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Advanced Neurology NPRL2 as possible actor in reflex seizures

due to a second-hit mechanism (germinal mutation + variants, it becomes apparent that this gene family may play
somatic mutation), and they may exhibit subtlety in the a role in benign forms of focal reflex seizures, including BE.
cases of FFEVF [12,14] .
In our case, the NPRL2 variant was inherited from Acknowledgments
the asymptomatic mother. It is well-established that None.
epilepsies associated with GATOR-pathway-related
genes often exhibit variable penetrance, with individuals Funding
carrying the same mutation displaying different types of None.
[14]
epilepsies or remaining asymptomatic . Therefore, it
is worth considering the potential causative role of the Conflict of interest
NPRL2 variant in the emergence of BE in our patient. In The authors declare that they have no competing interests.
particular, while the brain MRI did not reveal a distinct
cortical malformation — probably because the myelination Author contributions
process masks focal cortical dysplasias in some stages of
maturation – the observed asymmetry in the perirolandic Conceptualization: Tommaso Lo Barco
regions and the presence of the “power button sign” within Investigation: Luna Fontanelli, Ilaria Campari, Benedetta
the right central sulcus strongly suggest focal cortical Piccolo, Francesca Ormitti, Emanuela Claudia Turco
dysplasia type 2 . A second-hit mechanism, involving Writing – original draft: Tommaso Lo Barco
[7]
a somatic mutation causing a cortical dysplasia in the Writing – review and editing: Jacopo Proietti, Emanuela
sensorimotor cortex, and the inherited NPRL2 variant, Claudia Turco
may be responsible for this reflex epilepsy.
Ethics approval and consent to participate
Small lesions or epileptogenic zones within the
perirolandic areas are observed in patients whose seizures The patient’s caregiver gave verbal consent to participate
in the study.
are triggered by prolonged cutaneous contact, rubbing, or
tapping of specific areas. Typically, seizures in such cases Consent for publication
commence with ascending somatosensory sensations
followed by focal clonic movements, all while awareness is A verbal consent was obtained from patient’s caregiver for
maintained [15,16] . In contrast, our patient exhibited a different publication.
seizure semiology, and it is noteworthy that attempting to
induce a seizure by rubbing the ictogenic area without the Availability of data
presence of water failed to evoke the seizure. All data underlying the results are available as part of the
In “classic” cases of BE, it is reported that brain MRI article.
results are typically negative. However, due to the benign References
course of the condition, repeat MRI examinations are
seldom conducted after the onset [10,11,17,18] . These patients 1. Riney K, Bogacz A, Somerville E, et al., 2022, International
are often suspected of having a genetic etiology, but as of League against Epilepsy classification and definition of
now, no gene that is distinctive to BE has been identified. epilepsy syndromes with onset at a variable age: Position
Recently, the SYN1 gene has been associated with seizures statement by the ILAE Task Force on Nosology and
triggered by diverse stimuli, including bathing. However, Definitions. Epilepsia, 63: 1443–1474.
the onset of such seizures within the first 2 – 3 years of https://doi.org/10.1111/epi.17240
life is uncommon, cognitive impairment is frequent among 2. Palmini A, Halasz P, Scheffer IE, et al., 2005, Reflex seizures
affected individuals, and the condition predominantly in patients with malformations of cortical development and
affects males [5,19] . refractory epilepsy. Epilepsia, 46: 1224–1234.
4. Conclusion https://doi.org/10.1111/j.1528-1167.2005.52904.x
3. Solazzi R, Fiorini E, Parrini E, et al., 2018, Diaper changing-
We reported a case of an unusual manifestation of BE, induced reflex seizures in CDKL5-related epilepsy. Epileptic
characterized by seizures triggered by the act of pouring Disord, 20: 428–433.
water over genitalia. This patient carries a variant of the
NPRL2 gene, which could potentially be linked to the https://doi.org/10.1684/epd.2018.0999
development of focal cortical dysplasia or FFEVF. When 4. Jain P, Gulati P, Alsowat D, et al., 2018, Perineal stimulation
considering the landscape of epilepsy-related GATOR1 triggering seizures in a child with Dravet syndrome. Seizure,

Volume 2 Issue 4 (2023) 4 https://doi.org/10.36922/an.1379