Is Mesial Temporal Sclerosis Genetic?
Mesial temporal sclerosis (MTS) has a significant genetic component, with family history being a strong independent predictor, though it is not a simple monogenic disorder but rather a multifactorial condition involving complex gene-environment interactions.
Genetic Predisposition Evidence
The genetic basis of MTS is well-established through multiple lines of evidence:
Family history is a strong predictor: Studies demonstrate that genetic predisposition is an important causal factor for both febrile seizures and MTS, with the relationship between febrile seizures and later epilepsy frequently being genetic in nature 1.
High familial incidence: The genetic predisposition for MTS is clearly suggested by the high incidence of family history in patients with hippocampal sclerosis, and by familial mesial temporal lobe epilepsy (MTLE) with MTS 2.
Compelling genetic evidence exists: There appears to be a strong genetic component that predisposes some individuals to MTS, regardless of whether they experience an initial precipitating injury (IPI) such as prolonged febrile seizures 3.
Multifactorial Nature
MTS is not inherited as a simple genetic disease but involves complex interactions:
Multiple factors required: The "two-hit hypothesis" proposes that MTS development requires both an initial precipitating injury (such as prolonged febrile seizures, CNS infection, or head trauma) AND a second factor that increases vulnerability to neuronal injury 3.
Gene-environment interactions: The association between febrile seizures and temporal lobe epilepsy probably results from complex interactions between several genetic and environmental factors, rather than a single genetic mutation 1.
No single causative factor: It is clear that MTS is multifactorial, and there is no individual pathogenic factor either necessary or sufficient to generate this histopathological condition 2.
Clinical Implications
Understanding the genetic component has practical significance:
Variable penetrance: Some individuals with genetic predisposition may develop MTS following an initial injury, while others with similar injuries but without genetic susceptibility may not develop the condition 3, 1.
Syndrome-specific genes: Recent molecular genetic studies indicate there are several syndrome-specific genes for febrile seizures, which may contribute to later development of MTS 1.
Not purely hereditary: While genetic factors are important, MTS does not follow simple Mendelian inheritance patterns and environmental triggers play a crucial role in disease manifestation 2, 1.
Important Caveats
Contradictory evidence exists: While retrospective studies suggest complex febrile seizures are causative for MTS development, some prospective and retrospective studies have shown contradictory results regarding this relationship 1.
Hippocampal dysgenesis consideration: Hippocampal dysgenesis may account for febrile seizures and possibly MTS in a small subpopulation of patients with temporal lobe epilepsy, though larger studies are needed to confirm these findings 3.
Microdysgenesis not supported: There is currently no compelling evidence to support a role for microdysgenesis in MTS development 3.