Batten Disease

Batten Disease is the common name for a group of disorders called neuronal ceroid lipofuscinoses (or NCLs). The NCLs are rare genetic neurodegenerative disorders affecting the nerve cells in the brain, causing a progressive loss of physical and mental skills.

Batten Disease is the common name for a group of disorders called neuronal ceroid lipofuscinoses (or NCLs). The NCLs are rare genetic neurodegenerative disorders affecting the nerve cells in the brain, causing a progressive loss of physical and mental skills.

Infantile Batten Disease is the rarest of the NCL disorders and has the most aggressive progression.

What causes the disease?

Symptoms of Infantile Batten Disease and other NCLs are linked to a buildup of substances called lipofuscins (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 colour 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, others like fingerprints. These deposits are what doctors look for when they examine a skin sample to diagnose Batten Disease.

The biochemical defects that underlie several NCLs have recently been discovered. An enzyme called palmitoyl-protein thioesterase has been shown to be insufficiently active in the infantile form of Batten disease (this condition is now referred to as CLN1). In the late infantile form (CLN2), a deficiency of an acid protease, an enzyme that hydrolyzes proteins, has been found as the cause of this condition. A mutated gene has been identified in juvenile Batten Disease (CLN3), but the protein for which this gene codes has not been identified.

What are the main forms of 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.

• 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

How is it 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:

• 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.
• 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 electroretinograms ERG, can detect various eye problems common in childhood NCLs.
• brain scans – imaging can help doctors look for changes in the brain’s appearance. A commonly used imaging technique is computed tomography, or 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. Another imaging technique that is becoming 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 analysis – in families where the mutation in the gene for CLN3 is known, DNA analysis can be used to confirm the diagnosis or for the prenatal diagnosis of this form of Batten disease. When the mutation is known, DNA analysis can also be used to detect unaffected carriers of this condition for genetic counselling.

Does it have any alternative name?

At the beginning of the 20th century Dr Frederick Batten described a group of disorders that now bear his name. Over time it was discovered that there were several types of the disease with similar, but distinct, features and ages of presentation. Infantile Batten Disease was first described as a specific form of Batten Disease in 1968 and is sometimes called Neuronal Ceroid Lipofuscinosis (NCL) Type 1 or Santavuori-Hagberg Disease.

Is it inherited?

Infantile Batten Disease is an autosomal recessive disorder. This means that both parents are carriers of the disease. Human beings have about 30,000 to 40,000 different genes, each of which has a function in making an individual person. The genes are arranged in pairs (one of the pair from each parent) on 23 chromosomes. Inevitably, some of these genes are faulty; a normal gene can overcome a faulty one, but if both genes in the pair are faulty, the genetic instructions cannot work. Most people carry different faulty genes but in Batten’s (and other recessive conditions) parents, though healthy themselves, carry the same faulty genes, and risk passing them on to their children. Each pregnancy carries a:

• 25 per cent chance of the child being affected
  
  
• 75 per cent chance of the child not being affected.

Is pre-natal testing available?

In those families where the disease-causing mutation has been identified, prenatal and carrier testing is available for family members willing to be tested, and genetic counselling can assist them to make informed decisions according to their personal circumstances.

Siblings of an affected individual have a 25 % chance of also being affected, a 50% chance of being unaffected but being a carrier of the defective genes, and a 25% chance of being both unaffected and a non-carrier. Unaffected siblings of parents with an affected child also have a 50% chance of being carriers.

In families known to be carriers of the defective genes, prenatal testing can be performed at either 10-12 weeks (by chorionic villus sampling), or 16-18 weeks (amniocentesis) to discover if the foetus is affected.

How common is it?

The incidence of Infantile Batten Disease is not certain. The incidence of Late Infantile Batten’s disease is approximately 1: 200,000. Infantile Batten Disease is less common. Currently (2008) there are only three children in Australia known to have Infantile Batten Disease.

How does the disease progress?

For infants with Infantile Batten Disease or NCL1, development starts to slow down from six to twelve months of age. If he or she has learnt to walk, this skill is lost and co-ordination and manipulation become increasingly difficult. Over the following months the normal developmental skills (talking, sitting, responding to surroundings) go into reverse so that he or she becomes as dependent as a newborn baby again and vision deteriorates until it is eventually almost lost.

Many young children will develop repetitive hand movements (that look like knitting movements) and become very floppy (hypotonic) and increasingly unsteady (ataxic). If the head is measured, the growth is extremely slow and the size small for the child’s age. From about two years of age, the child will experience body jerks or jumps, which are epileptic (myoclonic) attacks and sometimes, but not always, generalised epileptic seizures may develop.

From about the age of three years the jerks often subside; at about this age the child’s limbs will then tend to become stiffer rather than floppy. The condition is not a painful one and the child will not be aware of what is happening. The brain’s control of the muscles responsible for chewing, swallowing, coughing and so on eventually becomes affected so that assistance with a feeding tube may be needed. Chestiness will develop and may lead to infections and increasing physical weakness. Eventually the combination of the diseased brain and physical weakness becomes too great to sustain life, and death usually occurs between the ages of three to five years (very occasionally up to eight to nine years). Parents and carers will be aware of the child’s increasing frailty, and death is usually relatively peaceful and expected when the time comes.

Is there any treatment?

Although there is no treatment yet available that can stop the disease, every effort is made to treat the symptoms as they occur. Drugs can be given to try to reduce the jerks and seizures (if they occur), relieve muscle spasms, and treat infections; pain relief and sedative drugs can be given if required, and feeding can be assisted. Physiotherapists and others can advise parents on positioning, seating and exercising the limbs to maintain comfort. Specialist nursery placements are available with visiting therapists and it can be important for young children to have this stimulating environment and social contact and, indeed for the parents to have some time for themselves and other family members and friends. Music is often particularly enjoyed even in the latest stages of the disease process. Though not scientifically proven, many young children gain some symptomatic relief from some of the complementary therapies, such as cranial osteopathy and massage.

Is there any research being done?

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 Infantile Batten Disease. 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 – American Chapter.

In late Infantile Batten Disease 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 initially 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 foetal 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.

Research is progressing rapidly with increasing understanding of genes and how they work; this is already bringing benefits in the area of prenatal diagnosis. Sadly, however, any treatment that could reverse the disease process is unlikely to be discovered quickly enough to help children who already have symptoms. Your neurologist and support group can keep you informed of research progress.

Are there support groups?

Yes, there are.

Australian Chapter of Batten Disease Support and Research Association Inc. (BDSRA) is located at:

9 Norton Avenue
Killarney Vale
NSW, Australia 2261

Website: http://www.battens.org.au

Chapter Facilitator and Public Officer

Name: Vanessa Anderson

Email: gvjcando@ozemail.com.au

Phone +61 (0)2 4334 5785

The Batten Disease Family Association (BDFA)
C/O Heather House
Heather Drive
Tadley
Hampshire RG26 4QR

Tel: +44 (0)7914 060742

Website: http://www.bdfa-uk.org.uk

Batten Disease Support and Research Association
166 Humphries Dr.
Reynoldsburg, OH  43068

Phone +1 800 448 4570

Website: http://www.bdsra.org

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