Gamma-Aminobutyric Acid Type A Receptor Genes and Their Related Epilepsies

Viviana Brafa Musicoro; Vincenzo Sortino; Giulia Pecora; Monica Tosto; Manuela Lo Bianco; Rachele Soma; Catia Romano; Raffaele Falsaperla; Andrea D. Praticò

doi:10.1055/s-0041-1727269

Journal of Pediatric Neurology, Table of Contents

Journal of Pediatric Neurology 2024; 22(01): 013-020
DOI: 10.1055/s-0041-1727269

Review Article

Gamma-Aminobutyric Acid Type A Receptor Genes and Their Related Epilepsies

Authors

Viviana Brafa Musicoro^*

¹Pediatric Postgraduate Residency Program, Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, Catania, Italy
Vincenzo Sortino^*

¹Pediatric Postgraduate Residency Program, Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, Catania, Italy
Giulia Pecora

¹Pediatric Postgraduate Residency Program, Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, Catania, Italy
Monica Tosto

¹Pediatric Postgraduate Residency Program, Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, Catania, Italy
Manuela Lo Bianco

¹Pediatric Postgraduate Residency Program, Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, Catania, Italy
Rachele Soma

²Unit of Rare Diseases of the Nervous System in Childhood, Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, Catania, Italy
Catia Romano

³Italian Blind Union, Catania Section, Italy
Raffaele Falsaperla

⁴Unit of Pediatrics and Pediatric Emergency, University Hospital “Policlinico Rodolico-San Marco”, Catania, Italy

⁵Unit of Neonatal Intensive Care and Neonatology, University Hospital “Policlinico Rodolico-San Marco”, Catania, Italy
Andrea D. Praticò

²Unit of Rare Diseases of the Nervous System in Childhood, Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, Catania, Italy

Abstract

Gamma-aminobutyric acid type A (GABA-A) receptor subunit gene mutations, which include GABRA1, GABRB3, GABRD, and GABRG2, are often involved in several genetic epilepsy syndromes and other neuropsychiatric diseases like autism spectrum disorder, schizophrenia, and anxiety. GABA-A are ligand-gated ionic channels, and are involved firstly in the fast inhibitory synaptic transmission of the central nervous system. The GABA receptors include the ionotropic GABA-A and GABA-C receptors and the metabotropic GABA-B receptors. According to the site in which mutations occur, they cause disorders in channel opening, “lock-and-pull” receptor system functioning, and capable of causing a specific epilepsy phenotype. The aim of this article is to summarize the most recent literature findings, considering genetic mutations, clinical features, genotype/phenotype correlation, and therapy about neurodevelopment diseases correlated to GABA receptors dysfunction, in particular epilepsy. According to our findings, we conclude that further mutation analysis could permit genotype–phenotype correlation and give more information about the best efficient treatment, even if—at present—more clinical and genetic studies are necessary.

Keywords

GABA receptor - metabotropic - ionotropic - epilepsies - encephalopathy

Full Text

References

References
1 Papandreou A, McTague A, Trump N. et al. GABRB3 mutations: a new and emerging cause of early infantile epileptic encephalopathy. Dev Med Child Neurol 2016; 58 (04) 416-420
2 Althoff T, Hibbs RE, Banerjee S, Gouaux E. X-ray structures of GluCl in apo states reveal a gating mechanism of Cys-loop receptors. Nature 2014; 512 (7514): 333-337
3 Du J, Lü W, Wu S, Cheng Y, Gouaux E. Glycine receptor mechanism elucidated by electron cryo-microscopy. Nature 2015; 526 (7572): 224-229
4 Hibbs RE, Gouaux E. Principles of activation and permeation in an anion-selective Cys-loop receptor. Nature 2011; 474 (7349): 54-60
5 Macdonald RL, Olsen RW. GABAA receptor channels. Annu Rev Neurosci 1994; 17: 569-602
6 Hirose S. Mutant GABA(A) receptor subunits in genetic (idiopathic) epilepsy. Prog Brain Res 2014; 213: 55-85
7 Hernandez CC, Macdonald RL. A structural look at GABA_A receptor mutations linked to epilepsy syndromes. Brain Res 2019; 1714: 234-247
8 Praticò AD, Falsaperla R, Ruggieri M, Corsello G, Pavone P. Prognostic challenges of SCN1A genetic mutations: report on two children with mild features. J Pediatr Neurol 2016; 14: 82-88
9 Pavone P, Briuglia S, Falsaperla R. et al. Wide spectrum of congenital anomalies including choanal atresia, malformed extremities, and brain and spinal malformations in a girl with a de novo 5.6-Mb deletion of 13q12.11-13q12.13. Am J Med Genet A 2014; 164A (07) 1734-1743
10 Pavone P, Praticò AD, Falsaperla R. et al. Congenital generalized hypertrichosis: the skin as a clue to complex malformation syndromes. Ital J Pediatr 2015; 41: 55
11 Ruggieri M, Iannetti P, Clementi M. et al. Neurofibromatosis type 1 and infantile spasms. Childs Nerv Syst 2009; 25 (02) 211-216
12 Lionetti E, Francavilla R, Maiuri L. et al. Headache in pediatric patients with celiac disease and its prevalence as a diagnostic clue. J Pediatr Gastroenterol Nutr 2009; 49 (02) 202-207
13 Salpietro V, Polizzi A, Di Rosa G. et al. Adrenal disorders and the paediatric brain: pathophysiological considerations and clinical implications. Int J Endocrinol 2014; 2014: 282489
14 Ruggieri M, Polizzi A, Pavone L, Musumeci S. Thalamic syndrome in children with measles infection and selective, reversible thalamic involvement. Pediatrics 1998; 101 (1 Pt 1): 112-119
15 Lionetti E, Leonardi S, Franzonello C, Mancardi M, Ruggieri M, Catassi C. Gluten psychosis: confirmation of a new clinical entity. Nutrients 2015; 7 (07) 5532-5539
16 Pavone P, Praticò AD, Ruggieri M. et al. Acquired peripheral neuropathy: a report on 20 children. Int J Immunopathol Pharmacol 2012; 25 (02) 513-517
17 Ruggieri M, Praticò AD, Serra A. et al. Early history of neurofibromatosis type 2 and related forms: earliest descriptions of acoustic neuromas, medical curiosities, misconceptions, landmarks and the pioneers behind the eponyms. Childs Nerv Syst 2017; 33 (04) 549-560
18 Ruggieri M, Praticò AD, Scuderi A, Sorge G, Polizzi A. The multiple faces of artwork diagnoses. Lancet Neurol 2017; 16 (06) 417-418
19 Ruggieri M, McShane MA. Parental view of epilepsy in Angelman syndrome: a questionnaire study. Arch Dis Child 1998; 79 (05) 423-426
20 Pavone P, Praticò AD, Vitaliti G. et al. Hydranencephaly: cerebral spinal fluid instead of cerebral mantles. Ital J Pediatr 2014; 40: 79
21 Ruggieri M, Rizzo R, Pavone P, Baieli S, Sorge G, Happle R. Temporal triangular alopecia in association with mental retardation and epilepsy in a mother and daughter. Arch Dermatol 2000; 136 (03) 426-427
22 Baumann SW, Baur R, Sigel E. Forced subunit assembly in alpha1beta2gamma2 GABAA receptors. Insight into the absolute arrangement. J Biol Chem 2002; 277 (48) 46020-46025
23 Zhu G, Okada M, Yoshida S. et al. Rats harboring S284L Chrna4 mutation show attenuation of synaptic and extrasynaptic GABAergic transmission and exhibit the nocturnal frontal lobe epilepsy phenotype. J Neurosci 2008; 28 (47) 12465-12476
24 Tanaka M, Olsen RW, Medina MT. et al. Hyperglycosylation and reduced GABA currents of mutated GABRB3 polypeptide in remitting childhood absence epilepsy. Am J Hum Genet 2008; 82 (06) 1249-1261
25 Zhang Y, Lian Y, Xie N. Early onset epileptic encephalopathy with a novel GABRB3 mutation treated effectively with clonazepam: a case report. Medicine (Baltimore) 2017; 96 (50) e9273
26 Pavone V, Signorelli SS, Praticò AD. et al. Total hemi-overgrowth in pigmentary mosaicism of the (hypomelanosis of) Ito type: eight case reports. Medicine (Baltimore) 2016; 95 (10) e2705
27 Pavone P, Falsaperla R, Ruggieri M, Praticò AD, Pavone L. West syndrome treatment: new roads for an old syndrome. Front Neurol 2013; 4: 113
28 Falsaperla R, Perciavalle V, Pavone P. et al. Unilateral eye blinking arising from the ictal ipsilateral occipital area. Clin EEG Neurosci 2016; 47 (03) 243-246
29 Incorpora G, Pavone P, Castellano-Chiodo D, Praticò AD, Ruggieri M, Pavone L. Gelastic seizures due to hypothalamic hamartoma: rapid resolution after endoscopic tumor disconnection. Neurocase 2013; 19 (05) 458-461
30 Sorge G, Ruggieri M, Polizzi A, Scuderi A, Di Pietro M. Short syndrome: a new case with probable autosomal dominant inheritance. Am J Med Genet 1996; 61 (02) 178-181
31 Ruggieri M, Milone P, Pavone P. et al. Nevus vascularis mixtus (cutaneous vascular twin nevi) associated with intracranial vascular malformation of the Dyke-Davidoff-Masson type in two patients. Am J Med Genet A 2012; 158A (11) 2870-2880
32 Ruggieri M, Iannetti P, Pavone L. Delineation of a newly recognized neurocutaneous malformation syndrome with “cutis tricolor”. Am J Med Genet A 2003; 120A (01) 110-116
33 Carvill GL, Weckhuysen S, McMahon JM. et al. GABRA1 and STXBP1: novel genetic causes of Dravet syndrome. Neurology 2014; 82 (14) 1245-1253
34 Lachance-Touchette P, Brown P, Meloche C. et al. Novel α1 and γ2 GABAA receptor subunit mutations in families with idiopathic generalized epilepsy. Eur J Neurosci 2011; 34 (02) 237-249
35 Galanopoulou AS. Mutations affecting GABAergic signaling in seizures and epilepsy. Pflugers Arch 2010; 460 (02) 505-523
36 Macdonald RL, Kang J-Q, Gallagher MJ. Mutations in GABAA receptor subunits associated with genetic epilepsies. J Physiol 2010; 588 (Pt 11): 1861-1869
37 Mizielinska S, Greenwood S, Connolly CN. The role of GABAA receptor biogenesis, structure and function in epilepsy. Biochem Soc Trans 2006; 34 (Pt 5): 863-867
38 Cossette P, Liu L, Brisebois K. et al. Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat Genet 2002; 31 (02) 184-189
39 Liu J, Tong L, Song S. et al. Novel and de novo mutations in pediatric refractory epilepsy. Mol Brain 2018; 11 (01) 48
40 Ruggieri M, Pavone V, De Luca D, Franzò A, Tiné A, Pavone L. Congenital bone malformations in patients with neurofibromatosis type 1 (Nf1). J Pediatr Orthop 1999; 19 (03) 301-305
41 Ruggieri M, Praticò AD, Serra A. et al. Childhood neurofibromatosis type 2 (NF2) and related disorders: from bench to bedside and biologically targeted therapies. Acta Otorhinolaryngol Ital 2016; 36 (05) 345-367
42 Cain SM, Garcia E, Waheed Z, Jones KL, Bushell TJ, Snutch TP. GABA_B receptors suppress burst-firing in reticular thalamic neurons. Channels (Austin) 2017; 11 (06) 574-586
43 Nishimura T, Schwarzer C, Gasser E, Kato N, Vezzani A, Sperk G. Altered expression of GABA(A) and GABA(B) receptor subunit mRNAs in the hippocampus after kindling and electrically induced status epilepticus. Neuroscience 2005; 134 (02) 691-704
44 Chen X, Liu F, Li JM. et al. Encephalitis with antibodies against the GABA_B receptor: seizures as the most common presentation at admission. Neurol Res 2017; 39 (11) 973-980
45 Vitaliti G, Pavone P, Guglielmo F, Spataro G, Falsaperla R. The immunomodulatory effect of probiotics beyond atopy: an update. J Asthma 2014; 51 (03) 320-332
46 Della Mina E, Borghesi A, Zhou H. et al. Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts. Proc Natl Acad Sci U S A 2017; 114 (04) E514-E523
47 Vita G, Migliorato A, Baradello A. et al. Expression of cytoskeleton proteins in central core disease. J Neurol Sci 1994; 124 (01) 71-76
48 Han HA, Cortez MA, Snead III OC. GABAB receptor and absence epilepsy. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV. eds. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th ed.. Bethesda (MD): National Center for Biotechnology Information (US); 2012
49 Kalinichev M, Girard F, Haddouk H. et al. The drug candidate, ADX71441, is a novel, potent and selective positive allosteric modulator of the GABA_B receptor with a potential for treatment of anxiety, pain and spasticity. Neuropharmacology 2017; 114: 34-47
50 Møller RS, Wuttke TV, Helbig I. et al. Mutations in GABRB3: From febrile seizures to epileptic encephalopathies. Neurology 2017; 88 (05) 483-492
51 Salpietro V, Mankad K, Kinali M. et al. Pediatric idiopathic intracranial hypertension and the underlying endocrine-metabolic dysfunction: a pilot study. J Pediatr Endocrinol Metab 2014; 27 (1-2): 107-115
52 Kodera H, Ohba C, Kato M. et al. De novo GABRA1 mutations in Ohtahara and West syndromes. Epilepsia 2016; 57 (04) 566-573
53 Pratico AD, Longo L, Mansueto S. et al. Off-label use of drugs and adverse drug reactions in pediatric units: a prospective, multicenter study. Curr Drug Saf 2018; 13 (03) 200-207
54 Pratico AD, Ruggieri M, Falsaperla R, Pavone P. A probable topiramate-induced limbs paraesthesia and rigid fingers flexion. Curr Drug Saf 2018; 13 (02) 131-136
55 Praticò AD, Pavone P, Scuderi MG. et al. Symptomatic hypocalcemia in an epileptic child treated with valproic acid plus lamotrigine: a case report. Cases J 2009; 2: 7394
56 Ruggieri M, Polizzi A, Marceca GP, Catanzaro S, Praticò AD, Di Rocco C. Introduction to phacomatoses (neurocutaneous disorders) in childhood. Childs Nerv Syst 2020; 36 (10) 2229-2268
57 Maljevic S, Krampfl K, Cobilanschi J. et al. A mutation in the GABA(A) receptor alpha(1)-subunit is associated with absence epilepsy. Ann Neurol 2006; 59 (06) 983-987
58 Johannesen K, Marini C, Pfeffer S. et al. Phenotypic spectrum of GABRA1: From generalized epilepsies to severe epileptic encephalopathies. Neurology 2016; 87 (11) 1140-1151
59 Allen AS, Berkovic SF, Cossette P. et al; Epi4K Consortium, Epilepsy Phenome/Genome Project. De novo mutations in epileptic encephalopathies. Nature 2013; 501 (7466): 217-221
60 Durant CF, Paterson LM, Turton S. et al. Using baclofen to explore GABA-B receptor function in alcohol dependence: insights from pharmacokinetic and pharmacodynamic measures. Front Psychiatry 2018; 9: 664