Uncovering genomic causes of co-morbidity in epilepsy: gene-driven phenotypic characterization of rare microdeletions

Abstract

Background: Patients with epilepsy often suffer from other important conditions. The existence of such co-morbidities is frequently not recognized and their relationship with epilepsy usually remains unexplained.

Methodology/principal findings: We describe three patients with common, sporadic, non-syndromic epilepsies in whom large genomic microdeletions were found during a study of genetic susceptibility to epilepsy. We performed detailed gene-driven clinical investigations in each patient. Disruption of the function of genes in the deleted regions can explain co-morbidities in these patients.

Conclusions/significance: Co-morbidities in patients with epilepsy can be part of a genomic abnormality even in the absence of (known) congenital malformations or intellectual disabilities. Gene-driven phenotype examination can also reveal clinically significant unsuspected condition.

Figure 1. Nerve excitability profile of Case 2.

In the nerve excitability profile, there was an abnormally enhanced late subexcitability of the recovery cycle (A) and a pronounced S2 accommodation and reduced TEd (90–100 ms) value at the end of the depolarising threshold electrotonus (upper trace in B). C,D: scatter plots of these nerve excitability parameters in the patient (filled circle) and 16 normal controls (open symbols). Dashed lines (A–D) show 95% confidence interval of the normal range. See Text S1 for detailed description of methods.

Figure 2. Attenuation of subcutaneous fat in Case 3.

(A) Coronal T2-weighted image showing the patient has attenuation of scalp subcutaneous fat (arrows). (B) Normal appearance in a patient with epilepsy without 17q12 deletion (arrows). Subcutaneous scalp fat was present on cranial MRI in 150 patients with temporal lobe epilepsy who did not carry this deletion.

Figure 3. Cerebellar atrophy in Case 3.

T1-weighted MRI reveals cerebellar atrophy. Note this is a T1-weighted image (not a T2-weighted image as in Figure 2A); the bright layer in the scalp is diploe, not subcutaneous fat.

Figure 4. Neuropathology of resection specimen from Case 3.

In the deep white (periventricular region) of the temporal lobectomy specimen of Case 3, a single cluster of globoid cells with granular cytoplasm was present. The cells showed PAS positivity, which could indicate glycogen storage, but the cells did not contain myelin debris and there was no evidence of demyelination. The cells were only present focally. Further investigation regarding histogenesis of these cells and characterization of cytoplasmic contents was not possible. Similar cell types were not noted in the hippocampus.

Figure 5. Cortical lamination in Case 3.

Examination with several cortical layer markers (antibodies against proteins denoted in each panel) revealed normal cortical lamination in Case 3.

Figure 6. Facial dysmorphism in Case 3.

(A) Dense surface morphology (DSM) results (See Text S1 for details). The scatter plot shows age (horizontally) against DSM distance (vertically) between the matched mean face and the patient and 200 control faces. Distance from the patient-matched mean face was linearly regressed against age for all controls. The patient was fitted to the appropriate regression and a 95% confidence interval was calculated for the predicted distance from the patient-matched mean. The scatter plot shows that Case 3 (square) is well outside the 95% confidence interval (bar). (B) Heat maps using a red–green-blue spectrum to depict inward–null-outward displacement along the surface normal for the patient face relative to its matched mean face using 50 control subjects. Displacement is expressed as the number of standard deviations (Stdv) from the mean. The lateral patches of red and yellow reflect an unusually narrow face. The red and yellow cheek patches and the null displaced green islands in the gonial region of the lower jaw reflect diminished fatty tissue rather than reduced gonial/skeletal width. Some fullness of the perioral region is shown (blue).