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Batten Disease

2010

Batten Disease is named after the British pediatrician who
first described it in 1903. Also known as
Spielmeyer-Vogt-Sjogren-Batten Disease, it is the most
common form of a group of disorders called Neuronal Ceroid
Lipofuscinoses (or NCLs). Although Batten Disease is
usually regarded as the juvenile form of NCL, it has now
become the term to encompass all forms of NCL. The forms
of NCL are classified by age of onset have the same basic
cause, progression and outcome but are all genetically
different.

Over time, affected children suffer mental impairment,
worsening seizures, and progressive loss of sight and motor
skills. Eventually, children with Batten Disease/NCL become
blind, bedridden, and unable to communicate and presently
is always fatal. Batten Disease is not contagious or, at this
time, preventable.

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.

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

Children's Brain Disease Foundation for Research
350 Parnassus Avenue, Suite 900
San Francisco, California 94117
(415) 566-5402

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:

Office of Scientific and Health Reports Neurological Institute
P.O. Box 5801
Bethesda, Maryland 20824
(301) 496-5751 (800) 352-9424

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.

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.

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.

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.

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.

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 (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.

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.

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.

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.

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.

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.

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.

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