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5 Treatment: Present Status and New Trends 5 Treatment: Present Status and New Trends John H. Walter, J. Ed Wraith 5.1 Introduction – 83 5.2 Reducing the Load on the Affected Pathway – 83 5.2.1 Substrate Reduction by Dietary Restriction – 83 5.2.2 Substrate Reduction by Inhibition of Enzymes Within the Pathway – 83 5.3 Correcting Product Deficiency – 84 5.3.1 Replenishing Depleted Products – 84 5.3.2 Increasing Substrate Supply – 84 5.3.3 Providing Alternative Substrates – 85 5.4 Decreasing Metabolite Toxicity – 85 5.4.1 Removing Toxic Metabolites – 85 5.4.2 Blocking the Effects of Toxic Metabolites – 85 5.5 Stimulating Residual Enzyme – 85 5.5.1 Co-Enzyme Treatment – 85 5.5.2 Enzyme Enhancement Therapy – 86 5.6 Transplantation – 87 5.6.1 Hematopoietic Stem Cell Transfer – 87 5.6.2 Other Organ Transplantation – 87 5.7 Pharmacologic Enzyme Replacement – 88 5.7.1 Gaucher Disease – 88 5.7.2 Fabry Disease – 88 5.7.3 Mucopolysaccharidosis Type I – 88 5.7.4 Mucopolysaccharidosis Type VI – 88 5.7.5 Pompe Disease – 88 5.7.6 Other Disorders – 89 5.8 Gene Therapy – 89 5.8.1 Gene Transfer – 89 5.8.2 Pharmacological Gene Therapy – 89 5.9 Conclusions – 89 References – 96 83 5 5.2 · Reducing the Load on the Affected Pathway 5.1 Introduction in the developed world and the recommendation that diet should be continued into adulthood have made it commer- Improvements in understanding of the biochemical and cially viable for specialist food manufacturers to invest in molecular basis of inborn errors have led to significant the necessary research. There have been some improve- developments in our ability to treat many of these disorders. ments in the palatability of aminoacid supplements, and in Such improvements, coupled with an ability to make more the range of available products. The need for dietary flexi- rapid diagnoses and advances in general medical care, par- bility, particularly important for adolescents and adults, has ticularly intensive care, are resulting in better long term led to the development of new products. Products have also prognosis for many patients. However the rarity of indi- been reformulated to increase the content of various miner- vidual disorders has often made it difficult, or impossible, als and trace elements, such as selenium, that have been to obtain sufficient data for assessment of treatments that recognised to be low in individuals on semi-synthetic diets would be considered evidence based. This should be kept in [1]. Clearly, though, there is some way to go before these mind when considering the efficacy of particular therapies. diets can be considered attractive. Anecdotal reports of improvements should be reviewed Limiting the availability of ingested substrate for ab- critically but equally it is important to remain open to new sorption by the gut is a further method for reducing sub- advances. This chapter discusses recent progress in the de- strate. Examples include the treatment of Wilson disease velopment of treatments. We have also included a list of with zinc and the use of ezetimibe in familial hypercholes- medications, with recommended dosages, that are current- terolaemia. A more novel approach is under investigation ly used in the treatment of inborn errors. Readers should for treatment for PKU using microencapsulated phenyla- refer to the relevant chapter for detailed information as to lanine ammonia-lyase [2]. the management of specific disorders. As the biochemical basis of various disorders has been The clinical phenotype of most inborn errors is caused determined a theoretical reason for dietary therapy has by the accumulation of substrate or other related metabo- become evident in some. The efficacy of such treatments lites or deficiency of products of the affected pathway. Al- varies, for example the use of medium chain- triglycerides though there is some overlap, treatments that are aimed at as a fat source in patients with very long chain acyl-CoA ameliorating these derangements can be broadly classified dehydrogenase deficiency and long chain hydroxy acyl- as follows: CoA dehydrogenase deficiency is generally accepted where- 1. Reducing the load on the affected pathway (substrate as the use of a low fat, high carbohydrate diet in medium restriction) chain acyl-CoA dehydrogenase deficiency is unnecessary 2. Correcting product deficiency [3–5]. Other disorders in which dietary therapy has been 3. Decreasing metabolite toxicity attempted but which has been found to be of limited benefit 4. Stimulating residual enzyme include a high cholesterol diet in Smith-Lemli-Opitz (SLO) 5. Enzyme replacement syndrome [6], and Lorenzo’s oil in X-linked adrenoleucod- ystrophy (ALD) [7, 8]. 5.2 Reducing the Load on the Affected Pathway 5.2.2 Substrate Reduction by Inhibition of Enzymes Within the Pathway 5.2.1 Substrate Reduction by Dietary Restriction The use of NTBC in tyrosinaemia type 1 demonstrates a novel approach to inherited metabolic disease. Inhibition of Restrictive diets are the treatment of choice for a number of 4-hydroxyphenylpyruvate dioxygenase, an enzyme proxi- inborn errors (. Table 5.1). Such diets are highly efficacious mal to fumarylacetoacetase, by NTBC, prevents the pro- in phenylketonuria (PKU), maple syrup urine disease duction of maleylacetoacetate, fumarylacetoacetate and (MSUD) and homocystinuria, disorders in which the de- succinylacetone, compounds that are the major toxic agents fective enzyme’s substrate can be effectively limited in the in this disease. diet and in which substrate levels in the body can be moni- In lysosomal storage disorders (LSD), reducing the rate tored. Dietary therapy is less successful in disorders in of production of macromolecules that normally have to be which the defect is further downstream in the affected path- degraded inside these organelles, allows the residual activi- way – for example propionic and methylmalonic acidaemia ties of the patient᾽s defective lysosome system to dispose of and disorders of the urea cycle. Improvements in the under- the toxic molecules that have already accumulated. To be standing of basic human nutritional requirements, food effective, some residual enzyme activity has to be present technology and of the biochemical abnormalities in spe- and so one would presume that this approach would be cific disorders have led to continued development. This is more beneficial in later onset forms of LSD. Small molecule exemplified by PKU. The relative frequency of this disorder inhibitors of ceramide glucosyltransferase which catalyses 84 Chapter 5 · Treatment: Present Status and New Trends I . Table 5.1. Dietary therapy Disorder Basis of diet Efficacy of dietary therapy alone Substrate restriction therapy Fat oxidation disorders (long chain) Long chain fat restriction +++ Familial hypercholesterolemia Low saturated fat +++ Galactosaemia Galactose free ++++ (on liver, kidney, eyes) + (on brain, ovarian functions) Glutaric aciduria type 1 Lysine restricted +++ Hereditary fructose intolerance Fructose free +++++ Homocystinuria Methionine restricted ++++ Lipoprotein lipase deficiency Low saturated fat +++ Maple syrup urine disease Leucine, isoleucine and valine restricted ++++ Ornithine aminotransferase deficiency Arginine restricted +++ Organic acidaemia Protein restricted + Pyruvate dehydrogenase deficiency Low CHO + Phenylketonuria Phe restricted +++++ Refsum’s disease Phytanic acid restriction ++ Tyrosinaemia 1 Phe and tyr restriction ++ Urea cycle disorders Protein restricted + Replenishing depleted products Glycogen storage disease CHO enriched +++ Providing alternative substrates GLUT1 deficiency Ketogenic diet +++ + minimal benefit to +++++ complete or almost complete resolution of disease related problems. the first step in glycosphingolipid biosynthesis have been the basis of treatment, for example the administration of developed, undergone trials in various animal models and carbohydrate in glycogen storage disease (GSD), arginine one product, the imino sugar N-butyldeoxynojirimycin or citrulline in urea cycle disorders and tyrosine in PKU. (NB-DNJ), has now entered clinical practice as Miglustat More recent developments are the use of serine and glycine (Zavesca, Actelion). This drug which is active orally has in 3-phosphoglycerate dehydrogenase deficiency [10] crea- approval for the treatment of Gaucher disease in patients tine in guanidinoacetate methyltransferase (GAMT) defi- unsuitable for enzyme replacement therapy [9]. As the drug ciency [11] and neurotransmitters in defects of biopterin is able to penetrate the blood brain barrier (unlike enzyme synthesis and primary disorders of neurotransmitter me- replacement therapy) a number of other possible therapeu- tabolism (7 Chap. 17 and 29). Cholesterol in SLO syndrome tic uses are being studied both in animal as well as human is active in increasing cholesterol plasma levels and decreas- clinical trials. ing 7,8-dehydrocholesterol accumulation but has little clinical effect. 5.3 Correcting Product Deficiency 5.3.2 Increasing Substrate Supply 5.3.1 Replenishing Depleted Products Giving pharmacological amounts of substrate may be effec- Where the deficiency of an enzyme’s product is important tive particularly in inborn errors of membrane transport in the aetiology of clinical illness its replacement may form proteins, for example L-carnitine in carnitine transporter 85 5 5.5 · Stimulating Residual Enzyme deficiency and ornithine in triple H syndrome. Such therapy block this effect. For example the use of N-methyl-D-aspar- is, of course, dependent upon the substrate itself having low tate (NMDA)
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