Lateralized periodic discharges due to mutated PLEKHG2 in an infant with congenital nephrotic syndrome: a case report and literature review

Introduction

Lateralized periodic discharges (LPDs) have historically been linked to acute focal lesions in the central nervous system. According to the most reports, the primary etiologies are commonly attributed to cerebrovascular disease and metabolic disorders, followed by mass lesions and infections (1,2). Congenital nephrotic syndrome (CNS) is a prevalent disorder occurring in early infancy, characterized by extensive plasma protein leakage. While neurological symptoms are uncommon, certain children may present with severe symptoms due to hyponatremia, infections, thrombosis, or genetic variants (3).

Pleckstrin homology and RhoGEF domain containing G2 (PLEKHG2) functions as a guanine nucleotide exchange factor for Rac and Cdc42, interacting with Gβγ subunits of heterotrimeric G proteins and exhibiting activation upon Gβγ co-expression across various cell types (4). PLEKHG2 plays vital roles in maturation of axonal, dendritic, and spine. Homozygosity of the p.Arg204Trp variation in the PLEKHG2 gene is associated with neurodevelopmental disorders, including microcephaly and leukodystrophy (5). The PLEKHG2 gene variants have been previously linked to the development of infantile-onset epileptic encephalopathy (6). Recently, the PLEKHG2 gene has emerged as a potential candidate gene for epilepsy (7). The current literatures have not reported any direct causal relationship between PLEKHG2 gene variants and electroencephalography (EEG) abnormalities characterized by LPDs. In this study, we reported a case of a male infant with CNS, whose EEG exhibited LPDs and featured triphasic waves. We present this article in accordance with the CARE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-441/rc).

Case presentation

This patient was the first son born via cesarean section at 36 weeks of gestation to healthy parents and weighted 2,330 g with normal head circumference. No discernible abnormal appearance was shown in the patient’s other conditions. This patient, however, presented with a fever 5 days postpartum and was subsequently admitted to our hospital. Physical examination at admission revealed mild jaundice with slightly dry skin but no other positive signs, including negative neurological findings. A comprehensive diagnostic workup was performed, including blood gas analysis, white blood cell count, cerebrospinal fluid (CSF) examinations, and tests to rule out immunological and infectious causes (e.g., antinuclear antibodies, blood ammonia, genetic metabolic profiling,tuberculosis, streptococcal infections). All test results were within normal limits. We initiated empirical therapy with a combination of penicillin and cefotaxime, along with fluid replacement and physical cooling measures. Following this treatment, the patient achieved complete resolution of fever and other symptoms. However, two days later, he presented with diminished responsiveness and groaning. Neurological examination revealed cervical stiffness and limb rigidity, with mild cutaneous edema beginning to develop. The cranial computed tomography (CT) indicated the present of cerebral edema (Figure 1A). Following two days of intracranial pressure-lowering treatment, cranial magnetic resonance imaging (MRI) revealed abnormal hyperintensities in the cerebral white matter on both T1- and T2-weighted images (Figure 1B). On the same day as the MRI, he exhibited seizures characterized by synchronous, erratic, or fragmentary myoclonic jerks. The EEG revealed a triphasic wave pattern accompanied by asynchronous spasmodic myoclonic jerks of the limbs. Notably, during brief periods of hand movements, EEG depicted rhythmic LPDs and spikes, exhibiting slow-wave activity with a frequency range of 1.5–2 Hz, localized to specific region within the bilateral brain hemisphere (Figure 2A).

Figure 1 Neuroimaging results. (A) At the age of 4 days CT scanning indicated cerebral edema. (B) T2 MRI at age 6 days showed hyperintensities in cerebral white matter. The black arrows indicate hyperintensities in cerebral white matter. CT, computed tomography; MRI, magnetic resonance imaging.

Figure 2 EEG recordings. (A) Rhythmic LPDs plus spikes with a frequency of 1.5–2 Hz slow marked activity localized to part of the bilateral brain hemisphere (day 7th). (B) Regular 2 or 3 Hz high-voltage slow activity is localized to part of the right temporal area, central region (day 17th). EEG recording parameters—paper speed: 20 mm/s, sensitivity: 70 μV/cm, filters: high-pass: 1.0 Hz, low-pass: 30.0 Hz, notch: 50 Hz. EEG, electroencephalogram; LPDs, lateralized periodic discharges.

The subsequent standard laboratory tests, including blood gas analysis, complete blood counts, serum electrolytes, leukocyte count in CSF, and serum and urinary amino acid analysis were conducted, all of which yielded normal results. Treatment with phenobarbital effectively alleviated the convulsive symptoms. At 17 days of age, a cranial ultrasound revealed the present of a right choroid plexus cyst, without any signs of cerebral edema or brain hernia. However, the EEG continued to display LPDs, characterized by periodic three-phase waves at a frequency of 2–3 Hz (Figure 2B). Whole-body electromyography yielded normal results.

After being perplexed by these findings, we conducted further biochemical tests, which revealed a total serum protein level of 28.9 g/L, albumin at 14.2 g/L, cholesterol measuring 8.3 mmol/L, blood creatinine at 28 µmmol/L, and urinary protein reaching 6460 mg/dl. The NPHS1 gene was found to have two heterozygous variants (c.2515delC, p.Q839Rfs*8 and c.821C>A, p.A274D) through genetic testing (Figure 3). Additionally, the PLEKHG2 gene exhibited one homozygous and one heterozygous variant (c.610C>T, p.R204W and c.3874C>T, p.R1292W) [Figure 4, The datasets analyzed during the current study are available in National Center for Biotechnology Information (NCBI) repository, https://www.ncbi.nlm.nih.gov/sra/PRJNA1124039]. As a result, we made a diagnosis of CNS. The patient was treated with infusions of plasma and albumin, oral enalapril maleate for proteinuria reduction, diuretic therapy, infection prophylaxis, as well as supplementation of vitamin D, calcium and nutritional support, but ultimately achieved minimal clinical improvement, the infant continued to exhibit massive proteinuria, hypoalbuminemia, and generalized edema. Due to the patient’s critically poor clinical status, low-density lipoprotein apheresis was not feasible and therefore not administered. Additionally, we abstained from glucocorticoid treatment due to the established role of NPHS1 gene variants in the pathogenesis of steroid-resistant nephrotic syndrome (8). Furthermore, repeated family conferences were held to discuss the disease course and the eventual necessity of renal transplantation. After considering the overall prognosis, the family opted not to pursue transplantation and decided to discontinue therapy, ultimately resulting in the infant’s discharged against medical advice. Subsequent telephone follow-up confirmed that the infant had died.

Figure 3 The Sanger sequence of NPSH1 gene showed a frameshift variant of c.2515delC (p.Q839Rfs*8) and no abnormality was found in the child’s father. The red arrows indicate variant sites.

Figure 4 Sanger sequencing of the PLEKHG2 gene. (A) The Sanger sequence of PLEKHG2 gene showed a missense variant of c.610C>T, (p.R204W), both parents are heterozygous. (B) The Sanger sequence of PLEKHG2 gene showed a missense variant of c.3874C>T (p.R1292W) and the variant comes from the child’s mother. The red arrows indicate variant sites.

All procedures performed in this study were in accordance with the ethical standards of the Children’s Hospital of Zhejiang University School of Medicine (No. 2024-IRB-0001-P-01). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Informed consent was obtained from the guardians of the infant. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

LPDs are a typical electroencephalographic pattern frequently observed in critically ill adults, often associated with conditions such as hepatic encephalopathy, diabetes mellitus, Creutzfeldt-Jakob disease, or focal unilateral cerebral hemisphere lesions (9,10). Although LPDs are relatively uncommon among newborns their underlying mechanism is notably complex. In the 1950s, Cobb et al. proposed an association between LPDs and large white matter lesions (11), while Raroque et al. later demonstrated their correlation with cortical/subcortical gray matter lesions combined with white matter involvement (12). Interestingly, numerous studies have indicated that the etiology of LPDs involves a metabolic disorder, including associations with hyperglycemia, hyponatremia, and other metabolic abnormalities. Kapinos et al. reported that regional glutamate overload may be a critical mechanism mediating the association between the aforementioned metabolic disturbances and LPDs (13). The present of transient LPDs was observed in a patient with hyponatremia, suggesting a potential with “hemispheric ischemic disturbance triggered by reduced blood sodium levels” (14). The initial neuroimaging findings of our patient revealed abnormalities; however subsequent follow-up examinations were consistently within normal limits. The child developed partial seizures, and the EEG showed LPDs, suggesting that the pathogenesis is not solely attributed to metabolic factors.

Our patient presented with CNS. Limited literature exists regarding neonatal convulsions associated with CNS in the absence of radiologic or pathologic evidence of focal cerebral lesions. The majority of reports suggest that seizures in nephrotic syndrome are attributed to cerebral venous thrombosis or hypertensive encephalopathy (15,16), neither of which were evident in our case. The occurrence of congenital nephrosis has been reported to be associated with microcephaly, as well as severe central nervous system malformations, such as Galloway-Mowat syndrome (17). These conditions often lead to seizures by leukodystrophy (18,19). Additionally, studies have implicated CNS as a result of variants in NPHS1 gene (20-22), which lead to the production of a truncated nephrin protein that may affect nephrin trafficking to the cell membrane (23). Our patient was diagnosed with CNS and carried two heterozygous NPHS1 variants, which is consistent with previous research. No direct association between NPHS1 gene variants and neonatal convulsions has been documented in the existing literature. In the present case, the patient’s CSF white blood cell count, blood culture, and complete blood count were all unremarkable; furthermore, a history of perinatal asphyxia was ruled out. These findings collectively exclude neonatal convulsions secondary to sepsis, intracranial infection, or hypoxic-ischemic encephalopathy. Therefore, we hypothesize that the infant’s seizures may be attributable to the identified PLEKHG2 gene variants. PLEKHG2 plays a crucial role in vesicle trafficking and cytoskeletal organization and is expressed in various tissues, including the brain, located on chromosome 19q13.32 (24). Although the precise function of PLEKHG2 remains incompletely understood, it is believed to play a key role in regulating vesicle trafficking and cytoskeletal organization. Variants in this gene have been associated with various neurological conditions, including cerebral palsy, intellectual disability, and epileptic encephalopathy (25). Previous studies have established a connection between neonatal convulsions and abnormal brain development as well as dystonia caused by PLEKHG2 variants (26). Simon Edvardson et al. reported on five patients with profound intellectual disability, dystonia, postnatal microcephaly, and common brain MRI findings, being homozygous for a pathogenic variant in one of the recently characterized RhoGEFs, PLEKHG2, which was found to impact the rearrangement of the actin cytoskeleton. Such disruption leads to failed neuronal migration, aberrant axonal and dendritic development, and synaptic dysfunction, which in turn cause abnormal cerebral cortex structure and disrupted basal ganglia motor circuitry, ultimately manifesting as intellectual disability, dystonia, epilepsy, and other related symptoms. Specifically, two patients carried the homozygous variant c.610 C>T in the PLEKHG2 gene (27). This finding aligns with the local gene variant observed in our pediatric patient. No direct biochemical interactions or shared signaling pathways between the NPHS1 and PLEKHG2 genes have been documented currently. These genes exhibit substantially divergent biological functions, cellular expression patterns, and disease associations. It is therefore unlikely that they cooperatively contribute to a unified composite phenotype. When pathogenic variants occur in both genes, the resulting clinical picture reflects an additive combination of the two distinct conditions rather than a novel syndromic entity. This perspective aligns with the case we present, in which the affected child exhibited two discrete clinical manifestations: nephrotic syndrome and epileptic seizures. Given this additive phenotypic pattern, the consistency further supports the hypothesis that seizures in our patient may be attributed to PLEKHG2 gene variants. However, there was no evidence of leukodystrophy or dystonia, nor was microcephaly observed in our patient. It is possible that the age of our patient may hinder the detection of abnormalities as the age, neuroimaging might reveal anomalies. Additionally, a c.3874C>T (p.R1292W) variant in the PLEKHG2 has been identified in our patient. No correlation for this specific locus has been reported in the literature database. We propose that this gene variant at this site might contribute as one of the factors triggering seizures shortly after birth.

Conclusions

In this study, we presented a case associated with NPHS1 and PLEKHG2 gene variants. The initial manifestation was convulsions, accompanied by EEG features displaying LPDs. The PLEKHG2 gene emerges as a novel potential candidate implicated in the development of cerebral white matter injury induced LPDs. However, there is limited literature in this field, necessitating further studies to confirm this association and comprehend the underlying mechanisms. Elucidating how PLEKHG2 variants contribute to LPDs might unveil innovative targets for therapeutic intervention in patients with refractory epilepsy and severe brain injury.

Acknowledgments

We would like to express our gratitude to the colleagues in the gene laboratory for their help to analyze the gene results.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-441/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-441/prf

Funding: This research was supported by Horizontal Fund of Zhejiang University (grant No. 2020-KYY-518055-0028).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-441/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the Children’s Hospital of Zhejiang University School of Medicine (No. 2024-IRB-0001-P-01). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Informed consent was obtained from the guardians of the infant. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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