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

Abstract

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.

Understanding acute metabolic decompensation in propionic and methylmalonic acidemias: a deep metabolic phenotyping approach

“…Plasma ammonia for example, is considered the best available biochemical read-out of AMD, but does not provide insight in other pathophysiological processes that may occur during AMD. Increased insight in the exact pathophysiological events during AMD could potentially pave the way towards optimized clinical care and better neurological outcomes [4,5].…”

Pathophysiology of propionic and methylmalonic acidemias. Part 1: Complications

“…For MMA the same mechanism of accumulating toxic metabolites leading to mitochondrial oxidative stress and acidosis in neurons and astrocytes ultimately leading to cellular necrosis has been proposed. 39 This claim is supported by several rat studies in which injection of anti-oxidants prevented the occurrence of neurological complications that were induced by either propionic acid or methylmalonic acid (reviewed in Haijes et al, 36 ). The involvement of the basal ganglia, especially the globus pallidus, is probably due to its high energy demand, rich vascularization and elevated metabolism in that location in the first year of life.…”

“…32 It is hypothesized that due to implementation of newborn screening and early initiation of treatment, neurological damage due to the first presentation might be prevented, 11 but reports on the effect of newborn screening in PA and MMA are still scarce. 11,[33][34][35] However, in patients with apparent good metabolic control, neurological complications can still arise over time, possibly caused by persistently increased levels of propionic acid, 2-methylcitrate, lactate and ammonia, that inhibit and deplete enzymes in the Krebs cycle (, 32 reviewed in Haijes et al, 36 ). In support, increased brain lactate on magnetic resonance spectroscopy during periods of apparent good metabolic control has been demonstrated in PA children.…”

Treatable Inherited Movement Disorders in Children: Spotlight on Clinical and Biochemical Features

“…Among the inherited disorders of the catabolism of branched chain amino acid (BCAAs) 4 conditions potentially detectable by NBS program—maple syrup urine disease, propionic acidemia, methylmalonic acidemia, and cobalamin C defects—may cause acute or subacute onset of MDs as result of the neurotoxic lesion of BG (Fig. ) . Although it is rather exceptional that these multisystem diseases present with MD and, if so, in patients with late‐onset presentation, more than 20% of late‐treated patients can experience dystonia and/or spasticity as a cumulative result of acute or subacute metabolic decompensations triggered by the increasing breakdown of BCAAs and circulating toxic metabolites .…”

“…2). 23 Although it is rather exceptional that these multisystem diseases present with MD 24 and, if so, in patients with late-onset presentation, 24 more than 20% of late-treated patients can experience dystonia and/or spasticity as a cumulative result of acute or subacute metabolic decompensations triggered by the increasing breakdown of BCAAs and circulating toxic metabolites. [24][25][26] Severe forms of propionic acidemia, methylmalonic acidemia, and maple syrup urine disease are candidates for early liver transplantation to prevent severe and irreversible neurological impairment.…”