abnormalities, and microarray testing showed he had a deletion of most of the GRIN2A gene. He had a wide gait (walking pattern) and was reported as being seizure-free for six months with the help of medication. After six months, he developed seizures again, and was unsteady on his feet. After adjustments in medication dosages and physical therapy, he once again became seizure-free and experienced an improvement in walking. Patient #1’s mother also had a history of childhood-onset seizures and was found to have the same gene change as her son.

Patient #2 was a 9-year-old boy who experienced multiple types of seizures beginning at age 4. He experienced over 100 seizures a day, and numerous medications and treatments failed to decrease the frequency of his seizures. Whole-exome sequencing showed he had a change in GRIN2A. His development was reported to have been normal initially but to have declined at age 4, after his seizures began. Patient #2’s father was found to have the same change. He did not report a history of seizures but did have a history of major depressive disorder. See the table below for a comparison of the two people’s characteristics.

These case studies, as well as other literature, show that people with a change in the GRIN2A gene can have a wide range of issues, including seizures. This research suggests that future genetic tests for childhood-onset epilepsy should screen for changes in GRIN2A.

 

Comparison of genetic and clinical findings (Table 1 from DeVries et al. paper)
	Patient 1	Patient 2
Genetic Findings	16p13.2 microdeletion involving the majority of the GRIN2A gene (292.09 kb), exons 4-14	V506A variant in the GRIN2A gene
Seizure type	Focal seizures	Focal seizures, Myoclonus, Atypical absence
Description	Left facial twitching, drooling, teeth grinding, arm/leg jerking followed by transient paralysis and postictal state	Arrest in activity, right hand twitching, upward eye deviation, jerking forward. He can say a few words, but cannot carry on a conversation.
Duration	1-3 min. Longest event 20 min	30 seconds to 15 min. Longest event greater than 1 hour
Frequency	One per 1-2 months	More than 100 per day
Current medications and treatments	Levetiracetam	Clobazam, felbamate, vagus nerve stimulator
Failed medications and treatments	Oxcarbazepine	Levetiracetam, zonisamide, lamotrigine, lacosamide, clonazepam, ethosuximide, brivaracetam, topiramate, oxcarbazepine, valproic acid, vitamin B6, ketogenic diet
Development	Delayed cognition, motor, and speech. Receives PT/OT and attends a special needs preschool	Normal when seizure free; cognitive and language delay when refractory
Electroencephalograph findings	Frequent, multifocal spikes, polyspike-wave discharges, left greater than right posterior quadrant	Generalized bisynchronous 2-2.5 Hz slow spike waves and left frontotemporal discharges and electrographic seizure from the left centrotemporal region.
Imaging	Noncontrast MRI normal	Noncontrast MRI normal PET: diffuse cortical hypometabolism, minimal asymmetry within the left lateral temporoparietal region SPECT: increased uptake near the vertex, at the frontoparietal junction, more extensive on the left side, more intense on the right
Parental testing	Mother with identical mutation.	Father with identical mutation.
Family history	Mother had childhood-onset epilepsy and is currently seizure-free off of AEDs. Maternal uncle with epilepsy.	Father: major depressive disorder
Abbreviations: AED = Antiepilepsy drug MRI = Magnetic resonance imaging NF-1 = Neurofibromatosis type 1 OT = Occupational therapy PET = Positron emission tomography PT = Physical therapy SPECT = Single photon emission computed tomography