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Meet the Children of
Chelsea’s Hope

 

In Memoriam

“Those we have held in our arms for a little while, we hold in our hearts forever.”

A Brief Overview of Lafora Disease

Lafora disease is the most severe form of human epilepsy. It is an inherited myoclonus epilepsy syndrome. Most cases of Lafora disease are caused by mutations in one of two known genes: EMP2A and EMP2B. Both genes are located in chromosome 6. The gene EPM2A makes the protein called Laforin and the gene EPM2B makes the protein called Malin. A few cases of Lafora disease are caused by an as yet unidentified gene(s). The disease most commonly starts as epileptic seizures in adolescence. Rarely, it begins in 5 to 6 year old children as a learning disorder. There is a higher incidence of the disease in children of Middle Eastern, Southern European (Spain, France and Italy), South Asian (India and Pakistan) and North African descent. The disease appears to affect males and females equally. Lafora disease causes seizures, muscle spasms, difficulty walking, dementia, and eventually death.

There is currently no therapy that has proven effective against disease progression. Therapy is primarily palliative and aimed at reducing seizures.

The following is an excerpt from Dr. Berge Minassian who is one of the leading experts in the field of Lafora research.
“The problem facing a Lafora patient is the conversion in brain cells of normal glycogen, a soluble sugar, into a starch-like insoluble sugar. This insoluble compound accumulates in the brain cells and devastates their function. How and why this happened was a great mystery until recently. We have now discovered that the problem is that normal glycogen in the Lafora patients acquires excessive phosphate, and that it is this phosphate that distorts normal glycogen and makes it become starch-like and insoluble. We now are trying very hard to uncover where this excess phosphate comes from, and then we will try to prevent this, or find ways to remove it so as to re-normalize the glycogen and keep it from precipitating and accumulating. If we can do this, we can treat or cure our patients. How long the way is from this point towards a treatment we do not know, but we now know we are on the right track”.

The extent of the disease is devastating. Although the child is born with Lafora, it does not manifest itself until roughly age 14 – 17, although there are cases of younger children having their first grand mal seizures around age 10. That is one of the cruelest things about it. You have a happy, normal, beautiful healthy child who has everything to live for, planning their lives, their careers and their dreams and it is all so cruelly snatched away from them and they are faced with nothing more than a “death sentence”. From manifestation (which is normally the first grand mal seizure) the prognosis is about 3 – 10 years. THERE IS NO CURE.

The Beginnings of Chelsea’s Hope

Chelsea’s Hope Lafora Children Research Fund initially began as a means to share our story with family and friends about what was happening in the life of our daughter, Chelsea. Experiencing her first grand mal seizure at age 14 ½, one month before her 8th grade graduation, our life and everything in it came to a screeching halt. Our family entered an unknown world of fear, devastation, isolation, medical emergencies and immense sadness as we watched our beautiful daughter’s vibrant life begin to slip away. Within 6 months of her first seizure, we received the diagnosis of Lafora Disease. As our neurologist spoke these words, “The test for Lafora disease is positive”….all sights, sounds, emotions, and the promise of a future… faded to BLACK.

To be told “There is no cure” and “There is no group to align with for support and guidance” was unacceptable. We could NOT live this tragedy alone. In this modern age of medical miracles…how could this be? We needed others to share our sorrow with, others who could relate exactly what we and our daughter were experiencing and we needed a miracle.

From a normal healthy child, you have to watch your child losing their independence bit by bit. They start to jerk; sometimes so bad they cannot even hold a cup or feed themselves. Cognitive decline sets in. Normal things like reading and writing are no longer possible. They need help to get dressed. They need help to be fed. Sometimes their legs won’t hold them up so they need aid to walk. There is a delay in their verbal reactions…eventually they speak no more. No medication can stop the jerking and anti epileptic medications are palliative and do not prevent grand mal seizures from wracking their bodies. These symptoms, as they are underlying symptoms of the disease, only get worse and result in status epileptus – uncontrolled seizure after seizure. Swallowing becomes difficult and oral suctioning is necessary. Eventually gastric tubes are put in place so that medication and nutrition can be obtained. Wheelchairs, breathing equipment, compression vests, shower chairs, hoyer lifts, hospital beds, and other equipment become the fixtures in our homes to support our children.

Lafora Disease currently receives very little, if any, funding from the Federal Government, in part, because of its “orphan” disease classification. Due to its rarity and difficulty in obtaining diagnosis, it is currently unknown how many children in the United States and elsewhere are suffering from Lafora Disease.

Dr. Minassian & Chelsea

Chelsea’s Hope Lafora Children’s Research Fund is committed to creating awareness, connecting families, funding Lafora research and maintaining HOPE for all our children so that they may have a chance for a future free of Lafora disease.

Symptoms

Lafora Disease symptoms usually appear in the late stages of childhood and early adolescence. In most cases, patients develop normally for roughly the first ten years of their life. The first symptom to usually manifest is called a tonic-clonic seizure, a seizure that affects the entire body. Tonic-clonic grand mal seizures are characterized by extreme muscle tension and rapid muscle contractions. In other cases, the first symptom may be a seizure, induced by flickering light, characterized by staring for 1-10 seconds (absences or petit mal seizures) with momentary loss of responsiveness and a disconnection with the surrounding environment. Eventually, all develop the characteristic lightning-like muscular jerks that shake the shoulders, arms, legs or body and face. Such quick myoclonic spasms can affect a fragment of muscles in arms and shoulders on one side or both sides of the body and are triggered by touch, light or sound, appear almost continuously and are the reason for calling Lafora Disease a myoclonic epilepsy. Other symptoms include temporary blindness, visual hallucinations, depression, diminishing performance in school, ataxia (difficulty walking), and dementia.

In general, the following are symptoms that may indicate possible Lafora disease. If your child begins to demonstrate the combination of the following symtoms, immediately speak with your child’s doctor about Lafora Disease and about having a skin biopsy and mutation analyses.

Both skin biopsy and mutation analyses are necessary to prove lafora disease.

Why Skin Biopsy:
Biopsy of sweat glands in the axilla (arm pit) should show the disease causing inclusion bodies that stain with PAS (periodic acid schiff) inside eccrine sweat duct cells or apocrine myoepithelial cells located in the arm pits. These inclusion bodies are made of abnormally branched glycogen called polyglucosan and was originally discovered by Gonzalo Lafora in the patients’ brains. This separates Lafora Disease from other progressive myoclonic epilepsies. The presence of PAS+ inclusion bodies means you (your child) have Lafora Disease. If the skin biopsy is negative but you (your child) still have the above symptoms of Lafora Disease, it is reasonable to get a muscle or liver biopsy.

Why Mutation Analyses:
There are two reasons for mutation analyses.

First, PAS+ inclusion bodies may be present in your skin biopsy but mutations in EPM2A or EPM2B are absent. This means you have the rare form caused by an as yet unidentified gene.

Secondly, it is now important to find out if the forms of mutations present are nonsense mutations. Nonsense mutations may respond to gentamycin treatment.

Words From One of Our Researchers

We essentially breathe, sleep, dream and ceaselessly work on this disease. Our hope is to understand it so fully that we can come up with a treatment. My personal dream is this: Next time a Matt or a Jessica or an Amanda is brought to a neurologist, and the diagnosis of Lafora is made, the doctor would simply write a prescription and say: you have Lafora, take this, all will be alright.

Based on the genes, we have found the proteins disturbed in this disease and we are now painstakingly finding all the interacting proteins and step by step reconstructing the biochemical pathway that is disturbed. We are certain that with understanding will come insights into the cure.

Lafora patients form Lafora bodies in their brain cells, which cause the horrible epilepsy these patients suffer from. In parallel to unraveling the disease processes that lead to Lafora body formation, we are designing a method to remove them from the brain, and return the patient to normalcy. We know that amylase, the starch-digesting enzyme in saliva, can digest Lafora bodies. We are working on a method to introduce amylase into neurons to melt the Lafora bodies away and cure our patients.

The hurdles are many and the work is large, but so is our commitment. The disease is rare, and hard to find government funding for. We therefore count on you.

- Berge Minassian, MD

Research Articles

Lafora Research Article (Sep, 2013)
Background: Lafora disease (LD) is the major teenage-onset progressive myoclonus epilepsy (PME). Insidious cognitive decline and escalating myoclonic, visual, convulsive, and other seizures follow an initial decade of normal development...read more

Inhibiting Glycogen Synthesis Prevents Lafora Disease in a Mouse Model (Aug., 2013)
Background:Lafora disease (LD) is a fatal progressive myoclonus epilepsy characterized neuropathologically by aggregates of abnormally structured glycogen and proteins (Lafora bodies [LBs]), and neurodegeneration. . . .read more

Increased Laforin and Laforin Binding to Glycogen Underlie Lafora Body Formation in Malin-Deficient Lafora Disease (Jun. 5, 2012)
Background: Laforin deficiency causes glycogen hyperphosphorylation, which converts glycogen to aggregate-prone poorly branced polyglucosans.. . . .read more

Glycogen and its metabolism: some new developments and old themes (Oct. 18, 2011)
Glycogen is a branched polymer of glucose that acts as a store of energy in times of nutritional sufficiency for utilization in times of need.. . .read more

Phosphorylation Prevents Polyglucosan Transport in Lafora Disease (Oct. 17, 2011)
Neuronal distal axons have limited access to glucose, their myelin sheaths preventing direct interface with blood, and their axoplasms being at great distances from their cell bodies . .read more

High Hopes for Future Treatment of Lafora Disease (May 27, 2011)
Lafora disease is a severe form of epilepsy which affects teenagers.

Seizures and cramps are accompanied by progressive dementia and lead to death at the age of around 25. Currently, there is no cure for this illness. A new study shows that mice with Lafora disease can be rescued by knocking out a specific gene, providing hope for a human treatment. . . .read more

Exciting Possible Scientific Breakthrough from Dr. Berge Minassian (May, 2011)
The article is certainly the most positive to date about controlling LD. Some of you might remember him mentioning at our annual fundraising of a possible good result in one animal, that needed confirmation. IT WORKED! In the simplest form and to the best of a parent’s understanding, the article says that by inhibiting PTG (protein targeting glycogen synthase), the glycogen concentrations in the brain are reduced (but not completely eliminated) and, most importantly, a dramatic reduction of the production of Lafora bodies occurs in brain, liver, and the skeleton muscle. . . .read more

PTG Depletion Removes Lafora Bodies and Rescues the Fatal Epilepsy of Lafora Disease (Apr. 28, 2011)
Lafora disease is the most common teenage-onset neurodegenerative disesase, the main teenage-onset form of progressive myclonus epilepsy (PME), and one of the severest epilepsies. Pathologically, a starch-like compound, polyglucosan, accumulates in neuronal cell bodies and overtakes neuronal small processes, mainly dendrites. read more

Phosphate Incorporation during Glycogen Synthesis and Lafora Disease (Mar. 2, 2011)
Glycogen is a branched polymer of glucose that serves as an energy store. Phosphate, a trace constituent of glycogen, has profound effects on glycogen structure, and phosphate hyperaccumulation is linked to Lafora disease, a fatal progressive myoclonus epilepsy that can be caused by mutations of laforin, a glycogen phosphatase. read more

Glycogen Synthase: An Old Enzyme with a New Trick (Mar. 2, 2011)
Phosphorylation of glycogen has been known for decades; however, the basic metabolic pathways responsible for this modification are unknown. In this issue, Tagliabracci et al. (2011) report the enzyme responsible for incorporating phosphate and the chemical nature of the phosphate linkage, providing a framework for expanding our understanding of a devastating form of epilepsy. read more

Research Update from Dr. Escueta (June 2010)
Dr. Antonio Delgado-Escueta's team continues to maintain the Lafora disease mouse colony at the VA Medical Center in West Los Angeles. This mouse model continues to be used to improve our understanding of the disease mechanisms of Lafora epilepsy and can also be used for drug trials and gene replacement therapy. . .read more

We have two aims in our lab. 1) Understanding how Lafora bodies form. 2) Finding a way to get rid of them. (September, 2009)
When you look in the brain of a patient who dies of Lafora disease, you see in the vast majority of synapses (the place where one neuron (brain cell) talks to another) these ugly accumulations of starch-like compounds (polyglucosans/Lafora bodies) . . .read more

Laforin, the most common protein mutated in Lafora disease, regulates autophagy (May 7, 2010)
Lafora disease (LD) is an autosomal recessive, progressive myoclonus epilepsy, which is characterized by the accumulation of polyglucosan inclusion bodies, called Lafora bodies, in the cytoplasm of cells in the central nervous system and in many other organs. read more

Dr. Antonio V. Delgado-Escueta and his team are developing two treatment approaches, including 1) gene therapy for all Lafora disease patients, and 2) gentamicin treatment for those patients with nonsense mutations. (Jan. 4, 2009)

1) Gene therapy
The stellate electroencephalography (EEG) machine arrived on November 19, 2008, and the team started EEG recordings on mice the same afternoon. With the new EEG machine, Dr. Escueta now has the capability to monitor the effects of gene therapy on seizures and epileptic form discharges. Expenses include supplies for the EEG machine, a new stereotactic apparatus to measure exact electrode placement, and monthly costs for the mice colony . . .read more

Meet the Experts

Dr. Minassian and Dr. Escueta



Dr. Berge Minassian, Hospital for Sick Children, Toronto, Canada (on left) &
Dr. Antonio Delgado-Escueta, UCLA Medical Center, Los Angeles, California



Berge Minassian, MD

Dr. Minassian graduated from McGill Medical School in Montreal, trained in adult neurology at the University of California, Los Angeles and in paediatric epileptology at The Hospital for Sick Children, Toronto. Dr. Minassian spends 80 per cent of his time in the laboratory to help further knowledge in his areas of specialty and design better treatments.

Dr. Minassian’s Lab works on a teenage-onset fatal inherited epilepsy syndrome (Lafora disease). Dr. Minassian and collaborators at SickKids have identified two genes for this disorder, EPM2A, encoding the laforin dual-specificity phosphatase, and EPM2B, encoding the malin E3 ubiquitin ligase. They are currently near identifying a third gene for this disorder. Dr. Minassian’s ultimate aim is to unravel the neuronal biochemcial pathway disrupted in Lafora disease, in order to gain insights towards treating the disorder. Dr. Minassian is also interested in Rett syndrome. His team has recently discovered a new isoform of the MECP2 protein, which is expressed at ten times the abundance of the traditional MECP2 isoform, and which is the disease-relevant form of the protein. Finally, Dr. Minassian’s group is working on a rare and pathologically unique form of muscular dystrophy (X-linked myopathy with excessive autophagy), the gene of which they are narrowing in on.

In collaboration with his previous post-doctoral fellow, Dr. Hannes Lohi, Dr. Minassian is using the great power of canine genetics to map disease genes. Their group identified the first canine epilepsy gene recently, and is now in a major endeavour to map many other genes. This effort will help breeders eliminate disease from their breed, but will also expedite the identification of corresponding disease genes in humans.

Antonio Delgado-Escueta, MD

Dr. Antonio Delgado-Escueta is a world-renowned physician-scientist and authority on Lafora progressive myoclonus epilepsy and other types of epilepsy. His laboratories first mapped the chromosome 6q24 locus for Lafora progressive myoclonus epilepsy with Jose Maria Serratosa in 1995. Together with previous and present postdoctoral students, notably Jose Maria Serratosa and Berge Minassian, and collaborators S. Ganesh and Kazuhiro Yamakawa from RIKEN Brain Science Institute, they have been mainly responsible for refined mapping and isolation of Lafora Disease genes. Together with S. Ganesh and K. Yamakawa, they developed a mouse model of Lafora Disease, which is deficient in the laforin/DSP gene. This mouse model has aided in our understanding of the mechanisms of Lafora disease and developing treatment.

For over 20 years, Dr. Delgado-Escueta has been working diligently to solve the mystery that is Lafora disease epilepsy, but progress has been severely hampered due to limited resources. In 2003, Dr. Delgado-Escueta received a small grant to provide seed funding from Citizens United for Research in Epilepsy (CURE) to support gene therapy research in Lafora-deficient scientific models. This grant helped initiate the research of Dr. Eain M. Cornford and Shigeo Hyman and resulted in their NIH funding and even greater progress in developing experimental gene replacement therapy in Lafora disease mice.

Dr. Delgado-Escueta’s former students and postdoctoral scholars and collaborator have started independent research groups that continue to study Lafora disease all over the world, including Spain (J. Serratosa), Canada (B. Minassian) and India (S. Ganesh).

Research Overview

MYSTERIES OF BRAIN METABOLISM AND LAFORA DISEASE
One of the mysteries of brain metabolism and for that matter Lafora Disease is why normal nerve cells do not store glycogen. Glucose is the main source of energy in the brain as in other cells and glycogen is the main storage for glucose. Hence glycogen is a source for chronic energy and yet glycogen is not present in normal nerve cells. In contrast, in Lafora Disease, a progressive and deadly form of epilepsy, excessive amounts of abnormally branched glycogen accumulate in toxic amounts and kill nerve cells. This suggested that there must be finely-tuned machinery in the brain that prevents glycogen from appearing much less accumulating in normal nerve cells. This mystery is rapidly being solved by expert biochemists in glycogen metabolism and protein phosphatases spurred on by the discoveries of the disease causing genes in Lafora Disease by clinician scientists. This separate group of scientists has worked furiously, independently but harmoniously, in the last 12 years. In spring of 2007, these scientists met for a Workshop in Sarlat, France, stimulating collaborations, speeding up research, triggering a spate of publications and helping set up the stage for treatment protocols in Lafora Disease.

Finding the Disease Causing Gene of Lafora Disease
The modern story of Lafora Disease started in 1995 in the Epilepsy Genetics/Genomics Laboratories at the Epilepsy Center of Excellence of the Greater Los Angeles VA Medical Center and the David Geffen School of Medicine at UCLA. There, the first chromosome locus (6p24) for Lafora Disease was discovered. This led to the eventual identification of EPM2A (Laforin) in 1998 and EPM2B (Malin) in 2003 by the Los Angeles scientists and previous PhD and postdoctoral students who had then branched out into their own independent laboratories in Toronto (Canada), Madrid (Spain) and Kanpur (India). The families being studied by the Lafora Disease researchers then showed that Laforin belonged to a group of enzymes called dual specificity phosphatases that targeted glycogen while Malin was an E3 ubiquitin ligase, an enzyme involved in the cell disposal unit (like the garbage disposal of a kitchen). By 2002, two mice models of lafora disease were made -- one where the laforin gene was knocked out in the developing embryo was made by collaboration between Los Angeles and Japanese scientists. Another, where a mutation of laforin was inserted in the developing embryo was prepared by Toronto scientists.

Setting the Stage for Laforin Gene Replacement Treatment
Enter the scientist experts on protein phosphatases and glycogen metabolism. First to help in 2005, was the protein phosphatase lab at UC San Diego which showed that EPM2B/malin actually tagged EPM2A/Laforin with a marker (ubiquitin) and set it on its way to the cell disposal unit. In the ensuing two years, the same group of scientists from UC San Diego and Norwich, UK, together with plant biologists in Austria, discovered the counterpart of Laforin in plant and other organisms and showed that humans and other organisms share the common function of laforin in purging excessive carbohydrates and glycogen and preventing glycogen buildup that is harmful to the plant and organism cells. Next came the experts on glycogen metabolism. In 2007, a consortium of scientists from Madrid, Barcelona and Valencia, confirmed by the same UC San Diego team, showed that a complex of Laforin and Malin acting together suppresses the enzyme machinery that makes glycogen in nerve cells. The same complex of Laforin and Malin also sets up for the cell disposal unit the Laforin docking regions for protein phosphatase-1 and glycogen synthase (enzymes necessary for making glycogen). This way, the Laforin-Malin complex ensures suppression and blockade of glycogen formation in nerve cells as well as elimination of glycogen and its necessary enzymes by the cell disposal unit. When nature places a mutation in either Laforin or Malin, not only is poorly branched glycogen formed in excess but elimination through the cell disposal unit of glycogen and its components and its control systems by the Laforin/Malin complex is also dysfunctional and nerve cells die.
Also in 2007, both UC San Diego scientists and Indiana University scientists independently demonstrated that Laforin could release phosphate from amylopectin, a plant carbohydrate similar to glycogen and actual mammalian glycogen. This is very important because it shows for the first time that glycogen like amylopectin is a substrate of Laforin. If Laforin acts as a glycogen phosphatase in vivo, then the phosphate content in glycogen would be elevated in Lafora Disease. This is what is found in the mice whose Laforin has been knocked out. Glycogen phosphatase assay could, thus, provide a way of monitoring treatment.

Blood Brain Barrier Experts in the Epilepsy Center of Excellence at Los Angeles
As the functions of Laforin and Malin were unraveling, so the mysteries of glycogen metabolism were being demystified. Meanwhile, a team of experts on the blood-brain barrier in Los Angeles started to devise a method to deliver Laforin from the blood through the blood-brain barrier into brain nerve cells of mice with Lafora Disease. If the function of Laforin is to purge glycogen from nerve cells, then delivering Laforin into the brain of Lafora Disease patients would clear the brain of Lafora inclusion bodies. Starting in 2002, these scientists in Los Angeles labored through the details of placing Laforin inside a vehicle that should be harmless to humans, namely, pegylated immunoliposomes. (Placing Laforin inside lipids contrasts to placing the gene inside adenoviruses which have now been suspected to cause death in 2 persons and possible leukemia in 2 children.) By 2006, Laforin delivered by immunoliposomes into brains of mice with Lafora Disease was shown to indeed purge and decrease the load of Lafora inclusion bodies. Now, the timing of delivery, the exact doses, the frequency of delivery, and the interval of delivery of Laforin are being fine-tuned in mice with Lafora Disease. All this information will be important when Laforin is actually delivered to patients with Lafora disease.

Monitoring Results of Laforin Gene Therapy
One other advantage gained from defining glycogen and amylopectin as substrates of Laforin is the deduction that the Lafora inclusion bodies must be made of poorly branched glycogen. This could allow the imaging of Lafora inclusion bodies in patients suffering from the disease using a positron emission labeled chemical that is part of Lafora inclusion bodies. This would be an important project for chemists -- to produce a ligand that targets a part of lafora inclusion bodies and that could be imaged on PET scans. This can be another way for monitoring the results of treatment. If Laforin can really purge excessive glycogen like the Lafora inclusion bodies, then we should be able to show the inclusion bodies decrease and even disappear on PET scans that image Lafora bodies.

Where is the Story of Lafora Disease Leading us
This story is taking us to the treatment protocols and studies that need to be developed and developed rapidly if we are to save lives.  Besides laboratory work and collaborations with various experts, this involves applications to the Institutional Review Boards to obtain approval for treatment in patients.

Thus, funds are urgently needed to develop a treatment team for Lafora Disease. This treatment team should address the following:

(1) A treatment team dedicated to

(2) An assay team that monitors gene replacement treatment results

(3) A PET scan team that assays turnover and purging of Lafora bodies during gene replacement treatment

December 28, 2007 - Progressive Myoclonus Epilepsy, Lafora Type

Lafora disease (LD) is characterized by fragmentary, symmetric, or generalized myoclonus and/or generalized tonic-clonic seizures, visual hallucinations (occipital seizures), and progressive neurologic degeneration including cognitive and/or behavioral deterioration, dysarthria, and ataxia beginning in previously healthy adolescents between 12 and 17 years. read more

Gentamicin Study


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