DRUG AND DIETARY THERAPY IN MITOCHONDRIAL CYTOPATHIES OF CHILDHOOD

Diagnostic tools for the studies of mitochondrial disorders of energy metabolism such as biochemical and molecular genetic techniques, have increased our knowledge on the clinical spectrum of mitochondrial cyto pathies (MC) and have enabled new insights in the etiology and pathoge nesis of these heterogeneous multisystem disorders. In contrast, the t herapeutical influence on the usually progressive clinical courses are very limited. A causal therapy has to take into account that biochemi cal defects are heterogeneous (pyruvate dehydrogenase complex, pyruvat e carboxylase, respiratory chain complexes), frequently show tissue-sp ecific and/or time-depending expression and may occur in combination w ith each other. To this date the following therapeutical principals ha ve been used: (1) decrease of the endogenic generation of toxic interm ediates (by dietary measures); (2)increase of residual enzymatic activ ities (by enzyme cofactors or activators); (3) bridging the enzyme def ects (by electron acceptors/donators); and (4) antioxidative and membr ane-protective measures. This review presents the mechanisms of agents used so far, and discusses their therapeutical effectiveness accordin g to the data from the literature and our experience with 26 patients suffering from different types of MC. It is shown that patients with p ure myopathic manifestations of complex I deficiency as well as cardio myopathy caused by carnitine depletion exhibit the greatest benefit fr om cofactor supplementation. The clinical course of patients with Kear ns-Sayre syndrome may be influenced by various therapeutical procedure s. In patients with diseases showing a predominantly encephalopathic p resentation (like Leigh syndrome), disturbed lactate/pyruvate metaboli sm tends to normalise under treatment. The therapeutical influence on the clinical course however, is at best limited to temporary improveme nt or delaying progression. Nevertheless, effects of any particular th erapy can not be predicted easily in any individual at any stage of th e disease. Thus, therapeutical trials are justified because of the low rate of side effects. Gene therapeutical strategies hopefully will of fer more effective treatments.