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Liver transplantation is not curative for methylmalonic acidopathy caused by methylmalonyl-CoA mutase deficiency
Paige Kaplan1, Can Ficicioglu, Alice T Mazur
1Section of Metabolism, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. kaplan@email.chop.edu
Abstract:
Methylmalonic acidopathy resulting from severe methylmalonyl-CoA mutase deficiency causes acute, potentially lethal ketoacidotic episodes, renal failure, and acute and chronic neurologic disease. As dietary and alkali therapy is suboptimal, liver transplantation during infancy has been touted as a potential cure. However, reports in liver transplant recipients about new onset neurologic disease, in the absence of ketoacidosis, and progressive renal insufficiency have cast doubt about its effectiveness. We report the long-term (9 years) outcome for the first patient with severe methylmalonic acidopathy transplanted in the USA and provide new biochemical data that indicate why transplanted patients are still susceptible to "metabolic strokes". In our 10-year-old male patient, there is clear evidence that the de novo synthesis of propionyl-CoA within the CNS leads to brain methylmalonate (MMA) accumulation that is largely unaffected by transplantation. Liver replacement is not a cure for methylmalonic acidopathy.
Insights
Liver transplantation does not cure methylmalonic acidopathy. Propionyl-CoA synthesis in the brain causes methylmalonate accumulation, leading to ongoing neurological issues despite a new liver.
Area of Science:
- Biochemistry
- Genetics
- Neurology
Background:
- Methylmalonic acidopathy, caused by methylmalonyl-CoA mutase deficiency, leads to severe health issues including ketoacidosis, renal failure, and neurological damage.
- Liver transplantation is considered a potential cure for this condition, especially when initiated in infancy.
Observation:
- Long-term outcomes of the first US patient with severe methylmalonic acidopathy who underwent liver transplantation are presented.
- New biochemical data suggest transplanted patients remain susceptible to neurological complications, termed 'metabolic strokes'.
Findings:
- In a 10-year-old male patient, de novo synthesis of propionyl-CoA within the central nervous system (CNS) was observed.
- This CNS propionyl-CoA synthesis leads to significant methylmalonate (MMA) accumulation in the brain, which is largely unaffected by the liver transplant.
Implications:
- Liver replacement is not a definitive cure for methylmalonic acidopathy.
- Ongoing neurological disease in transplanted patients may be due to endogenous propionyl-CoA production within the CNS, bypassing the transplanted liver's metabolic function.
