Genetic testing of metabolic disorders

Some hundreds of human hereditary biochemical disorders have been discovered. When the term metabolic disease is used as a query for the OMIM search program 429 entries are obtained, about half of which are due to a defective protein. The resulting phenotypes commonly appear in the early years of life. Most inborn errors of metabolism are individually rare but altogether they represent a considerable burden for the health system. Children with inborn errors of metabolism may present with one or more of a large variety of signs and symptoms. Once clinical suspicion of an inborn metabolic error is raised, a basic evaluation protocol should be followed, including: blood gas analysis, glucose, electrolytes, ammonia, lactic acid, uric acid, transaminases, calcium, lactate/pyruvate and 3-hydroxybutyrate/acetoacetate ratios; search for ketone bodies, alpha-keto acids and reducing substances in urine. Further information may derive from analysis of amino acids, organic acids, mucopolysaccharides, oligosaccharides in biological fluids. A third step is represented by the identification of a specific enzyme deficiency. DNA analysis represents a useful complement to conventional biochemical investigation, providing final confirmation of the diagnosis. For an increasing number of conditions, genotyping appears largely preferable, as compared to the traditional biochemical approach, in terms of cost, time and safety for the patient. Here we discuss some examples on inherited metabolic disorders including: X-linked ichthyosis, glycogenosis type 1, hereditary fructose intolerance, lysinuric protein intolerance, cystinuria, Gaucher disease, Smith-Lemli-Opitz syndrome, X-linked recessive chondrodysplasia punctata. Prenatal diagnosis and carrier identification of several metabolic disorders are available using conventional biochemical approaches. However, for other metabolic disorders this goal can be obtained by DNA analysis only. A new aspect of inherited metabolic traits is that they can be risk factors for multifactorial genetic disease. Moderate hyperhomocysteinemia clue to genetic variants of cystathionine-synthase and 5,10-methylenetetrahydrofolate reductase has been thoroughly investigated in early vascular disease and neural tube defects. Planning of the molecular diagnosis of a specific metabolic disorder needs a careful survey of mutations due to a high allelic heterogeneity frequently observed in Italian patients such as those affected by phenylketonuria, homocystinuria, lysinuric protein intolerance. The allelic heterogeneity raises the question about the cost of each mutational testing. Future development of new technologies, such as the in silico analysis, will make the molecular diagnosis more rapid and cheaper.