Imane Abdelmoumen1, Sandra Jimenez1, Ignacio Valencia1, Joseph Melvin1, Agustin Legido1, Mayela M Diaz-Diaz2, Christopher Griffith3, Lauren J Massingham4, Melissa Yelton5, Janice Rodríguez-Hernández2, Rhonda E Schnur6, Laurence E Walsh7, Ana G Cristancho8,9, Christina A Bergqvist8,9, Kirsty McWalter10, Iain Mathieson11, Gillian M Belbin12, Eimear E Kenny12, Xilma R Ortiz-Gonzalez8,9,13, Michael C Schneider1,13. 1. Section of Neurology, Department of Pediatrics, 14521St. Christopher's Hospital for Children Drexel University College of Medicine, Philadelphia, PA, USA. 2. 12320University of Puerto Rico Medical Sciences Campus, San Juan, PR, USA. 3. 7831University of South Florida, Genetics, Tampa, FL, USA. 4. 23325Rhode Island Hospital, Clinical Genetics, Providence, RI, USA. 5. 12311Penn State Health Children's Hospital, Clinical Genetics, Hershey, PA, USA. 6. Division of Genetics, Cooper Medical School of Rowan University, 363994Copper University Health Care, Camden, NJ, USA. 7. Indiana University School of Medicine, Neurology and Genetics, Indianapolis, IN, USA. 8. Department of Pediatrics, Division of Neurology, Epilepsy Neurogenetics Initiative, 6567Children's Hospital of Philadelphia, Philadelphia, PA, USA. 9. Department of Neurology, Perelman School of Medicine University of Pennsylvania, Philadelphia, PA, USA. 10. 486649GeneDx, Gaithersburg, MD, USA. 11. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 12. Institute for Genomic Health, 5925Icahn School of Medicine at Mount Sinai, New York, NY, USA. 13. These authors contributed equally to this work.
Abstract
OBJECTIVE: To describe a founder mutation effect and the clinical phenotype of homozygous FRRS1L c.737_739delGAG (p.Gly246del) variant in 15 children of Puerto Rican (Boricua) ancestry presenting with early infantile epileptic encephalopathy (EIEE-37) with prominent movement disorder. BACKGROUND: EIEE-37 is caused by biallelic loss of function variants in the FRRS1L gene, which is critical for AMPA-receptor function, resulting in intractable epilepsy and dyskinesia. METHODS: A retrospective, multicenter chart review of patients sharing the same homozygous FRRS1L (p.Gly246del) pathogenic variant identified by clinical genetic testing. Clinical information was collected regarding neurodevelopmental outcomes, neuroimaging, electrographic features and clinical response to antiseizure medications. RESULTS: Fifteen patients from 12 different families of Puerto Rican ancestry were homozygous for the FRRS1L (p.Gly246del) pathogenic variant, with ages ranging from 1 to 25 years. The onset of seizures was from 6 to 24 months. All had hypotonia, severe global developmental delay, and most had hyperkinetic involuntary movements. Developmental regression during the first year of life was common (86%). Electroencephalogram showed hypsarrhythmia in 66% (10/15), with many older children evolving into Lennox-Gastaut syndrome. Six patients demonstrated progressive volume loss and/or cerebellar atrophy on brain magnetic resonance imaging (MRI). CONCLUSIONS: We describe the largest cohort to date of patients with epileptic encephalopathy. We estimate that 0.76% of unaffected individuals of Puerto Rican ancestry carry this pathogenic variant due to a founder effect. Children homozygous for the FRRS1L (p.Gly246del) Boricua variant exhibit a very homogenous phenotype of early developmental regression and epilepsy, starting with infantile spasms and evolving into Lennox-Gastaut syndrome with hyperkinetic movement disorder.
OBJECTIVE: To describe a founder mutation effect and the clinical phenotype of homozygous FRRS1L c.737_739delGAG (p.Gly246del) variant in 15 children of Puerto Rican (Boricua) ancestry presenting with early infantile epileptic encephalopathy (EIEE-37) with prominent movement disorder. BACKGROUND: EIEE-37 is caused by biallelic loss of function variants in the FRRS1L gene, which is critical for AMPA-receptor function, resulting in intractable epilepsy and dyskinesia. METHODS: A retrospective, multicenter chart review of patients sharing the same homozygous FRRS1L (p.Gly246del) pathogenic variant identified by clinical genetic testing. Clinical information was collected regarding neurodevelopmental outcomes, neuroimaging, electrographic features and clinical response to antiseizure medications. RESULTS: Fifteen patients from 12 different families of Puerto Rican ancestry were homozygous for the FRRS1L (p.Gly246del) pathogenic variant, with ages ranging from 1 to 25 years. The onset of seizures was from 6 to 24 months. All had hypotonia, severe global developmental delay, and most had hyperkinetic involuntary movements. Developmental regression during the first year of life was common (86%). Electroencephalogram showed hypsarrhythmia in 66% (10/15), with many older children evolving into Lennox-Gastaut syndrome. Six patients demonstrated progressive volume loss and/or cerebellar atrophy on brain magnetic resonance imaging (MRI). CONCLUSIONS: We describe the largest cohort to date of patients with epileptic encephalopathy. We estimate that 0.76% of unaffected individuals of Puerto Rican ancestry carry this pathogenic variant due to a founder effect. Children homozygous for the FRRS1L (p.Gly246del) Boricua variant exhibit a very homogenous phenotype of early developmental regression and epilepsy, starting with infantile spasms and evolving into Lennox-Gastaut syndrome with hyperkinetic movement disorder.
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