Nowa mutacja genu CDKL5 u irańskiego dziecka z opornością na leki przeciwpadaczkowymi od wczesnego dzieciństwa
A novel de novo variant of CDKL5 in an Iranian child with infantile-onset refractory epilepsy
W skrócie
U małej dziewczynki z Iranu zidentyfikowano nowy defekt genetyczny w genie CDKL5, który powoduje ciężką epilepsję oporną na leczenie, opóźnienie rozwoju i osłabienie mięśni. Ten defekt genetyczny zmienia strukturę ważnego białka mózgu i powoduje jego przedwczesne zniszczenie. Dziewczynka dobrze reaguje na połączenie dwóch leków - walproinianu i lamotriginy, co pokazuje, że badania genetyczne pomagają w szybkim rozpoznaniu i wyborze odpowiedniego leczenia dla każdego pacjenta.
Oryginalny abstract (angielski)
BACKGROUND: Epilepsy is defined as a long-term brain disease with recurrent and spontaneous seizures that often begin in childhood and encompass a wide range of etiologies, including genetic factors. This study aimed to identify and characterize the genetic cause underlying developmental delay and refractory epilepsy in an Iranian patient. METHODS: We performed a prospective evaluation of an Iranian girl presenting with developmental delay, refractory seizures, and hypotonia. The case was referred to the Genetic Research Center, Meybod,, Iran. Whole exome sequencing and Sanger sequencing were performed to identify the disease-causing variant and validate it, respectively. Also, bioinformatic analyses were used to evaluate the predicted pathogenicity and structural consequences of the variants. RESULTS: A novel de novo frameshift variant in CDKL5 gene (c.1037_1038delTCinsCAGATCTAA, p.Ile346Thrfs*14) was identified and classified as pathogenic based on ACMG criteria. The variant is predicted to engender a premature stop codon, leading to extensive shortening of the protein and loss of essential functional domains. Additionally, Valproate-Lamotrigine combination therapy resulted in significant clinical effects, such as a considerable reduction in the number of seizures. CONCLUSION: The present study can expand the mutational spectrum of CDKL5 and highlight the clinical advantage of sequencing-based genetic testing for early diagnosis and personalized therapeutic management of refractory epilepsy.