Efficacy of Living Donor Liver Transplantation for Patients With Methylmalonic Acidemia

Abstract

Application of liver transplantation to methylmalonic acidemia (MMAemia) is controversial because MMAemia is caused by a systemic defect of methylmalonyl-CoA mutase. The clinical courses of seven pediatric patients with MMAemia undergoing living donor liver transplantation (LDLT) were reviewed. Serum and urinary methylmalonic acid (MMA) levels were found to be significantly decreased after LDLT, whereas serum and urinary MMA levels did not return to normal in any patient. One patient died of sepsis 44 days after LDLT. The other six patients are currently doing well. All patients had preoperative history of acute metabolic decompensation and/or metabolic stroke. However, no episode of acute metabolic decompensation or metabolic stroke was observed postoperatively in any surviving patients. In the preoperative period, all patients showed lethargy and cognitive deficit, both of which were eradicated after LDLT in all surviving patients. Preoperatively, all patients were subjected to dietary protein intake restriction and tube feeding, and were administered several metabolism-correcting medications. The metabolism-correcting medications being administered remained mostly unchanged after LDLT, whereas protein restriction was liberalized and tube feeding became unnecessary in all surviving patients. In addition, physical and neurodevelopmental growth delay remained in all surviving patients during the observation period, which ranged from 4 to 21 months with a median of 10.5 months.

Liver-Directed Recombinant Adeno-Associated Viral Gene Delivery Rescues a Lethal Mouse Model of Methylmalonic Acidemia and Provides Long-Term Phenotypic Correction

“…Our results clearly demonstrate the efficacy of this approach and are consistent with the suggestion offered by some authors to perform a liver transplantation as soon as possible as a treatment for this disorder (Morioka et al, 2007). Because the stable transduction of a small number of hepatocytes appears sufficient to obtain therapeutic effects in a mouse model that replicates a severe form of the condition, liver-directed gene therapy would likely benefit patients with methylmalonic acidemia and, possibly, other inborn errors of organic acid metabolism.…”

Early Liver Transplantation for Neonatal-Onset Methylmalonic Acidemia

“…Perioperative and longitudinal biochemical evaluations showed sustained (∼80%) and stable reduction of plasma methylmalonate (Figure 1). At time of writing, creatinine level is 1.05 mg/dL (normal range 0.47-0.73) and renal function is stable (Figure 1) 11 continues to be excellent.…”

Potential of AAV vectors in the treatment of metabolic disease

“…While metabolic control is more readily achieved following liver transplantation, ongoing metabolic damage to the kidneys and brain has been reported. 69,70 This may be explained by substantial production of methylmalonic acid by other tissues, such as skeletal muscle. 71 To date AAV2/2 and AAV2/8 vectors encoding cob(I)alamin adenosyltransferase have been produced and functionally validated in healthy mice following portal vein delivery.…”