Mutations in TMEM70, a gene coding for an assembly factor of complex V, can cause a severe encephalocardiomyopathy in the neonatal period as wel as mild non-progressive encephalopathy in adolescence

Recently, TMEM70 has been identified as a novel ancillary factor essential in biogenesis of mammalian complex V. We report clinical, biochemical and genetic data of two unrelated patients with pathogenic mutations in TMEM70. The two patients presented with remarkable difference in onset and severity of clinical symptoms. Oxidative phosphorylation (OXPHOS) enzyme activities were measured using spectrophotometrical analysis. Functional integrity of the five complexes was evaluated using blue native polyacrylamide gel electrophoresis (BN-PAGE) followed by in-gel activity staining. Western blotting was performed to document amounts of residual protein in the OXPHOS complexes. All coding exons and part of flanking introns of TMEM70 were PCR amplified and sequenced. In one patient, who presented with severe neonatal phenotype, sequencing of TMEM70 showed a homozygous splice site mutation (c.317-2A>G). The adolescent patient with milder symptoms was found to be compound heterozygote for the c.317-2A>G mutation and c.251delC deletion. In the adolescent patient, 3-methylglutaconic acid was detected in urine. Almost complete absence of functional holocomplex V was demonstrated in several tissues from both patients. Complex V deficiency caused by mutations in TMEM70 is apparently not extremely rare. Patients can present with a severe neonatal form, as well as with milder non-progressive encephalopathy.