PMC6205307_01
Clinical and genetic findings from proband with compound heterozygous CACNA2D2 variants. (a) Sagittal T1 weighted image from MRI demonstrating cerebellar volume loss (arrows). (b) Awake EEG showing spontaneous generalized 3 Hz spike and wave seizure activity with eye fluttering and low amplitude arm flinches. (c) Sanger sequencing traces showing CACNA2D2 variants inherited in a compound heterozygous fashion. Note: The CACNA2D2 gene is encoded by the minus strand of DNA. (d) Pedigree showing the inheritance pattern of the two variants. (e) Species protein alignment showing the evolutionary conservation of the two amino acid positions and prediction scores from in silico algorithms. D, deleterious; PrD, probably damaging; B, benign.
CRIG2018-6308283.001.jpg
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fig1
While brain MRIs were repeatedly normal during the first two years of life, an MRI at 29 months of age showed prominence of cerebellar fissures with a normal brainstem, consistent with cerebellar atrophy (Figure 1(a)). Several spontaneous (Figure 1(b)) and light-induced seizures were recorded by EEG, characterized by 2.5-3 Hz frontally predominant generalized spike and wave discharges accompanied by eye fluttering and arm flinches. During reanalysis of the WES, it was noted that the proband carried two rare missense variants in the CACNA2D2 gene (p.Pro261Leu and p.Leu1046Pro), which were inherited on separate alleles (Figures 1(c) and 1(d)).