Neurotoxicity including posterior reversible encephalopathy syndrome after initiation of calcineurin inhibitors in transplanted methylmalonic acidemia patients: Two case reports and review of the literature

Abstract

Introduction New neurological symptoms in methylmalonic acidemia (MMA) patients after liver and/or kidney transplantation (LKT) are often described as metabolic stroke‐like‐events. Since calcineurin inhibitors (CNIs) are a well‐known cause of new neurological symptoms in non‐MMA transplanted patients, we investigated the incidence of CNI‐induced neurotoxicity including posterior reversible encephalopathy syndrome (PRES) in post‐transplanted MMA patients. Methods We report the two MMA patients treated with LKT in our center. Additionally, we performed a systematic review of case reports/series of post‐transplanted MMA patients and determined if CNI‐induced neurotoxicity/PRES was a likely cause of new neurological symptoms. Definite CNI‐induced neurotoxicity was defined as new neurological symptoms during CNI treatment with symptom improvement after CNI dose reduction/discontinuation. PRES was defined as CNI‐induced neurotoxicity with signs of vasogenic edema on brain magnetic resonance imaging (MRI)‐scan post‐transplantation. Results Our two MMA patients both developed CNI‐induced neurotoxicity, one had PRES. In literature, 230 transplanted MMA patients were identified. Neurological follow‐up was reported in 54 of them, of which 24 were excluded from analysis since no anti‐rejection medication was reported. Thirty patients, all using CNI, were included. Sixteen patients (53%) had no new neurological symptoms post‐transplantation and five patients (17%) had definite CNI neurotoxicity of whom two had PRES. Including our cases this results in a pooled incidence of 22% (7/32) definite CNI neurotoxicity and 9% PRES (3/32) in post‐transplanted MMA patients on CNI. Conclusion In MMA post‐transplanted patients with new neurological symptoms CNI‐induced neurotoxicity/PRES should be considered. Early recognition of CNI‐induced neurotoxicity is essential to initiate dose reduction/discontinuation of CNI to minimize persistent neurologic damage and improve outcome. Concise one sentence take home message In all post‐transplanted MMA patients with new neurological symptoms CNI‐induced neurotoxicity/PRES should be considered, and directly reducing the dose/discontinuation of CNI is essential.

Liver and/or kidney transplantation in amino and organic acid‐related inborn errors of metabolism: An overview on European data

“…The use of calcineurin inhibitors (CNIs) as part of the immunosuppressive protocol 21 is a risk factor for CKD. CNI can also be neurotoxic and caution regarding its use is essential, especially in MMA Mut 0 patients, since these patients have an increased risk on posttransplant neurological complications 29 . The accumulation of neurotoxic metabolites in the brain compartment is unlikely to be reliably prevented by this therapeutic intervention 30‐32 …”

“…Several long‐term complications in OAD occur due to mitochondrial dysfunction 37 and FGF‐21 seems a good biomarker for the occurrence of long‐term mitochondrial complications 38 . Transplantation can potentially (partially) reverse this mitochondrial dysfunction, shown by a decrease in FGF‐21 levels after transplantation 29,39 . The potential role of FGF‐21 in decision making on transplantation needs further study and discussion.…”

Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: First revision

“…In the context of transplantation, it has to be considered that calcineurin inhibitors can be nephrotoxic, which was also found in MMA 96,186 and PA patients 86 …”

Combined liver-kidney transplantation for rare diseases

“…After CLKT levels of MA decrease by 80%-97%[ 121 , 122 ] and are lower than after isolated LT with better metabolic outcomes and reduced number of hospitalizations[ 123 - 125 ]. The majority of reports show improvements in neurodevelopment (enhanced motor skills, learning abilities, social engagement) and improved quality of life after CLKT[ 18 , 114 , 118 , 121 , 123 - 128 ].…”

“…In addition, neurological complications such as seizures, tremor, ataxia, worsening vision, and altered mental status were common and occurred in 15%-40% of patients after CLKD. Early after the procedure, the patients with their pre-existent mitochondrial dysfunction are particularly prone to the development of CNI-neurotoxicity while later neurological symptoms are more probably metabolically induced[ 115 , 116 , 121 , 122 ].…”