Modern Pediatrics. Ukraine. (2026).1(153): 146-156. doi: 10.15574/SP.2026.1(153).146156
Antypkin Yu. H.¹, Kyrylova L. H.¹, Miroshnykiv O. O.¹, Dolenko O. O.², Badiuk V. M.²
¹SI "Ukrainian Center of Maternity and Childhood of the NAMS of Ukraine", Kyiv
²LLC "ULTRAGENOME", Kyiv, Ukraine

For citation: Antypkin YuH, Kyrylova LH, Miroshnykiv OO, Dolenko OO, Badiuk VM. (2026). Epileptic encephalopathies in inborn errors of metabolism in young children: focus on pyridoxine-dependent epilepsy. Modern Pediatrics. Ukraine. 1(153): 146-156. doi: 10.15574/SP.2026.1(153).146156.
Article received: Nov 06, 2025. Accepted for publication: Feb 08, 2026.

Inborn errors of metabolism (IEM) represent one of the most clinically significant yet underdiagnosed causes of epileptic encephalopathies in young children. The team of the Department of Pediatric Neurology at the State Institution "Ukrainian Center of Maternity and Childhood of the NAMS of Ukraine" has been investigating this problem for over 25 years, which served as the foundation for the preparation of this publication. Particular attention is warranted by pyridoxine-dependent epilepsy (PDE) — a rare autosomal recessive disorder caused by pathogenic variants in the ALDH7A1 gene — as a classical example of a treatable metabolic epileptic encephalopathy.
Aim – to systematize current evidence on epileptic encephalopathies in inborn errors of metabolism in young children, and to elucidate the underlying pathogenetic mechanisms, clinical features, and approaches to diagnosis and treatment.
A systematic review of the scientific literature was conducted using PubMed/MEDLINE and OMIM databases, with a focus on publications from the past 10 years.
A clinical case of a 3-month-old girl with neonatal epilepsy refractory to standard therapy is presented. The diagnostic workup included prolonged video-EEG monitoring, brain MRI, biochemical investigations, and next-generation sequencing (NGS) using the CarrierSeq panel (420 genes). Epileptic seizures associated with IEM are characteristically resistant to standard antiseizure medications and may present as status epilepticus at onset. Age of manifestation serves as a key diagnostic indicator: the neonatal period is most typical for pyridoxine-dependent epilepsy, urea cycle defects, and nonketotic hyperglycinemia, while infancy is more characteristic of GLUT1 deficiency, biotinidase deficiency, and peroxisomal disorders. The diagnostic algorithm encompasses three tiers: a basic biochemical panel (glucose, lactate, pyruvate, ammonia, blood gas analysis, plasma amino acids, urine organic acids, acylcarnitine profile), specialized metabolic tests (α-aminoadipic semialdehyde, pipecolic acid, cerebrospinal fluid pyridoxal phosphate level), and molecular genetic analysis. An empirical therapeutic trial with pyridoxine (30 mg/kg/day for 3 days) is indicated in all neonates with seizures of unknown etiology refractory to conventional therapy. In the presented case, two pathogenic variants in compound heterozygous state were identified in the ALDH7A1 gene, confirming the diagnosis of PDE. Targeted therapy comprising pyridoxine, arginine, folinic acid, and a lysine-restricted diet resulted in sustained seizure remission and normalization of psychomotor development.
Conclusions. Early identification and verification of a metabolic defect enables pathogenetically targeted treatment with the potential to fundamentally alter the disease prognosis. Nutritional and vitamin-micronutrient therapy represents an effective therapeutic approach for treatable forms of metabolic epilepsy, particularly in pyridoxine-dependent epilepsies.
The authors declare no conflict of interest.
Keywords: inborn errors of metabolism, epileptic encephalopathy, metabolic epilepsy, pyridoxine-dependent epilepsy, ALDH7A1 gene, pyridoxine, neonatal seizures, drug-resistant epilepsy, young children.

REFERENCES

1. Aklamanu BW. (2025). A review of neuroimaging in epilepsy: Diagnostic strategies and clinical decision framework. Brain Disorders. 19; Suppl C: 100261. https://doi.org/10.1016/j.dscb.2025.100261

2. Almannai M, Al Mahmoud RA, Mekki M, El-Hattab AW. (2021, Jul 6). Metabolic Seizures. Front Neurol. 12: 640371. https://doi.org/10.3389/fneur.2021.640371; PMid:34295297 PMCid:PMC8290068

3. Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W et al. (2010). Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia. 51(4): 676-685. https://doi.org/10.1111/j.1528-1167.2010.02522.x; PMid:20196795

4. Coughlin CR 2nd, Swanson MA, Spector E, Meeks NJL, Kronquist KE, Aslamy M et al. (2019). The genotypic spectrum of ALDH7A1 mutations resulting in pyridoxine dependent epilepsy: A common epileptic encephalopathy. Journal of Inherited Metabolic Disease. 42(2): 353-361. https://doi.org/10.1002/jimd.12045; PMid:30043187 PMCid:PMC6345606

5. Dulac O, Plecko B, Gataullina S, Wolf NI. (2014, Jul). Occasional seizures, epilepsy, and inborn errors of metabolism. Lancet Neurol. 13(7): 727-739. https://doi.org/10.1016/S1474-4422(14)70110-3; PMid:24943345

6. Kava MP, Bryant L, Rowe P, Lewis B, Greed L, Balasubramaniam S. (2020). Beneficial outcome of early dietary lysine restriction as an adjunct to pyridoxine therapy in a child with pyridoxine dependant epilepsy due to Antiquitin deficiency. JIMD Reports. 54: 9-15. https://doi.org/10.1002/jmd2.12121; PMid:32685344 PMCid:PMC7358673

7. Kyrylova LH, Miroshnykov OO, Yuzva OO. (2018). Neirometabolichni porushennia v patohenezi epileptychnykh entsefalopatii i rozladiv autystychnoho spektra v ditei. Zhurnal nevrolohii im. B. M. Mankovskoho. 6; 1: 55-62.

8. Lin Lin Lee V, Kar Meng Choo B, Chung Y-S, P Kundap U, Kumari Y, Shaikh MF. (2018). Treatment, therapy and management of metabolic epilepsy: A systematic review. International Journal of Molecular Sciences. 19(3): 871. https://doi.org/10.3390/ijms19030871; PMid:29543761 PMCid:PMC5877732

9. Mills PB, Camuzeaux SS, Footitt EJ, Mills KA, Gissen P, Fisher L et al. (2014, May). Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome. Brain. 137; Pt 5: 1350-1360. Epub 2014 Mar 18. https://doi.org/10.1093/brain/awu051; PMid:24645144 PMCid:PMC3999720

10. Rahman S, Footitt EJ, Varadkar S, Clayton PT. (2013, Jan). Inborn errors of metabolism causing epilepsy. Dev Med Child Neurol. 55(1): 23-36. Epub 2012 Sep 24. https://doi.org/10.1111/j.1469-8749.2012.04406.x; PMid:22998469

11. Salih MA, Al Bakheet A, Almass R, Hamed AAA, AlOdaib A, Kaya N. (2024, Dec 23). Case report: Clinical and genetic characterization of a novel ALDH7A1 variant causing pyridoxine-dependent epilepsy, developmental delay, and intellectual disability in two siblings. Front Psychiatry. 15: 1501238. https://doi.org/10.3389/fpsyt.2024.1501238; PMid:39763688 PMCid:PMC11701133

12. Sesse A, Ladias P, Kostoulas C, Chatzistefanidis D, Georgiou I, Markoula S. (2025, Mar 14). Metabolic pathways and genes involved in treatable and non-treatable metabolic epilepsies. A comprehensive review and metabolic pathway analysis. Metab Brain Dis. 40(3): 152. https://doi.org/10.1007/s11011-025-01562-5; PMid:40085371 PMCid:PMC11909059

13. Sharma S, Prasad AN. (2017). Inborn errors of metabolism and epilepsy: Current understanding, diagnosis, and treatment approaches. International Journal of Molecular Sciences. 18(7): 1384. https://doi.org/10.3390/ijms18071384; PMid:28671587 PMCid:PMC5535877

14. Stockler S, Plecko B, Gospe SM Jr, Coulter-Mackie M, Connolly M, van Karnebeek C et al. (2011, Sep-Oct). Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up. Mol Genet Metab. 104(1-2): 48-60. Epub 2011 May 24. https://doi.org/10.1016/j.ymgme.2011.05.014; PMid:21704546

15. Tokatly Latzer I, Yang E, Pimenta de Figueiredo VL, Huang SY, Matsubara T, Pearl PL. (2025, Apr 22). Neuroimaging in Children With Inherited Metabolic Epilepsies. Neurology. 104(8): e213485. Epub 2025 Mar 25. https://doi.org/10.1212/WNL.0000000000213485; PMid:40132153 PMCid:PMC12334337

16. Tumiene B, Ferreira CR, Van Karnebeek CDM. (2022). 2022 Overview of metabolic epilepsies. Genes. 13(3): 508. https://doi.org/10.3390/genes13030508; PMid:35328062 PMCid:PMC8952328

17. Tumienė B, Peterlin B, Maver A, Utkus A. (2018, Dec). Contemporary scope of inborn errors of metabolism involving epilepsy or seizures. Metab Brain Dis. 33(6): 1781-1786. Epub 2018 Jul 13. https://doi.org/10.1007/s11011-018-0288-1; PMid:30006695

18. Van Karnebeek CDM, Jaggumantri S. (2015). Current treatment and management of pyridoxine-dependent epilepsy. Current Treatment Options in Neurology. 17(2): 7. https://doi.org/10.1007/s11940-014-0335-0; PMid:25639976

19. Van Karnebeek CDM, Sayson B, Lee JJY, Tseng LA, Blau N et al. (2018, Dec 3). Metabolic Evaluation of Epilepsy: A Diagnostic Algorithm With Focus on Treatable Conditions. Front Neurol. 9: 1016. https://doi.org/10.3389/fneur.2018.01016; PMid:30559706 PMCid:PMC6286965

20. Van Karnebeek CDM, Tiebout SA, Niermeijer J, Poll-The BT, Ghani A, Coughlin CR 2nd et al. (2016). Pyridoxine-dependent epilepsy: An expanding clinical spectrum. Pediatric Neurology. 59: 6-12. https://doi.org/10.1016/j.pediatrneurol.2015.12.013