Figure 6.

Individuals with NAE1 variants experience neurodegeneration and seizure frequency during infections

(A) Timeline showing the development and seizure frequency (red line) in individual 1 and 2. Development and seizure frequency were quantified by parents of individuals 1 and 2 (arbitrary units). If the red line drops below the 0-point (the black line), this indicates that development decelerated. Circles indicate infections, massive red circles indicate infections requiring admissions. The bigger the circle, the longer the time of admission.

(B) MRI images of individual 1, individual 3, and individual 4 are shown. For individual 1, MRI was taken at 10 months of age and at 20 months of age (after ICU admission). Note the brain loss occurring between this time. The MRI of individual 3 was taken at approximately 29 months of age, 6–7 months after his seizures began which were treated with ACTH. For individual 4, brain MRI was obtained at the age of 2.5 years, showing severe brain loss, resulting from multiple severe infections.

(C) Bar graph showing the lymphocyte count after 1 day of anti-CD3 (0.1 μg/mL) stimulation with and without the addition of MLN4924 (200 nM) in healthy controls (3 donors, 1 technical replicate each) and lymphocytes of individuals with NAE1 variants (2 donors, 1 technical replicate each). Bars represent mean value ± SD, two-way ANOVA, post hoc: Fisher’s LSD (^∗p < 0.05).

(D) Bar graph showing the percentage of death cells (PI positive) over the total amount of cells (counted using Hoechst) in fibroblasts, with or without MLN4924 treatment (500 nM) in healthy controls (3 donors, 1 technical replicate each, gray bars) and individuals with NAE1 variants (2 donors, 1 technical replicate each, black bars). Bars represent mean value ± SD, two-way ANOVA, post hoc: Fisher’s LSD. (not significant, p > 0.05).