Batten Disease - Batten Disease

Batten disease is an extremely rare and fatal autosomal recessive neurodegenerative disorder that begins in childhood. It is the most common form of a group of disorders called the neuronal ceroid lipofuscinoses (NCLs).

Although Batten disease is usually regarded as the juvenile form of NCL (or "type 3"), some physicians use the term Batten disease to describe all forms of NCL. Historically, the NCLs were classified by age of disease onset as infantile NCL (INCL), late infantile NCL (LINCL), juvenile NCL (JNCL) or adult NCL (ANCL).

At least twenty genes have been identified in association with Batten disease, but juvenile NCL, the most prevalent form of Batten disease, has been linked to mutations in the CLN3 gene.

Signs and symptoms

Early signs and symptoms of the disorder usually appear around ages 2â€"10, with gradual onset of vision problems, or seizures. Early signs may be subtle personality and behavior changes, slow learning or regression, repetitive speech or echolalia, clumsiness, or stumbling. There may be slowing head growth in the infantile form, poor circulation in lower extremities (legs and feet), decreased body fat and muscle mass, curvature of the spine, hyperventilation and/or breath-holding spells, teeth grinding, and constipation.

Over time, affected children suffer mental impairment, worsening seizures, and progressive loss of sight, speech and motor skills. Eventually, children with Batten disease become blind, bedridden, demented, and die. Batten disease is a terminal disease; life expectancy varies depending on the type or variation.

Females with juvenile Batten disease show first symptoms a year later than males but on average die a year sooner.

Cause

Batten disease is caused by genetic mutations that cause lipofuscins to accumulate within the body's tissues. Lipofuscin are substances consisting of fats and proteins that form distinctive deposits.The diagnosis of Batten disease is based on the presence of these deposits in skin samples as well as other criteria. Eight genes have now been identified that cause different types of Batten disease in children or adults, more having yet to be identified. Of the eight genes, two encode enzymes. The function of most of these genes is still unknown. The identification of these genes opens up the possibility of gene replacement therapy or other gene-related treatments. Batten disease is very rare and occurs in an estimated 2 to 4 out of every 100,000 births in the United States.

Genetics

Batten disease is inherited primarily in an autosomal recessive pattern, but it varies by age. In cases involving children, it is only inherited as an autosomal recessive trait. In adults, the inheritance pattern is still autosomally recessive but there is also a chance of it being inherited in an autosomal dominant fashion as well. Eight genes have been identified in the variety of NCLs, mutations in which contribute to the development of the phenotypic trait of the disorders:

• CLN1 or PPT1, encodes an enzyme called palmitoyl-protein thioesterase 1 that is insufficiently active in Infantile NCL.
• CLN2 or TPP1, produces an enzyme called tripeptidyl peptidase 1â€"an acid protease that degrades proteins. The enzyme is insufficiently active in Late Infantile NCL (also referred to as CLN2).
• CLN3 mutation is the most prevalent and major cause of Juvenile NCL. The gene encodes a hydrophobic integeral membrane protein called CLN3 or battenin. Battenin is found in the membranes of the cell (most predominantly in lysosomes and in related structures called endosomes). The protein’s function is currently unknown.
• CLN5, which causes variant Late Infantile NCL (vLINCL, also referred to as CLN5), produces a lysosomal protein called CLN5, whose function has not been identified.
• CLN6, which also causes Late Infantile NCL, encodes a protein called CLN6 or linclin. The protein is found in the membranes of the cell (most predominantly in a structure called the endoplasmic reticulum). Its function has not been identified.
• MFSD8, seen in variant Late Infantile NCL (also referred to as CLN7), encodes the MFSD8 protein that is a member of a protein family called the major facilitator superfamily. This superfamily is involved with transporting substances across the cell membranes. The precise function of MFSD8 has not been identified.
• CLN8 causes progressive epilepsy with mental retardation. The gene encodes a protein also called CLN8, which is found in the membranes of the cellâ€"most predominantly in the endoplasmic reticulum. The protein’s function has not been identified.
• CTSD, involved with Congenital NCL (also referred to as CLN10), encodes cathepsin D, a lysosomal enzyme that breaks apart other proteins. A deficiency of cathepsin D causes the disorder.

Diagnosis

Batten disease is a rare disease. Since it is a uncommon disease. Batten disease may result in misdiagnosis, which in turn cause increases in medical expenses, increases in family stress, and increases in the chance of using incorrect forms of treatment. Neverthless, Batten disease can be diagnosed if properly detected. Vision impairment is the most common observable symptom to detect the disease. Children are more prevalent, and should be suspected more for juvenile Batten disease. Children or someone suspected to have Batten disease, should initially be seen by an optometrist or ophthalmologist. A fundus eye examination that aids in the detection of common vision impairment abnormalities, such as granularity of the retinal pigment epithelium in the central macula will be performed.Even though it is also seen in a variety of other diseases as well, a loss of ocular cells should be a warning sign of Batten Disease potentially being present. If Batten Disease is the suspected diagn osis, a variety of tests are conducted to help accurately confirm its ascertainment including:

Blood or urine tests. Urinalysis and blood testing can help detect abnormalities that may indicate Batten disease. For example, elevated levels of dolichol in urine have been found in many individuals with NCL. The presence of vacuolated lymphocytesâ€"white blood cells that contain holes or cavities (observed by microscopic analysis of blood smears)â€"when combined with other findings that indicate NCL, is suggestive for the juvenile form caused by CLN3 mutations.

Skin or tissue sampling: Performed by extracting a small piece of tissue, which then is examined under an electron microscope. This helps and allows physicians to detect typical NCL deposits. These deposits are common in tissues, such as skin, muscle, conjunctiva, and rectal.This type of diagnostic technique is beneficial, however other invasive tests are more advantageous for diagnosing Batten disease.

Electroencephalogram (EEG). EEG is a techinque that uses special probes that are attached on to the individuals scalp. It records electrical currents/signals, which allow medical experts to analylze electrical pattern activity in the brain. Assist in observing if the patient has seizures.

Electrical studies of the eyes. As mentioned, vision loss is the most common characteristic of Batten disease. Visual-evoked responses and electroretinograms are effective test for detecting various eye conditions common in childhood NCLs.

Computed tomography (CT) or magnetic resonance imaging (MRI). Diagnostic imaging test allow physicians to better visualize the appearance of the brian. MRI imaging test uses magentic fields and radio waves to help create images of the brain. CT scan is another type of imaging test that uses x-rays and computers to create a detailed image of the brain's tissues and structures. Both diagnostic imaging test can help reveal brain areas that are decaying, or “atrophic,” in persons with NCL.

Measurement of enzyme activity. Measuring enzymatic activity specific to Batten disease, may help confirm or rule out certain diagnoses caused by different mutations. Elevated levels of palmitoyl-protein thioesterase is involved in CLN1. Acid protease is involved in CLN2. Cathepsin D is involved in CLN10.

DNA analysis. DNA analysis can be used to help confirm the diagnosis of Batten disease. When the mutation is known, DNA analysis can also be used to detect unaffected carriers of this condition for genetic counseling. If a family mutation has not previously been identified or if the common mutations are not present, recent molecular advances have made it possible to sequence all of the known NCL genes, increasing the chances of finding the responsible mutation(s).

Treatment

Batten disease is a terminal illness, with no cure. Palliative treatment is symptomatic and supportive.

Research

In June 1987, a Phase I clinical trial was launched at Weill Medical College of Cornell University to study a gene therapy method for treatment of the signs and symptoms of late infantile neuronal ceroid lipofuscinosis (LINCL). The experimental drug works by delivering a gene transfer vector called AAV2CUhCLN2 to the brain. Although the trial is not matched, randomized, or blinded and lacked a contemporaneous placebo/sham control group, assessment of the primary outcome variable suggests a slowing of progression of LINCL in the treated children.

Researchers believe the neurological deficits common in JNCL could be due to overactive AMPA receptors in the cerebellum. To test this hypothesis, researchers administered AMPA antagonist drugs into affected mice. The motor skills of the affected mice showed significant improvement after the antagonist treatment, which supported the hypothesis that the neurological deficits in JNCL are due to overactive AMPA receptors. This research could eventually help to alleviate neurological deficits of JNCL in humans.

In November 2006, after receiving FDA clearance, neurosurgeon Nathan Selden, pediatrician Bob Steiner, and colleagues at Doernbecher Children's Hospital at Oregon Health & Science University began a clinical study in which purified neural stem cells were injected into the brain of Daniel Kerner, a six-year-old child with Batten disease, who had lost the ability to walk and talk. This patient was the first of six to receive the injection of a stem cell product from StemCells Inc., a Palo Alto biotech company. These are believed to be the first-ever transplants of fetal stem cells into the human brain. By early December, the child had recovered well enough to return home, and it was reported that there were some signs of speech returning. Daniel Kerner died on April 12, 2010. The main goal of Phase I clinical trials, however, was to investigate the safety of transplantation. Overall, the Phase I data demonstrated that high doses of human neural stem cells, delivered by a direct transplantation procedure into multiple sites within the brain, followed by twelve months of immunosuppression, were well tolerated by all six patients enrolled in the trial. The patients’ medical, neurological and neuropsychological conditions, following transplantation, appeared consistent with the normal course of the disease.

Mycophenolate mofetil is being tested to determine its ability to safely slow or halt neurodegeneration. A non-randomised safety and efficacy trial of a gene transfer vector is underway.

History

Batten disease is named after the British pediatrician Frederick Batten, who first described it in 1903. Also known as Spielmeyer-Vogt-Sjögren-Batten disease, it is the most common form of a group of disorders called neuronal ceroid lipofuscinosis (or NCLs). Although Batten disease is usually regarded as the juvenile form of NCL, some physicians use the term Batten disease to describe all forms of NCL.