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History of Neuronal Ceroid Lipofuscinosis
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 an 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 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, the Swedish psychiatrist and geneticist, Torben Sjogren,
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 morophological 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.
What are the forms of NCL/Batten Disease?
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.
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Infantile NCL (Santavuori-Haltia disease):
*This is the type of Batten's
Disease that Macayla has been diagnosed with.
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.
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Late Infantile NCL (Jansky-Bielschowsky disease)
begins between ages 2 and 4. The typical early signs are loss of
muscle coordination (ataxia) and seizures along with progressive
mental deterioration.. This form progresses rapidly and ends in death
between ages 8 and 12.
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Juvenile NCL (Batten Disease)
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.
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Adult NCL (Kufs Disease or Parry's Disease)
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 four additional diseases included in the Batten Disease/NCL group:
Finnish Late Infantile - identified in Finland.
Variant Late Infantile - identified in Costa Rica, South America,
Portugal and other nations.
Turkish Late Infantile - identified in Turkey.
Northern Epilepsy/ERMP - Epilepsy with Mental Retardation -
identified in Finland. |
How many people have these disorders?
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
How are NCLs inherited?
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 (Parrys) 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.
What causes these diseases?
Symptoms of Batten Disease/NCLs are linked to a buildup of substances
called lipopigments 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. Inside the cells, these pigments form deposits
with distinctive shapes that can be seen under an electron
microscope. Some look like half-moons (or commas) and are called
curvilinear bodies, others look like fingerprints and are called
fingerprint inclusion bodies and still others resemble gravel (or
sand) and are called granual osmophilic deposits (grods). These
deposits are what doctors look for when they examine a skin sample to
diagnose Batten Disease.
The diseases cause death of neurons (specific cells found in the
brain, retina and central nervous system). The reason for neuron
death is still not known.
How are these disorders diagnosed?
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:
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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.
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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.
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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.
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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.
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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.
Is there any treatment?
As yet, no specific treatment is known that can halt or reverse the
symptoms of Batten Disease/NCL. However, seizures can be reduced or
controlled with anticonvulsant drugs, and other medical problems can
be treated appropriately as they arise. At the same time, physical
and occupational therapy may help patients retain function as long as possible.
Some reports have described a slowing of the disease in children with
Batten Disease who were treated with vitamins C and E and with diets
low in vitamin A. However, these treatments did not prevent the fatal
outcome of the disease.
Support and encouragement can help children and families cope with
the profound disability and losses caused by NCLs. The Batten Disease
Support and Research Association enables affected children, adults,
and families to share common concerns and experiences.
Meanwhile, scientists pursue medical research that will someday yield
an effective treatment.
What research is being done?
Within the 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 identificatiion 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.
Currently there are two drug trials underway for Infantile Batten
Disease/NCL. Both trials are using a drug by the name of Cystagon.
For additional information regarding this trial, contact BDSRA at 1-800-448-4570.
How can I help research?
The hope of the future lies in research. Scientists need blood and
tissue samples in order to develop cell lines for current and future
investigations. Cell lines of persons with Batten Disease and their
families are grown and maintained in cell banks located at Institute
for Basic Research in Staten Island, NY and at Massachusetts General
Hospital. Post mortem brain and other tissue is banked in the
National Neurological Research Specimen Bank in Los Angeles. These
"banks" provide samples for research worldwide. To
donate blood or tissue contact the Batten Disease Support and
Research Association at 1-800-448-4570 or e-mail: bdsra1@bdsra.org.
As everyone knows, scientific research of any kind is driven by
funding. BDSRA provides funding to keep research moving forward.
Financial assistance for scientific investigations into the cause and
future treatment of Batten Disease/NCL is always needed. Persons
interested in aiding research may also call BDSRA at 1-800-448-4570
or e-mail: bdsra1@bdsra.org.
Where can I find more information?
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Batten Disease Support and Research Association
120 Humphries Dr., Suite 2
Reynoldsburg, OH 43068
800-448-4570 or
740-927-4298
E-mail: bdsra1@bdsra.org |
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Children's Brain Disease Foundation for Research
350 Parnassus Avenue, Suite 900
San Francisco, California 94117
(415) 566-5402 |
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Institute for Basic Research in Developmental Disabilities
1050 Forest Hill Road
Staten Island,
New York 10314
(718) 494-0600 |
The Institute for Basic Research in Developmental Disabilities, part
of the New York state government, conducts research on NCL and
maintains the National Batten Disease Registry which supports
scientific efforts by identifying and gathering information about
those individuals who have Batten Disease/NCL and by providing
epidemiological and clinical data.
For more information on research programs of the NINDS, contact:
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Office of Scientific and Health Reports Neurological Institute
P.O. Box 5801
Bethesda, Maryland 20824
(301) 496-5751 (800) 352-9424 |
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