Pharmacological Therapy in Inborn Errors of Metabolism

  • Anibh M. DasEmail author
  • Sabine Illsinger
Living reference work entry


Different therapeutic principles can improve clinical outcome in patients suffering from inborn errors of metabolism (IEM). IEMs are inherited disorders which are based on a primary enzyme defect or deficiency of a cellular transporter. Substrate reduction by diet (exogenous substrate), pharmacological substrate reduction (endogenous substrate), supplementation of a missing cofactor/vitamin, activation of alternative pathways for the elimination of toxic compounds, augmentation of enzyme activity by chaperones and enzyme replacement therapy (in selected diseases like lysosomal storage diseases) are therapeutic options for alimentary and pharmacological treatment in IEM.In this chapter we will discuss options for pharmacological and/or dietary therapy in selected prototype IEM.

References and Further Reading

  1. Al Hafid N, Christodoulou J (2015) Phenylketonuria: a review of current and future treatments. Transl Pediatr 4(4):304–317. Scholar
  2. Banugaria SG, Prater SN, Ng YK, Kobori JA, Finkel RS, Ladda RL, Chen YT, Rosenberg AS, Kishnani PS (2011) The impact of antibodies on clinical outcomes in diseases treated with therapeutic protein: lessons learned from infantile Pompe disease. Genet Med 13(8):729–736. Scholar
  3. Bendadi F, de Koning TJ, Visser G, Prinsen HC, de Sain MG, Verhoeven-Duif N, Sinnema G, van Spronsen FJ, van Hasselt PM (2014) Impaired cognitive functioning in patients with tyrosinemia type I receiving nitisinone. J Pediatr 164(2):398–401. Scholar
  4. Benjamin ER, Flanagan JJ, Schilling A, Chang HH, Agarwal L, Katz E, Wu X, Pine C, Wustman B, Desnick RJ, Lockhart DJ, Valenzano KJ (2009) The pharmacological chaperone 1-deoxygalactonojirimycin increases alpha-galactosidase a levels in Fabry patient cell lines. J Inherit Metab Dis 32(3):424–440. Scholar
  5. Bennett LL, Mohan D (2013) Gaucher disease and its treatment options. Ann Pharmacother 47(9):1182–1193. Scholar
  6. Bickel H, Gerrard J, Hickmans EM (1954) The influence of phenylalanine intake on the chemistry and behaviour of a phenyl-ketonuric child. Acta Paediatr 43(1):64–77CrossRefPubMedGoogle Scholar
  7. Blau N, van Spronsen FJ, Levy HL (2010) Phenylketonuria. Lancet 376(9750):1417–1427. Scholar
  8. Boado BJ, Ka-Wai Hui E, Lu JZ, Pardridge WM, (2014) Insulin receptor antibody-iduronate 2-sulfatase fusion protein: Pharmacokinetics, anti-drug antibody, and safety pharmacology in Rhesus monkeys. Biotechnol Bioeng 111(11):2317–2325CrossRefPubMedPubMedCentralGoogle Scholar
  9. Boneh A, Allan S, Mendelson D, Spriggs M, Gillam LH, Korman SH (2008) Clinical, ethical and legal considerations in the treatment of newborns with non-ketotic hyperglycinaemia. Mol Genet Metab 94(2):143–147. Scholar
  10. Burton BK, Bausell H, Katz R, Laduca H, Sullivan C (2010) Sapropterin therapy increases stability of blood phenylalanine levels in patients with BH4-responsive phenylketonuria (PKU). Mol Genet Metab 101(2–3):110–114. Scholar
  11. Chao MM, Illsinger S, Yoshimi A, Das AM, Kratz CP (2017) Congenital Transcobalamin II deficiency: a rare entity with a broad differential. Klin Padiatr 229(6):335–357. Scholar
  12. Christ SE (2003) Asbjorn Folling and the discovery of phenylketonuria. J Hist Neurosci 12(1):44–54CrossRefPubMedGoogle Scholar
  13. Das AM, Lagler F, Beck M, Scarpa M, Lampe C (2017) Lysosomal storage diseases: challenges in multiprofessional patient care with enzyme replacement therapy. Klin Padiatr 229(3):168–174. Scholar
  14. Diaz GA, Krivitzky LS, Mokhtarani M, Rhead W, Bartley J, Feigenbaum A, Longo N, Berquist W, Berry SA, Gallagher R, Lichter-Konecki U, Bartholomew D, Harding CO, Cederbaum S, McCandless SE, Smith W, Vockley G, Bart SA, Korson MS, Kronn D, Zori R, Merritt JL 2nd, C S Nagamani S, Mauney J, Lemons C, Dickinson K, Moors TL, Coakley DF, Scharschmidt BF, Lee B (2013) Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate. Hepatology 57(6):2171–2179. Scholar
  15. Ellis MK, Whitfield AC, Gowans LA, Auton TR, Provan WM, Lock EA, Smith LL (1995) Inhibition of 4-hydroxyphenylpyruvate dioxygenase by 2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione and 2-(2-chloro-4-methanesulfonylbenzoyl)-cyclohexane-1,3-dione. Toxicol Appl Pharmacol 133(1):12–19. Scholar
  16. Ferreira CR, Gahl WA (2017) Lysosomal storage diseases. Transl Sci Rare Dis 2(1–2):1–71. Scholar
  17. Frampton JE (2016) Sebelipase alfa: a review in lysosomal acid lipase deficiency. Am J Cardiovasc Drugs 16(6):461–468. Scholar
  18. Franke D, Steffens R, Thomas L, Pavicic L, Ahlenstiel T, Pape L, Gellermann J, Müller D, Querfeld U, Haffner D, Zivicnjak M (2017) Kidney transplantation fails to provide adequate growth in children with chronic kidney disease born small for gestational age. Pediatr Nephrol 32(3):511–519. Scholar
  19. Garcia MI, de la Parra A, Arias C, Arredondo M, Cabello JF (2017) Long-term cognitive functioning in individuals with tyrosinemia type 1 treated with nitisinone and protein-restricted diet. Mol Genet Metab Rep 11:12–16. Scholar
  20. Garrod AE (1902) About Alkaptonuria. Med Chir Trans 85:69–78PubMedPubMedCentralGoogle Scholar
  21. Germain DP, Giugliani R, Hughes DA, Mehta A, Nicholls K, Barisoni L, Jennette CJ, Bragat A, Castelli J, Sitaraman S, Lockhart DJ, Boudes PF (2012) Safety and pharmacodynamic effects of a pharmacological chaperone on alpha-galactosidase a activity and globotriaosylceramide clearance in Fabry disease: report from two phase 2 clinical studies. Orphanet J Rare Dis 7:91. Scholar
  22. Giugliani R, Waldek S, Germain DP, Nicholls K, Bichet DG, Simosky JK, Bragat AC, Castelli JP, Benjamin ER, Boudes PF (2013) A phase 2 study of migalastat hydrochloride in females with Fabry disease: selection of population, safety and pharmacodynamic effects. Mol Genet Metab 109(1):86–92. Scholar
  23. Haberle J (2011) Role of carglumic acid in the treatment of acute hyperammonemia due to N-acetylglutamate synthase deficiency. Ther Clin Risk Manag 7:327–332. Scholar
  24. Haberle J, Boddaert N, Burlina A, Chakrapani A, Dixon M, Huemer M, Karall D, Martinell D, Crespo PS, Santer R, Servais A, Valayannopoulos V, Linder M, Rubio V, Dionisi-Vici C (2012) Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis 7:32. Scholar
  25. Hall MG, Wilks MF, Provan WM, Eksborg S, Lumholtz B (2001) Pharmacokinetics and pharmacodynamics of NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione) and mesotrione, inhibitors of 4-hydroxyphenyl pyruvate dioxygenase (HPPD) following a single dose to healthy male volunteers. Br J Clin Pharmacol 52(2):169–177CrossRefPubMedPubMedCentralGoogle Scholar
  26. Heintz C, Cotton RG, Blau N (2013) Tetrahydrobiopterin, its mode of action on phenylalanine hydroxylase, and importance of genotypes for pharmacological therapy of phenylketonuria. Hum Mutat 34(7):927–936. Scholar
  27. Horster F, Baumgartner MR, Viardot C, Suormala T, Burgard P, Fowler B, Hoffmann GF, Garbade SF, Kölker S, Baumgartner ER (2007) Long-term outcome in methylmalonic acidurias is influenced by the underlying defect (mut0, Mut-, cblA, cblB). Pediatr Res 62(2):225–230. Scholar
  28. Ishii S (2012) Pharmacological chaperone therapy for Fabry disease. Proc Jpn Acad Ser B Phys Biol Sci 88(1):18–30CrossRefPubMedPubMedCentralGoogle Scholar
  29. Ishii S, Chang HH, Kawasaki K, Yasuda K, Wu HL, Garman SC, Fan JQ (2007) Mutant alpha-galactosidase a enzymes identified in Fabry disease patients with residual enzyme activity: biochemical characterization and restoration of normal intracellular processing by 1-deoxygalactonojirimycin. Biochem J 406(2):285–295. Scholar
  30. Johnson FK, Mudd PN Jr, Bragat A, Adera M, Boudes P (2013) Pharmacokinetics and safety of Migalastat HCl and effects on Agalsidase activity in healthy volunteers. Clin Pharmacol Drug Dev 2(2):120–132. Scholar
  31. Jones SA, Breen C, Heap F, Rust S, de Ruijter J, Tump E, Marchal JP, Qiu Y, Chung JK, Nair N, Haslett PA, Wijburg FA (2016) A phase 1/2 study of intrathecal heparan-N-sulfatase in patients with mucopolysaccharidosis IIIA. Mol Genet Metab 118(3):198–205. Scholar
  32. Kienstra NS, van Reemst HE, van Ginkel VG, Daly A, van Dam E, MacDonald A, Burgerhof JGM, de Blaauw P, McKiernan PJ, Rebecca Heiner-Fokkema M, van Spronsen FJ (2018) Daily variation of NTBC and its relation to succinylacetone in tyrosinemia type 1 patients comparing a single dose to two doses a day. J Inherit Metab Dis 41(2):181–186Google Scholar
  33. Koch R, Burton B, Hoganson G, Peterson R, Rhead W, Rouse B, Scott R, Wolff J, Stern AM, Guttler F, Nelson M, de la Cruz F, Coldwell J, Erbe R, Geraghty MT, Shear C, Thomas J, Azen C (2002) Phenylketonuria in adulthood: a collaborative study. J Inherit Metab Dis 25(5):333–346CrossRefPubMedGoogle Scholar
  34. Labbe A, Baudouin C, Deschenes G, Loirat C, Charbit M, Guest G, Niaudet P (2014) A new gel formulation of topical cysteamine for the treatment of corneal cystine crystals in cystinosis: the Cystadrops OCT-1 study. Mol Genet Metab 111(3):314–320. Scholar
  35. Langman CB, Greenbaum LA, Sarwal M, Grimm P, Niaudet P, Deschênes G, Cornelissen E, Morin D, Cochat P, Matossian D, Gaillard S, Bagger MJ, Rioux P (2012) A randomized controlled crossover trial with delayed-release cysteamine bitartrate in nephropathic cystinosis: effectiveness on white blood cell cystine levels and comparison of safety. Clin J Am Soc Nephrol 7(7):1112–1120. Scholar
  36. Lenke RR, Levy HL (1980) Maternal phenylketonuria and hyperphenylalaninemia. An international survey of the outcome of untreated and treated pregnancies. N Engl J Med 303(21):1202–1208. Scholar
  37. Lidove O, Barbey F, Joly D (2016) Treatment of Fabry disease: successes, failures, and expectations. Nephrol Ther 12(Suppl 1):105–113. Scholar
  38. Longo N, Harding CO, Burton BK, Grange DK, Vockley J, Wasserstein M, Rice GM, Dorenbaum A, Neuenburg JK, Musson DG, Gu Z, Sile S (2014) Single-dose, subcutaneous recombinant phenylalanine ammonia lyase conjugated with polyethylene glycol in adult patients with phenylketonuria: an open-label, multicentre, phase 1 dose-escalation trial. Lancet 384(9937):37–44. Scholar
  39. Longo, N., Arnold, G. L., Pridjian, G., Enns, G. M., Ficicioglu, C., Parker, S.,. .. Safety, R. (2015). Long-term safety and efficacy of sapropterin: the PKUDOS registry experience. Mol Genet Metab, 114(4), 557–563. Scholar
  40. Lukina E, Watman N, Arreguin EA, Dragosky M, Iastrebner M, Rosenbaum H, Phillips M, Pastores GM, Kamath RS, Rosenthal DI, Kaper M, Singh T, Puga AC, Peterschmitt MJ (2010a) Improvement in hematological, visceral, and skeletal manifestations of Gaucher disease type 1 with oral eliglustat tartrate (Genz-112638) treatment: 2-year results of a phase 2 study. Blood 116(20):4095–4098. Scholar
  41. Lukina E, Watman N, Arreguin EA, Banikazemi M, Dragosky M, Iastrebner M, Rosenbaum H, Phillips M, Pastores GM, Rosenthal DI, Kaper M, Singh T, Puga AC, Bonate PL, Peterschmitt MJ (2010b) Improvement in hematological, visceral, and skeletal manifestations of Gaucher disease type 1 with oral eliglustat tartrate (Genz-112638) treatment: 2-year results of a phase 2 study. Blood 116(20):4095–4098. Scholar
  42. MacDonald A, Rylance G, Hall SK, Asplin D, Booth IW (1996) Factors affecting the variation in plasma phenylalanine in patients with phenylketonuria on diet. Arch Dis Child 74(5):412–417CrossRefPubMedPubMedCentralGoogle Scholar
  43. Macleod EL, Ney DM (2010) Nutritional Management of Phenylketonuria. Ann Nestle Eng 68(2):58–69. Scholar
  44. Mayorandan, S., Meyer, U., Gokcay, G., Segarra, N. G., de Baulny, H. O., van Spronsen, F.,. .. Das, A. M. (2014a). Cross-sectional study of 168 patients with hepatorenal tyrosinaemia and implications for clinical practice. Orphanet J Rare Dis, 9, 107. Scholar
  45. Mayorandan S, Meyer U, Hartmann H, Das AM (2014b) Glycogen storage disease type III: modified Atkins diet improves myopathy. Orphanet J Rare Dis 9:196. Scholar
  46. Muntau AC, Burlina A, Eyskens F, Freisinger P, De Laet C, Leuzzi V, Rutsch F, Serap Sivri H, Vijay S, Bal MO, Gramer G, Pazdírková R, Cleary M, Lotz-Havla AS, Munafo A, Mould DR, Moreau-Stucker F, Rogoff D (2017) Efficacy, safety and population pharmacokinetics of sapropterin in PKU patients <4 years: results from the SPARK open-label, multicentre, randomized phase IIIb trial. Orphanet J Rare Dis 12(1):47. Scholar
  47. Reski R, Parsons J, Decker EL (2015) Moss-made pharmaceuticals: from bench to bedside. Plant Biotechnol J 13(8):1191–1198. Scholar
  48. Sander J, Janzen N, Terhardt M, Sander S, Gokcay G, Demirkol M, Ozer I, Peter M, Das AM (2011) Monitoring tyrosinaemia type I: blood spot test for nitisinone (NTBC). Clin Chim Acta 412(1–2):134–138. Scholar
  49. Schlune A, Thimm E, Herebian D, Spiekerkoetter U (2012) Single dose NTBC-treatment of hereditary tyrosinemia type I. J Inherit Metab Dis 35(5):831–836. Scholar
  50. Shen J-S, Busch A, Day TS, Meng X-L, Chun IY, Dabrowska-Schlepp P, Fode B, Niederkrüger H, Forni S, Chen S, Schiffmann R, Frischmuth T, Schaaf A (2016) Mannose receptor-mediated delivery of moss-made alpha-galactosidase a efficiently corrects enzyme deficiency in Fabry mice. J Inherit Metab Dis 39(2):293–303. Scholar
  51. Shintaku H, Ohura T (2014) Sapropterin is safe and effective in patients less than 4-years-old with BH4-responsive phenylalanine hydrolase deficiency. J Pediatr 165(6):1241–1244. Scholar
  52. Summar ML, Koelker S, Freedenberg D, Le Mons C, Haberle J, Lee HS, Kirmse B (2013) The incidence of urea cycle disorders. Mol Genet Metab 110(1–2):179–180. Scholar
  53. van Spronsen FJ, Derks TG (2014) Recombinant phenylalanine ammonia lyase in phenylketonuria. Lancet 384(9937):6–8. Scholar
  54. van Wegberg AMJ, MacDonald A, Ahring K, Belanger-Quintana A, Blau N, Bosch AM, Burlina A, Campistol J, Feillet F, Gizewska M, Huijbregts SC, Kearney S, Leuzzi V, Maillot F, Muntau AC, van Rijn M, Trefz F, Walter JH, van Spronsen FJ (2017a) The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis 12(1):162. Scholar
  55. van Wegberg AMJ, MacDonald A, Ahring K, Bélanger-Quintana A, Blau N, Bosch AM, Burlina A, Campistol J, Feillet F, Giżewska M, Huijbregts SC, Kearney S, Leuzzi V, Maillot F, Muntau AC, van Rijn M, Trefz F, Walter JH, van Spronsen FJ (2017b) The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis 12(1):162. Scholar
  56. Vanier MT (2010) Niemann-pick disease type C. Orphanet J Rare Dis 5:16. Scholar
  57. Veys KR, Elmonem MA, Arcolino FO, van den Heuvel L, Levtchenko E (2017) Nephropathic cystinosis: an update. Curr Opin Pediatr 29(2):168–178. Scholar
  58. Wasserstein MP, Jones SA, Soran H, Diaz GA, Lippa N, Thurberg BL, Culm-Merdek K, Shamiyeh E, Inguilizan H, Cox GF, Puga AC (2015) Successful within-patient dose escalation of olipudase alfa in acid sphingomyelinase deficiency. Mol Genet Metab 116(1–2):88–97. Scholar
  59. Whyte MP (2017) Hypophosphatasia: enzyme replacement therapy brings new opportunities and new challenges. J Bone Miner Res 32(4):667–675. Scholar
  60. Williamson L (2014) Counterfeit drugs are everyone's business. Krankenpfl Soins Infirm 107(7):72–73PubMedGoogle Scholar
  61. Wolf B (1993) Biotinidase Deficiency. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A (eds) GeneReviews((R)). University of Washington, SeattleGoogle Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PaediatricsHannover Medical SchoolHannoverGermany
  2. 2.Department of NeuropaediatricsChildren’s Hospital OldenburgOldenburgGermany

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