Neuronal ceroid lipofuscinosis

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Overview
Neuronal Ceroid Lipofuscinoses (NCL, also known as Batten Disease) is the general name for a family of at least eight genetically separate neurodegenerative disorders that result from excessive accumlation of lipopigments (lipofuscin) in the body's tissues. These lipopigments are made up of fats and proteins. Their name comes from the technical word lipo, which is short for "lipid" or fat, and from the term pigment, used because they take on a greenish-yellow color when viewed under an ultraviolet light microscope. The lipopigments build up in cells of the brain and the eye as well as in skin, muscle, and many other tissues.

History
The first probable instances of this condition were reported in 1826 in a Norwegian medical journal by Dr. Christian Stengel, who described 4 affected siblings in a small mining community in Norway. Although no pathological studies were performed on these children the clinical descriptions are so succinct that the diagnosis of the Spielmeyer-Sjogren (juvenile) type is fully justified.

More fundamental observations were reported by F. E. Batten in 1903, and by Heinrich Vogt in 1905, who performed extensive clinicopathological studies on several families. Retrospectively, these papers disclose that the authors grouped together different types of the syndrome. Furthermore Batten, at least for some time, insisted that the condition that he described was distinctly different from Tay-Sachs disease, the prototype of a neuronal lysosomal disorder now identified as GM2 gangliosidosis type A. Around the same time, Spielmeyer reported detailed studies on three siblings, suffering from the Spielmeyer-Sjogren (juvenile) type, which led him to the very firm statement that this malady is not related to Tay-Sachs disease. Subsequently, however, the pathomorphological studies of Schaffer made these authors change their minds to the extent that they reclassified their respective observations as variants of Tay-Sachs disease, which caused confusion lasting about 50 years.

In 1913-14, M. Bielschowsky delineated the late infantile form of NCL. However, all forms were still thought to belong in the group of "familial amaurotic idiocies", of which Tay-Sachs was the prototype.

In 1931, Torben Sjogren, the Swedish psychiatrist and geneticist, presented 115 cases with extensive clinical and genetic documentation and came to the conclusion that the disease which we now call the Spielmeyer-Sjogren (juvenile) type is genetically separate from Tay-Sachs.

Departing from the careful morphological observations of Spielmeyer, Hurst, and Sjovall and Ericsson, Zeman and Alpert made a determined effort to document the previously suggested pigmentary nature of the neuronal deposits in certain types of storage disorders. Simultaneously, Terry and Korey and Svennerholm demonstrated a specific ultrastructure and biochemestry for Tay-Sachs disease, and these developments led to the distinct identification and also separation of the NCLs from Tay-Sachs disease by Zeman and Donahue. At that time, it was proposed that the Late Infantile (Jansky-Bielschowsky), the juvenile (Spielmeyer-Vogt), and the adult form (Kufs) were quite different from Tay-Sachs disease with respect to chemical pathology and ultrastructure and also different from other forms of sphingolipidoses.

Subsequently, it was shown by Santavuori and Haltia that an infantile form of NCL exists, which Zeman and Dyken had included with the Jansky Bielschowsky type.

Forms
There are four main types of NCL, including two forms that begin earlier in childhood and a very rare form that strikes adults. The symptoms are similar but they become apparent at different ages and progress at different rates.


 * Type 1 - Infantile NCL (Santavuori-Haltia disease, INCL, CLN1 ): begins between about 6 months and 2 years of age and progresses rapidly. Affected children fail to thrive and have abnormally small heads (microcephaly). Also typical are short, sharp muscle contractions called myoclonic jerks. Initial signs of this disorder include delayed psychomotor development with progressive deterioration, other motor disorders, or seizures. The infantile form has the most rapid progression and children live into their mid childhood years. The gene responsible for Infantile NCL has been identified in some cases of juvenile/adult onset.  It is thought these patients have some partial enzyme production.


 * Type 2 - Late Infantile NCL (Jansky-Bielschowsky disease, LINCL, CLN2 ) begins between ages 2 and 4. The typical early signs are loss of muscle coordination (ataxia) and seizures along with progressive mental deterioration, though afflicted children may show mild-severe delays in speech development well before other symptoms appear. This form progresses rapidly and ends in death between ages 8 and 12.


 * Type 3 - Juvenile NCL (Batten disease, JNCL, CLN3 ) begins between the ages of 5 and 8 years of age. The typical early signs are progressive vision loss, seizures, ataxia or clumsiness. This form progresses less rapidly and ends in death in the late teens or early 20s, although some may live into their 30s.


 * Type 4 - Adult NCL (Kufs disease or Parry's disease, ANCL, CLN4 ) generally begins before the age of 40, causes milder symptoms that progress slowly, and does not cause blindness. Although age of death is variable among affected individuals, this form does shorten life expectancy.

There are at least four additional diseases included in the Batten Disease/NCL group:
 * Type 5 - Finnish Late Infantile - identified in Finland.
 * Type 8 - Turkish Late Infantile - identified in Turkey.
 * Northern Epilepsy/ERMP - Epilepsy with Mental Retardation - identified in Finland.
 * Type 6 - Variant Late Infantile - identified in Costa Rica, South America, Portugal, the United Kingdom and other nations.
 * Type 9 - -potentially identified in Germany and Serbia.

Incidence, Causes, Diagnoses
Batten disease/NCL is relatively rare, occurring in an estimated 2 to 4 of every 100,000 births in the United States. The diseases have been identified worldwide. Although NCLs are classified as rare diseases, they often strike more than one person in families that carry the defective gene.

Childhood NCLs are autosomal recessive disorders; that is, they occur only when a child inherits two copies of the defective gene, one from each parent. When both parents carry one defective gene, each of their children faces one in four chance of developing NCL. At the same time, each child also faces a one in two chance of inheriting just one copy of the defective gene. Individuals who have only one defective gene are known as carriers, meaning they do not develop the disease, but they can pass the gene on to their own children.

Adult NCL may be inherited as an autosomal recessive (Kufs) or, less often, as an autosomal dominant (Parry's) disorder. In autosomal dominant inheritance, all people who inherit a single copy of the disease gene develop the disease. As a result, there are no unaffected carriers of the gene.

Because vision loss is often an early sign, Batten disease/NCL may be first suspected during an eye exam. An eye doctor can detect a loss of cells within the eye that occurs in the three childhood forms of Batten disease/NCL. However, because such cell loss occurs in other eye diseases, the disorder cannot be diagnosed by this sign alone. Often an eye specialist or other physician who suspects Batten disease/NCL may refer the child to a neurologist, a doctor who specializes in disease of the brain and nervous system. In order to diagnose Batten disease/NCL, the neurologist needs the patient's medical history and information from various laboratory tests.

Diagnostic tests used for Batten disease/NCLs include:


 * Skin or tissue sampling. The doctor can examine a small piece of tissue under an electron microscope. The powerful magnification of the microscope helps the doctor spot typical NCL deposits. These deposits are found in many different tissues, including skin, muscle, conjunctiva, rectal and others. Blood can also be used.
 * Electroencephalogram or EEG. An EEG uses special patches placed on the scalp to record electrical currents inside the brain. This helps doctors see telltale patterns in the brain's electrical activity that suggest a patient has seizures.
 * Electrical studies of the eyes. These tests, which include visual-evoked responses (VER) and electro-retinagrams (ERG), can detect various eye problems common in childhood Batten disease/NCLs.
 * Brain scans. Imaging can help doctors look for changes in the brain's appearance. The most commonly used imaging technique is computed tomography (CT), which uses x-rays and a computer to create a sophisticated picture of the brain's tissues and structures. A CT scan may reveal brain areas that are decaying in NCL patients. A second imaging technique that is increasingly common is magnetic resonance imaging, or MRI. MRI uses a combination of magnetic fields and radio waves, instead of radiation, to create a picture of the brain.
 * Enzyme assay. A recent development in diagnosis of Batten disease/NCL is the use of enzyme assays that look for specific missing lysosomal enzymes for infantile and late infantile only. This is a quick and easy diagnostic test.

Treatment
Currently there is no widely accepted treatment that can cure, slow down, or halt the symptoms of NCL. However, seizures may be controlled or reduced with use of anti-epileptic drugs. Additionally, physical, speech, and occupational therapies may help affected patients retain functioning for as long as possible.

Research
Within the United States Federal Government, the focal point for research on Batten Disease and other neurogenetic disorders is the National Institute of Neurological Disorders and Stroke (NINDS). The NINDS, a part of the National Institutes of Health (NIH), is responsible for supporting and conducting research on the brain and central nervous system. The Batten Disease Support and Research Association and the Children's Brain Diseases Foundation also provide financial assistance for research.

Through the work of several scientific teams, the search for the genetic cause of NCLs is gathering speed In September 1995, The International Batten Disease Consortium announced the identification of the gene for the juvenile form of Batten Disease. The specific gene, CLN3, located on Chromosome 16, has a deletion or piece missing. This gene accounts for 73% of all cases of Juvenile Batten Disease. The rest are the result of other defects of the same gene.

Also, in 1995, scientists in Finland announced the identification of the gene responsible for the infantile form of Batten Disease. The gene, CLN1, is located on Chromosome 1.

In September 1997, scientists at the Robert Woos Johnson Medical School and the Institute for Basic Research, NY, announced the identification of the gene for the "classic" Late Infantile form of Batten Disease/NCL. The gene, CLN2, is located on chromosome 11.

Scientists have also identified the gene responsible for Finnish Late Infantile (CLN5), variant Late Infantile (CLN6) and EPMR (CLN8). Research also continues toward identification of the gene for the adult form of Batten Disease/NCL, also known as Kufs Disease.

Identification of the specific genes for Infantile, Late Infantile, Variant Late Infantile and Juvenile Batten Disease/NCL has led to the development of DNA diagnostics, carrier and prenatal tests.

Scientists have discovered that the Infantile and Late Infantile diseases are missing key lysosomal enzymes, i.e. Palmitoyl Protein Thioesterase 1 (PPT1) for Infantile and Tripeptidyl Peptidase 1 (TPP1) for Late Infantile. Knowing that these enzymes are missing is now leading to the development of gene replacement and stem cell transplantation therapies.

Recent studies have shown a link between the Juvenile form and the body's autoimmune system. Although this link is not yet fully understood, it may eventually lead to a treatment.

Experimental Treatments
With recent advances in genetics research there is, for the first time, actual hope for treatment for several forms of NCL.

In 2001 it was reported a drug used to treat cystinosis, a rare genetic disease that can cause kidney failure if not treated, may be useful in treating the infantile form of NCL. Preliminary results report the drug has completely cleared away storage material from the white blood cells of the first six patients, as well as slowing down the rapid neurodegeneration of infantile NCL. It is preliminarily shown that the addition of another drug seems to be more effective than Cystagon alone and all patients on the trials, including the first six, are being put on this drug. Currently there are two drug trials underway for infantile Batten disease/NCL. Both trials are using the drug Cystagon. For additional information regarding this trial, contact the Batten Disease Support and Research Association.

In late infantile NCL research a controversial gene therapy trial, funded by several families gathered together under Nathan's Battle Foundation, started in June 2004. As a phase I trial trying to establish the safety of the gene therapy, the trial has been limited to eleven children and, so far, eight children have been treated. The trial was temporarily halted when the fourth child treated died after the having the procedure in November 2004. However, it is thought the actual gene therapy was not the cause of the child's death and the trial has since resumed, with subsequent patients reported to be doing well with surgical recovery. However the child's death has led to a reluctance of the doctors treating patients to operate on any more patients that are severely afflicted with late infantile NCL. This reluctance is now leading to possible legal action by a family whose child has been denied treatment after intitally promised a spot in the trial and having his surgery dates pushed back several times.

Media coverage of the trial, as well as information to the scientific community in general, has been very limited. However, several newspaper articles suggest that MRI scans show the therapy has been successful in halting, though not reversing, the progress of this disease. Nathan and P.J. Milto, among the first of the treated children and the sons of the Nathan's Battle Foundation founder, are reported to have no further progression of their disease and stable neurological status, though both remain severely handicapped. With less severely afflicted children now being treated, however, there is reason to hope and see if the late infantile NCL Gene Therapy Transfer could be an effective way of slowing or halting the progress of this condition.

In October 2005 three-year-old Jasmine Harris of London, England became the healthiest child to be treated in the late infantile NCL Gene Therapy trial so far. Due to an older brother, Jordan, being previously diagnosed with late infantile NCL in early 2003 after almost two years of deteriorating cognitive and motor skills Jasmine, though presyptomatic, was also tested for the disease at the end of 2003 and found to be positive for the condition at the age of twenty months. Although Jasmine has suffered several seizures and experienced a deterioration in her speech in the past year, MRI scans of her brain are reported to still be normal, and there is hope the treatment will prevent her from experiencing any more neurological degeneration. It will be months, even years, before scientists will fully know of the treatment has been successful in sparing Jasmine Harris the ravages of LINCL.

Additionally, a painkiller available in several European countries, Flupirtine, has been suggested to possibly slow down the progress of NCL, particularly in the juvenile and late infantile forms. No trial has been officially supported in this venue, however. Currently the drug is available to NCL families either from Germany, Duke University Medical Center in Durham, North Carolina, and the Hospital for Sick Children in Toronto, Ontario.

On October 20, 2005, the Food and Drug Administration approved a phase I clinical trial of neural stem cells to treat infantile and late infantile Batten disease. Subsequent approval from an independent review board also approved the stem cell therapy in early March 2006. This treatment will be the first ever transplant of fetal stem cells performed on humans. The therapy is being developed by Stem Cells Inc and is estimated to have six patients. The treatment will be carried out in Oregon.

Juvenile NCL has recently been listed on the Federal Clinical Trials website to test the effectiveness of bone marrow/stem cell transplants for this condition. A bone marrow transplant has been attempted in the late infantile form of NCL with disappointing results; while the transplant may have slowed the onset of the disease, the child eventually developed the disease and died in 1998. Trials testing the effectiveness of bone marrow transplants for infantile NCL in Finland have also been disappointing, with only a slight slowing of disease reported.