Peripheral Markers of the γ-Aminobutyric Acid (GABA)ergic System in Angelman's Syndrome

Abstract

It has recently been demonstrated that patients with Angelman's syndrome who exhibited a deletion on cytogenetic tests show more severe clinical pictures with drug-resistant epilepsy than patients with Angelman's syndrome not carrying the deletion. To verify if this difference in clinical severity can be attributed to genes for the three γ-aminobutyric acid (GABA)_A receptor subunits (GABRB3, GABRA5, GABRG3) located in the deleted region, a possible modification of peripheral markers of the GABAergic system was investigated in 12 subjects with Angelman's syndrome and 20 age-matched subjects (8 with idiopathic epilepsy and 12 not affected by neurologic diseases). The results confirmed a more severe clinical picture, and epilepsy syndrome in particular, in Angelman's syndrome patients with deletions versus patients without deletions. In contrast, biochemical study (based on dosage of plasma levels of GABA and diazepam binding inhibitor, an endogenous ligand of GABA_A and peripheral benzodiazepine receptors, showed contradictory results: patients with Angelman's syndrome showed significantly higher levels of GABA and diazepam binding inhibitor than patients without neurologic impairment but significantly lower levels than epileptic controls. (J Child Neurol 2003; 18: 21—25).

Get full access to this article

View all access options for this article.

References

Zori RT , Hendrickson J. , Woolven S. , et al: Angelman syndrome: Clinical profile. J Child Neurol 1992; 7: 270—280.

Williams CA , Angelman H. , Clayton-Smith J. , et al: Angelman syndrome: Consensus for diagnostic criteria. Am J Med Genet 1995;56: 237—238.

Angelman H. : “ Puppet children”: A report of three cases. Dev Med Child Neurol 1965; 7: 681—688.

Chan Ctj , Clayton-Smith J. , Cheng XJ , et al: Molecular mechanisms in Angelman syndrome: A survey of 93 patients . J Med Genet 1993;30:895—902.

Lalande M. , Minassian BA , DeLorey TM , Olsen RW : Parental imprinting and Angelman syndrome. Adv Neurol 1999; 79: 421—429.

Minassian BA , DeLorey TM , Olsen RW , et al: Angelman syndrome: Correlation between epilepsy phenotypes and genotypes. Ann Neurol 1998;43:485—493.

Nakatsu Y. , Tyndale RF , DeLorey TM , et al: A cluster of three GABA receptor subunit genes is deleted in a neurological mutant of the mouse P locus. Nature 1993;364:448—450.

De Lorey TM , Handforth A. , Anagnostaras SG , et al: Mice lacking the 3 subunit of the GABAA receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome. J Neurosci 1998;18:8505—8514.

Odano I. , Anezaki T. , Ohkubo M. , et al: Decrease in benzodiazepine receptor binding in a patient with Angelman syndrome detected by iodine-123 iomazenil and single emission tomography . Eur J Nucl Med 1996;23:598—604.

10.

Ebert MH , Schmidt DE , Thompson T. , Butler MG : Elevated plasma gamma-amino-butyric acid (GABA) levels in individuals with either Prader-Willi or Angelman syndromes. J Neuropsychiatry Clin Neurosci 1997;9:75—80.

11.

Arteaga R. , Herranz JL , Armijo JA : Platelet GABA-transaminase in epileptic children: Influence of epilepsy and anticonvulsivants. Epilepsy Res 1993;14:73—85.

12.

Erdal J. , Gram L. , Alvin J. , Locher W. : Changes in plasma GABA concentration during vigabatrin treatment of epilepsy: A prospective study. Epilepsy Res 1999;34:145—150.

13.

Engel JJr: A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: Report of the ILAE Task Force on Classification and Terminology . Epilepsia 2001;42:796—803.

14.

Borgatti R. , Piccinelli P. , Passoni D. , et al: Pervasive developmental disorders and GABAergic system in patients with inverted duplicated chromosome 15. J Child Neurol 2001; 16: 911—914.

15.

Ferrarese C. , Cogliati T. , Tortorella R. , et al: Diazepam binding inhibitor (DBI) in the plasma of paediatric and adult epileptic patients. Epilepsy Res 1998;29:129—134.

16.

American Psychiatric Association : Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC, American Psychiatric Press, 65—78.

17.

Viani F. , Romeo A. , Viri M. , et al: Seizure and EEG patterns in Angelman's syndrome. J Child Neurol 1995;10:467—471.

18.

Vezzani A. , Serafini R. , Stasi MA , et al: Epileptogenic activity of two peptides derived from diazepam binding inhibitor after intrahippocampal injection in rats. Epilepsia 1991;32:597—603.

19.

De Long RG : Autism new data suggest a new hypothesis. Neurology 1999;52:911—916.

20.

Rapin I. : Autism in search of a home in the brain. Neurology 1999; 52:902—904.

21.

De Lorey T , Olsen RW : GABA and epileptogenesis: Comparing GABRB3 gene-deficient mice with Angelman syndrome in man. Epilepsy Res 1999;36:123—132.

22.

Cook EH , Courchesne RY , Cox NJ , et al: Linkage disequilibrium mapping of autistic disorder, with 15q11-13 markers. Am J Hum Genet 1998;62:1077—1083.

23.

Bass MP , Menold MM , Wolpert CM , et al: Genetic studies in autistic disorders and chromosome 15. Neurogenetics 1999;2:219—226.

24.

Buxbaum JD , Silverman JM , Smith CJ , et al: Association between a GABRB3 polymorphism and autism. Mol Psychiatry 2002;7: 311—316.

25.

Löscher W. , Gram L. , Stefan H. : Plasma GABA and seizure control with vigabatrin. Lancet 1993;341:117.

26.

Löscher W. , Schmidt D. : Increase of human plasma GABA by sodium valproate. Epilepsia 1980;21:611—615.

27.

Ferrarese C. , Vaccarino F. , Alho H. , et al: Subcellular location and neuronal release of diazepam binding inhibitor (DBI). J Neurochem 1987;48:1093—1102.