Therapy for Inborn Errors of Metabolism

Inborn errors of metabolism are caused by a distortion of gene expression which ultimately leads to the inadequate synthesis of proteins. Although in some cases— e.g., sickle cell anemia—the primary insult can be traced to DNA, in others—such as thalassemia and most enzyme deficiencies—it is not known whether the primary injury results from damage to the DNA molecules, instabilities of the messenger, inadequacies in translation, or interference with other mechanisms still not discovered. 

An early form of therapy involves eliminating the substrate either by excluding the substrate from the diet, as in phenylketonuria, or by administering drugs—such as penicillamine in Wilson s disease or allopurinol in gout. Orotic aciduria can be corrected by the administration of uridine, which provides the substrate for the biosynthesis of the nucleosides used in RNA and DNA synthesis and is also a substrate for the biosynthesis of inhibitors of the carbamyl aspartate synthetase, the first enzyme in the formation of orotic acid. By this feedback inhibition, the levels of orotic acid in the urine are reduced by the administration of uridine. 

Just as orotic aciduria results from an increase in orotic acid accumulation and a uridine defect, homo-cystinuria is caused by accumulation of homocystine and low levels of cystine. The most effective therapy for that disease is a diet low in thiamine and supplemented with cystine. 

A number of inborn errors of metabolism— vitamin dependent genetic diseases— result from the inability 

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ENZYME REPLACEMENT THERAPY FOR INBORN ERRORS OF METABOLISM... 

The data presented in this study show that we have developed a quantitative analysis of free carnitine and acyl-camitine species in plasma or serum. The quantitative nature of this analysis enables good discrimination between normal and abnormal profiles and accurate therapy monitoring, although one should realize that mild cases exist which may have normal profiles in clinically stable episodes. Compared to other methods for quantitative acyl-camitine analysis like HPLC or GC/MS, the method described here is less laborious and allows determination of a wide variety of acyl-camitine species, including hydroxylated acyl-camitine species, which is not the case for the (laborious) GC/MS method. Since for selective screening for inborn errors of metabolism, apart from urine samples, mostly semm or plasma samples are send in, this method allows direct comprehensive acyl-camitine analysis in such materials, obviating the need for a separate blood-spot for acyl-camitine analysis which would allow qualitative or semi-quantitative acyl-camitine aniysis. ... 

To date, cellular and gene therapy products submitted to FDA have included clinical studies indicated for bone marrow marking, cancer, cystic fibrosis, AIDS, and inborn errors of metabolism and infectious diseases. Of the current active INDs approximately 78% have been sponsored by individual investigators or academic institutions and 22% have also been industry sponsored. In addition to the variety of clinical indications the cell types have also been varied. Examples include tumor infiltrating lymphocytes (TIL) and lymphocyte activated killer (LAK) cells, selected cells from bone marrow and peripheral blood lymphocytes, for example, stem cells, myoblasts, tumor cells and encapsulated cells (e.g., islet cells and adrenal chromaffin cells). 

Biotinidase deficiency represents a readily di-agnosable inherited metabolic disorder for which the symptoms can be prevented or ameliorated with simple, direct therapy. If a child must have an inborn error of metabolism, then biotinidase deficiency is the disorder to have. 

In summary, HMG-CoA lyase deficiency is a unique inborn error of metabolism with profound effects on both amino acid catabolism and metabolic homeostasis in the fasted state. Management of these patients is difficult and requires constant attention to daily nutrition and timely intervention during acute illness. Fortunately, nutritional therapy treatment that provides a diet adequate for growth but with limited intake of leucine and prevents fasting and hypoglycemia enables individuals with HMG-CoA lyase deficiency to live normal active lives. 

H.L. Levy. 1989. Nutritional therapy for selected inborn errors of metabolism J. Am. Coll. Nutr. 8 54S-60S. (PubMed)... 

Another, more recent, example is enzyme therapy for Gaucher s disease, an inborn error of metabolism, treated with Ceredase. The therapy, which requires more than a ton of placenta annually to extract and make the drug, can cost as much as 500,000 per year per person, depending on the dosage needed. A 1996 National Institutes of Health technology assessment panel addressed issues in diagnosis and treatment of the disease and concluded that despite the success of enzyme therapy, treatment is limited by the cost. 

The H-NMR pattern in vitro, 600 MHz) of cerebrospinal fluid (CSF) of a patient with creatine deficiency syndrome (a) compared with normal CSF (b). Note the near absence of creatine and creatinine in the patient s CSF. The ethosuximide observed in the patient s CSF is a drug used in antiepileptic therapy. [Reproduced with permission from A. Schulze et al., Creatine deficiency syndrome caused by guanidinoacetate methyltransferase deficiency diagnostic tools for a new inborn error of metabolism. J. Pediatr. 131, 626 (1997).]... 

The answer is b. (Murray, pp 238-249. Scriver, pp 2165-2194. Sack, pp 121—144. Wilson, pp 287—324.) In treating inborn errors of metabolism that present acutely in the newborn period, aggressive fluid and electrolyte therapy and caloric supplementation are important to correct the imbalances caused by the disorder. Calories spare tissue breakdown that can increase toxic metabolites. Since many of the metabolites that build up in inborn errors ol metabolism are toxic to the central nervous system, hemodialysis is recommended for any patient in stage II coma (poor muscle tone, few spontaneous movements, responsive to painful stimuli) or worse. Dietary therapy should minimize substances that cannot be metabolized—in this case fatty acids, since the oxidation of branched-chain fatty acids results in propionate. Antibiotics are frequently useful because meta-bolically compromised children are more susceptible to infection. 

The potential utility of enzymes as pharmaceuticals was noted many decades ago, and since then, nearly two dozen enzymes have been developed to treat a variety of diseases. Almost all enzyme therapies developed to date are used to deal with a loss of function defect (a mutation that diminishes activity, a low level of production, a deletion). Hence, most enzyme drugs are used as enzyme replacement therapies (ERT) for relatively rare, inborn errors of metabolism (lEMs). As a result, many enzyme therapeutics fall under the FDA s Orphan Drug Designation. However, a few enzyme therapies can also be used to treat much more common conditions such as cancer, heart attacks, and stroke. In the United States, the first enzyme to receive FDA approval was a tissue plasminogen activator called alteplase. This protein, which is now commonly used to treat strokes, was introduced in 1987 as Activase. Since then at least 16 other enzyme drugs have been introduced into the marketplace. Some of these are described in more detail below and in Table 6.1-3. 

The therapy for this disorder is often unsatisfactory and requires management and follow-up in a center equipped to deal with inborn errors of metabolism. Therefore, having made the diagnosis in a particular individual, it is essential that such children be followed periodically at a center. Since anesthesia increases the risk of intravascular coagulation, elective surgery under general anesthesia is absolutely contraindicated, as is angiography. 

The kidneys act to filter toxins out of the blood for excretion in the urine. There are complex mechanisms to recover electrolytes, carbohydrates, and amino acids. The kidney is also an endocrine organ, regulating vitamin D metabolism and signaling red blood cell proliferation through erythropoietin. While each of these unique roles is not specifically tied to an inborn error of metabolism, the kidneys are affected by several disorders and may be the source of chronic complications of disease. Symptoms of chronic kidney disease include osteoporosis, hypertension, anemia, and electrolyte abnormalities with the primary means of therapy being hemodialysis or transplant (Box 4.5). 

Early diagnosis of inborn errors of metabolism is important so treatment may be initiated before irreversible mental and/or physical damage occurs. In general, some of the approaches to treatment of inborn errors include (1) environmental modification, (2) dietary restriction and/or supplementation, (3) product, enzyme, or cofactor replacement or enhancement, (4) depletion of toxic levels of stored substances, (5) drug avoidance, (6) surgical intervention, and (7) possibly in the future, genetic engineering. For some inborn errors no known therapy is available. 

All of the approaches for the treatment of inborn errors of metabolism must be applied within the context of the recognized modes of therapy utilized in medicine. Unfortunately, not all of the modes of treatment are useful in treating inborn errors of metabolism. Psychotherapy and physical methods are not sufficiently specific and thus cannot be employed for the treatment of inborn errors except in a supportive manner. 

Analysis of BAs in urine, serum, bile and stool is crucial for the diagnosis of inborn errors of BA metabolism. It is also helpful for understanding their pathophysiological role in acquired hepatic diseases and for monitoring the effects of therapy on metabolism. Several different inborn defects affecting BA synthetic pathway, have been described over last 20 years [7]. 

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