JIMD Reports, Volume 30

Smith, Amanda, McBride, Skye, Marcadier, Julien L, Michaud, Jean, Al-Dirbashi, Osama Y, Schwartzentruber, Jeremy, Beaulieu, Chandree L, Katz, Sherri L, , , Majewski, Jacek, Bulman, Dennis E, Geraghty, Michael T, Harper, Mary-Ellen, Chakraborty, Pranesh, Lines, Matthew A, Amanda Smith, Skye McBride, Julien L. Marcadier, Jean Michaud, Osama Y. Al-Dirbashi, Jeremy Schwartzentruber, Chandree L. Beaulieu, Sherri L. Katz, FORGE Canada Consortium, Jacek Majewski, Dennis E. Bulman, Michael T. Geraghty, Mary-Ellen Harper, Pranesh Chakraborty, Matthew A. Lines, Marcadier, Julien L., Al-Dirbashi, Osama Y., Beaulieu, Chandree L., Katz, Sherri L., Bulman, Dennis E., Geraghty, Michael T., Lines, Matthew A.

Mutations of the mitochondrial citrate carrier (CIC) SLC25A1 cause combined D-2- and L-2-hydroxyglutaric aciduria (DL-2HGA; OMIM #615182), a neurometabolic disorder characterized by developmental delay, hypotonia, and seizures. Here, we describe the female child of consanguineous parents who presented neonatally with lactic acidosis, periventricular frontal lobe cysts, facial dysmorphism, recurrent apneic episodes, and deficient complex IV (cytochrome c oxidase) activity in skeletal muscle. Exome sequencing revealed a homozygous SLC25A1 missense mutation [NM_005984.4: c.593G>A; p.(Arg198His)] of a ubiquitously conserved arginine residue putatively situated within the substrate-binding site I of CIC. Retrospective review of the patient's organic acids confirmed the D- and L-2-hydroxyglutaric aciduria typical of DL-2HGA to be present, although this was not appreciated on initial presentation. Cultured patient skin fibroblasts showed reduced survival in culture, diminished mitochondrial spare respiratory capacity, increased glycolytic flux, and normal mitochondrial bulk, inner membrane potential, and network morphology. Neither cell survival nor cellular respiratory parameters were improved by citrate supplementation, although oral citrate supplementation did coincide with amelioration of lactic acidosis and apneic attacks in the patient. This is the fifth clinical report of CIC deficiency to date. The clinical features in our patient suggest that this disorder, which can potentially be recognized either by molecular means or based on its characteristic organic aciduria, should be considered in the differential diagnosis of pyruvate dehydrogenase deficiency and respiratory chain disorders. One-Sentence Summary A novel homozygous missense substitution in SLC25A1 was identified in a neonate presenting with lactic acidosis, intracerebral cysts, and an apparent mitochondrial complex IV defect in muscle.