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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 α-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 β-subunit-interacting surface, adjacent to the nearby β 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. © 2021. The Author(s), under exclusive licence to European Society of Human Genetics.


Matthew A Lines, Alexanne Cuillerier, Pranesh Chakraborty, Turaya Naas, M Laura Duque Lasio, Jean Michaud, Chantal Pileggi, Mary-Ellen Harper, Yan Burelle, Tomi L Toler, Neal Sondheimer, Heather P Crawford, Francisca Millan, Michael T Geraghty. A recurrent de novo ATP5F1A substitution associated with neonatal complex V deficiency. European journal of human genetics : EJHG. 2021 Nov;29(11):1719-1724

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PMID: 34483339

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