Pathophysiology of propionic and methylmalonic acidemias. Part 1: Complications

Abstract

Over the last decades, advances in clinical care for patients suffering from propionic acidemia (PA) and isolated methylmalonic acidemia (MMA) have resulted in improved survival. These advances were possible thanks to new pathophysiological insights. However, patients may still suffer from devastating complications which largely determine the unsatisfying overall outcome. To optimize our treatment strategies, better insight in the pathophysiology of complications is needed. Here, we perform a systematic data‐analysis of cohort studies and case‐reports on PA and MMA. For each of the prevalent and rare complications, we summarize the current hypotheses and evidence for the underlying pathophysiology of that complication. A common hypothesis on pathophysiology of many of these complications is that mitochondrial impairment plays a major role. Assuming that complications in which mitochondrial impairment may play a role are overrepresented in monogenic mitochondrial diseases and, conversely, that complications in which mitochondrial impairment does not play a role are underrepresented in mitochondrial disease, we studied the occurrence of the complications in PA and MMA in mitochondrial and other monogenic diseases, using data provided by the Human Phenotype Ontology. Lastly, we combined this with evidence from literature to draw conclusions on the possible role of mitochondrial impairment in each complication. Altogether, this review provides a comprehensive overview on what we, to date, do and do not understand about pathophysiology of complications occurring in PA and MMA and about the role of mitochondrial impairment herein.

Pathophysiology of propionic and methylmalonic acidemias. Part 2: Treatment strategies

“…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. Moreover, the therapeutic window of opportunity and the target tissue(s) are, to date, still not sufficiently understood …”

“…Moreover, the therapeutic window of opportunity and the target tissue(s) are, to date, still not sufficiently understood. 5 In summary, to further improve survival rate and, equally important, quality of life of PA and MMA patients, there is a need for systematic (re-)evaluation of each and everyone of the accepted and potential treatment strategies, ideally in (large) randomized clinical trials 109 but if that is not feasible, in smaller trials 85 or on an individual patient basis, 1,3 so that we can better determine who will benefit when and how from which treatment strategy.…”

“…In terms of treatment strategies, the three most important approaches are currently being explored: supplementation of anaplerotic substrates, supplementation of cofactors and supplementation of anti‐oxidants. While the most important co‐factors are already tested, the effects of some anaplerotic substances and anti‐oxidant candidates are yet to be explored, such as fumarate, malate or α‐ketoglutarate as anaplerotic substances and lipoic acid, retinol (vitamin A), β‐carotene or uric acid (only when glomerular filtration rate is normal, Haijes et al), as anti‐oxidants. However, it is not to be expected that these substances will achieve much better effects than the ones already investigated.…”

Retrospective evaluation of the Dutch pre‐newborn screening cohort for propionic acidemia and isolated methylmalonic acidemia: What to aim, expect, and evaluate from newborn screening?

“…Patients were categorised into six categories based on the number of mitochondrial complications present at a certain age. These mitochondrial complications included 21 complications likely to be caused by mitochondrial failure (Supplementary Notes S2). Complications with potential treatment‐related aetiology included decreased bone mineral density (BMD), growth retardation, and obesity (Supplementary Notes S2).…”

“…This neurological damage is often reflected by white matter lesions and/or basal ganglia hyperintensities on brain imaging. In addition, the clinical course is characterised by frequent AMD, cognitive deficits, and long‐term complications …”