Lafora Disease - A Disease In Need Of A Cure

Lafora Disease or Lafora Body Disease is a form of progressive myoclonic epilepsy (PME). It has been named after the Spanish Pathologist, Gonzalo Rodriguez Lafora, the discoverer of the microscopic findings in this disease. It is a fatal condition with few surviving beyond the age of 25 years. It is inherited in an autosomal recessive pattern.

The underlying pathology resulting in the clinical picture is that of neurological degeneration. However, the basic etiopathogenesis of this condition is a defect in the metabolism of Glycogen.

Loss of Function(LOF) mutations in laforin glycogen phosphatase gene (EPM2A) or Malin E3 ubiquitin ligase gene (NHLRC1) are deemed responsible for the initiation of the deleterious effects. Laforin is a protein that cleaves off phosphate from glycogen thereby regulating the level of glycogen phosphorylation in cells. Malin in-turn controls the level of production of Laforin.

The sequence of events can be summarized as follows:

Loss of Function(LOF) mutation in EMP2A and NHLRC1 genes

Reduced or absent Malin and Laforin protein levels

Excessive Glycogen Phosphorylation due to loss of regulation

Conformational change in Glycogen rendering it insoluble – called Polyglucosans

Neurotoxic effects

Clinical features

Overactivity of Glycogen Synthase has also been postulated in the pathogenesis of this disease.

Clinical features of this disease begin to present around adolescence and death usually occurs within 10 years of their onset. There usually is no evident feature noted in the first decade of life. The usual presentation consists of Myoclonic Seizures, sometimes with Generalized Tonic-Clonic Convulsions, Absence and Atonic Seizures. Visual hallucinations, blindness, ataxia with rapidly progressing dementia are also presenting features seen. Later on, these patients may have generalized confusion, speech defects, impaired memory and mental dulling. Features of Cerebellar involvement such as tremors, gait disturbances may occur.

Demonstration of aggregates of Polyglucosan – namely Lafora Bodies is considered pathognomonic. Skin biopsy is the preferred method for diagnosis and shows PAS-positive inclusions in peripheral cells of eccrine sweat ducts, axillary apocrine sweat glands or peripheral nerves. Electron microscopy reveals fine pale staining filaments, fine dark-staining granules, and dark-rimmed vacuoles within these non-membrane-bound inclusions. Lafora Bodies have also been demonstrated in the Thyroid gland, Pituitary, Liver, Heart.

No permanent cure has been devised for this condition, unfortunately. The treatment focuses on the prevention of the occurrence of seizures with standard anti-epileptic medication. A recent cohort study conducted in Bologna, Italy has demonstrated the role of Metformin in slowing the progression of the disease, courtesy of its neuroprotective action.

Further developments on this front include targeting genes that regulate glycogen metabolism and altering them favorably. The adipocyte hormone Leptin has also been discussed owing to its role in preventing excessive glucose uptake which could potentially slow down or prevent the formation of Lafora bodies. Researchers expect potential cures in human trials sooner rather than later.

The Lafora Epilepsy Cure Initiative (LECI) funded by the National Institutes of Health has been actively involved in investigating cures for this disease paving way for a brighter future for its sufferers.