Asude DURMAZ, Erdem ŞİMŞEK, Seda KANMAZ, Sanem YILMAZ, Gül AKTAN, Hasan TEKGÜL, Sarenur GÖKBEN, Ayça AYKUT, Hepsen Mine SERİN

Dirençli Epilepsinin Tedavi Edilebilir Bir Nedeni: PiridoksinBağımlı Epilepsi

Amaç: Piridoksin bağımlı epilepsi, tipik olarak bebeklik veya erken çocukluk döneminde inatçı nöbetler ile seyreden nadir görülen otozomal resesif bir hastalıktır. Nöbetler geleneksel antiepileptik tedavilere dirençli olup, farmakolojik dozda piridoksine yanıt verir. Bu çalışmada Piridoksin Bağımlı Epilepsi (PBE) tanısı ile izlediğimiz altı hastanın klinik ve genetik özelliklerini sunmayı amaçladık.Gereç ve Yöntemler: Çocuk Nöroloji Bilim Dalı’nda piridoksin bağımlı epilepsi tanısı ile izlenen altı olgunun klinik ve genetik özellikleri ile prognozu retrospektif olarak değerlendirildi.Bulgular: Çalışmaya alınan hastaların 5’i erkek, 1’i kız olup, yaş ortalaması 6.83±3.71 yıldı. Nöbet başlangıç yaşı ortalama 22.33±31.77 (3-90 gün) olup, bir hasta (n:4) hariç diğerleri yenidoğan döneminde başlamıştı. Üç hastada fokal motor nöbet, 2 hastada jeneralize motor nöbet ve 1 hastada epileptik spazm izlendi. Hastaların vitamin B6 tedavisi bir hasta hariç erken dönemde başlandı. Erken dönem tedavi başlanan bir hasta dışında diğer hastalarda mental retardasyon, stereotipik hareketler ve otistik bulgular izlendi. Yapılan moleküler genetik analizde 5 farklı mutasyon saptanmıştır [2 olguda homozigot c.1597delG (p.Ala533ProfsTer18), 1 olguda homozigot c.781 A>G (p.Met261Val),1 olguda birleşik heterozigot c.328C>T (p.Arg110Ter)/c.1566-1G>T, 1 olguda heterozigot c.328C>T (p.Arg110Ter) ve 1 olguda heterozigot c.1356 A>C (p.Lys452Asn)].Sonuç: Piridoksin Bağımlı Epilepsi tedavi edilebilir epilepsi nedenlerinden biri olup açıklanamayan dirençli nöbetleri olan bebeklerde mutlaka düşünülmeli ve terapotik dozda piridoksin tedavisine başlanmalıdır.

Objective: Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disorder that typically presents with refractory seizures in infancy or early childhood. Seizures are resistant to conventional antiepileptic treatments and responsive to pharmacologic doses of pyridoxine. In this study, we aimed to present the clinical and genetic features of six patients followed up in our clinic with PDE diagnosis.Material and Methods: Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disorder that typically presents with refractory seizures in infancy or early childhood. Seizures are resistant to conventional antiepileptic treatments and responsive to pharmacologic doses of pyridoxine. In this study, we aimed to present the clinical and genetic features of six patients followed up in our clinic with PDE diagnosis.Results: Among six patients five were male and one was female. Mean age was 6.83 ± 3.71 years. The mean age of onset for seizures was 22.33 ± 31.77 (3-90 days). Seizures had started in the newborn period in all patients except one patient (n: 4). Three patients had focal motor seizures, 2 patients had generalized motor seizures and 1 patient had epileptic spasms. Vitamin B6 therapy was started in the early period except one patient. Mental retardation, stereotypic movements and autistic findings were observed in the all patients except one patient who had received early treatment. Molecular genetic analysis revealed 5 different mutations [homozygous c.1597delG (p.Ala533ProfsTer18) in 2 cases, homozygous c.781 A> G (p.Met261Val) in 1 case, compound heterozygous c.328C> T (p.Arg110Ter) / c.1566- 1G>T, 1 case heterozygous c.328C> T (p.Arg110Ter) and 1 case heterozygous c.1356 A> C (p.Lys452Asn) ] .Conclusion: Pyridoxine-dependent epilepsy is a treatable cause of epilepsy and should come to mind in infants with unexplained refrac-tory seizures. Treatment with a therapeutic dose of pyridoxine should be started promptly.

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1. Hunt Ad Jr, Stokes J Jr, Mccrory Ww, Stroud Hh. Pyridoxine dependency: report of a case of intractable convulsions in an infant controlled by pyridoxine. Pediatrics 1954;13:140–5.
2. Baxter P. Pyridoxine-dependent and pyridoxine-responsive seizures. Dev Med Child Neurol 2001;43:416–20.
3. Gospe SM Jr. Pyridoxine-dependent seizures: new genetic and biochemical clues to help with diagnosis and treatment. Curr Opin Neurol 2006;19:148-53.
4. Mills PB, Footitt EJ, Mills KA, Tuschl K,Aylett S,Varadkar S, et al. Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency). Brain 2010;133:2148-59.
5. Mills PB, Struys E, Jakobs C, Plecko B, Baxter P, Baumgartner M, et al. Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nat Med 2006;12:307–9.
6. Plecko B, Paul K, Paschke E, Stoeckler-Ipsiroglu S, Struys E, Jakobs C, et al. Biochemical and molecular characterization of 18 patients with pyridoxine-dependent epilepsy and mutations of the antiquitin (ALDH7A1) gene. Hum Mutat 2007;28:19-26.
7. Stockler S, Plecko B, Gospe SM Jr. Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up. Mol Genet Metab 2011;104:48-60.
8. Gordon N. Pyridoxine dependency: an update. Dev Med Child Neurol 1997;39:63-5.
9. SM Gospe. Pyridoxine-dependent seizures: findings from recent studies pose new questions. Pediatr Neurol 2002;26:181–5.
10. Nabbout R, Soufflet C, Plouin P,Dulac O. Pyridoxine dependent epilepsy: a suggestive electroclinical pattern. Arch Dis Child Fetal Neonatal Ed 1999;81:125-9.
11. L. Hellstrom-Westas L, Blennow G, Rosen I. Amplitude-integrated encephalography in pyridoxine-dependent seizures and pyridoxine-responsive seizures. Acta Paediatr 2002;91:977–90.
12. Jansen LA, Hevner RF, Roden WH, Hahn SH, Jung S, Gospe SM Jr. Glial localization of antiquitin: implications for pyridoxine-dependent epilepsy. Ann Neurol 2014;75:22–32.
13. Jain-Ghai S, Mishra N, Hahn C, Blaser S, Mercimek-Mahmutoglu S. Fetal onset ventriculo- megaly and subependymal cysts in a pyridoxine dependent epilepsy patient. Pediatrics 2014;133:e1092– 6.
14. Perez B, Gonzalez L, Verdu A. Clinical, biomedical, and moleculer studies in pyridoxine-dependent epilepsy. Antisense therapy as possible new therapeutic option. Epilepsia 2013;54:239-48.
15. Cormier-Daire V, Dagoneau N, Nabbout R, Burglen L, Penet C, Soufflet C, et al. A Gene for Pyridoxine-Dependent Epilepsy Maps to Chromosome 5q31. Am J Hum Genet 2000;67: 991-3.
16. Tlili A, Hentati N, Chaabane R. Pyridoxine-dependent epilepsy in Tunisia is caused by a founder missense mutation of ALDH7A1 gene. Gene 2013; 518: 242-5.
17. Mefford HC, Zemel M, Geraghty E, Cook J, Clayton PT, Paul K, et al. Intragenic deletions of ALDH7A1 in pyridoxine-dependent epilepsy caused by Alu-Alu recombination. Neurology 2015;85:756-62.
18. Campistol J. Epilepsy in inborn errors of metabolism with therapeutic options. Semin Pediatr Neurol 2016;23:321-31.
19. Bok LA, Halbertsma FJ, Houterman S. Long-term outcome in pyridoxine-dependent epilepsy. Dev Med Child Neurol 2012;54:849-54.
20. Van Karnebeek CD, Jaggumantri S. Current treatment and management of pyridoxine-dependent epilepsy. Curr Treat Options Neurol 2015;17:335.