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Título

EPILEPSY SECONDARY TO GABRG2 MUTATION AND UNFAVORABLE EVOLUTION

Apresentação do caso único

Introduction: The GABRG2 gene encodes the gamma-2 subunit of the GABA A receptor, an essential component of the GABA A receptors, main mediators of inhibitory neurotransmission in the central nervous system (CNS). Dysfunctions in this gene lead to increased neuronal excitability predisposing epileptic seizures. The clinical spectrum ranges from epilepsy with febrile seizures plus (GEFS+), absence epilepsy, to Dravet syndrome. This paper aims to present a case of severe refractory epilepsy and early onset, secondary to a mutation in the GABRG2 gene, considered until recently a variant of uncertain significance (VUS).

Case report: MPVM, female, was brought to the child neurology clinic at 2 months of age with a history of epileptic seizures since birth. The parents were healthy, young, non-consanguineous. The child was born at term, elective caesarean section, appropriate for gestational age, no complications, discharged within 72 hours. The father had self-limited childhood epilepsy. The infant had three types of seizures: repeated eye movements, lasting seconds, always occurring when she fell asleep; head turn, switching sides, upper limb lift and hypertonia ipsilateral; and orofacial clonus, lasting seconds. The episodes were daily and occurred several times a day. On physical examination, the infant was drowsy, with global hypotonia and deficient bilateral palmar-plantar grip. The first electroencephalogram displayed disorganized baseline activity, bilateral frontotemporal epileptiform activity and five focal electroclinical seizures. Cranial nuclear magnetic resonance imaging was normal. Next generation sequencing detected probable pathogenic variants (c.747C>G and c.377G>A) in heterozygosis in the TUFM (NM_003321.5) and GAA (NM_000152.5) genes and at the time a variant of uncertain significance (VUS) in the GABRG2 gene (NM_198904.4):c.941C>A p.(Thr314Lys), which was later confirmed as the pathogenic variant responsible for the condition. Several attempts at treatment with anticonvulsant drugs (AEDs) in mono and polytherapy were unsuccessful and the patient came to die in her first year of life.

Discussão

Patients with mutations in the GABRG2 gene may present with drug resistant epilepsy associated with delayed neuropsychomotor development and behavioral changes.

Comentários finais

This clinical case, with its dramatic presentation, portrays the challenging treatment aspect of this mutation, considered VUS until recently, due to the refractory nature of its epilepsy.

Referências

1) FENG, Y.; WEI, Z. H.; LIU, C.; LI, G. Y.; QIAO, X. Z.; GAN, Y. J.; ZHANG, C. C.; DENG, Y. C. Genetic variations in GABA metabolism and epilepsy. Seizure, v. 101, p. 22-29, out. 2022. DOI: 10.1016/j.seizure.2022.07.007. Disponível em: https://pubmed.ncbi.nlm.nih.gov/35850019/. Acesso em: 14 jun. 2024.

2) YANG, Y.; NIU, X.; CHENG, M.; ZENG, Q.; DENG, J.; TIAN, X.; WANG, Y.; YU, J.; SHI, W.; WU, W.; MA, J.; LI, Y.; YANG, X.; ZHANG, X.; JIA, T.; YANG, Z.; LIAO, J.; SUN, Y.; ZHENG, H.; SUN, S.; SUN, D.; JIANG, Y.; ZHANG, Y. Phenotypic Spectrum and Prognosis of Epilepsy Patients With GABRG2 Variants. Frontiers in Molecular Neuroscience, v. 15, p. 809163, 14 mar. 2022. DOI: 10.3389/fnmol.2022.809163. Disponível em: https://pubmed.ncbi.nlm.nih.gov/35359574/. Acesso em: 14 jun. 2024.

3) HAERIAN, B. S.; BAUM, L.; KWAN, P. et al. Contribution of GABRG2 Polymorphisms to Risk of Epilepsy and Febrile Seizure: a Multicenter Cohort Study and Meta-analysis. Molecular Neurobiology, v. 53, p. 5457-5467, 2016. DOI: 10.1007/s12035-015-9457-y. Disponível em: https://doi.org/10.1007/s12035-015-9457-y. Acesso em: 13 jun. 2024.

Palavras Chave

GABRG2 gene; mutations; refractory epilepsy