Boricua Founder Variant in FRRS1L Causes Epileptic Encephalopathy With Hyperkinetic Movements

Area of Science:

• Genetics
• Neurology
• Pediatrics

Background:

• Early infantile epileptic encephalopathy (EIEE-37) is linked to the FRRS1L gene, crucial for AMPA-receptor function.
• Biallelic loss-of-function variants in FRRS1L cause intractable epilepsy and dyskinesia.

Purpose of the Study:

• To investigate the founder mutation effect of the FRRS1L c.737_739delGAG (p.Gly246del) variant.
• To describe the clinical phenotype in 15 children of Puerto Rican ancestry with homozygous FRRS1L variant and EIEE-37.

Main Methods:

• Retrospective, multicenter chart review of patients with the homozygous FRRS1L (p.Gly246del) variant.
• Collected data on neurodevelopmental outcomes, neuroimaging, electrographic features, and treatment response.

Main Results:

• Fifteen patients from 12 Puerto Rican families were homozygous for the FRRS1L (p.Gly246del) variant.
• Onset of seizures between 6-24 months; all patients had hypotonia, severe developmental delay, and hyperkinetic movements.
• Developmental regression (86%), hypsarrhythmia (66%), evolving into Lennox-Gastaut syndrome, and cerebellar atrophy on MRI observed.

Conclusions:

• Largest cohort of patients with this specific epileptic encephalopathy described.
• Founder effect accounts for 0.76% carrier frequency in unaffected Puerto Rican individuals.
• Homozygous FRRS1L (p.Gly246del) variant results in a homogenous phenotype: early developmental regression, epilepsy (infantile spasms to Lennox-Gastaut syndrome), and hyperkinetic movement disorder.