Voor het Angelman Syndroom

Flumazenil Positron Emission Tomography Analyses of Brain

[11C]Flumazenil Positron Emission Tomography Analyses of Brain Gamma-Aminobutyric Acid Type A Receptors in Angelman Syndrome

Related paper: Decreased binding of [11C] ?umazenilin Angelman syndrome patients with GABA-A receptor beta-3 subunit deletions. Holopainen IE, et al. Ann Neurol 2001;49:110-3

This paper investigates the GABA-A receptor properties in AS patients. GABA is an inhibiting neurotransmitter* often implicated in epilepsy: a reduced level of inhibition may cause epilepsy. The GABA interest in AS is not only coming from the epilepsy point of view, but also because "deletion positive" AS patients (which involves 4 out of every 5 AS patients) do not only lack the Ube3a gene, but also lack the genes for certain parts of the GABA-A receptor*. It has been speculated that this is the reason why the epilepsy phenotype in these patients is often more severe as compared to AS patients with an Ube3A mutation.

With [11C] Flumazenil Positron Emission Tomography, it can be established whether the total number of GABA receptors is indeed decreased in brains of AS patients. A (small) previous study (see Holopainen, 2001) indicated that this is indeed the case. However, this study by Asahina found no evidence for that. If anything it appeared that the amount of GABA-A receptors was increased. However, it should be noted that the number of investigated patients is again very small (7), so it is hard to draw firm conclusions from either study. It is also complicated by the fact that the patients take seizure medication, so it is hard to establish a clear cause and effect, and that the age of the patients varies from 6 to 30.

What can we learn from these two contradicting studies? It is likely that GABA-A receptor functioning in AS patients is not severely affected. If there is any significant contribution of these receptors to the AS phenotype (of deletion positive patients), then it is most likely during brain development, which occurs at a far younger age than the tested subjects. Furthermore it should be noted that the patient with the Ube3a mutation was not different from the deletion positive patients. Taken together, this emphasizes that investigating the role of the Ube3a gene, rather than the neighboring GABA genes is the best way to understand the core mechanisms underlying AS.

Glossary:Neuron: Neurons (also known as neurones and nerve cells) are responsive cells in the nervous system that process and transmit information by chemical signals.
Neurotransmitter: chemical used by neurons to communicate from neuron to neuron. The most common neurotransmitters are glutamate (which excites its target neuron) and GABA, which inhibits is target neuron.
Receptor (GABA-A): protein on the outside of a neuron that binds to a signaling chemical, in this case to GABA.

Authors: Naoko Asahina, Tohru Shiga, Kiyoshi Egawa, Hideaki Shiraishi and Shinji Saitoh

Journal: J Pediatr. 2008 Apr;152(4):546-9
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