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  • Print publication year: 2005
  • Online publication date: September 2009

10 - Treatment

Summary

The purpose of this chapter is to present some general principles of the management of inherited metabolic diseases using specific examples to illustrate various points. It is not meant to be a detailed guide to the specific treatment of any particular disease. Instead, it is intended to provide a conceptual scaffold to aid in understanding the strategy behind the management of various inborn errors of metabolism, particularly strategies involving environmental manipulation.

A logical approach to treatment would be to determine how various point defects in metabolism cause disease, and to reverse or neutralize them, either by dietary, pharmacologic, or some other form of metabolic manipulation. However, in many cases, our understanding of how a particular point defect in metabolism produces disease is still incomplete. Often the abnormality is metabolically or physically inaccessible to environmental manipulation. In the discussion to follow, examples are provided of how rational approaches to treatment grew out of an understanding of the primary and secondary consequences of inborn errors of metabolism. The emphasis is on instances in which treatment is at least partially successful.

Control of accumulation of substrate

When disease is caused by accumulation of the substrate of a reaction that is impaired as a result of deficiency of an enzyme or transport protein, a reasonable approach to treatment would be to try to control levels of the toxic metabolite, either by decreasing its accumulation or accelerating its removal by alternative reactions.

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Baldellou, A., Andria, G., Campbell, P. E., et al. (2004). Paediatric non-neuronopathic Gaucher disease: recommendations for treatment and monitoring. European Journal of Pediatrics, 163, 67–75.
Bosch, A. M., Grootenhuis, M. A., Bakker, H. D., Heijmans, H. S., Wijburg, F. A., Last, B. F. (2004). Living with classical galactosemia: health-related quality of life consequences. Pediatrics, 113, e423–8.
Brown, A. S., Fernhoff, P. M., Waisbren, S. E., et al. (2002). Barriers to successful dietary control among pregnant women with phenylketonuria. Genetics in Medicine, 4, 84–9.
Burdelski, M. & Ullrich, K. (1999). Liver transplantation in metabolic disorders: summary of the general discussion. European Journal of Pediatrics, 158 (Suppl 2), S95–S96.
Cabrera-Salazar, M. A., Novelli, E. & Barranger, J. A. 2002. Gene therapy for the lysosomal storage disorders. Current Opinions in Molecular Therapeutics, 4, 349–58.
Charrow, J., Andersson, H. C., Kaplan, P., et al. (2004). Enzyme replacement therapy and monitoring for children with type 1 Gaucher disease: consensus recommendations. Journal of Pediatrics, 144, 112–20.
Clarke, J. T. R. (2003). The maternal phenylketonuria project: a summary of progress and challenges for the future. Pediatrics, 112, 1584–7.
Cox, T. M., Aerts, F. G., Andria, G., et al. (2003). The role of the iminosugar N-butyldeoxynojirimycin (miglustat) in the management of type II (non-neuronopathic) Gaucher disease: a position statement. Journal of Inherited Metabolic Diseases, 26, 513–526.
Desnick, R. J. (2004). Enzyme replacement and enhancement therapies for lysosomal diseases. Journal of Inherited Metabolic Diseases, 27, 385–410.
DiMauro, S., Mancuso, M. & Naini, A. (2004). Mitochondrial encephalomyopathies: therapeutic approach. Annals of the New York Academy of Sciences, 1011, 232–45.
Enns, G. M. & Packman, W. (2002). The adolescent with an inborn error of metabolism: medical issues and transition to adulthood. Adolescent Medicine, 13, 315–29.
Frustaci, A., Chimenti, C., Ricci, R., et al. (2001). Improvement in cardiac function in the cardiac variant of Fabry's disease with galactose-infusion therapy. New England Journal of Medicine, 345, 25–32.
Grabowski, G. A. & Hopkin, R. J. (2003). Enzyme therapy for lysosomal storage disease: principles, practice, and prospects. Annual Review of Genomics and Human Genetics, 4, 403–36.
Grompe, M. (2001). The pathophysiology and treatment of hereditary tyrosinemia type 1. Seminars in Liver Disease, 21, 563–71.
Hanley, W. B. (2004). Adult phenylketonuria. American Journal of Medicine, 117, 590–5.
Ioannou, Y. A., Enriquez, A. & Benjamin, C. (2003). Gene therapy for lysosomal storage disorders. Expert Opinion on Biological Therapeutics, 3, 789–801.
Koch, R., Hanley, W., Levy, H., et al. (2003). The Maternal Phenylketonuria International Study: 1984–2002. Pediatrics, 112, 1523–9.
Krivit, W., Peters, C. & Shapiro, E. G. (1999). Bone marrow transplantation as effective treatment of central nervous system disease in globoid cell leukodystrophy, metachromatic leukodystrophy, adrenoleukodystrophy, mannosidosis, fucosidosis, aspartylglucosaminuria, Hurler, Maroteaux-Lamy, and Sly syndromes, and Gaucher disease type III. Current Opinions in Neurology, 12, 167–76.
Lee, P. J. (2002). Growing older: the adult metabolic clinic. Journal of Inherited Metabolic Diseases, 25, 252–60.
MacDonald, A. (2000). Diet and compliance in phenylketonuria. European Journal of Pediatrics, 159 (Suppl 2), S136–41.
Pastores, G. M. & Barnett, N. L. 2003. Substrate reduction therapy: miglustat as a remedy for symptomatic patients with Gaucher disease type 1. Expert Opinion on Investigational Drugs, 12, 273–81.
Pastores, G. M. & Thadhani, R. (2002). Advances in the management of Anderson-Fabry disease: enzyme replacement therapy. Expert Opinion on Biological Therapeutics, 2, 325–33.
Pastores, G. M., Weinreb, N. J., Aerts, H., et al. (2004). Therapeutic goals in the treatment of Gaucher disease. Seminars in Hematology, 41 (Suppl 5), 4–14.
Peters, C., Steward, C. G.; National Marrow Donor Program; International Bone Marrow Transplant Registry; Working Party on Inborn Errors, European Bone Marrow Transplant Group. (2003). Hematopoietic cell transplantation for inherited metabolic diseases: an overview of outcomes and practice guidelinesBone Marrow Transplantation, 31, 229–39.
Peters, C., Charnas, L. R., Tan, Y., et al. (2004). Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999. Blood, 104, 881–8.
Platt, F. M., Jeyakumar, M., Andersson, U., et al. (2001). Inhibition of substrate synthesis as a strategy for glycolipid lysosomal storage disease therapy. Journal of Inherited Metabolic Diseases, 24, 275–90.
Platt, L. D., Koch, R., Hanley, W. B., et al. (2000). The international study of pregnancy outcome in women with maternal phenylketonuria: report of a 12-year study. American Journal of Obstetrics and Gynecology, 182, 326–33.
Rouse, B. & Azen, C. (2004). Effect of high maternal blood phenylalanine on offspring congenital anomalies and developmental outcome at ages 4 and 6 years: the importance of strict dietary control preconception and throughout pregnancy. Journal of Pediatrics, 144, 235–9.
Russo, P. A., Mitchell, G. A. & Tanguay, R. M. (2001). Tyrosinemia: a review. Pediatric and Developmental Pathology, 4, 212–21.
Schwahn, B. C., Hafner, D., Hohlfeld, T., Balkenhol, N., Laryea, M. D. & Wendel, U. (2003). Pharmacokinetics of oral betaine in healthy subjects and patients with homocystinuria. British Journal of Clinical Pharmacology, 55, 6–13.
Schiffmann, R. & Brady, R. O. (2002). New prospects for the treatment of lysosomal storage diseases. Drugs, 62, 733–42.
Schon, E. A. & DiMauro, S. (2003). Medicinal and genetic approaches to the treatment of mitochondrial disease. Current Medicinal Chemistry, 10, 2523–33.
Scriver, C. R. & Lee, P. J. (2004). The last day of the past is the first day of the future: transitional care for genetic patients. American Journal of Medicine, 117, 615–7.
Singh, R. H., Kruger, W. D., Wang, L., Pasquali, M. & Elsas, L. J. II. (2004). Cystathionine beta-synthase deficiency: effects of betaine supplementation after methionine restriction in B6-nonresponsive homocystinuria. Genetics in Medicine, 6, 90–5.
Hout, J. M., Kamphoven, J. H., Winkel, L. P., et al. (2004). Long-term intravenous treatment of Pompe disease with recombinant human alpha-glucosidase from milk. Pediatrics, 113, e448–57.
Walter, J. H., Collins, J. E. & Leonard, J. V. (1999). Recommendations for the management of galactosaemia. Archives of Disease in Childhood, 80, 93–6.
Weinreb, N. J., Aggio, M. C., Andersson, H. C., et al. (2004). Gaucher disease type 1: revised recommendations on evaluations and monitoring for adult patients. Seminars in Hematology, 41 (Suppl 5), 15–22.
Weinreb, N. J., Charrow, J., Andersson, H. C., et al. (2002). Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher Registry. American Journal of Medicine, 113, 112–9.
Widaman, K. F. & Azen, C. (2003). Relation of prenatal phenylalanine exposure to infant and childhood cognitive outcomes: results from the International Maternal PKU Collaborative Study. Pediatrics, 112, 1537–43.
Wraith, J. E., Clarke, L. A., Beck, M., et al. (2004). Enzyme replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase). Journal of Pediatrics, 144, 581–8.
Zimran, A. & Elstein, D. (2003). Gaucher disease and the clinical experience with substrate reduction therapy. Philosophical Transactions of the Royal Society London B: Biological Sciences, 358, 961–6.