Mechanical unloading by miniature axial flow pumps in late cardiac allograft failure due to acute rejection.

Allograft failure secondary to rejection commonly requires a multimodal treatment, ultimately including mechanical circulatory support. A few case reports have demonstrated the use of Impella-devices due to its assumed favorable safety profile in this fragile cohort. However, this treatment option does not play a role in choice of anti-rejective therapy in clinical routine up to date. We summarize our institutional experiences and literature mini-review on Impella-based treatment strategies in allograft rejection after heart transplantation. In all seven cases, three from our institution and four reported in the literature, Impella-based therapies led to hemodynamic stabilization in allograft failure secondary to rejection. Adverse events included hemolysis, non-fatal bleeding and in one patient a relevant aortic valve insufficiency occurred. All patients showed an improvement of allograft function. Two patients died in context of severe immunosuppression or late secondary organ failure. Based on the limited available data, we propose that Impella-mediated mechanical unloading represents a valuable option for hemodynamic stabilization in severe allograft failure due to rejection, enabling an initiation of causal therapy and thereby potentially representing an opportunity to prevent mortality. Furthermore, we hypothesize it might add to the traditional therapeutic approaches by facilitating recovery by decompressing the myocardium in allograft rejection.

Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency.

Cerebral folate transport deficiency is an inherited brain-specific folate transport defect that is caused by mutations in the folate receptor 1 gene coding for folate receptor alpha (FRα). This genetic defect gives rise to a progressive neurological disorder with late infantile onset. We screened 72 children with low 5-methyltetrahydrofolate concentrations in the cerebrospinal fluid and neurological symptoms that developed after infancy. We identified nucleotide alterations in the folate receptor 1 gene in 10 individuals who shared developmental regression, ataxia, profound cerebral hypomyelination and cerebellar atrophy. We found four novel pathogenic alleles, one splice mutation and three missense mutations. Heterologous expression of the missense mutations, including previously described mutants, revealed minor decrease in protein expression but loss of cell surface localization, mistargeting to intracellular compartments and thus absence of cellular binding of folic acid. These results explain the functional loss of folate receptor alpha for all detected folate receptor 1 mutations. Three individuals presenting a milder clinical phenotype revealed very similar biochemical and brain imaging data but partially shared pathogenic alleles with more severely affected patients. Thus, our studies suggest that different clinical severities do not necessarily correlate with residual function of folate receptor alpha mutants and indicate that additional factors contribute to the clinical phenotype in cerebral folate transport deficiency.