Lafora disease is caused by specific genetic mutations that disrupt the normal function of cellular proteins.
Understanding Lafora Disease
Lafora disease is a rare, progressive form of epilepsy characterized by seizures, muscle spasms, and cognitive decline. The underlying cause is a problem with how the body processes glycogen, a form of sugar stored for energy. Specifically, it stems from issues with two key proteins: laforin and malin.
The Genetic Basis of Lafora Disease
Lafora disease arises from loss-of-function mutations in EPM2A or NHLRC1, which encode laforin and malin, respectively.
- EPM2A Gene: Mutations in this gene lead to problems with the production of laforin.
- NHLRC1 Gene: Mutations in this gene affect the production of malin.
When either of these proteins is absent or not functioning correctly, it leads to the accumulation of abnormal glycogen deposits called Lafora bodies.
How Laforin and Malin Work (or Don't)
Normally, laforin and malin work together to regulate glycogen synthesis and prevent it from becoming excessive or abnormally structured. Specifically:
- They ensure glycogen is properly branched.
- They prevent glycogen from becoming hyperphosphorylated (having too many phosphate groups attached).
When laforin or malin are missing or defective, the result is:
- Poorly Branched Glycogen: The glycogen structure is not properly formed.
- Hyperphosphorylated Glycogen: The glycogen has excessive phosphate groups attached.
- Lafora Body Formation: This abnormal glycogen precipitates (comes out of solution), aggregates (clumps together), and accumulates within cells, forming Lafora bodies.
Consequences of Lafora Body Accumulation
The accumulation of Lafora bodies disrupts normal cell function, particularly in the brain, leading to the symptoms of Lafora disease.
Summary Table
| Protein | Gene | Function | Result of Deficiency |
|---|---|---|---|
| Laforin | EPM2A | Regulates glycogen synthesis and branching. | Poorly branched, hyperphosphorylated glycogen. |
| Malin | NHLRC1 | Works with laforin to regulate glycogen. | Poorly branched, hyperphosphorylated glycogen. |
| Lafora body formation and cellular dysfunction. |
