Epilepsy is a recurrent chronic neurological disorder caused by sudden abnormal discharge of brain neurons, resulting in short-term brain dysfunction. A meta-analysis study estimated that the prevalence of epilepsy in China increased from 1.99‰ to 7.15‰ between 1990 and 2015 (1). Improved diagnostic methods have led to an increase in the number of reported epilepsy cases. Early diagnosis is crucial for proper management, given that nearly 30% of patients exhibit resistance to antiepileptic drugs. (2, 3).
The main genetic cause of infantile epilepsy is variability in the sodium voltage-gated channel alpha subunit 1 gene (SCN1A), and mutations in the protocadherin 19 gene (PCDH19) constitute the second most common cause (4). Mutations in the SCN1A gene have been associated with various seizure disorders, such as genetic epilepsy with febrile seizures plus (GEF+) and Dravet syndrome (5). PCDH19, a member of the cadherin super family, is mainly expressed in the nervous system. PCDH19 is located on chromosome Xq22, and its mutation leads to early infantile epileptic encephalopathy-9 (EIEE9, OMIM# 300088) (3).
EIEE9 is also called epilepsy and mental retardation limited to females (EFMR, MIM# 300088) and PCDH19-related epilepsy. It is an X-linked genetic disorder that affects heterozygous females and is transmitted through unaffected males. It is characterized by the onset of seizures during infancy sans cognitive impairment, various intellectual disturbances, and autistic features (3). Typical clinical features of PCDH19-related epilepsy include generalized or focal seizures, high sensitivity to fever, and occurrence in clusters (6).
Since the PCDH19 mutation was first reported to be related to EIEE9, many studies have expanded the clinical spectrum associated with variations in PCDH19(7–9). These studies demonstrated that next generation sequencing has the potential to elucidate the pathogenic mechanism underlying EIEE9 and yield information on gene mutation sites. This information can be useful for diagnosing individuals suspected with epilepsy and provide the basis for personalized treatment, genetic counseling, and disease risk assessment.
Our study aimed to identify causative variants of pathogenic genes and to confirm the diagnosis of epilepsy. In the current study, we identified a pathogenic de novo mutation with a high degree of association with the phenotype of PCDH19-related epilepsy in a girl. Our study introduces a pathogenic variant of EIEE9. This finding may contribute to more efficient diagnosis and treatment of this form of epilepsy.
Case presentation
Clinical phenotype and physical examination
The proband is a girl, 3 years and 10 months old, who had been experiencing recurrent epileptic seizures for more than 2 years. She was admitted to the pediatric ward of Shenzhen People’s Hospital in July 2020. At the age of 18 months, she had 3-day-long episodes of clustered febrile seizures characterized by loss of consciousness, eyes rolling upwards, drooling, and shaking limbs. Each episode lasted approximately 30 s to 1 min. Febrile convulsions occurred 2–3 times per year during the 2018–2019 period. In the same period, she also experienced recurrent febrile seizures, with such seizures lasting for 2–7 days. Although the patient did not exhibit any signs of intellectual disability (ID) or autism, she was inattentive and impulsive. Her parents were nonconsanguineous and had no family history of febrile seizures or epilepsy. Clinical data and physical examination did not indicate any signs of abnormalities. Head magnetic resonance imaging (MRI) findings were normal(Fig. 1). Serum ceruloplasmin and electrolyte levels were normal, and infection markers and autoimmune encephalitis antibodies were negative.
Electroencephalographic pattern and epilepsy diagnosis
Electroencephalography (EEG) was performed. The resting awake state (eyes closed) was characterized by a well-formed and fairly sustained posterior dominant rhythm of 5–6Hz of moderate amplitude, which was attenuated with eye opening. The frequency amplitude gradient was moderately well organized, and the background consisted of minimal delta, moderate theta, and decreased alpha and beta frequencies. No significant regional asymmetries of background activity were noted (Fig. 2A). The interictal period showed a few high-amplitude, generalized spike-and-wave or sharp-wave discharges (2–3.5 Hz) in the awake period, whereas a few high-amplitude spikes/sharps and spike/sharp waves were prominent in bifrontal areas in the awake and sleeping periods (Fig. 2B-D).
Seizure onset was signaled by a sudden jerk of the body while sleeping, eye opening, staring to the right, raised right upper limb, stiffness of the extremities, posture maintenance, and slight clonus. The synchronous EEG was characterized by generalized spike-and-wave or sharp-wave discharges, or by triphasic waves intermixed with low-amplitude fast activity. Generalized low-amplitude fast activity appeared in the initial portion of the epoch; activity gradually increased in frequency and amplitude and developed into continuous generalized spike waves. The high-frequency activity lasted for approximately 50–60 s and overlapped with many muscle artifacts recorded simultaneously in the electromyogram (EMG) bursts (Fig. 2E-H). The EEG features strongly supported the diagnosis of epileptic encephalopathy.