Project Details
Description
Variants (also known as mutations) in genes encoding γ- aminobutyric acid type A receptors (GABAAR) can cause range of epilepsies and neurodevelopmental disorders. GABAARs are the primary receptors mediating inhibitory neurotransmission in both the developing and adult brain. There are nineteen genes encoding subunits that make up GABAARs (termed α1-6, β1-3, γ1-3, δ, ε, π, θ, and ρ1-3). These subunits mix and match to form pentameric channels, with the most common composed of two α’s, two β’s and a γ2 subunit that are located predominantly at the connections between neurons that mediate inhibition. Each receptor subtype has a distinct cellular and regional distribution to regulate neurophysiological responses such as movement, learning, memory processes amongst other functions. Thus, mutations in individual subunits can cause a wide range of neuronal dysfunction.
To date most studies of GABAAR variants have concluded that these result in loss-of-function (LOF) of the affected GABAAR proteins which means that the GABAAR has a reduced activity/function (less inhibition). We recently discovered that the functional assessment of disease causing variants led to an equal distribution of loss- and gain-of-function (hyperactive receptor that leads to a higher neuronal inhibition). It is currently unknown how increased GABAAR function leads to developmental encephalopathies with epilepsy. We discovered that patients’ symptoms were linked to the functional evaluation of the variants and that gain variants are associated with more severe forms of treatment-resistant epilepsy.
Clinical and functional characterization of GABAA-receptor related disorders:
Translating genetic diagnostics into personalized treatment
Project ID: EMN-2024-01998
In the present study, we aim to explore the clinical manifestations associated with LoF or GoF variants in GABAAR genes (GABRA1, GABRA2, GABRA3, GABRA5, GABRB1, GABRB2, GABRB3, GABRG2, GABRD). These genes have been associated with a wide spectrum of neurological manifestations: Cognitively the patients can vary from having normal intelligence to various degrees of intellectual disability (ID), and their epilepsy can present from febrile seizures, treatable generalized or focal epilepsies to developmental encephalopathy with epilepsy. Furthermore, behavioral disturbances, neuropsychiatric disorder and movement disorders are frequently observed.
Purpose of the study
The main objectives of this research project are to:
1) Extensively describe clinical characteristics (signs and symptoms) and genetic correlations of patients with GABAAR related disorders. This will help describing the natural history of GABAAR-related disorders, identifying outcome measures and set up the basis for drug trial readiness.
2) Determine if there are specific findings (biomarkers) in tests (such as brain scans or EEGs) that would help clinicians and treating physicians recognizing this disorder rapidly.
3) Find commonalities and differences regarding symptoms, treatment response and test results between patients with variants in different GABAAR genes.
4) Provide patients, families, and treating teams insights on clinical variables and possible future treatment perspectives of GABAA-receptor related disorders.
We will receive detailed clinical information from families and treating physicians. Data will be stored in a pseudo-anonymized database, only accessible to members of the research team at the Danish Epilepsy Centre, Filadelfia.
To date most studies of GABAAR variants have concluded that these result in loss-of-function (LOF) of the affected GABAAR proteins which means that the GABAAR has a reduced activity/function (less inhibition). We recently discovered that the functional assessment of disease causing variants led to an equal distribution of loss- and gain-of-function (hyperactive receptor that leads to a higher neuronal inhibition). It is currently unknown how increased GABAAR function leads to developmental encephalopathies with epilepsy. We discovered that patients’ symptoms were linked to the functional evaluation of the variants and that gain variants are associated with more severe forms of treatment-resistant epilepsy.
Clinical and functional characterization of GABAA-receptor related disorders:
Translating genetic diagnostics into personalized treatment
Project ID: EMN-2024-01998
In the present study, we aim to explore the clinical manifestations associated with LoF or GoF variants in GABAAR genes (GABRA1, GABRA2, GABRA3, GABRA5, GABRB1, GABRB2, GABRB3, GABRG2, GABRD). These genes have been associated with a wide spectrum of neurological manifestations: Cognitively the patients can vary from having normal intelligence to various degrees of intellectual disability (ID), and their epilepsy can present from febrile seizures, treatable generalized or focal epilepsies to developmental encephalopathy with epilepsy. Furthermore, behavioral disturbances, neuropsychiatric disorder and movement disorders are frequently observed.
Purpose of the study
The main objectives of this research project are to:
1) Extensively describe clinical characteristics (signs and symptoms) and genetic correlations of patients with GABAAR related disorders. This will help describing the natural history of GABAAR-related disorders, identifying outcome measures and set up the basis for drug trial readiness.
2) Determine if there are specific findings (biomarkers) in tests (such as brain scans or EEGs) that would help clinicians and treating physicians recognizing this disorder rapidly.
3) Find commonalities and differences regarding symptoms, treatment response and test results between patients with variants in different GABAAR genes.
4) Provide patients, families, and treating teams insights on clinical variables and possible future treatment perspectives of GABAA-receptor related disorders.
We will receive detailed clinical information from families and treating physicians. Data will be stored in a pseudo-anonymized database, only accessible to members of the research team at the Danish Epilepsy Centre, Filadelfia.
Key findings
GABA-A receptor related disorders
Layman's description
The aim of our research project is to collect data on the clinical signs/symptoms and the development of GABAAR-associated disorders in order to obtain as detailed knowledge as possible on these disorders. The results of this study will serve as a basis for evaluating the effects of novel therapeutic approaches that are currently in development.
Given that GABAAR-associated disorders are very rare diseases, our research project aims to include patients at several centers worldwide in order to enroll as many patients as possible with GABAAR-associated disorders. In Denmark, the Department of Epilepsy Genetics and Personalized Medicine at the Danish Epilepsy Centre, Filadelfia is the leading study center.
Given that GABAAR-associated disorders are very rare diseases, our research project aims to include patients at several centers worldwide in order to enroll as many patients as possible with GABAAR-associated disorders. In Denmark, the Department of Epilepsy Genetics and Personalized Medicine at the Danish Epilepsy Centre, Filadelfia is the leading study center.
| Status | Not started |
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