Sara Matricardi1, Paola De Liso2, Elena Freri3, Paola Costa4, Barbara Castellotti5, Stefania Magri5, Cinzia Gellera5, Tiziana Granata3, Luciana Musante6, Gaetan Lesca7, Julie Oertel8, Dana Craiu9,10, Trine B Hammer11, Rikke S Møller11,12, Nina Barisic13, Rami Abou Jamra14, Tilman Polster15, Federico Vigevano2, Carla Marini1. 1. Department of Child Neuropsychiatry, Children's Hospital, Ancona, Italy. 2. Department of Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico, Bambino Gesù Children's Hospital, Rome, Italy. 3. Department of Pediatric Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico Foundation Carlo Besta Neurological Institute, Milan, Italy. 4. Department of Neuropsychiatry, Institute for Maternal and Child Health, Istituto di Ricovero e Cura a Carattere Scientifico Burlo Garofolo, Trieste, Italy. 5. Unit of Medical Genetics and Neurogenetics, Istituto di Ricovero e Cura a Carattere Scientifico Foundation Carlo Besta Neurological Institute, Milan, Italy. 6. Department of Medical Genetics, Institute for Maternal and Child Health, Istituto di Ricovero e Cura a Carattere Scientifico Burlo Garofolo, Trieste, Italy. 7. Department of Medical Genetics, Lyon Civil Hospices, Lyon, France. 8. Department of Medical Genetics, Archet Hospital 2, Nice University Hospital Center, Nice, France. 9. Department of Clinical Neurosciences, Carol Davila University of Medicine and Pharmacy Bucharest, Bucharest, Romania. 10. Pediatric Neurology Clinic, Alexandru Obregia Hospital, Bucharest, Romania. 11. Danish Epilepsy Center Filadelfia, Dianalund, Denmark. 12. Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark. 13. Division of Child Neurology, Department of Pediatrics, Clinical Medical Center Zagreb, University of Zagreb Medical School, Zagreb, Croatia. 14. Institute of Human Genetics, University Medical Center Leipzig, Leipzig, Germany. 15. Pediatric Epileptology, Mara Hospital, Bethel Epilepsy Center, Bielefeld, Germany.
Abstract
OBJECTIVE: Autosomal recessive pathogenic variants of the SLC13A5 gene are associated with severe neonatal epilepsy, developmental delay, and tooth hypoplasia/hypodontia. We report on 14 additional patients and compare their phenotypic features to previously published patients to identify the clinical hallmarks of this disorder. METHODS: We collected clinical features of 14 patients carrying biallelic variants in SLC13A5 and performed a PubMed search to identify previously published patients. RESULTS: All patients presented clonic or tonic seizures in the first days of life, evolving into status epilepticus in 57%. Analysis of seizure frequency and developmental milestones divided into five epochs showed an evolutionary trajectory of both items. In the first 3 years of life, 72% of patients had weekly/monthly seizures, often triggered by fever; 14% were seizure-free. Between the ages of 3 and 12 years, 60% become seizure-free; in the following years, up to age 18 years, 57% were seizure-free. After the age of 18 years, all three patients reaching this age were seizure-free. Similarly, 86% of patients at onset presented mild to moderate developmental impairment and diffuse hypotonia. In late childhood, all had developmental delay that was severe in most. Benzodiazepines, phenobarbital, phenytoin, and carbamazepine were the most effective drugs. Eight probands carried heterozygous compound variants, and homozygous pathogenic variants occurred in six. Literature review identified 45 patients carrying SLC13A5 gene pathogenic variants whose clinical features overlapped with our cohort. A peculiar and distinguishing sign is the presence of tooth hypoplasia and/or hypodontia in most patients. SIGNIFICANCE: Autosomal recessive pathogenic variants in SLC13A5 are associated with a distinct neonatal epileptic encephalopathy evolving into severe cognitive and motor impairment, yet with seizures that settle down in late childhood. Tooth hypoplasia or hypodontia remains the peculiar feature. The SLC13A5 gene should be screened in neonatal epileptic encephalopathies; its recessive inheritance has relevance for genetic counseling.
OBJECTIVE: Autosomal recessive pathogenic variants of the SLC13A5 gene are associated with severe neonatal epilepsy, developmental delay, and tooth hypoplasia/hypodontia. We report on 14 additional patients and compare their phenotypic features to previously published patients to identify the clinical hallmarks of this disorder. METHODS: We collected clinical features of 14 patients carrying biallelic variants in SLC13A5 and performed a PubMed search to identify previously published patients. RESULTS: All patients presented clonic or tonic seizures in the first days of life, evolving into status epilepticus in 57%. Analysis of seizure frequency and developmental milestones divided into five epochs showed an evolutionary trajectory of both items. In the first 3 years of life, 72% of patients had weekly/monthly seizures, often triggered by fever; 14% were seizure-free. Between the ages of 3 and 12 years, 60% become seizure-free; in the following years, up to age 18 years, 57% were seizure-free. After the age of 18 years, all three patients reaching this age were seizure-free. Similarly, 86% of patients at onset presented mild to moderate developmental impairment and diffuse hypotonia. In late childhood, all had developmental delay that was severe in most. Benzodiazepines, phenobarbital, phenytoin, and carbamazepine were the most effective drugs. Eight probands carried heterozygous compound variants, and homozygous pathogenic variants occurred in six. Literature review identified 45 patients carrying SLC13A5 gene pathogenic variants whose clinical features overlapped with our cohort. A peculiar and distinguishing sign is the presence of tooth hypoplasia and/or hypodontia in most patients. SIGNIFICANCE: Autosomal recessive pathogenic variants in SLC13A5 are associated with a distinct neonatal epileptic encephalopathy evolving into severe cognitive and motor impairment, yet with seizures that settle down in late childhood. Tooth hypoplasia or hypodontia remains the peculiar feature. The SLC13A5 gene should be screened in neonatal epileptic encephalopathies; its recessive inheritance has relevance for genetic counseling.
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