Defining the phenotypic spectrum of SLC6A1 mutations

doi:10.1111/epi.13986

. 2018 Feb;59(2):389-402.

doi: 10.1111/epi.13986. Epub 2018 Jan 8.

Defining the phenotypic spectrum of SLC6A1 mutations

Katrine M Johannesen^{1

2}, Elena Gardella^{1

2}, Tarja Linnankivi³, Carolina Courage^{4

5}, Anne de Saint Martin^{6

7}, Anna-Elina Lehesjoki^{4

5}, Cyril Mignot⁸, Alexandra Afenjar⁹, Gaetan Lesca^{10

11

12}, Marie-Thérèse Abi-Warde^{6

7}, Jamel Chelly^{13

14}, Amélie Piton^{13

14}, J Lawrence Merritt 2nd¹⁵, Lance H Rodan^{16

17}, Wen-Hann Tan^{16

17}, Lynne M Bird¹⁸, Mark Nespeca¹⁹, Joseph G Gleeson²⁰, Yongjin Yoo²¹, Murim Choi²¹, Jong-Hee Chae²², Desiree Czapansky-Beilman²³, Sara Chadwick Reichert²⁴, Manuela Pendziwiat²⁵, Judith S Verhoeven²⁶, Helenius J Schelhaas²⁶, Orrin Devinsky²⁷, Jakob Christensen²⁸, Nicola Specchio²⁹, Marina Trivisano²⁹, Yvonne G Weber³⁰, Caroline Nava^{31

32}, Boris Keren^{31

32}, Diane Doummar³³, Elise Schaefer³⁴, Sarah Hopkins³⁵, Holly Dubbs³⁶, Jessica E Shaw³⁶, Laura Pisani³⁶, Candace T Myers¹⁵, Sha Tang³⁷, Shan Tang³⁸, Deb K Pal³⁸, John J Millichap^{39

40}, Gemma L Carvill⁴⁰, Kathrine L Helbig³⁷, Oriano Mecarelli⁴¹, Pasquale Striano⁴², Ingo Helbig^{25

35}, Guido Rubboli^{1

43}, Heather C Mefford¹⁵, Rikke S Møller^{1

2}

Affiliations

¹ The Danish Epilepsy Center Filadelfia, Dianalund, Denmark.
² Institute for Regional Health Services Research, University of Southern Denmark, Odense, Denmark.
³ Department of Child Neurology, Children's Hospital, Helsinki University Hospital Helsinki, University of Helsinki, Helsinki, Finland.
⁴ The Folkhälsan Institute of Genetics, University of Helsinki, Helsinki, Finland.
⁵ Research Programs Unit, Molecular Neurology and Neuroscience Center, Helsinki, Finland.
⁶ Department of Pediatrics, Pediatric Neurology, University Hospital of Strasbourg, Strasbourg, France.
⁷ Reference Center for Rare Epilepsies, Strasbourg, France.
⁸ Department of Genetics, Center for Rare causes of Intellectual Disabilities and UPMC Research Group "Intellectual Disabilities and Autism", Paris, France.
⁹ APHP, Genetic Services, Hospital Trousseau, Paris, France.
¹⁰ Departments of Genetics, Lyon University Hospitals, Lyon, France.
¹¹ Claude Bernard Lyon I University, Lyon, France.
¹² Lyon Neuroscience Research Center, CNRS UMRS5292, INSERM U1028, Lyon, France.
¹³ Department of Translational Medicine and Neurogenetics, Institut Génétique Biologie Moléculaire Cellulaire (IGBMC), Illkirch, France.
¹⁴ Laboratory of Genetic Diagnosis, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
¹⁵ Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA.
¹⁶ Boston Children's Hospital, Boston, MA, USA.
¹⁷ Harvard Medical School, Boston, MA, USA.
¹⁸ Division of Genetics, Department of Pediatrics, Rady Children's Hospital San Diego, University of California San Diego, San Diego, CA, USA.
¹⁹ Division of Neurology, Rady Children's Hospital, University of California, San Diego, CA, USA.
²⁰ Rady Children's Institute for Genomic Medicine, Howard Hughes Medical Institute, University of California, San Diego, CA, USA.
²¹ Department of Biomedical Sciences, Seoul National University School of Medicine, Seoul, South Korea.
²² Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University School of Medicine, Seoul, South Korea.
²³ Pediatric Neurology, Gillette Children's Specialty Healthcare, Burnsville, MN, USA.
²⁴ Children's Minnesota, Minneapolis, MN, USA.
²⁵ Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany.
²⁶ Department of Neurology, Academic Center for Epileptology, Heeze, The Netherlands.
²⁷ NYU Epilepsy Center, New York, NY, USA.
²⁸ Department of Neurology, Aarhus University Hospital, Aarhus, Denmark.
²⁹ Neurology Unit, Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
³⁰ Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tüebingen, Tüebingen, Germany.
³¹ Department of Genetics, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
³² Sorbonne Universities, UPMC Univ Paris 06, UMR S 1127, Inserm U 1127, CNRS UMR 7225, ICM, Paris, France.
³³ Assistance Publique-Hôpitaux de Paris, Neuropediatric Services, Hospital Armand Trousseau, Paris, France.
³⁴ Medical Genetics, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
³⁵ Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
³⁶ Division of Clinical Genetics, Department of Pediatrics, Columbia University Medical Center, New York, NY, USA.
³⁷ Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA, USA.
³⁸ Department of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
³⁹ Epilepsy Center and Division of Neurology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
⁴⁰ Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁴¹ Department of Neurology and Psychiatry, Neurophysiopathology and Neuromuscular Diseases, University of Sapeinza, Rome, Italy.
⁴² Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health, University of Genoa 'G. Gaslini" Institute, Genova, Italy.
⁴³ University of Copenhagen, Copenhagen, Denmark.

PMID: 29315614
PMCID: PMC5912688
DOI: 10.1111/epi.13986

Defining the phenotypic spectrum of SLC6A1 mutations

Katrine M Johannesen et al. Epilepsia. 2018 Feb.

. 2018 Feb;59(2):389-402.

doi: 10.1111/epi.13986. Epub 2018 Jan 8.

Authors

Affiliations

¹ The Danish Epilepsy Center Filadelfia, Dianalund, Denmark.
² Institute for Regional Health Services Research, University of Southern Denmark, Odense, Denmark.
³ Department of Child Neurology, Children's Hospital, Helsinki University Hospital Helsinki, University of Helsinki, Helsinki, Finland.
⁴ The Folkhälsan Institute of Genetics, University of Helsinki, Helsinki, Finland.
⁵ Research Programs Unit, Molecular Neurology and Neuroscience Center, Helsinki, Finland.
⁶ Department of Pediatrics, Pediatric Neurology, University Hospital of Strasbourg, Strasbourg, France.
⁷ Reference Center for Rare Epilepsies, Strasbourg, France.
⁸ Department of Genetics, Center for Rare causes of Intellectual Disabilities and UPMC Research Group "Intellectual Disabilities and Autism", Paris, France.
⁹ APHP, Genetic Services, Hospital Trousseau, Paris, France.
¹⁰ Departments of Genetics, Lyon University Hospitals, Lyon, France.
¹¹ Claude Bernard Lyon I University, Lyon, France.
¹² Lyon Neuroscience Research Center, CNRS UMRS5292, INSERM U1028, Lyon, France.
¹³ Department of Translational Medicine and Neurogenetics, Institut Génétique Biologie Moléculaire Cellulaire (IGBMC), Illkirch, France.
¹⁴ Laboratory of Genetic Diagnosis, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
¹⁵ Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA.
¹⁶ Boston Children's Hospital, Boston, MA, USA.
¹⁷ Harvard Medical School, Boston, MA, USA.
¹⁸ Division of Genetics, Department of Pediatrics, Rady Children's Hospital San Diego, University of California San Diego, San Diego, CA, USA.
¹⁹ Division of Neurology, Rady Children's Hospital, University of California, San Diego, CA, USA.
²⁰ Rady Children's Institute for Genomic Medicine, Howard Hughes Medical Institute, University of California, San Diego, CA, USA.
²¹ Department of Biomedical Sciences, Seoul National University School of Medicine, Seoul, South Korea.
²² Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University School of Medicine, Seoul, South Korea.
²³ Pediatric Neurology, Gillette Children's Specialty Healthcare, Burnsville, MN, USA.
²⁴ Children's Minnesota, Minneapolis, MN, USA.
²⁵ Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany.
²⁶ Department of Neurology, Academic Center for Epileptology, Heeze, The Netherlands.
²⁷ NYU Epilepsy Center, New York, NY, USA.
²⁸ Department of Neurology, Aarhus University Hospital, Aarhus, Denmark.
²⁹ Neurology Unit, Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
³⁰ Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tüebingen, Tüebingen, Germany.
³¹ Department of Genetics, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
³² Sorbonne Universities, UPMC Univ Paris 06, UMR S 1127, Inserm U 1127, CNRS UMR 7225, ICM, Paris, France.
³³ Assistance Publique-Hôpitaux de Paris, Neuropediatric Services, Hospital Armand Trousseau, Paris, France.
³⁴ Medical Genetics, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
³⁵ Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
³⁶ Division of Clinical Genetics, Department of Pediatrics, Columbia University Medical Center, New York, NY, USA.
³⁷ Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA, USA.
³⁸ Department of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
³⁹ Epilepsy Center and Division of Neurology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
⁴⁰ Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁴¹ Department of Neurology and Psychiatry, Neurophysiopathology and Neuromuscular Diseases, University of Sapeinza, Rome, Italy.
⁴² Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health, University of Genoa 'G. Gaslini" Institute, Genova, Italy.
⁴³ University of Copenhagen, Copenhagen, Denmark.

PMID: 29315614
PMCID: PMC5912688
DOI: 10.1111/epi.13986

Abstract

Objective: Pathogenic SLC6A1 variants were recently described in patients with myoclonic atonic epilepsy (MAE) and intellectual disability (ID). We set out to define the phenotypic spectrum in a larger cohort of SCL6A1-mutated patients.

Methods: We collected 24 SLC6A1 probands and 6 affected family members. Four previously published cases were included for further electroclinical description. In total, we reviewed the electroclinical data of 34 subjects.

Results: Cognitive development was impaired in 33/34 (97%) subjects; 28/34 had mild to moderate ID, with language impairment being the most common feature. Epilepsy was diagnosed in 31/34 cases with mean onset at 3.7 years. Cognitive assessment before epilepsy onset was available in 24/31 subjects and was normal in 25% (6/24), and consistent with mild ID in 46% (11/24) or moderate ID in 17% (4/24). Two patients had speech delay only, and 1 had severe ID. After epilepsy onset, cognition deteriorated in 46% (11/24) of cases. The most common seizure types were absence, myoclonic, and atonic seizures. Sixteen cases fulfilled the diagnostic criteria for MAE. Seven further patients had different forms of generalized epilepsy and 2 had focal epilepsy. Twenty of 31 patients became seizure-free, with valproic acid being the most effective drug. There was no clear-cut correlation between seizure control and cognitive outcome. Electroencephalography (EEG) findings were available in 27/31 patients showing irregular bursts of diffuse 2.5-3.5 Hz spikes/polyspikes-and-slow waves in 25/31. Two patients developed an EEG pattern resembling electrical status epilepticus during sleep. Ataxia was observed in 7/34 cases. We describe 7 truncating and 18 missense variants, including 4 recurrent variants (Gly232Val, Ala288Val, Val342Met, and Gly362Arg).

Significance: Most patients carrying pathogenic SLC6A1 variants have an MAE phenotype with language delay and mild/moderate ID before epilepsy onset. However, ID alone or associated with focal epilepsy can also be observed.

Keywords: MAE; SLC6A1; epilepsy; epilepsy genetics.

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Conflict of interest statement

DISCLOSURE OF CONFLICT OF INTEREST

ST and KLH are employed by Ambry Genetics. CC was funded by the SNSF Early Postdoc fellowship. YW and IH were funded by DFG We4896/3-1; He5415/6-1. The remaining authors have no conflicts of interest to disclose. added. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Figures

**FIGURE 1**
Pedigrees of families 1 and 2

**FIGURE 2**
The *SLC6A1* gene with the missense variants found in this study. Recurrent variants are highlighted

**FIGURE 3**
Similar EEG pattern in 3 different patients diagnosed as MAE-like (Patient 20), unclassified generalized (Patient 2), and typical MAE (Patient 31). The EEG abnormalities consisted of prolonged bursts of irregular generalized 2.5–3.5 Hz slow waves with and without prominent spikes/polyspikes component, typically starting gradually in the occipital regions. In Patient 20, roughly the same EEG pattern can give rise to clinical manifestations consisting of atypical absence (to the left), or to a seizure with a brief atonic and myoclonic component (to the right). EEG parameters are the following. Patient 20: band pass filter 1–35 Hz, time constant 0.1 s, sensitivity 20 μV/mm; Patient 2: band pass filter 1–70 Hz time constant 0.3 s, sensitivity 10 μV/mm; Patient 31: band pass filter 1–30, time constant 0.16 s, sensitivity 10 μV/mm

**FIGURE 4**
Nocturnal sleep EEG in Patient 26 at the age of 4 y and 5 mo. During NREM sleep (to the left) the EEG is characterized by almost continuous spike and slow waves in the right hemisphere, with occasional spreading diffuse (spike–wave index 82%). During REM sleep (to the right) the epileptiform abnormalities are less frequent and more focal in the temporocentral region. This EEG picture strongly resembles hemispheric ESES, although the clinical correlate is vague. In the right upper corner, the amplitude map corresponding to the pick of the spike shows a radial orientation of the dipole. EEG parameters: band pass filter 1–70 Hz, time constant 0.1 s

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References

1. Madsen KK, Hansen GH, Danielsen EM, et al. The subcellular localization of GABA transporters and its implication for seizure management. Neurochem Res. 2015;40:410–9. - PubMed
1. Zhou Y, Danbolt NC. GABA and glutamate transporters in brain. Front Endocrinol (Lausanne) 2013;4:165. - PMC - PubMed
1. Scimemi A. Structure, function, and plasticity of GABA transporters. Front Cell Neurosci. 2014;8:161. - PMC - PubMed
1. Cope DW, Di Giovanni G, Fyson SJ, et al. Enhanced tonic GABAA inhibition in typical absence epilepsy. Nat Med. 2009;15:1392–8. - PMC - PubMed
1. Dikow N, Maas B, Karch S, et al. 3p25.3 microdeletion of GABA transporters SLC6A1 and SLC6A11 results in intellectual disability, epilepsy and stereotypic behavior. Am J Med Genet A. 2014;164a:3061–8. - PubMed

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[1] Madsen KK, Hansen GH, Danielsen EM, et al. The subcellular localization of GABA transporters and its implication for seizure management. Neurochem Res. 2015;40:410–9. - PubMed

[2] Madsen KK, Hansen GH, Danielsen EM, et al. The subcellular localization of GABA transporters and its implication for seizure management. Neurochem Res. 2015;40:410–9. - PubMed

[3] Zhou Y, Danbolt NC. GABA and glutamate transporters in brain. Front Endocrinol (Lausanne) 2013;4:165. - PMC - PubMed

[4] Zhou Y, Danbolt NC. GABA and glutamate transporters in brain. Front Endocrinol (Lausanne) 2013;4:165. - PMC - PubMed

[5] Scimemi A. Structure, function, and plasticity of GABA transporters. Front Cell Neurosci. 2014;8:161. - PMC - PubMed

[6] Scimemi A. Structure, function, and plasticity of GABA transporters. Front Cell Neurosci. 2014;8:161. - PMC - PubMed

[7] Cope DW, Di Giovanni G, Fyson SJ, et al. Enhanced tonic GABAA inhibition in typical absence epilepsy. Nat Med. 2009;15:1392–8. - PMC - PubMed

[8] Cope DW, Di Giovanni G, Fyson SJ, et al. Enhanced tonic GABAA inhibition in typical absence epilepsy. Nat Med. 2009;15:1392–8. - PMC - PubMed

[9] Dikow N, Maas B, Karch S, et al. 3p25.3 microdeletion of GABA transporters SLC6A1 and SLC6A11 results in intellectual disability, epilepsy and stereotypic behavior. Am J Med Genet A. 2014;164a:3061–8. - PubMed

[10] Dikow N, Maas B, Karch S, et al. 3p25.3 microdeletion of GABA transporters SLC6A1 and SLC6A11 results in intellectual disability, epilepsy and stereotypic behavior. Am J Med Genet A. 2014;164a:3061–8. - PubMed

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Defining the phenotypic spectrum of SLC6A1 mutations

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Defining the phenotypic spectrum of SLC6A1 mutations

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