Spektrum zmian genetycznych i objawy kliniczne u pacjentów z epilepsją spowodowaną zaburzeniami glikozylacji związanymi z wariantami genu GPAA1

OBJECTIVE: To delineate the genotype and phenotype of epilepsy patients with GPAA1-related congenital disorders of glycosylation (CDG). METHODS: Whole-exome sequencing was performed to all epilepsy patients suspected with genetic etiology from June 2017 to October 2025. Clinical data of five patients with GPAA1 variants from our study and 19 patients from published studies were collected and analyzed. RESULTS: This study collected five epilepsy patients with biallelic GPAA1 variants. Eight different GPAA1 variants were identified. All patients exhibited global developmental delay and hypotonia. Seizure occurred at 3-12 months of age. All five patients had myoclonic seizures, four patients had 2 or more seizure types. Cranial MRI revealed cerebellar atrophy in one patient. All patients had drug-resistant epilepsy. When combining data from this study and published studies, 28 variants were identified, including 19 missense variants, 5 frameshift variants, 3 intronic splicing variants, and one nonsense variant. The clinical manifestations included global developmental delay (100%), hypotonia (95.8%), and epilepsy (83.3%). 60% of patients experienced seizure onset before the age of one. The main seizure types were generalized tonic-clonic seizures (GTCS) (82.4%) and myoclonic seizures (70.6%). Febrile sensitivity was presented in 66.7% of patients. 60.9% of patients had cerebellar atrophy. CONCLUSIONS: The phenotypes of patients with GPAA1 variants included global developmental delay, hypotonia, and epilepsy. The main seizure types were GTCS and myoclonic seizures, and two-thirds of patients' seizures were characterized by febrile sensitivity. Cerebellar atrophy occurred in 60.9% of patients.