Prenatal FBXL4 ‐Associated Mitochondrial DNA Depletion Syndrome‐13: A New Case and Review of the Literature

ABSTRACT Objective Mitochondrial DNA depletion syndrome‐13 associated with FBXL4 (MTDPS13) is an autosomal recessive disorder characterized by encephalopathy, hypotonia, lactic acidosis, and severe global developmental delay. This report aims to provide a comprehensive analysis of a new prenatal‐onset case of MTDPS13 and to review previously documented cases. Method We report a prenatal‐onset case of MTDPS13 and review the three previously published cases. Results The fetus initially presented with abnormal ultrasound findings at 20 weeks of gestation, including a mega cisterna magna, hypoplasia of the cerebellar vermis, and large bilateral choroid plexus cysts. At 23 weeks of gestation, fetal magnetic resonance imaging (MRI) confirmed the ultrasound findings and revealed small periventricular cystic areas suggestive of cavitations in the ganglionic eminences. At 31 weeks, MRI identified vermian hypoplasia with an increased retrocerebellar space, elevated tentorial insertion, and unilateral ventriculomegaly. Later in pregnancy, exome sequencing identified the homozygous pathogenic variant NM_012160.4:c.141del in the FBXL4 gene, thereby confirming the diagnosis of MTDPS13. Conclusion This case illustrates the prenatal onset of MTDPS13, with central nervous system abnormalities apparent from the second trimester. Only three similar cases have been reported, all in males, presenting at least one truncating variant in FBXL4 gene. The literature and our case highlight that the prenatal clinical manifestations can include ventriculomegaly, periventricular cysts, mega cisterna magna, cerebellar vermis hypoplasia, and cardiac anomalies.