Congenital lactic acidosis, cerebral cysts and pulmonary hypertension in an infant with FOXRED1 related complex I deficiency

Delia Apatean; Bojana Rakic; Catherine Brunel-Guitton; Glenda Hendson; Renkui Bai; Michael A Sargent; Pascal M Lavoie; Millan Patel; Sylvia Stockler-Ipsiroglu

doi:10.1016/j.ymgmr.2018.12.006

Congenital lactic acidosis, cerebral cysts and pulmonary hypertension in an infant with FOXRED1 related complex I deficiency

Mol Genet Metab Rep. 2019 Jan 18:18:32-38. doi: 10.1016/j.ymgmr.2018.12.006. eCollection 2019 Mar.

Authors

Delia Apatean¹, Bojana Rakic², Catherine Brunel-Guitton³, Glenda Hendson⁴, Renkui Bai⁵, Michael A Sargent⁶, Pascal M Lavoie⁷, Millan Patel⁸, Sylvia Stockler-Ipsiroglu⁹

Affiliations

¹ Division of Biochemical Diseases, Department of Pediatric, University of British Columbia, BC Children's Hospital, Room K3-206, 4480 Oak Street, Vancouver, BC V6H 3V4, Canada.
² BC Newborn Screening Program and Biochemical Genetics Lab, BC Children's Hospital, BC Women's Hospital & Health Centre, 2F16-4500 Oak Street, Vancouver, BC V6H 3N1, Canada.
³ Department of Pediatrics, CHU Sainte-Justine, 3175, chemin Cote Sainte-Catherine, Montreal, Quebec H3T 1C5, Canada.
⁴ Department of Pathology, BC Children's Hospital, BC Women's Hospital & Health Centre, 2H56-4500 Oak Street, Vancouver, BC V6H 3N1, Canada.
⁵ GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, United States.
⁶ University of British Columbia, Department of Radiology, BC Children's Hospital, Room 1L72, 4480 Oak Street, Vancouver, BC V6H 3V4, Canada.
⁷ BC Children's Hospital Research Institute, Room A4-147, 4th floor Translational Research Building, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada.
⁸ Department of Medical Genetics, University of British Columbia, Room C234, 4500 Oak Street, Vancouver, BC V6H 3N1, Canada.
⁹ University of British Columbia, Head Division of Biochemical Genetics, BC Children's Hospital, Room K3-205, 4480 Oak Street, Vancouver, BC V6H 3V4, Canada.

Abstract

Mitochondrial complex I is encoded by 38 nuclear-encoded and 7 mitochondrial-encoded genes. FOXRED1 is one of the 13 additional nuclear genes known as assembly factors. So far, four patients have been described with complex I deficiency caused by autosomal recessive mutations in FOXRED1. Here, we report the fifth patient with FOXRED1 related complex 1 deficiency presenting with prenatal onset of bilateral periventricular cysts, congenital lactic acidosis, and persistent life-limiting pulmonary hypertension. Whole exome sequencing identified a compound heterozygosity for a known pathogenic variant (c.612_615dupAGTG; p.A206SfsX15) (paternal) and a likely pathogenic variant (c.874G > A; p.Gly292Arg) (maternal). Deficiency of complex I was demonstrated by the absence of complex I on Blue Native Gel Electrophoresis and by a significantly reduced complex I enzyme activity in the patient's fibroblasts. Compared with the previous known FOXRED1 cases, unique clinical features observed in our patient include bilateral periventricular cysts and severe pulmonary hypertension. Whole exome sequencing was instrumental in recognizing the underlying gene defect in this patient.