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Minerva Biotecnologica 2000 June;12(2):65-69


lingua: Inglese

Genetic testing of metabolic disorders

Andria G., Parenti G., Melis D., Sebastio G.

Department of Pediatrics, Federico II University, Naples, Italy


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 due 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.

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