Advances and challenges in the treatment of branched‐chain amino/keto acid metabolic defects

Abstract

Summary Disorders of branched-chain amino/keto acid metabolism encompass diverse entities, including maple syrup urine disease (MSUD), the ‘classical’ organic acidurias isovaleric acidemia (IVA), propionic acidemia (PA), methylmalonic acidemia (MMA) and, among others, rarely described disorders such as 2-methylbutyryl-CoA dehydrogenase deficiency (MBDD) or isobutyryl-CoA dehydrogenase deficiency (IBDD). Our focus in this review is to highlight the biochemical basis underlying recent advances and ongoing challenges of long-term conservative therapy including precursor/protein restriction, replenishment of deficient substrates, and the use of antioxidants and anaplerotic agents which refill the Krebs cycle. Ongoing clinical assessments of affected individuals in conjunction with monitoring of disease-specific biochemical parameters remain essential. It is likely that mass spectrometry-based ‘metabolomics’ may be a helpful tool in the future for studying complete biochemical profiles and diverse metabolic phenotypes. Prospective studies are needed to test the effectiveness of adjunct therapies such as antioxidants, ornithine-alpha-ketoglutarate (OKG) or creatine in addition to specialized diets and to optimize current therapeutic strategies in affected individuals. With the individual lifetime risk and degree of severity being unknown in asymptomatic individuals with MBDD or IBDD, instructions regarding risks for metabolic stress and fasting avoidance along with clinical monitoring are reasonable interventions at the current time. Overall, it is apparent that carefully designed prospective clinical investigations and multicenter cohort-controlled trials are needed in order to leverage that knowledge into significant breakthroughs in treatment strategies and appropriate approaches.

Methylmalonic acidaemia in pregnancy

“…The prognosis is dependent on the severity and vitamin B 12 -responsivity of the disease. Long-term sequelae are neurological problems, renal failure, pancreatitis and cardiomyopathy 3 4…”

Mitochondria-targeted heme oxygenase-1 decreases oxidative stress in renal epithelial cells

“…This is evident from the mitigation of loss of membrane potential and apoptosis in these cells, accompanied by modulation of the levels of the TCA cycle intermediates. Appropriate functioning of the TCA cycle under conditions of bioenergetic stress is important since many of the metabolic intermediates, such as the ␣-keto acids (e.g., ␣-ketoglutarate), can have both important signaling functions and may also contribute to antioxidant defenses (15,17,29,38). A more detailed flux analysis is required to define precisely which enzymes in the TCA cycle are modulated by the targeting of HO-1 to the mitochondrion.…”

Aspects of Newborn Screening in Isovaleric Acidemia

“…In individuals with this disease, urine analysis reveals marked elevations of 2-methylbutyrylglycine [51,54]. Symptoms reported in the literature range from developmental delay, seizures, and autism to neonatal crises [49,55], and protein restriction and supplementation with L-carnitine have been suggested for treatment [49,55,56]. However, most patients seem to be asymptomatic despite metabolic abnormalities.…”

“…L-glycine may be omitted from long-term treatment, especially in individuals with the mild phenotype. If given, the dosage is usually between 100 and 300 mg/kg × day in three doses [56].…”