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Advanced Neurology ADGRV1 and MED13L mutation

signals and transcription factors to the RNA polymerase waking up from sleep with sudden deviation of both
II machinery, thereby enabling the regulation of the eyes followed by stiffening of all four limbs lasting for
expression of specific genes. This is important for the 10 – 20 s. The initial frequency of the events was 10 – 11
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early embryonic development of the heart and brain. episodes per day. She was admitted and evaluated elsewhere
MED13L haploinsufficiency syndrome is characterized initially and was started on anti-seizure medications
by moderate intellectual disability, speech impairment, (oxcarbazepine, levetiracetam, clobazam, zonisamide,
and dysmorphic features, which can be accompanied with and phenobarbitone); however, her seizures remained
complex congenital heart defects and behavioral issues in refractory. At 1 year of age, the frequency of her seizures
some cases. Only a few patients have been reported to increased up to 20 episodes per day. Her anti-seizure
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develop epilepsy due to mutations in MED13L, specifically medications were optimized to lamotrigine, lacosamide,
missense mutations rather than truncating type. 3 clobazam, and perampanel, which reduced her seizure
The human adhesion G protein-coupled receptor V1 frequency to 10 episodes daily. We also noted an increase
(ADGRV1) gene encodes a very large G protein-coupled in her seizure frequency when valproate was attempted.
receptor-1 (VLGR1), which is localized at synaptic Although she had mild global developmental delay, she
junctions and acts in concert to regulate synaptic function. displayed a disproportionate delay in language milestones.
It is also termed the monogenic audiogenic seizures- Examination showed facial dysmorphism (Figure 1) with
susceptibility 1 gene, G protein-coupled receptor 98 gene, a depressed nasal bridge, a bulbous nose tip, low set ears,
or VLGR1 gene. Three VLGR1 mRNA isoforms, namely, and a happy face. She had good auditory and visual regard
VLGR1a, VLGR1b, and VLGR1c, are expressed in the and had no focal neurological deficits. Her complete
cochlea, brain, eyes, and connective tissues. VLGR1b, blood count, serum electrolyte levels, thyroid profile,
the largest full-length isoform, has a large extracellular and metabolic profile, including her urine organic acid
domain, which encompasses a signal peptide, seven profile and plasma tandem mass spectroscopy findings,
epilepsy-associated repeats (i.e. epitempin repeats), and 35 were all normal. Her brain magnetic resonance imaging
calcium exchanger β (CalX-β) motifs. Variants associated (Figure 2), two-dimensional echocardiography, and
with epilepsy mainly affected VLGR1b and VLGR11c abdominal ultrasound findings were also normal. Video
rather than VLGR1a. Variants in ADGRV1 have been electroencephalogram data revealed normal awake record
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associated with audio-visual disorders, typically usher with activation of left frontocentral interictal epileptiform
syndrome type 2, which is characterized by moderate to discharges during sleep (Figure 3) and recorded events
severe congenital sensorineural hearing loss and postnatal with the following semiology: (i) sudden staring with
retinitis pigmentosa. Recent studies have identified slight eye deviation to the left and behavioral arrest lasting
ultra-rare ADGRV1 missense variants in patients with for a few seconds, (ii) waking up during sleep with tonic
myoclonic epilepsy, genetic generalized epilepsy, and posturing of all four limbs followed by brief clonic jerks
atypical Rolandic epilepsy. A recent study by Zhou et al. and eye blinks, and (iii) sudden staring with slight head
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revealed that ADGRV1 is potentially associated with febrile drop and abduction of both upper limbs, all with the left
seizure-related epilepsy as a susceptibility gene. Most of hemispheric ictal onset.
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the seizures are self-limiting or can be controlled with Based on the presence of facial dysmorphism, global
monotherapy. developmental delay, and normal neuroimaging and
Here, we report a rare case of a child who presented with metabolic profiles, we considered the possibility of a
developmental delay and refractory epilepsy harboring genetic etiology. She underwent chromosomal microarray,
novel variants in MED13L and ADGRV1, which represents
a rare genetic combination not reported previously. This
report can help us further delineate the clinical phenotype
of these pathogenic variants, which can aid in genetic
counseling. Understanding how these genetic mutations
interact and contribute to epilepsy can provide insights
into the underlying mechanisms of the disorder, which can
potentially lead to more targeted therapies or interventions.
2. Case presentation
A 2-year-old girl, born of non-consanguineous parents
with no perinatal insult, presented with a history of Figure 1. Facial dysmorphism in the child characterized by a depressed
refractory seizures from 5½ months of age. She reported nasal bridge, bulbous nasal tips, and low set ears

Volume 4 Issue 1 (2025) 111 doi: 10.36922/an.3602