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
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|
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