Genetics and Diagnostic Testing for FTLE

Diagnosing familial temporal lobe epilepsy (FTLE) is like solving a puzzle where the pieces come from your symptoms, your brain’s electrical activity, and your family tree ^[1]. Because your brain structure may look perfectly healthy on standard scans, the diagnosis relies heavily on the “story” of your family history ^[2].

The Genetic Landscape

It is helpful to think of FTLE genetics in two ways: monogenic (caused by a single gene variant) and polygenic (caused by many genetic variations) ^[1].

Monogenic Causes (The Single Switch)

In some families, a single “glitch” in one gene drives the seizures. If a parent has a confirmed heterozygous pathogenic autosomal dominant variant, there is a 50% chance of passing that gene to each child ^[3]. Key genes include:

• LGI1 and RELN: These genes are found in some families who experience auditory symptoms (hearing sounds or voices) ^[4][5].
• DEPDC5, NPRL2, and NPRL3: These belong to the GATOR1 complex, which helps regulate cell growth in the brain. Variants here are broader familial focal epilepsy genes that can cause a variety of focal seizures ^[6][7].

Polygenic Causes (The Complex Map)

For many other families, especially those with mesial symptoms (like déjà vu), there isn’t one single known “seizure gene.” Instead, they may have inherited a collection of many small genetic traits (polygenic risk) ^[1]. Note that polygenic risk scores are currently a research concept and not established as routine clinical tests for diagnosing patients.

The Concept of Incomplete Penetrance

One of the most confusing parts of genetic epilepsy is incomplete penetrance. This means that even if you inherit a pathogenic gene variant, you might never actually have a seizure ^[8].

In some FTLE families, penetrance is variable ^[8][9]. Because of this, absence of seizures does not rule out carrier status—your parent might carry the gene but simply never had a seizure ^[10].

Standard Diagnostic Tools

To confirm a diagnosis of FTLE, your care team will use several tools:

1. 3-Generation Family History: This is a crucial tool. Your doctor will ask about parents, siblings, children, aunts, uncles, and grandparents to look for a pattern of seizures or “spells” ^[1].
2. High-Resolution MRI: Doctors use a specific “epilepsy protocol” MRI to look for tiny changes, such as hippocampal sclerosis (scarring in the memory center) ^[1]. However, in many types of FTLE, the MRI is completely normal because the issue is in electrical communication, not visible structure ^[1][11].
3. Video-EEG: This test records your brain’s electrical activity and your physical movements at the same time. It is a central tool for seeing where a seizure starts ^[12]. However, a routine scalp EEG or even video-EEG can sometimes miss deep mesial temporal seizures unless a typical event is captured, or invasive monitoring is used.
4. Neuropsychological Testing: These are memory and language “puzzles.” Normal memory scores do not rule out epilepsy ^[11].

The Role of Genetic Testing

Genetic testing is increasingly recommended for people with focal epilepsy and a family history ^[13].

• Why Test? Finding a specific gene can sometimes help confirm the diagnosis and inform family risk assessment. While it occasionally influences medication choices, genetic testing in FTLE is usually more useful for counseling than for picking a specific drug ^[14].
• Genetic Counseling: Before testing, it is vital to speak with a genetic counselor. They can explain what results might mean for you and your relatives ^[15][13].
• Variants of Uncertain Significance (VUS): Testing may reveal a VUS. A VUS should not be used to guide treatment or predictive testing for relatives.
• A “Negative” Result: A negative genetic test simply means a known mutation wasn’t found; it does not rule out familial epilepsy ^[1]. The diagnosis is based on your full clinical picture.