A recurrent de novo ATP5F1A substitution associated with neonatal complex V deficiency

Mitochondrial disorders are a heterogeneous group of rare, degenerative multisystem disorders affecting the cell's core bioenergetic and signalling functions. Spontaneous improvement is rare. We describe a novel neonatal-onset mitochondriopathy in three infants with failure to thrive, hyperlactatemia, hyperammonemia, and apparent clinical resolution before 18 months. Exome sequencing showed all three probands to be identically heterozygous for a recurrent de novo substitution, c.620G>A [p.(Arg207His)] in ATP5F1A, encoding the alpha-subunit of complex V. Patient-derived fibroblasts exhibited multiple deficits in complex V function and expression in vitro. Structural modelling predicts the observed substitution to create an abnormal region of negative charge on ATP5F1A's beta-subunit-interacting surface, adjacent to the nearby beta subunit's active site. This disorder, which presents with life-threatening neonatal manifestations, appears to follow a remitting course; the long-term prognosis remains unknown.

Automated summary

Mitochondrial disorders are a rare group of degenerative multisystem disorders affecting core bioenergetic and signalling functions of cells. This study identified a novel neonatal-onset mitochondriopathy in three infants, characterized by failure to thrive, high lactate and ammonia levels. Exome sequencing revealed a recurrent de novo substitution in ATP5F1A, leading to deficits in complex V function and expression in patient-derived fibroblasts. The long-term prognosis of this disorder, which presents with life-threatening neonatal manifestations, remains unclear.