Ammonia role in glial dysfunction in methylmalonic acidemia

Case report: Is exchange transfusion a possible treatment for metabolic decompensation in neonates with methylmalonic aciduria in the setting of limited resources?

“…In patients with MMA, the abnormal accumulation of propionyl-CoA inhibits the urea cycle by reducing the synthesis of N-acetylglutamate, an essential activator of carbamylphosphate synthetase ( 5 ). As a result, the ammonia produced by protein degradation cannot be detoxified in the liver by binding it to the urea cycle, resulting in high ammonia concentration in the blood ( 6 ). Moreover, the synthesis of succinyl-CoA in MMA is impaired, which facilitates the degradation of glutamine to produce α-ketoglutarate to improve the activity of the Krebs cycle activity, which contributed to chronic hyperammonemia ( 2 ).…”

New insights into the pathophysiology of methylmalonic acidemia

“…28 Additionally, methylmalonate and propionate injection into rat cerebral cortexes led to decreased phosphorylation of cytoskeletal proteins which was hypothesized to further contribute to altered brain cytoskeletal metabolism resulting in altered structures in the central nervous system (CNS). 29 More recent studies in which ammonia and/or methylmalonate was administered as an intracerebroventricular injection into newborn mice (12 h of age), suggest these metabolites can reduce working memory, 30 and activate glial cells resulting in increased cytokine production which could ultimately adversely affect brain development. 30 In addition to oxidative damage, cytoskeletal arrangement alteration, and glial cell activation, methylmalonate was tested for direct inhibition of mitochondrial enzymatic functions resulting in energy production deficiencies seen in MMA.…”

“…29 More recent studies in which ammonia and/or methylmalonate was administered as an intracerebroventricular injection into newborn mice (12 h of age), suggest these metabolites can reduce working memory, 30 and activate glial cells resulting in increased cytokine production which could ultimately adversely affect brain development. 30 In addition to oxidative damage, cytoskeletal arrangement alteration, and glial cell activation, methylmalonate was tested for direct inhibition of mitochondrial enzymatic functions resulting in energy production deficiencies seen in MMA.…”

“…Early investigations focused on the effects of methylmalonate on metabolite transport in the liver and brain 24–41 . Through studies using liver mitochondria isolated from rats and hepatocytes from guinea pigs, methylmalonate was proposed to inhibit malate oxidation as well as PC and downstream gluconeogenesis by blocking malate transport 24,25 .…”

“…Early investigations focused on the effects of methylmalonate on metabolite transport in the liver and brain. [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] Through studies using liver mitochondria isolated from rats and hepatocytes from guinea pigs, methylmalonate was proposed to inhibit malate oxidation as well as PC and downstream gluconeogenesis by blocking malate transport. 24,25 Other experiments carried out in rat brains indicate methylmalonate incubation via subcutaneous injection at day 15 of life increased brain glucose uptake but decreased uptake of β-hydroxybutyrate and thus led to indirect inhibition of β-hydroxybutyrate dehydrogenase (HBDH).…”