Dados do Trabalho

Título

HIPPOCAMPAL ATROPHY, BEHAVIORAL DISORDER, AND EPILEPSY ASSOCIATED WITH ATP1A3 GENE MUTATION - A CASE REPORT.

Apresentação do caso único

JSBC, male, 17 years old, born to consanguineous parents, followed due to a history of tonic-clonic and bilateral myoclonic epileptic seizures associated with autonomic symptoms since 1 month and 27 days of age, along with delayed neuropsychomotor development, intellectual deficit, and attention deficit hyperactivity disorder. Clinical evaluation revealed dysmorphisms including flat forehead, thin eyebrows, bilateral convergent strabismus, high nasal bridge, hypoplastic ears, and flat valgus feet. He had a history of postnatal microcephaly, cryptorchidism, and asymmetric gynecomastia since age 14. Audiological evaluation was normal, and brain MRI showed left mesial temporal sclerosis with hippocampal hypoplasia, along with diffuse slowing of background activity on EEG. Given these findings, a genetic syndrome was suspected, and karyotyping and CGH-array analysis were normal. Exome sequencing revealed a heterozygous pathogenic variant in ATP1A3: c.2116G>A (p.Gly706Arg). His epileptic seizures were controlled with multiple anti-epileptic drugs (AEDs) until a breakthrough at age 17. He experienced progressive behavioral deterioration despite medication and moderate intellectual deficit despite psychostimulant use. He continues multidisciplinary clinical follow-up.

Discussão

Mutations in ATP1A3 gene are associated with neurological conditions, including refractory epilepsy. The patient presented with bilateral tonic-clonic, focal, and myoclonic seizures starting early in life, triggered by stress, extreme temperatures, physical exertion, and changes in lighting. Diagnosis is through genetic testing identifying pathogenic variants causing Na+/K+-ATPase dysfunction leading to neuronal hyperexcitability. EEG typically shows focal or generalized epileptiform discharges and diffuse disorganization, suggesting encephalopathy. Hippocampal sclerosis was also observed, possibly related to status epilepticus and damage in the mesial temporal region. Treatment is challenging due to AED resistance, with success rates below 50%. A significant portion of patients do not achieve seizure control even with combined treatments. Ketogenic diet is effective in some cases.

Comentários finais

Mutations in the ATP1A3 represent a significant genetic cause of epilepsy, often associated with other severe neurological manifestations. Variability in treatment response underscores the need for personalized therapeutic approaches and ongoing investigation to better understand underlying mechanisms.

Referências

1. Vezyroglou A, Akilapa R, Barwick K, Koene S, Brownstein CA, Holder-Espinasse M, Fry AE, Németh AH, Tofaris GK, Hay E, Hughes I, Mansour S, Mordekar SR, Splitt M, Turnpenny PD, Demetriou D, Koopmann TT, Ruivenkamp CAL, Agrawal PB, Carr L, Clowes V, Ghali N, Holder SE, Radley J, Male A, Sisodiya SM, Kurian MA, Cross JH, Balasubramanian M. The Phenotypic Continuum of ATP1A3-Related Disorders. Neurology. 2022 Oct 4;99(14):e1511-e1526. doi: 10.1212/WNL.0000000000200927. Epub 2022 Jul 18. PMID: 36192182; PMCID: PMC9576304.
2. Amadori E, Pellino G, Bansal L, Mazzone S, Møller RS, Rubboli G, Striano P, Russo A. Genetic paroxysmal neurological disorders featuring episodic ataxia and epilepsy. Eur J Med Genet. 2022 Apr;65(4):104450. doi: 10.1016/j.ejmg.2022.104450. Epub 2022 Feb 24. PMID: 35219921.
3. Gasser M, Boonsimma P, Netbaramee W, Wechapinan T, Srichomthomg C, Ittiwut C, Krenn M, Zimprich F, Milenkovic I, Abicht A, Biskup S, Roser T, Shotelersuk V, Tacke M, Kuersten M, Wagner M, Borggraefe I, Suphapeetiporn K, von Stülpnagel C. ATP1A3-related epilepsy: Report of seven cases and literature-based analysis of treatment response. J Clin Neurosci. 2020 Feb;72:31-38. doi: 10.1016/j.jocn.2020.01.041. Epub 2020 Jan 17. PMID: 31959558.
4. Heinzen EL, Arzimanoglou A, Brashear A, Clapcote SJ, Gurrieri F, Goldstein DB, Jóhannesson SH, Mikati MA, Neville B, Nicole S, Ozelius LJ, Poulsen H, Schyns T, Sweadner KJ, van den Maagdenberg A, Vilsen B; ATP1A3 Working Group. Distinct neurological disorders with ATP1A3 mutations. Lancet Neurol. 2014 May;13(5):503-14. doi: 10.1016/S1474-4422(14)70011-0. PMID: 24739246; PMCID: PMC4238309.
5. Heinzen EL, Arzimanoglou A, Brashear A, Clapcote SJ, Gurrieri F, Goldstein DB, Jóhannesson SH, Mikati MA, Neville B, Nicole S, Ozelius LJ, Poulsen H, Schyns T, Sweadner KJ, van den Maagdenberg A, Vilsen B; ATP1A3 Working Group. Distinct neurological disorders with ATP1A3 mutations. Lancet Neurol. 2014 May;13(5):503-14. doi: 10.1016/S1474-4422(14)70011-0. PMID: 24739246; PMCID: PMC4238309.

Palavras Chave

epilepsy; ATP1A3 gene mutation; hippocampal atrophy