Cofactor supplementation, treatment

Iron, zinc and copper are the most prevalent metals in the body, and perhaps not surprisingly are the most common supplementation treatments. Of these, iron dehciency is the most commonly observed and there are over 40 preparations of iron used therapeutically (including iron(II) sulfate iron(ll) fumarate iron(II) gluconate and iron(ll) succinate), compared with 3 for zinc (including zinc(II) sulfate). Notably, as folate plays a vital role as a cofactor in the biosynthesis of haeme (for haemoglobin), sometimes it is necessary to co-administer iron with folic acid in so-called compound oral iron preparations . 

Other causes of PKU secondary to defective tetrahydrobiopterin synthesis include GTP cyclohydrolase deficiency and 6-pyravoyltetrahydrobiopterin synthase deficiency. Patients with either defect have psychomotor retardation, truncal hypotonia with limb hypertonia, seizures and a tendency to hyperthermia. The intravenous administration of BH4 may lower blood phenylalanine levels but this cofactor may not readily cross the blood-brain barrier. Treatment with synthetic pterin analogs or supplementation with tryptophan and carbidopa may prove more efficacious, particularly if treatment is started early in life. 

The homocystinurias are a group of disorders involving defects in the metabolism of homocysteine. The diseases are inherited as autosomal recessive illnesses, characterized by high plasma and urinary levels of homocysteine and methionine and low levels of cysteine. The most common cause of homocystinuria is a defect in the enzyme cystathionine /3-synthase, which converts homocysteine to cystathionine (Figure 20.21). Individuals who are homozygous for cystathionine [3-synthase deficiency exhibit ectopia lentis (displace ment of the lens of the eye), skeletal abnormalities, premature arte rial disease, osteoporosis, and mental retardation. Patients can be responsive or non-responsive to oral administration of pyridoxine (vitamin B6)—a cofactor of cystathionine [3-synthase. Bg-responsive patients usually have a milder and later onset of clinical symptoms compared with B6-non-responsive patients. Treatment includes restriction of methionine intake and supplementation with vitamins Bg, B, and folate. 

Pyridoxine (vitamin Bb, in the form of pyridoxal phosphate) is a cofactor in the formation of dopamine from L-DOPA. It used to be thought that pyridoxine supplements would be helpful to treat Parkinson s disease. The opposite was found vitamin B6 apparently also enhances L-DOPA conversion to dopamine in other areas of the body. This means that less of the administered L-DOPA is available for entry into tlie brain. Therefore, Be treatment presently is contraindicated in Parkinson s disease. 

In propionic and methylmalonic aciduria, metronidazole, given orally, inhibits the production of propionic acid by gut bacteria. In isovaleric aciduria and methylcrotonyl-CoA carboxylase deficiency, glycine accompanied by carnitine supplementation inCTeases the elimination of toxic metabolites. In many severe conditions, empiric administration of substances that act as cofactors proves to be helpful, and this treatment option should not be neglected (Table 5.3) [19]. 

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. 

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