Lafora disease

Definition: Lafora disease is an inborn error of carbohydrate metabolism with storage of a polyglucosan in various tissues including brain and liver. Lafora disease is characterized by pathognomonic inclusions, Lafora bodies (LB), in neurons and other cell types.

Lafora disease, also called Lafora progressive myoclonic epilepsy, is a fatal autosomal recessive genetic disorder characterized by the presence of inclusion bodies, known as Lafora bodies, within neurons and the cells of the heart, liver, muscle, and skin.

Most patients with this disease do not live past the age of twenty-five, and death within ten years of symptoms is usually inevitable. At this time there is no cure or treatment for this disease.

Clinical synopsis

Epilepsy occurs in one percent of all humans. Progressive Myoclonic Epilepsies (PME) account for about one percent of all epilepsies. Lafora disease is one of the common PMEs. Symptoms of Lafora disease begin to manifest themselves in children from 10 to 17 years old. Males and females are equally affected.

Patients develop the first symptoms mainly during adolescence. Major problems include seizures, drop attacks, myoclonus, ataxia, and, most significantly, a quickly developing, progressive and severe dementia.

Microscopic synopsis

 brain
 skin

• PAS-positive inclusions (Lafora bodies) in numerous peripheral cells of eccrine sweat ducts, in eccrine sweat glands or in apocrine sweat glands (6796905, 14663053)

 skeletal muscle
 peripheral nerve
 liver: hepatic Lafora disease (2172143)

• ground-glass hepatocytes due to inclusions (Lafora bodies) (2172143)

 heart

• third-degree atrioventricular block (10593553)
• cardiac arrhythmia (10593553)

 Lafora bodies

• Lafora disease is distinguished by the presence of inclusions called "Lafora bodies" within the cytoplasm of cells.
• Lafora bodies are composed of abnormal glycogen called "polyglucosan". These starch-like polyglucosans are insoluble and hence precipitate inside cells.
• Polyglucosan bodies appear with age; in Lafora disease, their numbers have increased enormously.
• Lafora bodies have been observed in virtually all organs of patients with the disease.
• In the brain, their presence appears to be restricted to neurons; they do not seem to present in astrocytes.
• Their morphology varies from tissue to tissue, but they generally contain a central core and have a peripheral fluffy appearance

Differential diagnosis

 Lafora-like bodies (Lafora body like inclusions)

• isolated (2172143)
• alcohol aversion therapy by cyanamide or disulfiram

 type IV glycogenosis (amylopectinosis)

Electron microscopy

 the inclusions consisted of polyglucosan-type material, not bounded by a membrane (6791573)

Etiology

Lafora disease is an autosomal recessive disorder, caused by mutations in one of two known genes, EPM2A and EPM2B. At least one other gene is thought to contribute to the disease. Both discovered genes are present on chromosome 6 in humans.

 germline mutations in the EPM2A gene coding for laforin protein at 6q24

• EPM2A-associated Lafora disease
• EPM2A codes for the protein laforin, a dual specificity phosphatase (DSP) with a carbohydrate binding domain (CBM-20).
• Surprisingly, vertebrates have only one such protein with DSP domain as well as CBM-20 domain.

 germline mutations in the NHLRC1 (EPM2B) gene coding for malin at 6p22.3 (MIM.608072)

• NHLRC1-associated Lafora disease
• NHLRC1 (EPM2B) encodes the protein malin, an E3 ubiquitin ligase.

Pathophysiology

Normal glycogen is soluble in the cellular environment, a fact that has been attributed to its fractal structure.

By contrast, the "abnormal glycogen" in Lafora bodies has an excessive phosphate content and branches at abnormally short intervals. It has been shown that laforin dephosphorylates glycogen and preserves its solubility. Hence, in a laforin mutation glycogen would be hyperphosphorylated. This has been confirmed in laforin knock-out mice.

Research literature suggests that overactivity of glycogen synthase, the key enzyme in synthesizing glycogen, can lead to the formation of polyglucosans.

Glycogen synthase can be inactived by phosphorylation at various amino acid residues by many molecules including GSK-3beta.

Protein Phosphatase-1 can take out these phosphate moieties and make glycogen synthase active.

However, PP-1 needs other proteins like PTG (Protein Targeted to Glycogen) to assist.

Malin, another protein mutated in Lafora disease, aids in the degradation of PTG, with assistance from laforin via the ubiquitin proteasome system (UPS). Hence in a malin mutation, PTG might accumulate and cause excessive glycogen synthase activity leading to abnormal glycogen production. However, this supposition has not been confirmed by animal models.

Neurons, though having a capacity to express glycogen synthase, lack capacity to degrade it. They seem not to have glycogen phosphorylase, which is present in astrocytes to degrade glycogen.

Astrocytes contribute almost exclusively to brain glycogen storage yet do not develop Lafora bodies, a fact which might highlight the importance of the capacity to degrade glycogen.

In a laforin or malin mutation, a laforin-malin complex would cease to exist and drive neurons to make glycogen. This could be detrimental to neuronal function and possibly result in the manifestation of dementia.

Removal of PTG in mice resulted in the near-complete disappearance of polyglucosans and in resolution of neurodegeneration and myoclonic epilepsy

Diagnosis

Diagnosis is based on the demonstration of Lafora bodies within the apocrine sweat gland of the skin by an axillary skin biopsy examination.

The inclusion bodies, which seem to contain high levels of carbohydrates, are typically labeled by a specific stain called PAS (Periodic acid-Schiff) which is resistant to diastase treatment.

Under strong clinical suspicion, liver and brain biopsies may be undertaken.

Currently the preferred method of certain diagnosis is DNA sequencing.

Prognosis

There is no treatment, and therapy is mainly supportive and symptomatic.

Although seizure and myoclonus can be controlled for a long period by using antiepileptic drugs, patients rarely survive beyond one or two decades due to the devastating effects of dementia and ataxia.

Zonisamide has been shown to lengthen the life of those with the disease. This medication helps control and decrease the severity of the seizures affected patients often experience.

Gene therapy strategies are being tried in a mouse model.

History

The disease is named after Gonzalo Rodriguez Lafora (1886–1971), a Spanish neuropathologist who first recognized small inclusion bodies in Lafora patients

References

 Ganesh S, Puri R, Singh S, Mittal S, Dubey D. Recent advances in the molecular basis of Lafora’s progressive myoclonus epilepsy. J Hum Genet. 2005 Nov 26; PMID: 16311711

 Andrade DM, Ackerley CA, Minett TS, Teive HA, Bohlega S, Scherer SW, Minassian BA. Skin biopsy in Lafora disease: genotype-phenotype correlations and diagnostic pitfalls. Neurology. 2003 Dec 9;61(11):1611-4. PMID: 14663053

 Ng IO, Sturgess RP, Williams R, Portmann B. Ground-glass hepatocytes with Lafora body like inclusions—histochemical, immunohistochemical and electronmicroscopic characterization. Histopathology. 1990 Aug;17(2):109-15. PMID: 2172143