Phenotype and surgical management of drug-resistant epilepsy in patients with COL4A1 and COL4A2 variants.

Objective: To summarize the clinical features of collagen type IV alpha 1/2 chain (COL4A)1/2-related epilepsy and the seizure outcomes of patients undergoing epilepsy surgery.

Methods: We retrospectively analyzed the clinical, electroencephalography, and neuroimaging data; genetic characteristics; surgical details; and prognosis of 8 patients (4 boys) treated for COL4A1/2-related epilepsy at Tsinghua University Yuquan Hospital.

Results: Two of the probands had COL4A1 variants and six had COL4A2 variants. Four of the variants were de novo. Prenatal abnormalities consisted of intrauterine growth retardation and ventriculomegaly. Three patients had a low birth weight, and one had perinatal retinal hemorrhage. The median age of seizure onset was 8 months, with 75% (6/8) experiencing epilepsy before age 1. Status epilepticus occurred in 38% (3/8) of patients. All patients experienced focal seizures, and 50% (4/8) had focal epileptic spasms. Hemiparesis was observed in 88% (7/8) of patients, and all 8 had developmental delays. The median number of anti-seizure drugs was 5, and all patients had drug-resistant epilepsy. Seven patients had seizures localized to one of the posterior quadrants, consistent with the magnetic resonance imaging features of blurring of the gray-white matter junction and positron emission tomography features of metabolic abnormalities. Other neuroimaging features included bilateral mild white matter abnormalities; unilateral porencephaly near the basal ganglia; ventriculomegaly; focal cerebral calcification; contralateral schizencephaly; and contralateral cortical thickening and cerebellar abnormalities. Six patients underwent unilateral posterior quadrant disconnection, five (83%) of whom had no recurrence for at least 11 months and experienced developmental improvement. No surgical complications were reported. Pathological examination revealed malformations of cortical development in all six surgical cases (five with focal cortical dysplasia [FCD] type Ia and one with FCD type II).

Significance: The results of this case series suggest that early surgical intervention in patients with COL4A1/2-related epilepsy with well-defined epileptogenic zones may improve seizure control and developmental outcomes.

Plain Language Summary: In this case series of eight patients, epilepsy related to variants in the collagen type IV alpha 1/2 chain genes was characterized by drug-resistant localized seizures with an early onset, one-sided muscle weakness, and developmental delay. Neuroimaging revealed various brain abnormalities. Structural abnormalities outside the seizure-onset zone did not appear to affect surgical prognosis. Early surgical intervention in patients with well-defined seizure-onset zones improved seizure control and developmental outcomes.