دورية أكاديمية
أعرض في EDS

Intrafamilial variability in SLC6A1 -related neurodevelopmental disorders.

التفاصيل البيبلوغرافية
العنوان: Intrafamilial variability in SLC6A1 -related neurodevelopmental disorders.
المؤلفون: Kassabian B; Department of Epilepsy Genetics and Precision Medicine, Danish Epilepsy Center, Member of the European Reference Network EpiCARE, Dianalund, Denmark.; Neurology Unit, Department of Neuroscience, University of Padua, Padua, Italy., Fenger CD; Department of Epilepsy Genetics and Precision Medicine, Danish Epilepsy Center, Member of the European Reference Network EpiCARE, Dianalund, Denmark.; Amplexa Genetics, Odense, Denmark., Willems M; Département Génétique Médicale, Maladies Rares et Médecine Personnalisée, Hôpital Arnaud de Villeneuve, CHU de Montpellier Institute for Neurosciences of Montpellier, Univ Montpellier, INSERM, Montpellier, France., Aledo-Serrano A; Epilepsy and Neurogenetics Program-Vithas Madrid La Milagrosa University Hospital, Vithas Hospital Group, Madrid, Spain., Linnankivi T; Department of Pediatric Neurology, New Children's Hospital and Pediatric Research Center, Epilepsia Helsinki, Helsinki University Hospital and University of Helsinki, Helsinki, Finland., McDonnell PP; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, United States.; Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States.; Epilepsy Neurogenetics Initiative, Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, United States., Lusk L; Epilepsy Neurogenetics Initiative, Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, United States., Jepsen BS; Pediatric Department, Danish Epilepsy Center, Dianalund, Denmark., Bayat M; Department of Neurology and Center for Rare Diseases, Aarhus University Hospital, Aarhus, Denmark., Kattentidt A; Genetic Department, Stichting Zuidwester, Middelharnis, Netherlands., Vidal AA; Department of Clinical and Molecular Genetics, University Hospital Vall d'Hebron and Medicine Genetics Group Vall d'Hebron Research Institute (VHIR), Barcelona, Spain., Valero-Lopez G; Neurology Department, Virgen de la Arrixaca University Hospital, Murcia, Spain., Alarcon-Martinez H; Department of Pediatric Neurology, Virgen de la Arrixaca University Hospital, Murcia, Spain., Goodspeed K; Department of Pediatrics, Division of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, United States.; Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, United States., van Slegtenhorst M; Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands., Barakat TS; Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands.; Discovery Unit, Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands.; ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus MC University Medical Center, Rotterdam, Netherlands., Møller RS; Department of Epilepsy Genetics and Precision Medicine, Danish Epilepsy Center, Member of the European Reference Network EpiCARE, Dianalund, Denmark.; Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark., Johannesen KM; Department of Epilepsy Genetics and Precision Medicine, Danish Epilepsy Center, Member of the European Reference Network EpiCARE, Dianalund, Denmark.; Department of Genetics, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark., Rubboli G; Department of Epilepsy Genetics and Precision Medicine, Danish Epilepsy Center, Member of the European Reference Network EpiCARE, Dianalund, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
المصدر: Frontiers in neuroscience [Front Neurosci] 2023 Jul 12; Vol. 17, pp. 1219262. Date of Electronic Publication: 2023 Jul 12 (Print Publication: 2023).
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Frontiers Research Foundation Country of Publication: Switzerland NLM ID: 101478481 Publication Model: eCollection Cited Medium: Print ISSN: 1662-4548 (Print) Linking ISSN: 1662453X NLM ISO Abbreviation: Front Neurosci Subsets: PubMed not MEDLINE
أسماء مطبوعة: Original Publication: Lausanne : Frontiers Research Foundation
مستخلص: Introduction: Phenotypic spectrum of SLC6A1 -related neurodevelopmental disorders ( SLC6A1 -NDD) includes intellectual disability (ID), autistic spectrum disorders (ASD), epilepsy, developmental delay, beginning from early infancy or after seizure onset, and other neurological features such as hypotonia and movement disorders. Data on familial phenotypic heterogeneity have been rarely reported, thus in our study we aimed to investigate intrafamilial phenotypic variability in families with SLC6A1 variants.
Methods: We collected clinical, laboratory and genetic data on 39 individuals, including 17 probands, belonging to 13 families harboring inherited variants of SLC6A1 . Data were collected through an international network of Epilepsy and Genetic Centers.
Results: Main clinical findings in the whole cohort of 39 subjects were: (a) epilepsy, mainly presenting with generalized seizures, reported in 71% of probands and 36% of siblings or first/second-degree relatives. Within a family, the same epilepsy type (generalized or focal) was observed; (b) ID reported in 100% and in 13% of probands and siblings or first/second-degree relatives, respectively; (c) learning disabilities detected in 28% of the SLC6A1 carriers, all of them were relatives of a proband; (d) around 51% of the whole cohort presented with psychiatric symptoms or behavioral disorders, including 82% of the probands. Out of the 19 patients with psychiatric symptoms, ASD were diagnosed in 40% of them; (e) neurological findings (primarily tremor and speech difficulties) were observed 38.5% of the whole cohort, including 10 probands. Our families harbored 12 different SLC6A1 variants, one was a frameshift, two stop-gain, while the remaining were missense. No genotype-phenotype associations were identified.
Discussion: Our study showed that first-or second-degree relatives presented with a less severe phenotype, featuring mainly mild intellectual and/or learning disabilities, at variance with the probands who suffered from moderate to severe ID, generalized, sometimes intractable, epileptic seizures, behavioral and psychiatric disorders. These findings may suggest that a proportion of individuals with mild SLC6A1 -NDD might be missed, in particular those with an older age where genetic testing is not performed. Further studies on intrafamilial phenotypic variability are needed to confirm our results and possibly to expand the phenotypic spectrum of these disorders and benefit genetic counseling.
Competing Interests: KG has consulted for Taysha Gene Therapy, Jaguar Gene Therapy, Astellas Gene Therapy, and all Stripes for unrelated work. She also serves as co-chair of the Clinical Advisory Board (unpaid) for the non-profit COMBINEDBrain, which involves collaborations on SLC6A1-NDD. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2023 Kassabian, Fenger, Willems, Aledo-Serrano, Linnankivi, McDonnell, Lusk, Jepsen, Bayat, Kattentidt, Vidal, Valero-Lopez, Alarcon-Martinez, Goodspeed, van Slegtenhorst, Barakat, Møller, Johannesen and Rubboli.)
التعليقات: Erratum in: Front Neurosci. 2023 Aug 11;17:1270299. (PMID: 37638311)
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فهرسة مساهمة: Keywords: SLC6A1; epilepsy; intellectual disability; intrafamilial variability; neurodevelopmental disorders
تواريخ الأحداث: Date Created: 20230728 Latest Revision: 20230829
رمز التحديث: 20230830
مُعرف محوري في PubMed: PMC10368872
DOI: 10.3389/fnins.2023.1219262
PMID: 37502687
قاعدة البيانات: MEDLINE
الوصف
تدمد:1662-4548
DOI:10.3389/fnins.2023.1219262