Lafora's disease, a rarely explained 'déjà vu' story
By Edwige Smague
INTRODUCTION
Before the onset of adolescence, children affected by Lafora's disease lead a conventional life, hanging out with their friends and attending school independently. The first symptoms appear around 13 or 14, followed by the first seizures. Over time, symptoms worsen, and cognitive faculties decline [1].
Description of symptoms
Lafora's disease is a rare form of very aggressive epilepsy, the origin of which is now known, caused by a genetic mutation [2]. It is transmitted in an autosomal recessive manner, meaning both parents must carry the mutated gene for their child to develop the disease. It results in prolonged and frequent seizures, causing significant brain damage and leading to irreversible cognitive and motor deficiencies. For example, affected children report unusual symptoms, including déjà-vu experiences, altered perception of time and out-of-body experiences. Some patients report visual and auditory hallucinations, as well as episodes of blurred vision or flickering lights. These symptoms are caused by microscopic deposits called Lafora's bodies, which accumulate in the brain and disrupt normal brain function [3] [4].
The condition develops over a long period, and patients survive into adulthood, developing clinical signs and symptoms such as psychosis with prolonged bouts of agitation and screaming, spasticity and hyperreflexia, confusion, mutism and incontinence.
Diagnosis and treatment
Over time, patients can no longer eat, move or feed themselves. Generally, patients have a life expectancy of no more than ten years after the onset of the first symptoms.
Despite its seriousness, Lafora's disease remains poorly understood, with a worldwide prevalence of only four cases per million [5]. Diagnosis is difficult due to its rarity and the need for more awareness among healthcare professionals. However, biopsies of the skin under the armpit (axillary skin) can confirm the diagnosis [6].
Treatment is generally palliative and consists of treating and controlling epileptic seizures when they are present. The only treatment currently available is limited to anti-epileptic and antimyoclonic drugs to prevent symptoms. In any case, these treatments do not halt the progression of the disease. Most patients succumb to complications within ten years due to degeneration of the central nervous system [7]. Lafora's disease affects not only the patient but also the whole family. The individual's emotional burden is gigantic, and the person assisting the patient needs to develop a range of strategies for dealing with the progression of the disease. Contacting associations is often a source of support for the whole family.
Gene therapy as a solution?
Recent research has brought new hope for the treatment of Lafora's disease through the application of gene therapy.
In an attempt to counteract the disease's effects, scientists explored gene therapy by administering intracerebroventricular injections of a recombinant adeno-associated virus carrying the human EPM2A gene. This restored certain functions to the damaged pathways.
This treatment reduced epileptic activity, neuronal hyperexcitability and the formation of Lafora's bodies. The studies showed positive changes in the molecular pathways altered by the disease, suggesting that gene therapy could be the key to modifying its progression.
However, although the results prove that the principle that gene therapy can be used to treat Lafora's disease is significant, these tests are still at an experimental stage [8].
Conclusion
Lafora's disease is distinguished from other forms of epilepsy by its rapid progression, its genetic origins, its resistance to treatment and the rapid cognitive decline that accompanies it. As researchers continue to search for a cure, the battle against this fatal disease continues, and families have only limited hope for the future [9].In any case, genetic diagnosis is a crucial step in the management of epilepsy.
REFERENCES
[1] brahim F, Murr NI. Lafora's Disease [National Library of Medicine]
[2]B. Murray, MS, K. Schmidt, MS, B. Tucker, MS, M.A. Campion, EdD, MS, and R. J. Levy MD. Stanford University Report (2023) [National Organization for rare disorders], [Science Direct]
[3]Turnbull, J., Tiberia, E., Striano, P., Genton, P., Carpenter, S., Ackerley, C. A., & Minassian, B. A. (2016). Lafora's disease. [National Library of Medicine]
[4]Panayiotopoulos, C. P. (2010). A clinical guide to epileptic syndromes and their treatment. [Springer]
[5]Turnbull, J., Tiberia, E., Striano, P., Genton, P., Carpenter, S., Ackerley, C. A., & Minassian, B. A. (2016). Lafora's disease. Epileptic disorders : international epilepsy journal with videotape, 18(S2), 38–62 [PubMed]
[6] Busard HL, Gabreëls-Festen AA, Renier WO, Gabreëls FJ, Stadhouders AM. Axilla skin biopsy: a reliable test for the diagnosis of Lafora's disease. Ann Neurol. 1987 Jun;21(6):599-601[PubMed]
[7]Pondrelli, F., Muccioli, L., Licchetta, L., Mostacci, B., Zenesini, C., Tinuper, P., Vignatelli, L., & Bisulli, F. (2021). Natural history of Lafora's disease: a prognostic systematic review and individual participant data meta-analysis. Orphanet journal of rare diseases, 16(1), 362 [PubMed]
[8]EPM2A EPM2A glucan phosphatase, laforin[Homo sapiens] Gene ID: 7957, updated on 19-Sep-2024 [NCBI]
[9] Ibrahim F, Murr NI. Lafora's Disease. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2024 Jan-[NIH].
