Table 11.

Prevention of Primary Manifestations in Individuals with Isolated Methylmalonic Acidemia

PrinciplePreventionConsiderations/Other
Protection against metabolic instability 1 Liver transplantation 2
  • The underlying biochemical parameters & frequency of metabolic decompensation improve significantly in persons undergoing liver transplantation despite persistent metabolic abnormalities.
  • Liver transplantation is not curative. Patients remain at risk for long-term complications incl renal disease, basal ganglia injury & neurologic complications, & optic nerve atrophy. 3 High CSF concentrations of methylmalonic acid have been reported, especially when protein intake is liberalized.
  • Neurotoxicity due to calcineurin inhibitors has been described in transplanted patients. 4
Kidney transplantation 5
  • More mildly affected persons w/mut- or cblA MMA subtypes who have primarily renal failure may undergo isolated renal transplantation.
  • Elective kidney transplantation, before the onset of renal disease, cannot stabilize persons w/mut0 MMA and is not recommended. Double liver kidney transplant offers a higher amount of enzyme activity and allows for better control of kidney rejection. 6
1.

Most of the metabolic conversion of propionate occurs in the liver, so liver transplantation has the potential to provide enough enzymatic activity to avert severe metabolic crises for the most significantly affected individuals (MMA mut0 subtype) and is performed electively in younger people to avoid recurrent hospitalizations.

2.

More than 100 individuals with MMA have undergone living-donor [Kasahara et al 2006, Morioka et al 2007, Kasahara et al 2014, Sakamoto et al 2016, Jang et al 2021] or cadaveric, orthotopic, or partial liver transplantation, or combined liver-kidney transplantation [van 't Hoff et al 1998, van't Hoff et al 1999, Kayler et al 2002, Nyhan et al 2002, Hsui et al 2003, McGuire et al 2011, Niemi et al 2015, Sloan et al 2015, Spada et al 2015, Critelli et al 2018, Jiang & Sun 2019, Chu et al 2019, Pillai et al 2019, Brassier et al 2020, Yap et al 2020, Molema et al 2021b]. Living-related donor transplants from heterozygote (carrier) parents may be associated with higher incidence of steatosis in the graft liver [Irie et al 2020].

3.

Liver transplantation is associated with complications related to surgery (hepatic artery thrombosis, bile duct stenosis, perforation), graft rejection, and lifelong immunosuppressive therapy [Chakrapani et al 2002, Nyhan et al 2002, Kaplan et al 2006, Cosson et al 2008, McGuire et al 2011, Vernon et al 2014].

4.

Neurotoxicity from calcineurin inhibitors, including posterior reversible encephalopathy syndrome (PRES), has been reported [Molema et al 2021b].

5.

A smaller number (~20) of individuals with MMA (mostly with milder mut- or cblA subtypes) have received isolated renal allografts [Van Calcar et al 1998, Coman et al 2006, Cosson et al 2008, Clothier et al 2011, Lubrano et al 2013].

6.

Brassier et al [2013], Brassier et al [2020]. One patient died after developing hepatoblastoma, neurologic deterioration accompanied by CSF lactic acidosis, and multiorgan failure; a second patient developed progressive neurologic symptoms; and two others developed metabolic decompensations post-transplant.

From: Isolated Methylmalonic Acidemia

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