Clinical and Genetic Characteristics of Mitochondrial Encephalopathy Due to FOXRED1 Mutations: Two Chinese Case Reports and a Review of the Literature

Abstract

Background: As one of the assembly factors of complex I in the mitochondrial respiratory chain, FOXRED1 plays an important role in mitochondrial function. However, only a few patients with mitochondrial encephalopathy due to FOXRED1 defects have been reported. Methods: Two Chinese patients with mitochondrial encephalopathy due to mutations in FOXRED1 were identified through trio whole-exome sequencing. The clinical presentation, laboratory data, brain imaging findings, and genetic results were collected and reviewed. All previously reported cases with FOXRED1-related mitochondrial encephalopathy were collected using a PubMed search, and their data were reviewed. Results: Two patients presented with severe neurodevelopmental delay, epilepsy, high lactic acid levels, and remarkable diffuse brain atrophy and polycystic encephalomalacia during early infancy. Trio whole-exome sequencing revealed compound heterozygous variants in both patients: one case harbored a c.606_607delAG frameshift variant and a c.1054C>T (p.R352W) variant. At the same time, the other carried a novel c.352C>T (p.Q118X) variant and a reported c.1054C>T (p.R352W) variant. To date, nine patients have been reported with FOXRED1 defects, including our two cases. The most common presentations were neurodevelopment delay (100%), epilepsy (80%), poor feeding (30%), and vision loss (20%). Multisystem involvement comprised cardiovascular dysfunction (30%), abnormal liver function (20%), and hypoglycemia (10%). The neuroimaging results ranged from normal to severe cerebral atrophy and polycystic encephalomalacia in early infancy. Eleven pathogenic variants in FOXRED1 have been reported, comprising six missense variants, two non-sense variants, two frameshift variants, and one splice variant; among these the c.1054C>T (p.R352W) and c.612_615dupAGTG (p.A206SfsX15) variants are more common. Conclusion: FOXRED1-related mitochondrial disorders have high clinical and genetic heterogeneity. Our study expanded the clinical and genetic spectrum of FOXRED1 defects. Early infantile onset and progressive encephalopathy are the most common clinical presentations, while the variants c.1054C>T (p.R352W) and c.612_615dupAGTG (p.A206SfsX15) may be critical founder mutations.

Keywords: FOXRED1; complex I defect; cystic encephalomalacia; mitochondrial encephalopathy; neuroimage.

Figure 1

Brain magnetic resonance imaging results of the two patients in the present study. Brain magnetic resonance imaging of patient one in our study at 1 month old revealed cerebral atrophy and partial encephalomalacia, a diffuse abnormal signal in the cerebral white matter, with a low signal in T1WI (A) and a high signal in T2WI (B), and high signals in the bilateral occipital and temporal lobes, basal ganglia and thalamus (C). An MRI of patient two at 3 months old indicated polycystic encephalomalacia and diffuse cerebral atrophy, with diffuse abnormal signals in the brain, low signals on T1WI and high signals on T2WI and DWI (D–F), and a high signal in the cerebral peduncle (G–I).

Figure 2

Family pedigrees of our cases and all the reported pathogenic variants mapped on the FOXRED1 gene structure. (A) Two patients from unrelated families in our study both harbored compound heterozygous mutations in the FOXRED1 gene. (B) The FOXRED1 gene comprises 11 exons, which are illustrated in blue. The pathogenic variants identified in this study are illustrated on the upper side of the exons with novel variants highlighted in bold; other previously reported variants are on the lower side.