Which are the causes of Unverricht-Lundborg Disease?

TL;DR: Unverricht-Lundborg disease (ULD) is a rare, inherited form of progressive myoclonus epilepsy caused by mutations in the CSTB gene, which codes for the protein cystatin B. This genetic disruption leads to the progressive loss of specific brain cells, resulting in the hallmark symptoms of involuntary muscle jerks and seizures.

What is the genetic cause of Unverricht-Lundborg disease?

The primary cause of Unverricht-Lundborg disease is a mutation in the CSTB gene located on chromosome 21q22.3. In most individuals with Unverricht-Lundborg disease, the mutation involves an expansion of a "dodecamer repeat" (a sequence of 12 DNA building blocks) within the gene's promoter region. While healthy individuals typically have 2 to 3 of these repeats, those with Unverricht-Lundborg disease often carry 30 to over 100 repeats, which prevents the body from producing enough functional cystatin B protein.

How does the lack of cystatin B affect the brain?

Cystatin B acts as a "protease inhibitor," essentially acting as a housekeeper that prevents certain enzymes from over-activating and damaging cells. In Unverricht-Lundborg disease, the deficiency of this protein leads to the following mechanisms:

• Neurodegeneration: The brain becomes more susceptible to oxidative stress, leading to the gradual loss of neurons in the cerebellum and cerebral cortex.


• Hyperexcitability: The imbalance of neural signals causes the brain to become hypersensitive to sensory stimuli, which triggers the characteristic myoclonus (involuntary muscle twitches).


• Inflammatory response: Research suggests that the lack of cystatin B may trigger a chronic neuroinflammatory response, further contributing to the progression of Unverricht-Lundborg disease.

Is Unverricht-Lundborg disease hereditary?

Yes, Unverricht-Lundborg disease is inherited in an autosomal recessive pattern. This means that an affected individual must inherit one mutated copy of the CSTB gene from each parent. Parents who are carriers of the mutation typically do not show symptoms of the disease themselves, but there is a 25% chance for each child of two carrier parents to develop the condition.

What is the current status of research into the etiology?

While the genetic basis of Unverricht-Lundborg disease is well-understood, scientists are currently focusing on how to restore cystatin B function or mitigate the downstream effects of its absence. Current research is investigating potential therapies to reduce neuroinflammation and stabilize neuronal activity to improve the quality of life for our 19 community members at DiseaseMaps.org living with this condition.

Next steps

• Consult with a clinical geneticist to discuss family planning and carrier testing.


• Speak with a neurologist specializing in epilepsy to manage myoclonus and seizure triggers.


• Join the DiseaseMaps.org community to connect with others sharing their experiences with Unverricht-Lundborg disease.

Medical disclaimer: This content is for informational purposes only and does not constitute professional medical advice, diagnosis, or treatment; always seek the guidance of a qualified physician regarding any medical condition.

References

• NIH Genetic and Rare Diseases Information Center (GARD): Unverricht-Lundborg disease.


• Orphanet: Progressive myoclonus epilepsy, Unverricht-Lundborg type.


• OMIM (Online Mendelian Inheritance in Man): Cystatin B (CSTB) gene entry.