CACNA1A - Related Pediatric Epilepsy International Multicenter Retrospective Study Preliminary Results

Michael Schnapper ^1,2 Yael Michaeli ^3,4 Keren Yosovich ⁵ Andrea Nemeth ⁶ Ginevra Zanni ⁷ Deborah A. Sival ⁸ Alfons Macaya ⁹ Tal Gilboa ¹⁰ Inbar Hartmann ¹¹ Iris Noyman ¹² Roni Cohen ¹³ Ilan Linder ¹⁴ Agathe Roubertie ¹⁵ Lilach Shemer Meiri ¹⁶ Stephanie Libzon ^4,19 Mira Ginzberg ⁴ Ricki Sokol ⁴ Ronen Hadi-Cohen ⁴ Neamma Yosha-Orpaz ⁴ Andrea Nissenkorn ^2,3,4 Dorit Lev ²⁰ Tamar Gur-Hartman ^4,17,18 Tally Lerman-Sagie ^2,3,4 Lubov Blumkin ^2,4

¹Pediatric Department, Wolfson Medical Center, Holon, Israel, ישראל
²Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, ישראל
³Pediatric Epilepsy Clinic, Wolfson Medical Center, Holon, Israel, ישראל
⁴Pediatric Neurology Unit, Wolfson Medical Center, Holon, Israel, ישראל
⁵Molecular Genetics Laboratory, Wolfson Medical Center, Holon, Israel, ישראל
⁶Nuffield Department of Clinical Neurosciences, University of Oxford, בריטניה
⁷Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, IRCCS Bambino Gesu, Children’s Hospital, איטליה
⁸Department of Pediatrics, University Medical Center Groningen, הולנד
⁹Vall d'Hebron Research Institute, Pediatric Neurology Research Group, Autonomous University of Barcelona, ספרד
¹⁰Child Neurology Unit, Hadassah Medical Center, ישראל
¹¹Department of Pediatric Neurology and Epilepsy, Shamir (Assaf Harofe) Medical Center, ישראל
¹²Pediatric Neurology Unit, Soroka University Medical Center, ישראל
¹³Institute of Neurology, Schneider Children's Medical Center of Israel, ישראל
¹⁴Pediatric Epilepsy & Neurology Service, Barzilai University Medical Center, ישראל
¹⁵Departement de Neuropediatrie, CHU Gui de Chauliac, Institut des Neurosciences de Montpellier, צרפת
¹⁶Pediatric Neurology Unit, Carmel Medical Center, ישראל
¹⁷Israel School of Psychological Sciences, Israel School of Psychological Sciences, Tel-Aviv University, Israel, ישראל
¹⁸Department of Health Systems Management, Ariel University, ישראל
¹⁹Physical Therapy Department, Physical Therapy Department, Sackler Faculty of Medicine, ישראל
²⁰Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel, ישראל

Introduction: Non-poly Q CACNA1A- related disorders present with two main phenotypes: persistent movement abnormality and paroxysmal epileptic and non-epileptic events-PNEE.
Clinical spectrum ranges from mild paroxysmal attacks to developmental and epileptic encephalopathy.

Objective: To describe different seizure types and anti-epileptic drug`s efficacy; to define associated comorbidities and to compare psychomotor outcome of patients with CACNA1A related phenotypes with and without epilepsy.

Methods: An international multicenter retrospective study.

Results: Clinical and electro-radiologic features of 30 patients (age 2 months -7 years) were analyzed, De-novo variants were found in 80%, autosomal dominant variants in 20%. Febrile seizures presented in a third of patients. Most common seizure type was generalized tonic-clonic seizures. PNEE developed in 63% of patients` and 63% presented global developmental delay before seizures onset. Most effective anti-epileptic medications valproic acid, levetiracetam and benzodiazepines.

Seizure control was achieved in 63% of cases. Intellectual difficulties were found in 73%. Autism spectrum disorder was demonstrated in 33%. Brain MRI depicted abnormal findings in 40%, mostly cerebellar atrophy.

Progressive course was demonstrated 23%, non-progressive course in 46% and improvement in 30%.

Conclusions: CACNA1A - related pediatric epilepsy is a developmental and epileptic encephalopathy. These patients develop cognitive difficulties regardless of seizure control. Seizures in patients with CACNA1A variants is a risk factor for ASD.
Febrile seizures in patients with CACNA1A variants are common and a risk factor for epilepsy.