International Medical Case Reports Journal (Dec 2022)
Myoclonic-Atonic Epilepsy Caused by a Novel de Novo Heterozygous Missense Variant in the SLC6A1 Gene: Brief Discussion of the Literature and Detailed Case Description of a Severely Intellectually Disabled Adult Male Patient
Abstract
Willem Verhoeven,1– 3 José Zuijdam,4 Anneke Scheick,4 Frederiek van Nieuwenhuijsen,5 Anne-Suus Zwemer,5 Rolph Pfundt,6,7 Jos Egger3,6,7 1Department of Psychiatry, Erasmus University Medical Center, Rotterdam, the Netherlands; 2Centre for Consultation and Expertise, Utrecht, the Netherlands; 3Vincent van Gogh Centre of Excellence for Neuropsychiatry, Venray, the Netherlands; 4Raphael Institute Breidablick, Centre for People with Intellectual Disabilities, Middenbeemster, the Netherlands; 5ASVZ, Centre for People with Intellectual Disabilities, Sliedrecht, the Netherlands; 6Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands; 7Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the NetherlandsCorrespondence: Willem Verhoeven, Centre of Excellence for Neuropsychiatry, Stationsweg 46, Venray, 5803 AC, the Netherlands, Tel +31651156556, Fax +31478584765, Email [email protected]: Diagnostic exome sequencing has yielded over the past decades a great number of molecular diagnoses for genetic disorders in which both intellectual disability and epilepsy are present. One of these syndromes is myoclonic-atonic epilepsy (MAE) that is caused by pathogenic variants in the SLC6A1 gene located at 3p25.3. The most relevant clinical characteristics are intellectual disability, several forms of mostly treatment-resistant epilepsy starting at young age, serious disinhibitory behavioural problems, language impairment, higher pain tolerance, and symptoms from the autism spectrum, all in the absence of any consistent dysmorphism or malformation.Methods: After an overview of the literature, here, the developmental trajectory of a 55-year-old severely intellectually disabled male with therapy-resistant epilepsy and aggressive outburst is reported in detail, in whom no etiological diagnosis had been performed. Next to genetic, neurological, and neuropsychiatric examination, psychological assessment with validated instruments was performed.Results: Exome sequencing and targeted analysis of the patient and both his parents demonstrated a de novo missense variant in the SLC6A1 gene which was never before described in the literature nor in control databases. The phenotypical presentation of the patient with treatment-resistant epilepsy, especially absences and myoclonic seizures, as well as sleep disturbances and autism, corresponds with a diagnosis of MAE.Discussion: This case stresses that exome sequencing should be the first-tier diagnostic test for patients with unexplained neurodevelopmental disorders, regardless of their age, and that as yet the most suitable approach is the formation of an interdisciplinary team for treatment design and clinical management.Keywords: myoclonic-atonic epilepsy, SLC6A1, missense variant, intellectual disability, epilepsy, autism
