Applications médicales et perspectives thérapeutiques déduites des connaissances en pathologie moléculaire

Abstract

The rapid development of knowledge in the field of genetic metabolic blocks, of abnormalities of transport systems, of cellular receptors and of diseases of lysosomes has completely modified, in medical practice , the approach to many old problems. One must thus progressively set up a new organization in four main areas: o 1) The biochemical and enzymatic diagnosis of these diseases, and the study of new data. 2) The screening for these abnormalities during the neonatal period i.e. phenylketonuria, galactosemia and leucinosis. 3) Prenatal diagnosis, through early amniocentesis and examination of amniotic fluid. 4) Recognition of heterozygotes. All these measures converge to help genetic counseling, prevention and treatment of these diseases. One can hope that in the future, significant advances will be made in therapeutics, when the molecular basis of abnormalities of the genetic message are better understood and when corrections or substitution of this message become possible in the human species. A few examples will be developed concerning present therapeutical possibilities, which are not negligible. Replacement of an absent or abnormal macromolecule . This system has been applied with success to the treatment of hemophilia, afibrinogenemia and genetic abnormalities of the immunoglobulins; limited results have been obtained in the event of abnormal hemoglobins. Genetic metabolic blocks . They induce toxic effects above the block, and carential effects beneath it. Three types of direct treatment of these blocks are used. Replacement of the deficient enzymatic activity . This is seldom possible. Maltase can be given orally in genetic intolerance to saccharose or isomaltose. Stimulation of vitamin dependency . The dependence on vitamins of certain genetic blocks have been established for thiamine, pyridoxine, cholecalciferol and vitamin B 12. The problem of vitamin B 12 dependency and its therapeutical consequences will be discussed with respect to methylmalonic acidemia. Administration of the final product of a blocked metabolic chain . In two cases, brilliant results are obtained: administration of cortisol and or mineralocorticoids in genetic blocks of adrenal hormono-synthesis and of T3 or T4 or iodide in genetic abnormalities of synthesis of thyroid hormones. Suppression of a nutrient used at the top of a metabolic chain to prevent toxic effects, and eventually administration of a substitutive product below the block to prevent carential effects . Three examples will be discussed, with their results : genetic abnormalities of disaccharide hydrolysis, galactosemia and fructose intolerance, and some disorders of amino-acids metabolism (phenylketonuria, leucinosis and tyrosinosis). Aid to the urinary elimination of excess metabolites . This will be discussed with respect to genetic uricemia of Lesch-Nyhan and to Wilson's disease. Abnormalities of hydrolysis by lysosomes . No direct treatment of these abnormalities exist at the present time. Some trials have been made in cystinosis, which probably belongs to this type of disease. Long term results of sulfur-poor diets and of penicillamine have been been nil in our experience. Abnormalities of transport systems . The molecular bases of the abnormalities are still obscure. However, some have benefited from effective treatment, for instance: exclusion diets in abnormalities of intestinal transfert of hexoses subject to an active transportmechanism (glucose and galactose); partial exclusion diet and penicillamine in disorders of intestinal and renal transfer of dibasic aminoacids (cystinuria); administration of sodium and potassium bicarbonate in abnormalities of H + ion elimination by the distal renal tubule. Abnormalities of cellular receptor systems . Here also, the molecular basis of these abnormalities are not sufficiently clear. However, a few therapeutical measures are effective: sodium supplements when the renal tubule is insensitive to the action of aldosterone, administration of calcium and 25-OH cholecalciferol in the syndrome of tubular insensitivity to parathormone, and finally chlorothiazide derivatives, which lower free water clearance and partially simulate the action of vasopressin, in the syndrome of tubular insensitivity to this hormone. Indirect and complementary therapeutical measures . Finally, a certain number of indirect therapeutical measures have been developed, which have no logical relationship to the metabolic disorder but act on their long-term consequences. Thus, though much is known at present concerning many types of neonatal acidosis linked to genetic abnormalities of aminoacid metabolism, good therapeutical results are obtained by simply giving the children glucose and sodium bicarbonate. Peritoneal dialysis is an effective and rapid means of ridding the organism of toxic metabolites, for instance in leucinosis. Finally, renal transplantations have sometimes met with success when the metabolic disorder principally affects the kidney as in cystinosis, oxalosis and distal tubular acidosis.