Batten disease

What is Batten Disease?
Batten Disease is the common, catch-all name for Neuronal Ceroid Lipofuscinosis
(NCL). The NCLs are in actuality a group of disorders but because the name is so
difficult to pronounce the name Batten Disease has been adopted to indicate all of them
together. They all have a common denominator and that is that they are also known as
lysosomal storage disorders and have the same basic cause, progression and outcome.
Being lysosomal storage means that the lysosome, a small membrane bound structure
or compartment found in most cells stores material that it would normally recycle. The
lysosome contains enzymes whose job it is to break down other proteins for recycling or
elimination. A missing lysosomal protein can cause a build of proteins.

Who is affected by Batten Disease ?
Children are affected with this disease, although there is a rare form of NCL that affects
adults. Depending upon the type or form of Batten Disease the age of onset will vary.
Generally speaking children are born well and reach many developmental goals in the
first few years of life. Onset is defined as the time when the illness manifests itself. Onset
may be very subtle in the beginning. Initial symptoms may be any of three, i.e. seizures,
diminishing vision, or “clumsiness”. All of these are common in many diseases/disorders
and because Batten Disease is so rare initial diagnosis may be incorrect. Those initial
diagnoses often include epilepsy, retinitis pigmentosa, macular degeneration and
developmentally delayed or mentally retarded. However, as the disease progresses it soon
becomes obvious that these simplistic diagnoses are incorrect and the hunt for the real
disease begins. Batten Disease is, at best, extremely difficult to diagnose.
Over time, affected children suffer mental impairment, worsening seizures, and
progressive loss of sight and motor skills. Eventually, children with Batten Disease
become blind, bedridden, and unable to communicate. Batten Disease is always fatal. The
illness does not affect any two children exactly the same. In general, it can be said that
the children will have seizures, loose their vision, etc. However, the disease knows no
timetable and it can not be predicted when these things will occur, nor can the severity of
certain aspects of the disease. The same is true concerning the age at death.
Batten Disease is not contagious or, at this time, preventable.
History of Neuronal Ceroid Lipofuscinosis
The first probable instances of this condition were reported in 1826 by Dr. Christian
Stengel in a Norwegian medical journal, 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 biochemistry 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?
When we discuss the different NCLs we often refer to them as “forms” of Batten
Disease in order to simplify understanding. The chart below will act as a reference that
can be used in the later descriptions of the different “forms” of Batten Disease.
Form Name Age of Onset Gene Known ? Gene designation
________________________________________________________________________
Infatile Haltia- 6 mos. - 2 yrs. Yes CLN1
Santavuori
“Classic” Jansky- 2 - 4 years Yes CLN2
Late Infantile Bielschowsky
“Variant” 2 - 5 years Yes CLN6
Late Infantile
Juvenile Batten- 5 - 10 yrs. Yes CLN3
Spielmeyer-Vogt
Adult Kufs Usually before age 40 No CLN4
Parry
“Finnish” ????? 4.5 - 6 years Yes CLN5
Late Infantile
“Turkish” ????? 1 - 6 years Yes CLN7
Late Infantile
Northern EPMR 5 - 10 years Yes CLN8
Epilepsy
“Variant” vJNCL 5 – 10 years No CLN9
Juvenile
Congenital CTSD Birth Yes CTSD
Infantile NCL (Santavuori-Haltia disease): 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 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.
How many people have these disorders?
Batten Disease and other forms of NCL are relatively rare, occurring in an estimated 2
to 4 of every 100,000 births in the United States. These disorders appear to be more
common in Finland, Sweden, other parts of northern Europe; and Newfoundland,
Canada. The disease has 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 a 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) 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 and other 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 comas) 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 granule osmophilic deposits (grods). These
deposits are what doctors look for when they examine a tissue sample to diagnose Batten
Disease.
The biochemical defects causing NCLs have not been identified. Some scientists
suspect these abnormal deposits result from a shortage of enzymes normally responsible
for the breakdown of lipopigments. According to this theory, diseased cells produce
inadequate amounts of enzymes or manufacture defective enzymes that function poorly.
As a result, the cells cannot process enough of the lipopigments that occur within them,
and the lipopigments accumulate. Scientists have pinpointed what specific enzymes are at
fault for Infantile and “Classic” Late Infantile (PPT1 and TPP1 respectively) only.
However it has not been determined how the stored lipopigments damage nerve cells.
Other scientists believe that abnormal lipopigment buildup may result from a glitch in
the cell's production or processing. For example, diseased cells could be producing too
much of a normally needed lipoprotein.
How are these disorders diagnosed?
Because vision loss is often an early sign, Batten Disease 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 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 NCL may refer the child to a neurologist, a doctor who
specializes in diseases of the brain and nervous system. In order to diagnose NCL, the
neurologist needs the patient's medical history and information from various laboratory
tests.
Diagnostic tests used for NCLs include:
blood or urine tests: These tests can detect abnormalities that may indicate Batten
Disease. For example, elevated levels of a chemical called
dolichol are found in the urine of many NCL patients.
Electronmicroscopy of blood may reveal inclusion bodies or
deposits.
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 common in skin cells, especially those
from sweat glands.
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 and electro-
retinagrams, can detect various eye problems common in child-
hood NCLs.
brain scans: Imaging can help doctors look for changes in the brain's appear-
ance. 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 atrophying 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.
DNA: Extracted from a blood sample, specific genes are examined for
defects.
Enzyme Assay: Infantile & Late Infantile are missing a lysosomal enzyme (PPT1
& TPP1 respectively). A blood test will measure enzyme levels. Is there any treatment?
As yet, no specific treatment is known that can halt or reverse the symptoms of Batten
Disease or other NCLs. 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 could 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
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 defect
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. It
was then found that an enzyme is missing from the lysosome as a result of the defective
CLN1 gene. This enzyme is known as Palmitoyl Protein Thioesterase 1 or PPT1. In 1998, the gene for “Classic” Late Infantile, CLN2, was identified and is located on
Chromosome 11. In addition, it was found that there was a missing lysosomal enzyme
associated with Late Infantile. This missing enzyme is known as TPP1.
Identification of the specific genes for Infantile, “Classic” Late Infantile and Juvenile
Batten Disease has led to the development of DNA diagnostics, carrier and prenatal tests.
Scientists are continuing to work toward identifying the remaining genes for the other
forms of NCL, additional enzymes and proteins associated with the specific genes.
Additionally, some are working to identify a possible gene that is common to all forms of
NCL.
At the same time, other investigators are working to identify what substances the lipo-
pigments contain. Although scientists know lipopigment deposits contain fats and
proteins, the exact identity of the many molecules inside the deposits has been elusive for
many years. Recently, however, scientists have unearthed potentially important clues.
Researchers have found in the late infantile and juvenile forms that a large portion of this
built-up material is a protein called Subunit C. This protein is normally found inside the
cell's mitochondria, small structures that produce the energy cells need to do their jobs.
Storage material for the infantile form has been identified as a protein called Saposins A
& D, also known as sphingolipid activator proteins. Scientists are now working to
understand what role these proteins may play in NCL, including how this protein winds
up in the wrong location and accumulates inside diseased cells. Other investigators are
also examining deposits to identify the other molecules they contain.
In addition, research scientists are working with NCL animal models to improve under-
standing and eventually develop treatment of these disorders. At this time there are sheep
dog, fly, nematode, cow and zebrafish models for some forms of NCL. Mouse models
have also been development. Mouse models make it easier for scientists to study the
genetics of these diseases, since mice breed quickly and frequently.
At this time there are research initiatives underway to develop means for doing enzyme
replacements, gene therapy, stem cell transplantation and possibly drug/chemical
treatment.