Despite realizing increased survival rates for propionic acidemia (PA) and methylmalonic acidemia (MMA) patients, the current therapeutic regimen is inadequate for preventing or treating the devastating complications that still can occur. The elucidation of pathophysiology of these complications allows us to evaluate and rethink treatment strategies. In this review we display and discuss potential therapy targets and we give a systematic overview on current, experimental and unexplored treatment strategies in order to provide insight in what we have to offer PA and MMA patients, now and in the future. Evidence on the effectiveness of treatment strategies is often scarce, since none were tested in randomized clinical trials. This raises concerns, since even the current consensus on best practice treatment for PA and MMA is not without controversy. To attain substantial improvements in overall outcome, gene, mRNA or enzyme replacement therapy is most promising since permanent reduction of toxic metabolites allows for a less strict therapeutic regime. Hereby, both mitochondrial-associated and therapy induced complications can theoretically be prevented. However, the road from bench to bedside is long, as it is challenging to design a drug that is delivered to the mitochondria of all tissues that require enzymatic activity, including the brain, without inducing any off-target effects. To improve survival rate and quality of life of PA and MMA patients, there is a need for systematic (re-)evaluation of accepted and potential treatment strategies, so that we can better determine who will benefit when and how from which treatment strategy.
Keywords: methylmalonic acidemia; pathophysiology; propionic acidemia; treatment strategies.
© 2019 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.