Pathogenic SLIRP variants as a novel cause of autosomal recessive mitochondrial encephalomyopathy with complex I and IV deficiency.

In a Dutch non-consanguineous patient having mitochondrial encephalomyopathy with complex I and complex IV deficiency, whole exome sequencing revealed two compound heterozygous variants in SLIRP. SLIRP gene encodes a stem-loop RNA-binding protein that regulates mitochondrial RNA expression and oxidative phosphorylation (OXPHOS). A frameshift and a deep-intronic splicing variant reduced the amount of functional wild-type SLIRP RNA to 5%. Consequently, in patient fibroblasts, MT-ND1, MT-ND6, and MT-CO1 expression was reduced. Lentiviral transduction of wild-type SLIRP cDNA in patient fibroblasts increased MT-ND1, MT-ND6, and MT-CO1 expression (2.5-7.2-fold), whereas mutant cDNAs did not. A fourfold decrease of citrate synthase versus total protein ratio in patient fibroblasts indicated that the resulting reduced mitochondrial mass caused the OXPHOS deficiency. Transduction with wild-type SLIRP cDNA led to a 2.4-fold increase of this ratio and partly restored OXPHOS activity. This confirmed causality of the SLIRP variants. In conclusion, we report SLIRP variants as a novel cause of mitochondrial encephalomyopathy with OXPHOS deficiency.

Fumarase Deficiency: A Case With a New Pathogenic Mutation and a Review of the Literature.

Fumarase deficiency (FD) is a rare and severe autosomal disorder, caused by inactivity of the enzyme fumarase, due to biallelic mutations of the fumarase hydratase (FH) gene. Several pathogenic mutations have been published. The article describes an infant with failure to thrive, microcephaly, axial hypotonia, and developmental retardation with increased excretion of fumarate, no activity of fumarase and a homozygous mutation of the FH gene, which was until recently only known as a variant of unknown significance. Carriers of pathogenic mutations in the FH gene are at risk for developing renal cell carcinoma and should therefore be screened. Both parents were healthy carriers of the mutation and had decreased levels of enzyme activity. In addition, the article presents an overview and analysis of all cases of FD reported thus far in the literature.

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

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.