The ROGDI gene consists of 11 exons and codes for a 287 amino acid protein. It is highly conserved across various species, mainly expressed in the human brain and spinal cord (16). Prior to 2017, little was known about the protein encoded by ROGDI. However, the ROGDI protein is enriched at synaptic sites and co-localizes with the presynaptic scaffolding Bassoon protein, as well as the synaptic vesicle markers Synaptophysin, Synapsin-1, VAMP2/Synaptobrevin, and Mover (17). ROGDI plays a crucial role in presynaptic targeting and facilitates efficient signal transmission.
ROGDI-related KTS has been reported in 43 cases, and the loss of function (LOF) has been proposed as a pathological mechanism (3). Null mutations, including deletions, duplications, frameshifts, and intronic variations, have been identified in various cases of ROGDI mutations and may potentially lead to the complete LOF (5). The c.507del deletion variant (located in exon 7) was found to be the genetic cause in 15.9% of KTS cases, leading to a frameshift mutation of ROGDI and LOF. Additionally, the c.229_230del deletion variant (located in exon 4) and the intronic variant c.531 + 5G > C (located in intron 7) were identified in 4.5% and 13.6% of KTS cases, respectively, and the latter was predicted to disrupt the splice donor site of ROGDI, both resulting in LOF. The c.45 + 9_45 + 20del intronic variant (located in intron 1) was identified in 6.8% of KTS cases, which might cause a splicing error that led to LOF of ROGDI. Furthermore, the nonsense variant c.469C > T (located in exon 7) was identified in 36.4% of KTS cases, predicted to cause premature termination of the peptide chain. The c.201-1G > T intronic variant (located in exon 3) was identified in 6.8% of KTS cases, predicted to have disrupted the splice acceptor site in exon 4, resulting in LOF of ROGDI. In this study, we also identified a homozygous variant (c.46–37_46–30del) in intron 1, predicted to have disrupted the splice acceptor site in exon 2, causing complete LOF of ROGDI. The rest variants listed in Table 2 were identified once yet. However, the number of cases is not sufficient for a possible mutational hot spot definition (2).
Epilepsy is the most common initial symptom in KTS patients. The age of seizure onset varies widely, with a median age of 10 months (range: 0–48 months). At present, no evidence indicates that early-onset seizures are a risk factor for a negative prognosis (1, 13, 14). Seizure frequency typically decreases with age, expect individuals with RE (5, 13). Our knowledge of KTS-related epilepsy is limited, and seizures can manifest in diverse forms without discernible patterns, as noted in prior studies (12, 14, 18). Furthermore, the existing evidence does not adequately account for the relationship between genotype and seizure phenotype. This is exemplified by the observation that families with the same variation c.46–37_ 46–30del display diverse seizure patterns (14). The assistance offered by VEEG/EEG results is also severely limited (5, 10, 12–14, 18). Based on our summary of the VEEG/EEG results of the 44 KTS patients, we did not find any correlation between genotypes and discharge patterns. The exact pathogenesis of epilepsy in KTS patients caused by ROGDI gene mutations remains unknown. In view of the exocytosis of neurotransmitters and synaptic vesicle recycling are hallmarks of presynaptic function at mature synapses, Donatus Riemann et al. put forward one possibility that ROGDI may regulate exocytosis in neurons and the dysfunctional exocytosis would affect neural development and synaptic function (17). Notably, BASSOON, which encodes the BASSOON protein and co-localizes with the ROGDI protein, has been recently identified as an epilepsy gene (19). Additionally, ROGDI is involved in sleep regulation via dopaminergic signaling mediated by GABAergic pathways (20). Therefore, ROGDI gene mutation might affect the expression of the ROGDI protein, affect the expression of the co-located BASSOON protein, and disrupt the ROGDI-GABAergic signaling pathway, ultimately leading to epilepsy. Nevertheless, this hypothesis needs further functional validation through experiments on animals or cells by silencing ROGDI expression and monitoring changes in BASSOON expression and the GABAergic signaling pathway.
Amelogenesis imperfecta is another significant symptom of KTS. To date, all KTS patients involve amelogenesis imperfecta. However, the underlying mechanism of ROGDI-related amelogenesis imperfecta remains unknown. KTS patients had very thin, soft, rough enamel and brown-stained enamel, which is susceptible to disintegration (1). Yellow enamel was discovered when our patient was one year old. She was already displaying global developmental delay and epilepsy. However, due to the rarity of KTS and the lack of awareness among clinicians, a diagnosis of KTS was not made, and genetic testing was not completed at once. It is advisable to remain vigilant about the potential for KTS and complete genetic testing as soon as possible when there is a link between amelogenesis imperfecta, global developmental delay, and epilepsy.
Global developmental delay frequently causes significant distress for both KTS patients and their families. While most KTS cases exhibited global developmental delay or regression after the onset of epilepsy, approximately 20% of patients showed global retardation before epilepsy occurred (2–5, 11, 13, 14, 18). According to the reported cases, such children usually start walking at 2–5 years of age (5, 8, 11, 13, 21), and some may lose the ability to walk during long-term follow-up due to spasms and abnormal gait (2, 13). With a long period of uninterrupted rehabilitation training, our patient started walking when she was 25 months old. She could walk alone without spasms and abnormal gait for now, but his gait was not very stable yet (Supplementary material: Video 1). No genotype has been found to be associated with the degree of dyskinesia so far. Even patients with the same genotype can exhibit varying degrees of dyskinesia. For instance, two patients with the same mutation as in this study started walking independently at 24 and 21 months, respectively, which were similar to our patient (14). However, one of the two patients was unable to stand up even at six years old. Therefore, we believe that this phenomenon is not only associated with the heterogeneity of clinical presentation but also with the persistence of rehabilitation training over six years.
Additionally, the language disabilities of KTS patients are significantly impacted. The ROGDI gene codes for a protein involved in the development of glial cells and neuron migration. Mutations in this gene may result in connectivity and communication issues between brain regions, which can affect both language development and comprehension (22, 23). Table 1 presented a summary of our findings that indicated varying degrees of language impairment among all KTS patients for whom data was available. Language impairment manifests as either a complete absence of verbal communication or severely limited verbal abilities. The patient in our study also exhibited limited verbal communication skills.
There is currently no evidence that the frequency of seizures is associated with early-onset developmental delays in KTS patients (3, 5, 13, 18). However, when it comes to epilepsy and developmental delays, epilepsy may lead to developmental delay, particularly with prolonged or frequent seizures. Conversely, developmental delay may increase the risk of epilepsy. Some genetic mutations, including ROGDI gene mutations, can result in the simultaneous occurrence of epilepsy and developmental delay. Hence, it is crucial to consider and manage both conditions concurrently in clinical management.
It is not clear whether KTS is associated with any comorbidities. However, our analysis of the limited number of cases available (Table 1) suggested that five patients had ADHD and one patient had suspected ASD (2, 8, 13, 18). Although this evidence is not definitive, we speculate that there may be a link between KTS and comorbidities. Given that some KTS patients have exhibited self-harm behaviors, aggression, or impulsivity, it is strongly recommended to pay close attention to the possible presence of comorbidities (2, 11–13). We advocate for strengthening psychological interventions and adopting multidisciplinary management approaches for KTS patients to prevent accidental injury.
Currently, no recommendations exist regarding the use of ASMs for these patients. However, we observed a positive response to PMP in the patient described in this report, which is consistent with a case reported by Lelde Liepina (12). Following PMP treatment, the patient remained seizure-free for five months and exhibited a significant reduction in epileptic discharges, as evidenced by VEEG results. Moreover, the patient’s mother reported that her child made notable improvements in gross motor development following PMP treatment. PMP is an anticonvulsant with a unique pharmacological profile. It acts as a non-competitive antagonist of AMPA receptors, which inhibits the AMPA receptor-mediated current in single neurons (24, 25). The anticonvulsant effect of PMP is due to its ability to disrupt the AMPA receptor-dependent recruitment of pyramidal-inhibitory neuronal network oscillations. This disruption is achieved through dynamic glutamatergic and GABAergic transmission (26). Given that ROGDI can influence GABA neurotransmission and the mechanism of PMP in treating epilepsy, we speculate that this may explain why PMP is effective in treating KTS patients (20). Nonetheless, the exact pharmacological mechanisms require additional investigation and clinical evidence. Regardless, we suggest that clinicians may contemplate PMP therapy for KTS patients with epilepsy as it could potentially decrease seizure frequency and enhance motor development.