Neuropediatrics 2015; 46(04): 287-291
DOI: 10.1055/s-0035-1554098
Short Communication
Georg Thieme Verlag KG Stuttgart · New York

SYNGAP1 Mutation in Focal and Generalized Epilepsy: A Literature Overview and A Case Report with Special Aspects of the EEG

Celina von Stülpnagel
1   Hospital for Neuropediatrics and Neurological Rehabilitation, Epilepsy Center for Children and Adolescents, Vogtareuth, Germany
2   Paracelsus Medical University Salzburg, Salzburg, Austria
Claudia Funke
3   CEGAT GmbH, Tübingen, Germany
Caroline Haberl
4   Praxis für Neuropädiatrie, Starnberg, Germany
Konstanze Hörtnagel
3   CEGAT GmbH, Tübingen, Germany
Jerome Jüngling
3   CEGAT GmbH, Tübingen, Germany
Yvonne G. Weber
5   Department for Neurology and Epileptology, Hertie Institute for Clinical Brain Research, Tübingen, Germany
Martin Staudt
1   Hospital for Neuropediatrics and Neurological Rehabilitation, Epilepsy Center for Children and Adolescents, Vogtareuth, Germany
6   Department for Neuropediatrics and Developmental Neurology, University Hospital for Children and Adolescents, Tübingen, Germany
Gerhard Kluger
1   Hospital for Neuropediatrics and Neurological Rehabilitation, Epilepsy Center for Children and Adolescents, Vogtareuth, Germany
2   Paracelsus Medical University Salzburg, Salzburg, Austria
› Author Affiliations
Further Information

Publication History

05 November 2014

09 March 2015

Publication Date:
25 June 2015 (online)


BackgroundSYNGAP1, which encodes a RAS-GTPase-activating protein, is located on the short arm of chromosome 6. Heterozygous SYNGAP1 gene mutations have been associated with autism spectrum disorders, delay of psychomotor development, acquired microcephaly, and several forms of idiopathic generalized epilepsy. Here, we report a patient with a new SYNGAP1 stop mutation, and compare the phenotype with published cases with SYNGAP1 mutations and epilepsy.

Patient This 15-year-old nondysmorphic girl with intellectual disability developed drop attacks at the age of 2 years, later clonic and clonic–tonic as well as myoclonic seizures predominantly during sleep. The epilepsy was well-controlled by valproic acid (VPA) and later on with levetiracetam. Electroencephalogram (EEG) showed a complete EEG-normalization with eye opening as well as photosensitivity. Magnetic resonance imaging was normal. Genetic analysis revealed a de novo heterozygous stop mutation (c.348C > A, p.Y116*) in exon 4 of the SYNGAP1 gene.

Discussion The main clinical features of our patient (i.e., intellectual disability and idiopathic epilepsy) are compatible with previous reports on patients with SYNGAP1 mutations. The unusual feature of complete EEG normalization with eye opening has not been reported yet for this genetic abnormality. Furthermore, our case provides further support for efficacy of VPA in patients with SYNGAP1 mutation–related epilepsy.

  • References

  • 1 Lemke JR, Riesch E, Scheurenbrand T , et al. Targeted next generation sequencing as a diagnostic tool in epileptic disorders. Epilepsia 2012; 53 (8) 1387-1398
  • 2 Scheffer IE. Epilepsy genetics revolutionizes clinical practice. Neuropediatrics 2014; 45 (2) 70-74
  • 3 Brodie MJ, Covanis A, Gil-Nagel A , et al. Antiepileptic drug therapy: does mechanism of action matter?. Epilepsy Behav 2011; 21 (4) 331-341
  • 4 Hildebrand MS, Dahl HH, Damiano JA, Smith RJ, Scheffer IE, Berkovic SF. Recent advances in the molecular genetics of epilepsy. J Med Genet 2013; 50 (5) 271-279
  • 5 Kim JH, Liao D, Lau LF, Huganir RL. SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family. Neuron 1998; 20 (4) 683-691
  • 6 Kim JH, Lee HK, Takamiya K, Huganir RL. The role of synaptic GTPase-activating protein in neuronal development and synaptic plasticity. J Neurosci 2003; 23 (4) 1119-1124
  • 7 Clement JP, Aceti M, Creson TK , et al. Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses. Cell 2012; 151 (4) 709-723
  • 8 Hamdan FF, Daoud H, Piton A , et al. De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism. Biol Psychiatry 2011; 69 (9) 898-901
  • 9 Berryer MH, Hamdan FF, Klitten LL , et al. Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency. Hum Mutat 2013; 34 (2) 385-394
  • 10 Writzl K, Knegt AC. 6p21.3 microdeletion involving the SYNGAP1 gene in a patient with intellectual disability, seizures, and severe speech impairment. Am J Med Genet A 2013; 161A (7) 1682-1685
  • 11 Zollino M, Gurrieri F, Orteschi D, Marangi G, Leuzzi V, Neri G. Integrated analysis of clinical signs and literature data for the diagnosis and therapy of a previously undescribed 6p21.3 deletion syndrome. Eur J Hum Genet 2011; 19 (2) 239-242
  • 12 Klitten LL, Møller RS, Nikanorova M, Silahtaroglu A, Hjalgrim H, Tommerup N. A balanced translocation disrupts SYNGAP1 in a patient with intellectual disability, speech impairment, and epilepsy with myoclonic absences (EMA). Epilepsia 2011; 52 (12) e190-e193
  • 13 Carvill GL, Heavin SB, Yendle SC , et al. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet 2013; 45 (7) 825-830
  • 14 Hamdan FF, Gauthier J, Spiegelman D , et al; Synapse to Disease Group. Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. N Engl J Med 2009; 360 (6) 599-605
  • 15 de Ligt J, Willemsen MH, van Bon BW , et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med 2012; 367 (20) 1921-1929
  • 16 Vissers LE, de Ligt J, Gilissen C , et al. A de novo paradigm for mental retardation. Nat Genet 2010; 42 (12) 1109-1112