Table 1.
Clinical and genetic characteristics of FOXRED1-related mitochondrial encephalopathy.
| Case | FOXRED1 variants | Prenatal period | Onset | CNS symptoms | Multisystem presentation | Brain MRI | Lac (<2.1 mmol/L) | Survival | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Variants | Zygo | Developmental delay | Epilepsy | Vision | Other | |||||||
| 1 (8) | c.694C>T (p.Q232X) c.1289A>G (p.N430S) | Het | – | neonatal | loss of milestones; no language | + | N/A | hypotonia | hypoglycemia | decreased attenuation in the putamen bilaterally; significant cerebellar atrophy (6y) | high | alive (22 y) |
| 2 (5) | c.1054C>T (p.R352W) | Hom | – | neonatal | severe | myoclonic | roving eyes bilateral optic atrophy | poor feeding | mild non-obstructive left ventricular hypertrophy; hepatomegaly | delayed myelination, ventricular dilatation and abnormal signal in the thalami and basal ganglia (8 m) | 6.8 | alive (10 y) |
| 3 (9) | c.1308G>A (p.V421M) | Hom | – | infantile | + | + | N/A | N/A | N/A | N/A | N/A | N/A |
| 4 (10) | c.406C>T (p.R136W) c.612_615dupAGTG (p.A206SfsX15) | Het | – | <6 m | + | – | – | – | – | N/A | – | progressive |
| 5 (11) | c.612_615dupAGTG (p.A206SfsX15) c.874G>A (p.G292R) | Het | IUGR | neonatal | + | generalized | N/A | mild hypertonia, wrist and ankle contracture | pulmonary artery hypertension, enlargement of the right atrium/ventricle, patent ductus arteriosus; patent foramen ovale | diffusely abnormal brain with large periventricular cysts, edematous white matter, delayed myelination, thin and undersulcated cortex particularly anteriorly (13 d) | 20 | died at 3 m |
| 6 (12) | c.920G>A (p.G307E) c.733+1G>A | Het | IUGR | 2 m | + | refractory | latent strabismus of the right eye | ataxia | Bronchospasm episodes during infancy | normal (2 m, 4 y, 7 y 3 m) | elevated | alive (15 y) |
| 7 (12) | c.920G>A (p.G307E) c.733+1G>A | Het | – | 4 y | learning disorders | – | clumsiness | – | normal | elevated after exercise | alive (19 y) | |
| 8 (14) (this study) | c.606_607delAG c.1054C>T (p.R352W) | Het | IUGR | neonatal | severe | partial tonic; myoclonic; refractory | vision loss | poor feeding | patent ductus arteriosus; patent foramen ovale; pulmonary artery hypertension | diffuse abnormal signal in the cerebral white matter, bilateral occipital and temporal lobe, basal ganglia and thalamus, cerebral atrophy, partial encephalomalacia (1 m) | 5.0 | died at 3 y |
| 9(this study) | c.352C>T (p.Q118X) c.1054C>T (p.R352W) | Het | preeclampsia, preterm at 36+6w | neonatal | severe | myoclonic | – | – | elevated liver function | polycystic encephalomalacia, diffuse cerebral atrophy, diffuse abnormal signal in the brain, agenesis of corpus collosum (3 m) | 6.2 | progressive (10 m) |
DD, developmental delay; zygo, heterozygous or homozygous state; IUGR, intrauterine growth restriction; –, normal or within normal range; N/A, information not available. Cases 6 and 7 are siblings.