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) channel agonists, such as dextromethorphan toxicity. Similar treatment has been attempted in Menkes and ketamine in nonketotic hyperglycinemia (NKH), limit disease with copper histidine (with variable effect) [12, 13] the neuroexcitatory effect on glycine on the NMDA recep- and in disorders with single enzyme deficiencies such as tor [24–26]. Although there have been reports of successful mannose in carbohydrate deficient glycoprotein syndrome treatments the variable phenotype has made the efficacy type 1b (phosphomannose isomerase deficiency) [14]. difficult to access. Our experience, with a number of infants presenting with the severe neonatal form of this disorder, has not been encouraging. 5.3.3 Providing Alternative Substrates

In GLUT1 deficiency there is a failure of glucose to be trans- 5.5 Stimulating Residual Enzyme ported across the blood brain barrier. The ketogenic diet provides an alternative fuel for the brain [15]. A ketogenic 5.5.1 Co-Enzyme Treatment diet has also been used in pyruvate dehydrogenase (PDH) deficiency. Other examples of this form of therapy include Some metabolic disorders are caused by mutations that medium chain triglycerides (MCT) in disorders of long affect the metabolism or binding of a co-enzyme or co- chain fatty acid oxidation and carnitine transport and factor, necessary for normal enzyme activity. Treatment folinic acid in cerebral folate transporter disorder [16]. with the co-enzyme may lead to a complete reversal of the clinical phenotype, for example biotin in biotinidase deficiency. Most disorders with co-enzyme responsive variants 5.4 Decreasing Metabolite Toxicity show a more limited improvement, for example a majority of patients with vitamin B12 responsive methylmalonic 5.4.1 Removing Toxic Metabolites acidaemia continue to produce abnormal, albeit smaller, quantities of methylmalonic acid. Other disorders may not A number of medications are used to expedite removal of be fully correctable because of difficulties in getting the normal metabolites that accumulate to toxic levels in par- co-enzyme to the appropriate location. This is the case in ticular inborn errors. These include well established treat- disorders of biopterin synthesis (GTP cyclohydrolase defi- ments such as sodium benzoate and sodium phenylbutyrate ciency, 6 pyruvoyltetrabioterin deficiency) where oral tetra- in disorders associated with hyperammonaemia, glycine in hydrobiopterin (BH4) rapidly corrects the hyperphenyla- isovaleric acidaemia and L-carnitine in organic acidaemias. laninaemia (HPA) by its effect on liver phenylalanine hy- Although there have been no rigorous clinical trials to droxylase (PAH). However BH4 does not easily cross the demonstrate its efficacy, L-carnitine has become an estab- blood brain barrier and is consequently not available to lished treatment for organic acidaemias where there is a tyrosine hydroxylase or tryptophan hydroxylase. The pro- reduction in plasma carnitine and an increase in the acyl: found neurotransmitter deficiency associated with these free L-carnitine ratio [17–19]. The role of L-carnitine in the conditions is therefore not improved by BH4 therapy. treatment of medium chain acyl-CoA dehydrogenase Many single enzyme disorders are due to mutations deficiency is not established and it is our experience that that prevent any enzyme production and cannot therefore children do well following diagnosis without this treatment improve with co-enzyme therapy. For example this is the [20]. However it remains possible that L-carnitine may im- case with probably all patients with propionic acidaemia prove exercise tolerance and might have a protective effect and nearly all those with MSUD even though both propionyl on metabolic decompensation[21]. Further studies are still CoA carboxylase and D-ketoacid dehydrogenase require a necessary to clarify its role in this disorder. In carnitine co-enzyme (biotin and thiamine, respectively). Mutations transport defect, however, the effect of supplementation is that affect protein folding and subsequently limit co- dramatic with a resolution of cardiomyopathy and preven- enzyme binding may be amenable to treatment with phar- tion of further episodes of hypoketotic hypoglycaemia [22]. maceutical doses of the co-enzyme. This is exemplified by Animal studies suggest that carnitine may also have a pro- BH4 therapy which in some of the milder forms of HPA due tective role in hyperammonaemia [23]. to PAH deficiency may be an alternative to dietary phe restriction. In the future it may be possible to use pharmacological agents, other than co-enzymes, to rescue of confor- 5.4.2 Blocking the Effects of mationally-defective proteins [27]. Disorders with known Toxic Metabolites co-enzyme responsive variants are listed in . Table 5.2. The appropriate form of the co-enzyme must be used Disorders in which the phenotype is related to metabolites for the particular disorder. For example, pyridoxal phos- binding to receptors may be amenable to treatments that phate and not pyridoxine, is effective for pyridox(am)ine 86 Chapter 5 · Treatment: Present Status and New Trends

I . Table 5.2. Disorders for which co-factor responsive variants have been described

Disorder Co-factor Therapeutic dose Frequency of responsive variants

Methylmalonic acidaemia (CblA, CblB) Hydroxycobalamin 1 mg IM weekly Some

Biotinidase deficiency Biotin 5–10 mg/day All cases

Holocarboxylase synthetase Biotin 10–40 mg/day Most (Multiple carboxylase deficiency)

Glutaric aciduria type I Riboflavin 20–40 mg/day Rare

Homocystinuria : Classical CBS deficiency Pyridoxine 50–500 mg/day Approx. 50% CblC Hydroxycobalamin 1 mg IM daily Frequent MTHF deficiency Folic acid 20 mg/day Rare

Maple syrup urine disease Thiamine 10–50 mg/day Rare

Respiratory chain disorders Ubiquinone 100–300 mg/day Anecdotal evidence

Propionic acidaemia Biotin 5–10 mg/day Possibly never

Hyperphenylalaninaemia due to Tetrahydrobiopterin 5–20 mg/day All – but no improvement in disorders of biopterin metabolism CNS neurotransmitter levels

Hyperphenylalaninaemia due to PAH Tetrahydrobiopterin 7–20 mg/day Rare for classical PKU, more deficiency common for milder variants

Ornithine aminotransferase deficiency Pyridoxine 300–600 mg/day Rare

Pyridox(am)ine 5’-phosphate oxidase Pyridoxal phosphate 10 mg/kg of pyridoxal-P All deficiency 6-hourly

B6-responsive seizures Pyridoxine 5–10 mg/kg/day All

Cerebral folate deficiency syndrome Folinic acid 0.5–1mg/kg/day All

Thiamine responsive megaloblastic anemia Thiamine 200 mg/day (?)All

Cbl, cobalamin; CBS, cystathionine-E synthase, PAH, phenylalanine hydroxylase; MTHF, methylene tetrahydrofolate reductase.

5ʹ-phosphate oxidase deficiency [28]; folinic acid, which is Most co-enzymes are safe even in large doses and it is accessible to the central nervous system (CNS), rather than appropriate to treat patients, who have disorders that are folic acid is required for folate responsive disorders affect- known to have responsive variants, with the relevant co- ing the brain; and although the active coenzymes for meth- enzyme. The cases for giving a cocktail of various vitamins ylmalonyl CoA mutase and S-adenosylmethyltransferase in patients before a diagnosis has been made is less strong. are adenosylcobalamin and methylcobalamin, respectively, Disorders presenting in the newborn period, or soon after, only hydroxycobalamin is effectively transported into cells are likely to be due to severe enzyme deficiencies that are and consequently used in the treatment of cbl responsive not co-enzyme responsive. Furthermore, the majority of disor ders affecting these enzymes. clinicians will have access to rapid metabolic investiga- On occasions it may be difficult to determine whether tions by specialist laboratories. However, if there is likely a particular patient is responsive to co-enzyme therapy. to be a delay in diagnostic investigations the intelligent This may arise due to confounding factors that cause a con- use of a number of vitamins or co-factors may be indicated comitant decrease in a particular biochemical marker (such (. Table 5.3). as the concentration of a particular metabolite) unrelated to the administration of the co-enzyme. For example the patient may have entered a recovery phase following a 5.5.2 Enzyme Enhancement Therapy period of metabolic decompensation or may have recently started a dietary therapy. Standard protocols may be helpful In disorders where the primary genetic defect leads to either in such situations but further assessment may be required protein misfolding or a protein trafficking defect, attempts when the patient is more stable. have been made to rescue the phenotype by the use of 87 5 5.6 · Transplantation

all of the reported cases are either anecdotal or consist of . Table 5.3. The vitamin cocktail very few cases from the same centre. The first disorder Biotin 10 mg/day treated by this method was mucopolysaccharidosis (MPS) type I (Hurler syndrome) [32] and the greatest clinical Thiamine 200 mg/day experience exists with this disorder. There can be no doubt Lipoic acid 100 mg/day that a successful bone marrow transplantation (BMT) in MPS I alters the natural history of the disease, but there L-carnitine 25 mg/kg 6 hourly are considerable residual problems especially with spinal

Coenzyme-Q10 5 mg/kg/day deformity and joint disease [33]. In addition BMT must be

Vitamin C 100 mg/kg/day performed early (ideally < 18 months) if neurological pro- gression is to be prevented. Whilst the risks of graft versus Riboflavin 100–300 mg/day host disease have lessened with improvements in tissue- Pyridoxine 50–500 mg/day typing and drug therapy, primary graft rejection remains a problem in this group of patients. Other cell sources in- Pyridoxal phospate 20 mg/kg/day cluding umbilical cord blood cells are now routinely used Folinic acid 20 mg/day and are giving promising results in MPS patients [34]. With other disorders the role of HSCT is less clear-cut and is probably contra-indicated in disorders with very chemical and pharmacological chaperones. This approach aggressive neurodegeneration e.g. MPS III (Sanfilippo syn- to treatment has been labeled enzyme enhancement therapy drome). There is some evidence that the use of umbilical- (EET) [29]. Pharmacological chaperones are likely to be cord blood transfer from unrelated donors before the devel- small molecules that are active orally and they may have a opment of symptoms (neonatal period) may favorably alter different tissue distribution from an enzyme whose delivery the natural history of infantile Krabbe’s disease [35]. The will be dependent on receptor mediated uptake. This ad- role of HSCT in metabolic disorders has been reviewed vantage may also include the ability to cross the blood recently [36]. In the future one might expect an increased brain barrier a current weakness with intravenous enzyme use of alternative stem cells such as bone marrow derived replacement therapy (ERT). mesenchymal stem cells (MSCs) and the adjunctive use of Proof of this concept has been demonstrated in the ERT in disorders where recombinant enzyme is available, cardiac variant of Fabry disease. Affected patients have re- e.g., MPS I to try to improve outcome in these difficult pa- sidual D-galactosidase activity and a later, milder clinical tients. phenotype compared to classically affected male patients. An affected patient with severe heart disease was rescued from cardiac transplantation by the use of intravenous 5.6.2 Other Organ Transplantation galactose (1 g/kg) which acted as a competitive inhibitor that could bind to the active site and rescue the mutant Liver transplantation has been used as a successful therapy enzyme, promoting proper folding and processing and for a number of inborn errors of metabolism including urea preventing the proteosomal degradation of the mutant cycle disorders, organic acidaemias, homozygous familial enzyme glycopeptides [30]. hypercholesterolaemia and severe forms of GSD [37]. Certain enzymes may also be stimulated by specific Whilst the indications for transplant in disorders such as medication. For example dichloroacetate (DCA) increases Crigler-Najjar syndrome, GSD IV, or fulminant hepatic PDH activity by its inhibitory effect on PDH kinase. An failure secondary to Wilson disease may be clear-cut, the open-label trial of its use in 37 patients with a variety of indications in other inborn errors are not and the decision- mitochondrial disorders suggested that it might have a making process is often very difficult. The mortality associ- beneficial effect in some patients [31]. ated with liver transplantation is often high in patients with severe disorders of intermediary metabolism. Furthermore in organic acidaemias transplantation does not necessarily 5.6 Transplantation remove the risk of disease related complications occurring [38, 39]. Nevertheless for those conditions that are associ- 5.6.1 Hematopoietic Stem Cell Transfer ated with a poor prognosis with conventional medical therapy liver transplant may be an effective treatment. Hepato- Hematopoetic stem cell transfer (HSCT) readily corrects cyte transplantation has also been attempted in GSD 1a and the enzyme deficiencies associated with lysosomal and in ornithine transcarbamoylase (OTC) deficiency [40, 41]. peroxisomal disorders at least in cells of hematopoetic Renal transplantation has been used for the treatment origin. An attempt has been made to treat almost all of the of end stage renal failure in inborn errors of metabolism lysosomal disorders by this method. Unfortunately, almost such as cystinosis, however, this treatment is of limited 88 Chapter 5 · Treatment: Present Status and New Trends

value for those disorders where the primary defect resides of all the currently available ERTs. There is no evidence that I primarily outside of the kidney. For example in patients any can penetrate the blood brain barrier and treatment with primary hyperoxaluria type I where the disorder is is therefore limited to the systemic or non-neurological primarily within the liver, the transplanted kidney is ex- manifestations of the disorders. posed to oxalate resulting in a shortened graft survival (7 Chap. 43). Combined liver-kidney transplantation has been performed in both methylmalonic acidaemia [42] and 5.7.2 Fabry Disease primary hyperoxaluria type I [43], although, in the latter, a pre-emptive liver transplant from a live, related donor For patients with Fabry disease two recombinant enzyme may be most appropriate [44]. products became available (Replagal, Shire and Fabrazyme, Genzyme), after both demonstrated efficacy in clinical trials [52, 53]. In Fabry disease it is important to recognize 5.7 Pharmacologic Enzyme and treat patients as early as possible if they are to benefit Replacement from ERT as there will be a point in the process of tissue damage beyond which ERT will be unable to rescue the Early attempts at pharmacologic enzyme replacement ther- affected organ. Future objectives will also include under- apy (ERT) were disappointing since the need for targeting standing how the two available products compare and the enzymes to the tissue of interest was not appreciated. determining the optimal dose necessary to achieve the best It was only after placental extracted glucocerebrosidase clinical outcome. was modified to uncover the signalling mannose residues that efficient uptake into macrophages and subsequent disease correction was observed. Endocytosis via the man- 5.7.3 Mucopolysaccharidosis Type I nose and mannose-6-phosphate receptor is pivotal to the success of ERT and commercially produced enzymes are Aldurazyme (Genzyme) has been licensed to treat the non- modified in the manufacturing process in an attempt to neurological manifestations of MPS type I (D-L-iduroni- maximise uptake. dase deficiency) following a successful clinical trial [54]. In Although not considered in detail in this chapter this study affected patients showed an improvement in (7 Chap. 35), the first successful ERT was with polyethylene pulmonary function and endurance following Aldurazyme glycol-modified adenosine deaminase in adenosine deami- therapy. The indications for use in patients with severe MPS nase deficiency [45]. I (Hurler syndrome) are limited by the product’s inability to cross the blood brain barrier but there may be a role as an adjunct to hematopoetic stem cell transfer. 5.7.1 Gaucher Disease

ERT is proving to be the most useful of a number of new 5.7.4 Mucopolysaccharidosis Type VI therapeutic approaches to treatment specifically for lysosomal storage disease [46]. Gaucher disease (E-glucocere- Naglazyme (Biomarin) has been approved by both the FDA brosidase deficiency) was the first disorder for which ERT and the EMEA to treat MPS VI (Maroteaux-Lamy syn- (using macrophage targeted enzyme, Cerezyme, Genzyme) drome) following a successful clinical trial [55]. Enzyme has become the standard therapy to treat non-neurological treated patients demonstrated improvements in endurance manifestations of the disease. There are now many years of as well as a range of other positive benefits. experience with this product and when initiated in a timely manner and in adequate dosage prevents progressive manifestations of the disease including bone marrow failure, 5.7.5 Pompe Disease organomegaly and bone crises [47]. Recommendations on diagnosis, evaluation and monitoring have been published Myozyme has been approved by the EMEA to treat both for both adults [48] and children [49, 50] with type I disease. infantile and late-onset Pompe disease (GSD II) [56, 57]. ERT is also systemically effective in type III (chronic neuro- In classical infantile patients ERT leads to rapid improve- nopathic) Gaucher disease but the dosage required (60–120 ment in cardiomyopathy, but response in skeletal muscle is U/kg/2 weeks) is often higher than the dose required to more variable. obtain a satisfactory outcome in type I patients (15–60 units/kg/2 weeks). A European consensus on management of patients with type III disease has also been published [51]. In patients with acute neuronopathic (type II) Gaucher disease ERT is ineffective and this is one of the weaknesses 89 5 5.9 · Conclusions

5.7.6 Other Disorders fetal haemoglobin may be stimulated by various agents such as hydroxyurea, 5-azacytidine and sodium phenylbutyrate ERT is at an advanced stage of development for MPS II [58] [61–63]. Similarly in cystic fibrosis sodium phenylbutyrate where phase 3 clinical studies are in progress. Other disor- increases CTFR gene expression [64]. Kemp et al. have ders are at any earlier stage of development or are being demonstrated that sodium phenylbutyrate, in cells from explored in animal models. This whole area has been re- patients with X-linked ALD and from X-ALD knockout viewed recently [29]. mice, increased E-oxidation and decreased VLCFAs by enhancing the expression of a peroxisomal membrane ABC transporter protein gene coding for ALD related pro- 5.8 Gene Therapy tein (ALDRP) [65]. Furthermore, dietary treatment of the X-ALD mice with sodium phenylbutyrate led to a substan- 5.8.1 Gene Transfer tial decrease in VLCFAs in both the brain and adrenal glands. ALDRP is closely related to ALD protein (ALDP), Initial enthusiasm for gene therapy as a potential treatment the product of the X-ALD gene. The ALDRP gene appears for single gene disorders has been dampened by a number to be redundant in normal individuals. Other agents have of important challenges which include the targeting and also been studied [66]. It remains to be seen whether this efficiency of gene transfer as well as the magnitude and du- form of therapy may be useful in the management of ration of subsequent gene expression. A great deal of work human disease. however has been achieved and there has been steady progress within the field even though there have been very few successful treatment protocols. Successful therapy for 5.9 Conclusions metabolic disorders must combine appropriate disease targeting with an efficient delivery system which ensures long Although the outcome for many inborn errors remains term expression with no toxicity. This has proved to be an poor there have been very encouraging developments in elusive goal, but promising results have been obtained in recent years particularly the use of ERT in lysosomal dis- animal studies [59]. More success has been achieved in orders. However formidable obstacles remain particularly hematological disorders and gene therapy for adenosine for those disorders where there is significant in utero deaminase deficiency has moved from early trials of safety damage or where the CNS is primarily affected. and feasibility to more recent studies reporting on efficacy and clinical benefit [60].

5.8.2 Pharmacological Gene Therapy

Stimulating the expression of endogenous redundant genes by pharmacological agents may provide treatment for some inborn errors. In haemoglobinopathies, the production of 90 Chapter 5 · Treatment: Present Status and New Trends

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t mg/kg/day l – – 5

g/m mg/kg

mg/kg/day mg/day Ora mg/kg/day

7 mg 00 5 –1 .3 .0 – 0 5 1 1 300 doses 1 (infants), 1 every 5 divided 1 1 1

some

ism,

l ycine l VI aciduria),

deficiency

defect ipidaemia Adu

) l transferase aemia l T l type metabo

synthase orotic

deficiency,

inism absorption, deficiency, l l

hyper (AGA

arginine:g

; methy estero

amin l UMP l ma

synthesis

4 transporter

acidosis 50mg/kg/day

ate l BH coba synthase

synthase ate fo

(hereditary l

hyperinsu

combined ysaccharidosis actic

fo l disease hypercho deficiency

l l ene ) or l deficiency,

T ia l Disorders deficiency methionine hereditary Primary DHPR methy amidinotransferase disorders Mixed cerebra (GAM Mucopo

fa- l of ; human ine

s su l

ll l of break- by 4

l copper Menkes ce beza- Chinese

eve

l cystine Cystinosis ar source absorption Fami in

G l l ogue e u l ude l T l ll activity antagonist NKH 5

(CHO) kinase secretion Persistent

l ana inc

periphera in creatine Guanidinoacetate

estero l

fenofibrate l

actosamine PDH l

PDH ysosoma

intrace CNS -dopa

the action Disorders Recommended accessib

Ovary l

decrease l ga insu cho

and channe

of ates of for

fibrates l

etes manufactured enishes l

l ate l down inhibiting fo Dep other fibrate, Rep Recombinant N-acety tase Hamster Fibrates l

mono-

histidine Increases

acid Provides

fase l azyme) oroacetate Stimu l l su inic l l Entacapone Prevents Dextromethorphan NMDA Fo Ezetimibe Inhibits Cysteamine/phosphocysteamine Diazoxide Inhibits Dich Copper Creatine hydrate Medication Mode Gemfibrozi Ga (Nag 92 Chapter 5 · Treatment: Present Status and New Trends

I ters 9, p 29 26 28 29 23

9, 7, 9 7, 3, 6 20, 1 1

1 20 1 20,

s l s l

eve min

l eve 90 l

5HIAA HVA

over

racemic

dose: mg/kg/day

:5) CSF CSF -dopa/carbidopa

1 use decompensation l

600

or as

0 not to oading

1 l : 1 Give Monitor during ( Monitor (200mg/kg) mixture Up l1 IV 24 IV Do IV IV

ora

or or or l l l l l l l or

SC Ora Ora Ora IV 39 IM Ora Ora

def) to

doses once per

y 5 l

doses –

dosages: CPS mg

mg/kg/ 3

doses doses Ora

ow doses some U/kg l 0

and

days IV 36

s in

gradua 70

4 and

60 divided 1 AL

T higher divided in to for

dose 4 divided divided y

divided l disease l (OC

4 4

in 3

y /day dai l ora in in 2 dose Route Remarks Cha week

in increasing

;

increasing weeks mg/kg/day

l dai deficiency: 2 week IV 39

per y 00

T l once Gaucher

1 mg/kg/day gm/m

recommend

per per

mg/kg/day Ora

3 III OC

week dai

once

regimens: mg/kg/day

LPI: 3.8 mg/kg/day

700 IM

2 70 200 and U/kg mg/kg/day U/kg mg/kg/day mg/kg or

–

type

0mg/kg/day

U/kg to

deficientiy) g/kg

twice –1 –1 2 2mg/kg/day 30mg/kg/day 4

mg weeks inicians µ 0 –1

20 00 50 00 – l 1 doses, 1 1– 8 2.5 2 For c 1 or Up AS 50 CPS day 1 1– 1 1

ism ] l

1– 68 I

[ arginine

LPI type metabo carnitine

Ic 5

;

MELAS Ib, synthesis ;

def

amin T l GSD

in ternative

secondary neurotransmitter coba L-dopa l

a disorders

and

of of of acidaemia

e disease Various ysaccharidosis l

l and an

def porphyrias 3

eric as cyc l

CPS

Acute Disorders synthesis Isova Neutropenia Disorders Urea Gaucher Used in NKH Mucopo Primary deficiencies

acid

; manu- of of ony with inter-

ine (NDMA)

the and acement Disorders precursor

inic l ; l ma Hamster l

-CoA ine ogue ogue stores ycine rep l

l l ocyte l

Chinese ll l evu

l neurotrans- g

l (CHO) within

acy

ana ana

of ine

methy

citru arginine body l ery earance

l ucocerebrosidase l Chinese l granu

oxide for from

l -D-aspartate

toxic action Disorders Recommended Ovary in l

antagonist

5-amino β-g α-L-iduronidase

isova (CHO) of ates

l rena

enishes enishes acement enishes l l l l nitrous

Inhibits synthase mutase Co-factor high production mitters of human manufactured Hamster Recombinant arginine channe human factured Ovary Recombinant mitochondria mediates removes

amin l

)

2 1 B

ine Rep arginate ll

ucerase l durazyme) l ycine Forms l Heme Hydroxycoba (vitamin G-CSFG Stimu Medication Mode L-dopa Rep 5-Hydroxytryptophan Neurotransmitter L-Arginine Rep Laronidase (A Imig (Cerezyme) L-citru Ketamine N-methy L-carnitine Rep 93 5 5.9 · Conclusions ters p 9 1 8 0 25 26 32 24 37 20 39 4 1 1 26 26

l / who in

mod-

for

tyr, to mo

enzyme

d µ l maintain ow

for disease benefit

]

mi therapy

e to 600

< with

with diet

69, tyr

[ proven

Gaucher recommended

of phe acement

unsuitab y l

l asma l ow Not On Combine erate are rep CDG patients p l l l l l l l l l l l l1 l SC IV/ora Ora Ora Ora Ora

y, to l

ution /kg/ or l

doses doses 3

dai

pump so

doses Ora doses Ora in

weeks

mmo doses

doses

doses Ora 4

times –

1 3.5 divided 2 divided 3

max.

given day Ora doses Ora

–

5 4

divided a divided

–

to day Ora

mg 6 0.7 3 in 3

divided

over divided continuous

divided

up 3 in MgSO4 in in 3

2 g/day, y by l 200

times in dose Route Remarks Cha divided

µ –

1– Mg or 5

times dai

60 00 in

in 1

three to /kg/day mg/day

increased

mg/kg/day

y doses three mg/day mg/day Ora times m

maintenance

ll mg/kg/day, mg/kg/day

l 3 600 dose: ementa

.5 l 300 t g/day mg/kg/day mg g l e 000

–

30 300

/kg/day mg/kg to

–1

ora µ – – – 2 1 ; g 0 5 00 00 00 mg/kg/day 1 1 1 Up day 1 of 0.5 IV 1 7.5 divided Adu gradua 1– 1 1

defi-

for

deficiency

with

onic l synthetase

erance 20 Chap. ma

l inism l dehydrogenase l

synthase cemia I

l into (see

methy

type

ycerate deficiency) l

phosphate hypoca

l hyperinsu utamate and

protein disease disorder 50

g hypomagnesemia

l (PMI

ipidaemia l Ib

yrosinaemia deficiency NKH Hyper secondary ciency Propionic acidaemia Carbamoy Gaucher N-acety indications) T

the

ipid of l

re- fatty

l ; pyru- which l

state Hartnup

free

utamate l production acid

ceramide

l of tissue g estero

l l ogue Persistent enzyme ation CDG l

l antagonist

ycosphingo l ease ana l first ucosy g

absorption Lysinuric

Mg Primary deficiency serine 3-phosphog

re ycosy g

l N-acety adipose

agent Cystinuria for the g kynurenic

HDL-cho

of action Disorders Recommended propionate

4-hydroxypheny the l ysine

receptor bacteria l

ates

l synthesis from

dioxygenase ating enishes enishes enishes

l l l l endogenous gut ows

ll Rep NMDA an acids increases Che by (GSL) sponsib Stimu synthase synthase, vate Inhibits A - l (niacin) Inhibits ben- -

e Reduces l l hexane- l l avesca) Inhibitor

l Z (

acid 2-nitro-4-tri-

[ (tiopronin)

,3-cyc (2-

1 - ustat l l] Carbamoy BC ysine-HC

ycine utamate l T l l uoro-methy l L-serine Rep L-tryptophan Increases Mannose Improves Medication Mode L- Magnesium Nicotinic N- Mercaptopropiony g Nicotinamide Rep Metronidazo Mig g Octreotide Somatostatin f N zoy dione) 94 Chapter 5 · Treatment: Present Status and New Trends 5 43 1

I ters 3, 9 p 33 37 22, 36,

1 1

, 2, 7 7 2, 1 9 32, 26, 29 1 1 2 29, 20

;

? thia-

min mg

in CLA

PDH

90 in 1] 1

doses 300 7

l [ to

over used

dai neuropathy dose:

mg/day

with

l up deficiency

contraindicated

mg of

responsive been

2000

mg/kg reference occur –

oading 000 DHPR l

Doses Periphera May 500 have mine in can >1 250 IV IV IV 20

or or l l1 l l l1 l l l l l Ora Ora Ora Ora Ora Ora Ora Ora

;

doses Ora

doses See

by or

hyper-

dose

l ; or seizures:

regarding doses

ora doses Ora

mg/day)

divided

(maintenance mg/kg/day divided with severe

deficiency

4 doses

if defects

500 20

max. 4

to 2

; monitoring days PAH ed

divided

to l

three

divided BH

3 in statins (min in discussion

4 dose Route Remarks Cha

in –

l in

up .73m

EEG

divided 2

for

1 infusion in

doub for

in in

dependency 2g/

doses be 32 with

mg/kg/day

iv mg/day mg/day

disease:

mg/day individua

may mg/day) mg/kg/day

650 5

50 mg/day mg/day mg 0.25mg/day mg/kg/day Chap. of

–

0 500

son g/day mg/kg/day l –1

–

–1 20 3 divided

1– 0 – –1 00 00 5 1 See use Cystinuria: in 40mg/kg/day 0. 7 1– 5 continuous Dose ammonaemia 20 1 50 Pyridoxine 1 30 1

;

1 F/

ing l E

astic type l MSUD, of

and

defi-

actic T of oxidase l

recyc

deficiency 1

uria aciduria l experi-

or ex

l (CBS) responsive

siderob PAH

cystathionase

variants

dependency responsive γ

with of used d

variants l

comp deficiency)

congenita inked mi utaconic ; l hyperoxa

1 l

I, synthesis g

been X- l and 5’-phosphate cystinuria Wi

forms ex 4

; l ; defects β-synthase pyridoxine

therapy

; 4 BH SCAD has

SLO pyridoxine pyridoxine

responsive to

; ; of BH responsive primary

methy

; (comp aciduria and

y in

disease

ipidaemias ll

l II seizures deficiency

deficiency

responsive

son T adjunct 4 l F-DH

utaric l T hiamine ype T ciency PDH BH deficiency Simvastatin menta Disorders deficiency deficiency L-dopa Hyperammonaemia 250 E Hyperammonaemia 250 cystathionine with acidosis anaemia OA T

form nitro- which

high utamine

ammonia inhibitor As to l

g A

inhibitors Hyper acetate

has l

4 ood l ycine b l with utamine

BH earance l Removes

l g

g c l of pheny which l

to with

reductase agent Wi

co-enzyme

action Disorders Recommended rena acid reduces

pheny

of earance.

co-factor Pyridox(am)ine l combines of

c ating l acement and l high

form

pen hippuric Rep to which Converted rena has ) Monoamine-oxidase-B l

- l acid Source -depreny

l (

-Phosphate Active l benzoate Combines pheny

amine Che ine l ll avin Co-enzyme G l ) 4 egi l hiamine Co-factor etrahydrobiopterin Sodium T Pyridoxa Sodium butyrate Statins HMG-CoA Penici Medication Mode Panothenic Ribof Pyridoxine Co-factor Pyridoxine Se T (BH 95 5 5.9 · Conclusions ters 1 3

; p 3 32

1 con-

; , 8, 5 2, 30, 37 35 1 37 30 29 CLA ;

d s reductase l l

ycinaemia, l

– be isomerase

ation fie

l l eve l iron

may

other

hyperg ycosy

visua y: l

in e ll cytopathies

e benefit l g GABA

l l

serum of

ements used CSF l

carefu

possib dihydropteridine

, reduce supp non-ketotic irreversib

been

unproven

defects

phosphomannose

l , DHPR May Has Monitor mitochondria but necessary iron and increases deficits ; NKH PMI ; ; acid

congenita

, l l l l l l l1 l l1 acidaemia

CDG Ora Ora Ora Ora Ora ;

onic

l t dehydrogenase

t l ma l adu docosahexanoeic synthase

l , adu

doses) Ora doses Ora

pyruvate

increasing methy DHA ,

necessary , ; (initia

if ories Ora

doses l

PDH divided ; ca divided

MMA doses

; l

factor ; 2

in ic ase

mg/day l in

ll (maintenance

tota

cystathionine-β divided

2.4g/day ,

n/day ating 4 dose Route Remarks Cha l of

600

– of divided Z

3 CBS

in ;

mg in 30%

mg/day

stimu mg/day

mg/day homovani mg/kg/day

00 , mg/kg/day

disease:

Give 300 50 000 –1 ony

l 300 00 transcarbamoy maximum mg/day mg/kg/day mg/kg/day Ora

HVA

– –1 –1

co son mg/kg/day provide

a l l; –1

00 00 0 00 00 o T 1 to 50 200 1 1 dose). AE: Wi dose), 1 utary ocyte l l

g ornithine l

]1 tetrahydrobiopterin

4 pyru- granu ; 72

l OTC , [ ; BH ; newborn (AE)

G-CSF

the (hereditary

deficiency deficiency

of dehydrogenase

synthesis

deficiency deficiency

synthase

1 PC hydroxypheny 3-hydroxy-3-methy deficiency)

;

, ohexanedione l CoQ (4

dehyde synthetase, deficiency enteropathica l

III of

synthase synthetase synthetase HMG

; ,3-cyc tyrosinaemia 1

semia

)- l deficiency disease 600 errors disease

ipoproteinaemia aciduria) l

synthase dioxygenase

disease

phosphate son son argininosuccinate l l

l utathione utathione utathione , l l l yrosinaemia ransient benzoy orotic Succinic deficiency Inborn vate T T G Abeta G Acrodernatitis Wi l AS ; storage

yase l carbamoy free

, ; uoromethy ycogen l CPS l absorp-

; g GABA

, stores

of E

GSD ; system

impairs agininosuccinate

vitamin UMP UMP ; , substrate VLCAD

scavenger G inhibitor

monophosphate

l antioxidant Hawkinsinuria agent Wi 2-(2-nitro-4-trif e

l ; Z , action Disorders Recommended ;

nervous scavenger l of transferase l

erotic l l radica acid ating enishes enishes

l l l NTBC uridine

; , centra

transaminase Che Rep radica tion , methy

UMP ; eaceatic CNS l

; i-Opitz -D-aspartate l

l 0) 1 m l acidosis

Q pha

l tetramine

) l

E C Co-factor AFree actic

phate Increases ene N-methy l 5-hydroxyindo l guanidinoacetate

, , , su Smith-Le

, inc riheptanoin Anap riethy GAMT NMDA genita Uridine Rep T Vigabatrin Irreversib T (trientine) Medication Mode Ubiquinone (Co-enzyme SLO Vitamin Vitamin tocophero Vitamin Z 5HIAA 96 Chapter 5 · Treatment: Present Status and New Trends

References 22. Waber LJ, Valle D, Neill C et al (1982) Carnitine deficiency presenting I as familial cardiomyopathy: a treatable defect in carnitine trans- 1. Acosta PB, Stepnick Gropper S, Clarke Sheehan N et al (1987) Trace port. J Pediatr 101:700-705 element status of PKU children ingesting an elemental diet. J 23. Igisu H, Matsuoka M, Iryo Y (1995) Protection of the brain by carni- Parenter Enteral Nutr 11:287-292 tine. Sangyo Eiseigaku Zasshi 37:75-82 2. Safos S, Chang TM (1995) Enzyme replacement therapy in ENU2 24. Hamosh A, McDonald JW, Valle D et al (1992) Dextromethorphan phenylketonuric mice using oral microencapsulated phenylalanine and high-dose benzoate therapy for nonketotic hyperglycinemia ammonia-lyase: a preliminary report. Artif Cells Blood Substit in an infant [see comments]. J Pediatr 121:131-135 Immobil Biotechnol 23:681-692 25. Alemzadeh R, Gammeltoft K, Matteson K (1996) Efficacy of low- 3. Brown-Harrison MC, Nada MA, Sprecher H et al (1996) Very long dose dextromethorphan in the treatment of nonketotic hyper- chain acyl-CoA dehydrogenase deficiency: successful treatment of glycinemia. Pediatrics 97(6 Pt 1):924-926 acute cardiomyopathy. Biochem Mol Med 58:59-65 26. Matsuo S, Inoue F, Takeuchi Y et al (1995) Efficacy of tryptophan for 4. Pollitt RJ (1995) Disorders of mitochondrial long-chain fatty acid the treatment of nonketotic hyperglycinemia: a new therapeutic oxidation. J Inherit Metab Dis 18:473-490 approach for modulating the N- methyl-D-aspartate receptor. Pedi- 5. Morris AA, Clayton PT, Surtees RA et al(1997) Clinical outcomes in atrics 95:142-146 long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. 27. Ulloa-Aguirre A, Janovick JA, Brothers SP et al (2004) Pharmaco- J Pediatr 131:938 logic rescue of conformationally-defective proteins: implications 6. Irons M, Elias ER, Abuelo D et al (1997) Treatment of Smith-Lemli- for the treatment of human disease. 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43. Jamieson NV, Watts RW, Evans DB et al (1991) Liver and kidney 63. Charache S, Dover G, Smith K et al (1983) Treatment of sickle cell transplantation in the treatment of primary hyperoxaluria. Trans- anemia with 5-azacytidine results in increased fetal hemoglobin plant Proc 23:1557-1558 production and is associated with nonrandom hypomethylation of 44. Gruessner RW (1998) Preemptive liver transplantation from a living DNA around the gamma-delta-beta-globin gene complex. Proc related donor for primary hyperoxaluria type I [letter]. N Engl J Med Natl Acad Sci U S A 80:4842-4846 338:1924 64. Rubenstein RC, Egan ME, Zeitlin PL (1997) In vitro pharmacologic 45. Hershfield MS, Buckley RH, Greenberg ML et al (1987) Treat- restoration of CFTR-mediated chloride transport with sodium 4- ment of adenosine deaminase deficiency with polyethylene gly- phenylbutyrate in cystic fibrosis epithelial cells containing delta col-modified adenosine deaminase. N Engl J Med 316:589- F508-CFTR. J Clin Invest 100:2457-2465 596 65. Kemp S, Wei HM, Lu JF et al (1998) Gene redundancy and pharma- 46. Schiffmann R, Brady RO (2002) New prospects for the treatment of cological gene therapy: implications for X- linked adrenoleukodys- lysosomal storage diseases. Drugs 62:733-742 trophy. Nat Med 4:1261-1268 47. Weinreb NJ, Charrow J, Andersson HC et al (2002) Effectiveness of 66. McGuinness MC, Zhang HP, Smith KD (2001) Evaluation of pharma- enzyme replacement therapy in 1028 patients with type 1 Gaucher cological induction of fatty acid beta-oxidation in X-linked adreno- disease after 2 to 5 years of treatment: a report from the Gaucher leukodystrophy. Mol Genet Metab 74:256-263 Registry. Am J Med 113:112-119 67. Zeng WQ, Al Yamani E, Acierno JS, Jr et al (2005) Biotin-responsive 48. Charrow J, Esplin JA, Gribble TJ et al (1998) Gaucher disease: recom- basal ganglia disease maps to 2q36.3 and is due to mutations in mendations on diagnosis, evaluation, and monitoring. 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