Lafora disease
Encyclopedia
Lafora disease, also called Lafora progressive myoclonic epilepsy or MELF http://www.rightdiagnosis.com/medical/melf.htm, is a fatal autosomal recessive
Recessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...

 genetic disorder
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....

 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.

Statistics

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.

Causes

Lafora disease is an autosomal recessive disorder, caused by mutations in one of two known genes, EPM2A and EPM2B. 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. EPM2B encodes the protein malin, an E3 ubiquitin ligase
Ubiquitin ligase
A ubiquitin ligase is a protein that in combination with an E2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein via an isopeptide bond; the E3 ubiquitin ligase targets specific protein substrates for degradation by the proteasome...

. At least one other gene is thought to contribute to the disease. Both discovered genes are present on chromosome 6 in humans.

Lafora Bodies

Lafora disease is distinguished by the presence of inclusions called "Lafora bodies" within the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...

, the viscous fluidic matrix inside of cells. Lafora bodies are composed of abnormal glycogen called polyglucosans. 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.

Presentation

Patients develop the first symptoms mainly during adolescence
Adolescence
Adolescence is a transitional stage of physical and mental human development generally occurring between puberty and legal adulthood , but largely characterized as beginning and ending with the teenage stage...

. Major problems include seizures, drop attacks, myoclonus
Myoclonus
Myoclonus is brief, involuntary twitching of a muscle or a group of muscles. It describes a medical sign and, generally, is not a diagnosis of a disease. Brief twitches are perfectly normal. The myoclonic twitches are usually caused by sudden muscle contractions; they also can result from brief...

, ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...

, and, most significantly, a quickly developing, progressive and severe dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...

.

Eponym

The disease is named after Gonzalo Rodriguez Lafora
Gonzalo Rodriguez Lafora
Gonzalo Rodríguez-Lafora was a Spanish neurologist. He was best known now for describing the intracytoplasmic inclusion bodies in "Lafora disease". In total, he published approximately 200 papers covering a wide range of subjects in neurology, psychiatry, and neuropathology...

 (1886–1971), a Spanish neuropathologist who first recognized small inclusion bodies in Lafora patients.

Diagnosis

Diagnosis
Medical diagnosis
Medical diagnosis refers both to the process of attempting to determine or identify a possible disease or disorder , and to the opinion reached by this process...

 is based on the demonstration of Lafora bodies within the apocrine sweat gland
Sweat gland
Sweat glands, or sudoriferous glands, are small tubular structures of the skin that produce sweat. There are two kinds of sweat glands:...

 of the skin
Human skin
The human skin is the outer covering of the body. In humans, it is the largest organ of the integumentary system. The skin has multiple layers of ectodermal tissue and guards the underlying muscles, bones, ligaments and internal organs. Human skin is similar to that of most other mammals,...

 by an axillary skin biopsy
Biopsy
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...

 examination. The inclusion bodies, which seem to contain high levels of carbohydrate
Carbohydrate
A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...

s, are typically labeled by a specific stain called PAS (Periodic acid-Schiff
Periodic acid-Schiff
Periodic acid-Schiff is a staining method used to detect glycogen and other polysaccharides in tissues. The reaction of periodic acid oxidizes the diol functional groups in glucose and other sugars, creating aldehydes that react with the Schiff reagent to give a purple-magenta color...

) which is resistant to diastase
Diastase
A diastase is any one of a group of enzymes which catalyses the breakdown of starch into maltose. Alpha amylase degrades starch to a mixture of the disaccharide maltose, the trisaccharide maltotriose, which contains three α -linked glucose residues, and oligosaccharides known as dextrins that...

 treatment. Under strong clinical suspicion, liver and brain biopsies may be undertaken. Currently the preferred method of certain diagnosis is DNA sequencing
DNA sequencing
DNA sequencing includes several methods and technologies that are used for determining the order of the nucleotide bases—adenine, guanine, cytosine, and thymine—in a molecule of DNA....

.

Pathophysiology

Current understanding of pathophysiology is largely restricted to understanding the generation of Lafora bodies, and their exclusive appearance in neurons and not in astrocytes.

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.

Prognosis

There is no treatment, and therapy is mainly supportive and symptomatic
Symptomatic treatment
Symptomatic treatment is any medical therapy of a disease that only affects its symptoms, not its cause, i.e., its etiology. It is usually aimed at reducing the signs and symptoms for the comfort and well-being of the patient, but it also may be useful in reducing organic consequences and sequelae...

. 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. One medication, 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.

External links

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