DEPDC5 mutations in familial epilepsy syndrome: genetic insights and therapeutic approaches

INTRODUCTION / ВВЕДЕНИЕ

DEPDC5 (disheveled, Egl-10 and pleckstrin domain-containing protein 5) familial epilepsy syndrome is a group of epilepsy disorders caused by the activation of the mechanism target of rapamycin (mTOR) pathway. It is associated with mutations in the recently discovered DEPDC5 gene, which is a part of the gap activity towards rag 1 (GATOR1) complex responsible for regulating mTOR signaling [1]. The mTOR pathway is vital for cellular growth and proliferation, particularly in the brain, where it contributes to neuronal differentiation, synaptogenesis, and dendrite formation, shaping the complex structure of the cerebral cortex [2]. DEPDC5 encodes an inhibitory component of mTOR, and mutations in DEPDC5 result in the hyper activation of mTOR, contributing to the development of the syndrome [1]. This syndrome manifests in various seizure types, including focal seizures, generalized tonic-clonic seizures, SUDEP, and myoclonic seizures [3].

It is worth noting that DEPDC5 variants have been detected in approximately 20% of patients with different brain lesions, making it challenging to differentiate between pathological brain conditions and normal brain structure [4].

Brain imaging such as magnetic resonance imaging (MRI), electroencephalography (EEG) and genetics have played a crucial role in not only identifying brain lesions but also in diagnosing them. Long-term EEG monitoring reveals progressive features of epileptic encephalopathy associated with DEPDC5 mutations, including increasing frequency of multifocal discharges originating from multiple regions in either hemisphere [2]. Individuals with DEPDC5 mutations exhibit distinct EEG patterns, such as stronger theta oscillations and pronounced gamma oscillations, indicating increased cortical excitability and hyperactive mTOR signaling [5]. Brain MRI scans often show bilateral polymicrogyria, macrocephaly, and abnormalities in the corpus callosum, pons, and basal ganglia. However, normal MRI results are also common [1].

The clinical significance of missense or splice-region variants in DEPDC5 is not fully understood, the incomplete penetration of variants adds to the challenge of interpreting these mutations clinically [2]. Despite advancements in genetic testing, brain MRI, and EEG, some cases of this familial epilepsy syndrome remain idiopathic [6]. Additionally, certain patients do not respond to treatment [7]. Therefore, further research is necessary to understand the harmful effects of DEPDC5 gene mutations and improve the clinical interpretation and therapeutic of this condition.

CASE REPORT / КЛИНИЧЕСКИЙ СЛУЧАЙ

A 6-year-old South-Asian girl was born at 34 weeks from non-consanguineous marriage without any prenatal events. She had hyperbilirubinemia by week 1, which was successfully treated with phototherapy.

History of disease / Анамнез

The patient had first seizure episode at 3 months, 2 days after “vaccination fever” subsided. It was considered a simple-febrile seizure and no treatment was given. At 3.5 months, she started having recurrent seizures. Workup including MRI/infectious/metabolic panel was non-conclusive. Despite being on multiple anti-epileptic drugs (levetiracetam, valproate, phenobarbital and biotin) she has refractory epilepsy.

By 10 months of age, she was able to hold her neck and turn prone, fixate her eyes on objects occasionally, and turn her neck in response to auditory stimuli from both sides. However, her tonic labyrinthine reflex and neck righting reactions still persisted, indicating a delay in the development of cortical reflexes. Consequently, the patient was unable to maintain a sitting position and could only sit up from a supine or prone position, lacking the ability to bear weight. Moreover, she exhibited a lack of basic exploratory play and struggled to maintain eye contact with her family and others. The dynamic sitting and static balance were notably poor. Additionally, at 10 months, the child could not consume mashed food, showed fear towards simple sounds, and struggled with sitting and holding objects. Her tongue, lip, and jaw movements were impaired, resulting in an inability to suck or blow. Furthermore, she engaged in stereotypic behaviors such as rocking her head and body while sitting and flexing her head and trunk forward, leading to frequent falls.

The seizure event was characterized by widening of the eyeballs followed by flickering of right eyelids and tonic-clonic movement of all limbs. Around age 1 year the patient presented with status epilepticus, followed by seizure episode daily.

EEG and MRI data / Данные ЭЭГ и МРТ

EEG during the initial presentation showed epileptiform activity from the left temporal region (Fig. 1a). Subsequently, EEG at 2.5 years showed inter-ictal bi-hemispheric epileptiform activity. EEG at 5 years showed inter-ictal spikes and wave discharges from bilateral fronto-temporal region with secondary generalization (Fig. 1b).

At age 3.5 months, MRI was normal with no focal abnormality seen (Fig. 2a). By 3 years, MRI showed mildly deformed corpus callosum with inadequate thickening of splenium (Fig. 2b).

DNA analysis / Анализ ДНК

DNA analysis confirmed heterozygous missense mutation in exon 16 of DEPDC5 gene, without chromosomal abnormalities. Mother is heterozygous for the same mutation and father is normal.

The patient has grossly delayed milestones. The corrected age is approximately 1 year for Fine motor and Language, 1.5 years for Gross motor, 2.5 years for Cognition, Social, and Emotional skills. She has autism, impaired auditory/visual processing, and is hypersensitive to external stimuli. She has hypotonia (Right>Left), wide-based gait, and extrapyramidal movements.

Developmental growth / Возрастное развитие

On examination of the first episode of seizure at 3.5 months, the patient had no response to name and short attention span, no crawling. She had head control and turned prone.

10.5 months: the child showed response to name, short attention span, stereotypes, tried to reach to object.

1 year 7 months: the patient recognized parents, throwed and held objects, made single vowel sounds, began separation anxiety, established meaning of no.

2 year 3 months: the child stood with support, walked a few steps with support, had multiple stereotypes.

3 years: she had action tremors, no orientation respond to simple command, mixed ataxia, started speaking bisyllables words.

5 years: the patient had wide based gait and extrapyramidal movements which increased during evening, comprehended the command, meaningless bisyllables, biting repetitive activities.

6 years: she walked with support, was not toilet trained, had hypotonia Rt>Lt.

Chronological therapy / Терапия

Physiotherapy started at 6 months. Occupational therapy and sensory integration treatment started at 8 months.

After administering infant/toddler sensory profile (7–36 months) the patient had probably low functioning in auditory and visual processing areas. She was hypersensitive to tactile, auditory and proprioceptive stimulation and had bilateral integration problems.

Speech therapy started at 2 years. The patient still couldn't perform regular activities, played and talked normally.

Due to physiotherapy, speech therapy, occupational therapy and special education on a daily basis, the improvements were found.

Currently, the patient is on topiramate (100 mg twice daily), oxcarbazepine (5 ml twice daily), clobazam (5 mg twice daily).

DISCUSSION / ОБСУЖДЕНИЕ

DEPDC5 familial epilepsy syndrome comprises a collection of epilepsy conditions triggered by the stimulation of the mTOR pathway. This syndrome is linked to mutations in the newly identified DEPDC5 gene. This gene is a component of the GATOR1 complex, which plays a role in overseeing the signaling of the mTOR pathway [1]. The DEPDC5 gene plays a crucial role in shaping the dendrites and spines of neurons, and when this function is disrupted by mutations in DEPDC5, it can lead to increased excitatory transmission and the development of epilepsy; moreover, abnormal shaping of neurons is linked to neuropsychiatric disorders, explaining the observed psychiatric and autistic symptoms in patients with DEPDC5 mutations [3].

The precise occurrence and prevalence of DEPDC5 familial epilepsy syndromes remain insufficiently established. However, C. Martin et al.'s research into recurrent epilepsy linked with DEPDC5 mutations identified an incidence of 5% (4/79) among individuals with such mutations [4]. Mutations in the DEPDC5 gene could potentially explain up to 10% of cases of familial focal epilepsy [4]. Furthermore, L.M. Dibbens et al. indicated that among 82 families afflicted by the disorder, 12% exhibited the DEPDC5 mutation, underscoring its role as a potential cause of familial epilepsy syndrome [6]. Within a sample of 15 families affected by familial epilepsy syndrome, the DEPDC5 gene harbored five mutations: one missense mutation and four nonsense mutations. This same study revealed that there is evidence suggesting that 37% of patients with familial epilepsy syndrome carry a loss-of-function mutation in the DEPDC5 gene [8].

Table 1 discusses pediatric and adolescent familial epilepsy syndromes, which comprises a range of genetic disorders characterized by recurrent seizures typically emerging during childhood or adolescence. These syndromes, including Dravet syndrome, childhood absence epilepsy, juvenile myoclonic epilepsy, Lennox–Gastaut syndrome, benign familial neonatal epilepsy, and early myoclonic encephalopathy, result from mutations in various genes such as SCN1A, GABRG2, EFHC1, KCNQ2, KCNQ3, and STXBP1. The inheritance patterns vary, with some following autosomal dominant patterns (e.g., benign familial neonatal epilepsy, early myoclonic encephalopathy) and others being sporadic (e.g., Lennox–Gastaut syndrome). Understanding these genetic factors is essential for accurate diagnosis, management, and potential treatments of these epilepsy syndromes. Ongoing research continues to unveil new mutations and genes associated with these conditions.

Table 2 offers a concise summary of several research studies focused on different diseases, the associated genetic mutations, and the more recent targeted therapies employed for their treatment. These investigations provide insights into potential advancements in managing various medical conditions and enhancing patient outcomes. In our case study, the patient is currently undergoing a triple therapy regimen consisting of topiramate 100 mg twice daily, clobazam 5 mg twice daily, and oxcarbazepine 5 ml twice daily. Additionally, the patient is receiving a combination of physiotherapy, occupational therapy, and speech therapy. Despite this comprehensive, multidisciplinary approach, the patient has not yet achieved complete recovery. This underscores the critical need for the development of innovative-targeted therapy approaches.

Table 3 encompasses a compilation of studies delving into DEPDC5-related epilepsy, a specific type of genetic focal epilepsy. Most of these studies revealed normal results in brain MRI scans, with the exception of a single study reporting a mix of normal and abnormal findings [22]. DEPDC5 mutations were identified across all the studies, and the individuals included in the research covered a wide range of age groups. Additional assessments, such as EEG and genetic testing, were conducted to confirm the presence of DEPDC5 mutations. The primary approach to managing this condition typically involved the administration of antiepileptic medications, though the response to treatment varied among individuals.

In our own case report, a DNA analysis confirmed the presence of a heterozygous missense mutation in exon 16 of the DEPDC5 gene, with no observed chromosomal abnormalities. Our case report also highlighted an abnormal MRI result, characterized by a mildly deformed corpus callosum with insufficient thickening of the splenium by the age of 3 years (see Fig. 2b). However, the MRI conducted at approximately 3.5 months of age yielded inconclusive results (see Fig. 2a).

The strength of this case lies in the confirmation of genetic testing aligning with the abnormal MRI findings, specifically the mildly deformed corpus callosum with inadequate thickening of the splenium (see Fig. 2a). Additionally, the EEG assessments at various time points (3 months, around 2.5 years, and 5 years) further support the diagnosis, with observations of epileptiform activity from the left temporal region at 3 months (see Fig. 1a), inter-ictal bi-hemispheric epileptiform activity around 2.5 years, and interictal spikes and wave discharges from the bilateral fronto-temporal region with secondary generalization at 5 years (see Fig. 1b).

It is important to note that while these findings validate the specific case under consideration, they cannot be generalized as representative of all cases due to the unique nature of each individual's condition. Besides, we do not have a full familial and/or hereditary picture of the patient except for the fact that the mother is heterozygous for the mutation.

Future directions / Направления дальнейших исследований

Valuable insights into the clinical features, diagnostic tools, and management of DEPDC5 gene mutation familial epilepsy syndrome are needed to shed light on this rare and challenging diagnosis. The variability in brain MRI results, ranging from positive to negative findings, further adds to the complexity of the syndrome. Despite advancements in genetic testing and personalized medicine, some patients still do not respond to treatment, highlighting the need for further research and therapeutic advancements. The rarity of the disease and the challenges it presents serve as compelling reasons to document this case report on DEPDC5 gene mutation familial epilepsy syndrome, aiming to enhance understanding and improve patient care in the future.

CONCLUSION / ЗАКЛЮЧЕНИЕ

DEPDC5 familial epilepsy syndrome is a group of epilepsy disorders caused by mutations in the DEPDC5 gene, which is part of the GATOR1 complex involved in regulating the mTOR pathway. These mutations lead to hyperactivation of the mTOR pathway, disrupting the shaping of neurons and resulting in increased excitatory transmission and the development of epilepsy. The incidence and prevalence of DEPDC5 familial epilepsy syndromes are not well established, but studies suggest it may account for up to 10% of familial focal epilepsy cases. Genetic testing, EEG, and brain MRI are important in diagnosing the disorder, although normal MRI results are common.