Although there are many known Mendelian genes linked to epileptic or developmental and epileptic encephalopathy (EE/DEE), its genetic architecture is not fully explained. Here, we address this incompleteness by analyzing exomes of 743 EE/DEE cases and 2366 controls. We observe that damaging ultra-rare variants (dURVs) unique to an individual are significantly overrepresented in EE/DEE, both in known EE/DEE genes and the other non-EE/DEE genes. Importantly, enrichment of dURVs in non-EE/DEE genes is significant, even in the subset of cases with diagnostic dURVs (
P
= 0.000215), suggesting oligogenic contribution of non-EE/DEE gene dURVs. Gene-based analysis identifies exome-wide significant (
P
= 2.04 × 10
−6
) enrichment of damaging de novo mutations in
NF1
, a gene primarily linked to neurofibromatosis, in infantile spasm. Together with accumulating evidence for roles of oligogenic or modifier variants in severe neurodevelopmental disorders, our results highlight genetic complexity in EE/DEE, and indicate that EE/DEE is not an aggregate of simple Mendelian disorders.
Keywords:Post-encephalitic/encephalopathic epilepsy Refractory epilepsy Blood-brain barrier dysfunction Albumin quotient
A B S T R A C TPurpose: This study aimed to elucidate the characteristics and effects of chronic blood-brain barrier (BBB) dysfunction in patients with post-encephalitic/encephalopathic epilepsy (PEE), using brain images and the cerebral spinal fluid (CSF)/serum albumin ratio (albumin quotient, QAlb) as a marker of BBB function. Methods: We examined the albumin levels in CSF and serum samples from 312 patients with refractory epilepsy in our center between 2004 and 2015. Sixty samples from patients with PEE and 97 samples from age-and sexmatched disease controls (DC) were evaluated. We classified PEE patients into a widespread lesion group and a focal lesion group by severity on brain magnetic resonance images in the chronic phase after acute encephalitis/ encephalopathy. Results: Median QAlb was higher in PEE than in DC [median (range) ×10 3 : PEE 3.6 (1.0-10.3) versus DC 2.7 (1.0-6.7), p = 0.007]. In a linear regression analysis of the relationship between QAlb and patient's age at CSF examination or duration of epilepsy, the slope of the regression line was greater in PEE than in DC. Furthermore, in patients under ten years of age, linear regression analysis of QAlb versus seizure frequency showed a weak but positive correlation. Among PEE patients, seizure frequency was higher in the widespread lesion group than in the focal lesion group [300 (4-3000) versus 30 (1-1500) seizures/month, p < 0.001]. Conclusion: Our study suggests that patients with PEE have more severe BBB dysfunction, and that the BBB dysfunction is associated with refractory epilepsy.In this retrospective study, we examined the albumin levels in CSF
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