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Treatable Genetic Metabolic Epilepsies

  • Pediatric Neurology (R-M Boustany, Section Editor)
  • Published:
Current Treatment Options in Neurology Aims and scope Submit manuscript

Opinion statement

In the absence of a culprit epileptogenic lesion, pharmacoresistant seizures should prompt the physician to consider potentially treatable metabolic epilepsies, especially in the presence of developmental delays. Even though the anti-seizure treatment of the epilepsies remains symptomatic and usually tailored to an electroclinical phenotype rather than to an underlying etiology, a thorough metabolic workup might reveal a disease with an etiology-specific treatment. Early diagnosis is essential in the case of treatable metabolic epilepsies allowing timely intervention. Despite the advances in genetic testing, biochemical testing including cerebrospinal fluid studies are still needed to expedite the diagnostic workup and potential therapeutic trials. The diagnostician should have a high index of suspicion despite potential clinical digressions from seminal publications describing the initial cases, as these index patients may represent the most severe form of the condition rather than its most common presenting form. The often gratifying developmental outcome and seizure control with early treatment calls for a prompt diagnostic consideration of treatable metabolic diseases; even though relatively rare or potentially only seemingly so.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: •   Of importance ••  Of major importance

  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(2):140–5.

    CAS  PubMed  Google Scholar 

  2. 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(3):307–9.

    Article  CAS  PubMed  Google Scholar 

  3. •• Darin N, Reid E, Prunetti L, Samuelsson L, Husain RA, Wilson M, et al. Mutations in PROSC disrupt cellular pyridoxal phosphate homeostasis and cause vitamin-B 6-dependent epilepsy. Am J Hum Genet. 2016;99(6):1325–37. Identified a new gene that can cause pyridoxine-dependent epilepsy

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ebinger M, Schultze C, Konig S. Demographics and diagnosis of pyridoxine-dependent seizures. J Pediatr. 1999;134(6):795–6.

    Article  CAS  PubMed  Google Scholar 

  5. van Karnebeek CD, Tiebout SA, Niermeijer J, Poll-The BT, Ghani A, Coughlin CR, et al. Pyridoxine-dependent epilepsy: an expanding clinical spectrum. Pediatr Neurol. 2016;59:6–12.

    Article  PubMed  Google Scholar 

  6. Samanta D. A 15-year-old with seizures: late diagnosis of pyridoxine-dependent epilepsy. Acta Neurol Belg. 2016;116(4):667–9.

    Article  PubMed  Google Scholar 

  7. Marguet F, Barakizou H, Tebani A, Abily-Donval L, Torre S, Bayoudh F, et al. Pyridoxine-dependent epilepsy: report on three families with neuropathology. Metab Brain Dis. 2016;31(6):1435–43.

    Article  CAS  PubMed  Google Scholar 

  8. Jain-Ghai S, Mishra N, Hahn C, Blaser S, Mercimek-Mahmutoglu S. Fetal onset ventriculomegaly and subependymal cysts in a pyridoxine dependent epilepsy patient. Pediatrics. 2014;133(4):e1092–6.

    Article  PubMed  Google Scholar 

  9. Gospe SM Jr. Neonatal vitamin-responsive epileptic encephalopathies. Chang Gung Med J. 2010;33(1):1–12.

    PubMed  Google Scholar 

  10. van Karnebeek CD, Jaggumantri S. Current treatment and management of pyridoxine-dependent epilepsy. Curr Treat Options Neurol. 2015;17(2):1–12.

    Google Scholar 

  11. Al Teneiji A, Bruun TU, Cordeiro D, Patel J, Inbar-Feigenberg M, Weiss S, et al. Phenotype, biochemical features, genotype and treatment outcome of pyridoxine-dependent epilepsy. Metab Brain Dis. 2016:1–9.

  12. Gallagher RC, Van Hove JL, Scharer G, Hyland K, Plecko B, Waters PJ, et al. Folinic acid-responsive seizures are identical to pyridoxine-dependent epilepsy. Ann Neurol. 2009;65(5):550–6.

    Article  CAS  PubMed  Google Scholar 

  13. Mills PB, Surtees RA, Champion MP, Beesley CE, Dalton N, Scambler PJ, et al. Neonatal epileptic encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine 5′-phosphate oxidase. Hum Mol Genet. 2005;14(8):1077–86.

    Article  CAS  PubMed  Google Scholar 

  14. •• Plecko B, Paul K, Mills P, Clayton P, Paschke E, Maier O, et al. Pyridoxine responsiveness in novel mutations of the PNPO gene. Neurology. 2014;82(16):1425–33. Challenged the idea that patients with PNPO mutations only respond to PLP treatment

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. De Vivo DC, Trifiletti RR, Jacobson RI, Ronen GM, Behmand RA, Harik SI. Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. N Engl J Med. 1991;325(10):703–9.

    Article  PubMed  Google Scholar 

  16. • Appavu B, Mangum T, Obeid M. Glucose transporter 1 deficiency: atreatable cause of opsoclonus and epileptic myoclonus. Pediatr Neurol. 2015;53(4):364–6. Found that GLUT1DS manifestations can mimic BMEI

    Article  PubMed  Google Scholar 

  17. Brockmann K. The expanding phenotype of GLUT1-deficiency syndrome. Brain and Development. 2009;31(7):545–52.

    Article  PubMed  Google Scholar 

  18. •• HaoJ, KellyDI, SuJ, PascualJM. Clinical aspects of glucose transporter type 1 deficiency: information from a global registry. JAMA Neurol2017 Apr 24. Studied the treatment and outcome of 181 GLUT1DS patients from an electronic registry.

  19. Mullen SA, Marini C, Suls A, Mei D, Della Giustina E, Buti D, et al. Glucose transporter 1 deficiency as a treatable cause of myoclonic astatic epilepsy. Arch Neurol. 2011;68(9):1152–5.

    Article  PubMed  Google Scholar 

  20. • Larsen J, Johannesen KM, Ek J, Tang S, Marini C, Blichfeldt S, et al. The role of SLC2A1 mutations in myoclonic astatic epilepsy and absence epilepsy, and the estimated frequency of GLUT1 deficiency syndrome. Epilepsia. 2015;56(12):e203–8. Described SLC2A1 mutations in electroclinical phenotypes compatible with childhood absence epilepsy and myoclonic astatic epilepsy

    Article  CAS  PubMed  Google Scholar 

  21. Wang D, Kranz-Eble P, De Vivo DC. Mutational analysis of GLUT1 (SLC2A1) in Glut-1 deficiency syndrome. Hum Mutat. 2000;16(3):224–31.

    Article  CAS  PubMed  Google Scholar 

  22. Gumus H, Bayram AK, Kardas F, Canpolat M, Çağlayan AO, Kumandas S, et al. The effects of ketogenic diet on seizures, cognitive functions, and other neurological disorders in classical phenotype of glucose transporter 1 deficiency syndrome. Neuropediatrics. 2015;46(05):313–20.

    Article  CAS  PubMed  Google Scholar 

  23. Fujii T, Ho Y, Wang D, Darryl C, Miyajima T, Wong H, et al. Three Japanese patients with glucose transporter type 1 deficiency syndrome. Brain Dev. 2007;29(2):92–7.

    Article  PubMed  Google Scholar 

  24. Klepper J. GLUT1 deficiency syndrome in clinical practice. Epilepsy Res. 2012;100(3):272–7.

    Article  CAS  PubMed  Google Scholar 

  25. WangD, PascualJM, DeVivoD. Glucose transporter type 1 deficiency syndrome. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, et al, editors. GeneReviews(R) Seattle (WA): University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved; 1993.

  26. Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, et al. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6. 2 and permanent neonatal diabetes. N Engl J Med. 2004;350(18):1838–49.

    Article  CAS  PubMed  Google Scholar 

  27. Shimomura K, Horster F, de Wet H, Flanagan SE, Ellard S, Hattersley AT, et al. A novel mutation causing DEND syndrome: a treatable channelopathy of pancreas and brain. Neurology. 2007;69(13):1342–9.

    Article  CAS  PubMed  Google Scholar 

  28. Hattersley AT, Ashcroft FM. Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy. Diabetes. 2005;54(9):2503–13.

    Article  CAS  PubMed  Google Scholar 

  29. Proks P, Antcliff JF, Lippiat J, Gloyn AL, Hattersley AT, Ashcroft FM. Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features. Proc Natl Acad Sci U S A. 2004;101(50):17539–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Peña-Almazan S. Successful transition to sulfonylurea in neonatal diabetes, developmental delay, and seizures (DEND syndrome) due to R50P KCNJ11 mutation. Diabetes Res Clin Pract. 2015;108(1):e18–20.

    Article  PubMed  Google Scholar 

  31. Bahi-Buisson N, Roze E, Dionisi C, Escande F, Valayannopoulos V, Feillet F, et al. Neurological aspects of hyperinsulinism–hyperammonaemia syndrome. Dev Med Child Neurology. 2008;50(12):945–9.

    Article  Google Scholar 

  32. Raizen DM, Brooks-Kayal A, Steinkrauss L, Tennekoon GI, Stanley CA, Kelly A. Central nervous system hyperexcitability associated with glutamate dehydrogenase gain of function mutations. J Pediatr. 2005;146(3):388–94.

    Article  CAS  PubMed  Google Scholar 

  33. Bahi-Buisson N, Roze E, Dionisi C, Escande F, Valayannopoulos V, Feillet F, et al. Neurological aspects of hyperinsulinism–hyperammonaemia syndrome. Dev Med Child neurol. 2008;50(12):945–9.

    Article  PubMed  Google Scholar 

  34. Bahi-Buisson N, El Sabbagh S, Soufflet C, Escande F, Boddaert N, Valayannopoulos V, et al. Myoclonic absence epilepsy with photosensitivity and a gain of function mutation in glutamate dehydrogenase. Seizure. 2008;17(7):658–64.

    Article  PubMed  Google Scholar 

  35. Stanley CA, Lieu YK, Hsu BY, Burlina AB, Greenberg CR, Hopwood NJ, et al. Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med. 1998;338(19):1352–7.

    Article  CAS  PubMed  Google Scholar 

  36. Hussain K, Aynsley-Green A, Stanley CA. Medications used in the treatment of hypoglycemia due to congenital hyperinsulinism of infancy (HI). Pediatr Endocrinol Rev. 2004;2(Suppl 1):163–7.

    PubMed  Google Scholar 

  37. Rosenberg EH, Almeida LS, Kleefstra T, Yntema HG, Bahi N, Moraine C, et al. High prevalence of SLC6A8 deficiency in X-linked mental retardation. Am J Hum Genet. 2004;75(1):97–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. SharerJD, BodamerO, LongoN, TortorelliS, WamelinkMM, YoungS. Laboratory diagnosis of creatine deficiency syndromes: a technical standard and guideline of the American College of Medical Genetics and Genomics. Genet Med 2017.

  39. Dunbar M, Jaggumantri S, Sargent M, Stockler-Ipsiroglu S, van Karnebeek CD. Treatment of X-linked creatine transporter (SLC6A8) deficiency: systematic review of the literature and three new cases. Mol Genet Metab. 2014;112(4):259–74.

    Article  CAS  PubMed  Google Scholar 

  40. Dhar S, Scaglia F, Li F, Smith L, Barshop B, Eng C, et al. Expanded clinical and molecular spectrum of guanidinoacetate methyltransferase (GAMT) deficiency. Mol Genet Metab. 2009;96(1):38–43.

    Article  CAS  PubMed  Google Scholar 

  41. Mikati AG, Gheida IA, Shamseddine A, Mikati MA, Karam PE. Epileptic and electroencephalographic manifestations of guanidinoacetate-methyltransferase deficiency. Epileptic Disord. 2013;15(4):407–16.

    PubMed  Google Scholar 

  42. Stockler S, Holzbach U, Hanefeld F, Marquardt I, Helms G, Requart M, et al. Creatine deficiency in the brain: a new, treatable inborn error of metabolism. Pediatr Res. 1994;36(3):409–13.

    Article  CAS  PubMed  Google Scholar 

  43. Schulze A. Creatine deficiency syndromes. Mol Cell Biochem. 2003;244(1):143–50.

    Article  CAS  PubMed  Google Scholar 

  44. BlauN, DuranM, GibsonKM, Dionisi-ViciC, BlaskovicsME. Physician’s guide to the diagnosis, treatment, and follow-up of inherited metabolic diseases. : Springer;2014.

  45. El-Hattab AW, Shaheen R, Hertecant J, Galadari HI, Albaqawi BS, Nabil A, et al. On the phenotypic spectrum of serine biosynthesis defects. J Inherit Metab Dis. 2016;39(3):373–81.

    Article  CAS  PubMed  Google Scholar 

  46. De Koning T, Jaeken J, Pineda M, Van Maldergem L, Van der Knaap M. Hypomyelination and reversible white matter attenuation in 3-phosphoglycerate dehydrogenase deficiency. Neuropediatrics. 2000;31(06):287–92.

    Article  PubMed  Google Scholar 

  47. Benke PJ, Hidalgo RJ, Braffman BH, Jans J, Gassen KLIV, Sunbul R, et al. Infantile serine biosynthesis defect due to phosphoglycerate dehydrogenase deficiency: variability in phenotype and treatment response, novel mutations, and diagnostic challenges. J Child Neurol. 2017;32(6):543–9.

    Article  PubMed  Google Scholar 

  48. Tabatabaie L, Klomp L, Rubio-Gozalbo M, Spaapen L, Haagen A, Dorland L, et al. Expanding the clinical spectrum of 3-phosphoglycerate dehydrogenase deficiency. J Inherit Metab Dis. 2011;34(1):181–4.

    Article  CAS  PubMed  Google Scholar 

  49. Hart CE, Race V, Achouri Y, Wiame E, Sharrard M, Olpin SE, et al. Phosphoserine aminotransferase deficiency: a novel disorder of the serine biosynthesis pathway. Am J Hum Genet. 2007;80(5):931–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. De Koning T, Klomp L, Van Oppen A, Beemer F, Dorland L, Van Den Berg I, et al. Prenatal and early postnatal treatment in 3-phosphoglycerate-dehydrogenase deficiency. Lancet. 2004;364(9452):2221–2.

    Article  PubMed  Google Scholar 

  51. De Koning T, Duran M, Maldergem LV, Pineda M, Dorland L, Gooskens R, et al. Congenital microcephaly and seizures due to 3-phosphoglycerate dehydrogenase deficiency: outcome of treatment with amino acids. J Inherit Metab Dis. 2002;25(2):119–25.

    Article  PubMed  Google Scholar 

  52. Thöny B, Blau N. Mutations in the BH4-metabolizing genes GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase, sepiapterin reductase, carbinolamine-4a-dehydratase, and dihydropteridine reductase. Hum Mutat. 2006;27(9):870–8.

    Article  PubMed  Google Scholar 

  53. Opladen T, Hoffmann GF, Blau N. An international survey of patients with tetrahydrobiopterin deficiencies presenting with hyperphenylalaninaemia. J Inherit Metab Dis. 2012;35(6):963–73.

    Article  CAS  PubMed  Google Scholar 

  54. Jäggi L, Zurflüh MR, Schuler A, Ponzone A, Porta F, Fiori L, et al. Outcome and long-term follow-up of 36 patients with tetrahydrobiopterin deficiency. Mol Genet Metab. 2008;93(3):295–305.

    Article  PubMed  Google Scholar 

  55. Friedman J, Roze E, Abdenur JE, Chang R, Gasperini S, Saletti V, et al. Sepiapterin reductase deficiency: a treatable mimic of cerebral palsy. Ann Neurol. 2012;71(4):520–30.

    Article  CAS  PubMed  Google Scholar 

  56. •• Carducci C, Santagata S, Friedman J, Pasquini E, Carducci C, Tolve M, et al. Urine sepiapterin excretion as a new diagnostic marker for sepiapterin reductase deficiency. Mol Genet Metab. 2015;115(4):157–60. Described a new test for sepiapterin deficiency, which, unlike the other tetrahydrobiopterin deficiencies, is not detected in the newborn phenylketonuria screening

    Article  CAS  PubMed  Google Scholar 

  57. AlSubhi S, AlShahwan S, AlMuhaizae M, AlZaidan H, Tabarki B. Sepiapterin reductase deficiency: report of 5 new cases. Eur J Paediatr Neurol. 2017;21(3):583–6.

    Article  PubMed  Google Scholar 

  58. Biasucci G, Valsasina R, Giovannini M, Brioschi M, Saleri L, Riva E. Neuroradiological improvement after one year of therapy in a case of DHPR deficiency. Chem Biol Pteridines. 1989:438–44.

  59. Ramaekers V, Sequeira JM, Quadros EV. Clinical recognition and aspects of the cerebral folate deficiency syndromes. Clin Chem Lab Med. 2013;51(3):497–511.

    Article  CAS  PubMed  Google Scholar 

  60. Cario H, Bode H, Debatin KM, Opladen T, Schwarz K. Congenital null mutations of the FOLR1 gene: a progressive neurologic disease and its treatment. Neurology. 2009;73(24):2127–9.

    Article  CAS  PubMed  Google Scholar 

  61. Ramaekers VT, Rothenberg SP, Sequeira JM, Opladen T, Blau N, Quadros EV, et al. Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. N Engl J Med. 2005;352(19):1985–91.

    Article  CAS  PubMed  Google Scholar 

  62. Steinfeld R, Grapp M, Kraetzner R, Dreha-Kulaczewski S, Helms G, Dechent P, et al. Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism. Am J Hum Genet. 2009;85(3):354–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Pineda M, Ormazabal A, López-Gallardo E, Nascimento A, Solano A, Herrero MD, et al. Cerebral folate deficiency and leukoencephalopathy caused by a mitochondrial DNA deletion. Ann Neurol. 2006;59(2):394–8.

    Article  CAS  PubMed  Google Scholar 

  64. Wolf B. The neurology of biotinidase deficiency. Mol Genet Metab. 2011;104(1–2):27–34.

    Article  CAS  PubMed  Google Scholar 

  65. Wolf B. Biotinidase deficiency should be considered in individuals exhibiting myelopathy with or without and vision loss. Mol Genet Metab. 2015;116(3):113–8.

    Article  CAS  PubMed  Google Scholar 

  66. Yilmaz S, Serin M, Canda E, Eraslan C, Tekin H, Ucar SK, et al. A treatable cause of myelopathy and vision loss mimicking neuromyelitis optica spectrum disorder: late-onset biotinidase deficiency. Metab Brain Dis. 2017;9

  67. Dulac O, Plecko B, Gataullina S, Wolf NI. Occasional seizures, epilepsy, and inborn errors of metabolism. Lancet Neurol. 2014;13(7):727–39.

    Article  PubMed  Google Scholar 

  68. Hoover-Fong JE, Shah S, Van Hove JL, Applegarth D, Toone J, Hamosh A. Natural history of nonketotic hyperglycinemia in 65 patients. Neurology. 2004;63(10):1847–53.

    Article  CAS  PubMed  Google Scholar 

  69. Hennermann JB, Berger J, Grieben U, Scharer G, Van Hove JL. Prediction of long-term outcome in glycine encephalopathy: a clinical survey. J Inherit Metab Dis. 2012;35(2):253–61.

    Article  CAS  PubMed  Google Scholar 

  70. Dinopoulos A, Matsubara Y, Kure S. Atypical variants of nonketotic hyperglycinemia. Mol Genet Metab. 2005;86(1–2):61–9.

    Article  CAS  PubMed  Google Scholar 

  71. Brunel-Guitton C, Casey B, Coulter-Mackie M, Vallance H, Hewes D, Stockler-Ipsiroglu S, et al. Late-onset nonketotic hyperglycinemia caused by a novel homozygous missense mutation in the GLDC gene. Mol Genet Metab. 2011;103(2):193–6.

    Article  CAS  PubMed  Google Scholar 

  72. Coughlin CR II, Swanson MA, Kronquist K, Acquaviva C, Hutchin T, Rodríguez-Pombo P, et al. The genetic basis of classic nonketotic hyperglycinemia due to mutations in GLDC and AMT. Genet Med. 2016;19(1):104–11.

    Article  PubMed  Google Scholar 

  73. Van Hove JL, Vande Kerckhove K, Hennermann JB, Mahieu V, Declercq P, Mertens S, et al. Benzoate treatment and the glycine index in nonketotic hyperglycinaemia. J Inherit Metab Dis. 2005;28(5):651–63.

    Article  PubMed  Google Scholar 

  74. Obeid M, Wyllie E, Rahi AC, Mikati MA. Approach to pediatric epilepsy surgery: state of the art, Part I: General principles and presurgical workup. Eur J Paediatr Neurol. 2009;13(2):102–14.

    Article  PubMed  Google Scholar 

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Assi, L., Saklawi, Y., Karam, P.E. et al. Treatable Genetic Metabolic Epilepsies. Curr Treat Options Neurol 19, 30 (2017). https://doi.org/10.1007/s11940-017-0467-0

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