The Children’s Brain Diseases Foundation ( 501c3)

Batten Disease Symptoms

Early symptoms of Batten disease are confusing. Often, they begin with overt changes in personality and behavior and a decline in learning ability. Clumsiness, stumbling and failing vision soon follow. Most patients have seizures. The infants or children deteriorate progressively. Motor coordination is impaired, blindness develops, and dementia becomes severe along with more frequent seizures. These changes are particularly devastating in young children who have just begun to enjoy life; their decline is often quite precipitous and most die within a few years after having been wheelchair-bound and finally, bedridden.

The onset of specific symptoms varies with each of the four major forms of Batten disease. The infantile type has an onset at approximately age two, with seizures and rapid deterioration and death by age 10 The late infantile disease strikes toddlers at three to four years of age with death by 12 and in rare cases, into the forties Juveniles may live with blindness, seizures and mental retardation into the 20s and rarely in the 40s. The adult form beginning in early adulthood, progresses more slowly, but patients die in about ‘5 years.

CAUSE:

The NCLs are lysosomal storage disorders. The lysosomal disorders include several hundred similar genetic defects. All of these disorders involve the failed metabolism of products of cell and membrane metabolism. These products are digested in normal cells, but in the NCLs the undegraded products are stored as autofluorescent products or ceroid lipfuscin. Eventually, when the nerve cells die, an autopsy will reveal that all the brain cells are filled with ceroid lipfuscin. At this time, these pigments are considered to be the end result of a combination of metabolic derangements and mark the end result of progressive deterioration in brain function. Interestingly, the ceroid pigment shows some similarity to age pigment, which accumulates more slowly during the normal aging process. In Batten disease, however, the accumulation is quite rapid and destructive. The specific reasons for the loss in brain function are not known. While there is some promising new information, we still have limited understanding of the specific cause or biochemical mechanism involved in all types of Batten ,disease.

All of these disorders primarily affect the brain and often affect the eye, causing blindness.

Seizures are a serious prognostic indicator that must be controlled to prevent additional and progressive losses in brain function. Generally, the affected child shows a gradual deterioration of all body functions, and eventually, requires round the clock nursing care. At the present time, there is no treatment or cure for any form of Batten disease.

DIAGNOSIS:

Batten disease is difficult to diagnose because of the variability in symptoms, insidiousness and age of onset. Children are often thought to have epilepsy or a form of mental retardation. Adults are sometimes labeled as schizophrenics. Often, the first diagnostic clue comes with a visit to the ophthalmologist who observes pathological changes in the retina. Additional tests of neurological and retinal function will suggest the diagnosis. Once the diagnosis has been suggested, Medical Centers throughout the world will use gene or enzyme analysis may confirm the specific diagnosis.

The first definitive gene defect was reported in 1995. Mutations in the palmitoyl protein thioesterase gene localized on chromosome 1p32 were found to be the cause of the infantile form of Batten disease. The gene for the classical late infantile form of Batten disease was identified on chromosome 11p15 and shown to code for a specific protein degrading enzyme, tripeptidylpeptidase1. Just recently, mutations in another protease, cathepsin D was shown to cause Late Infantile Battens. The genes for other variant forms of the late infantile have been identified on chromosomes 13q21 (CLN5), 15q23 (CLN6), 4q28.1 (CLN7) and 8p23 (CLN8). Also in 1995, the genetic defect in the juvenile form of Batten disease (CLN3 or JNCL) was found to be on chromosome 16p12. This gene also codes for a membrane protein involved in complex processing and transport within the brain cell.

PREVENTION:

As with any disease. prevention is always better than treatment. If parents on either side, the prospective mother or father do not test as carriers, then there is no chance of an affected child. However. if there is a family history of Batten disease and both parents are carriers, cells from the fetus can be tested to determine if the child will be normal, a carrier or affected. However. this choice is an important decision that only the family can make with appropriate counseling. Newborn infants should be tested in a similar manner. so that when definitive treatment becomes available, it can be started early before irreversible brain damage takes place.

TREATMENT:

Today there is no satisfactory treatment or cure for Batten disease. To a large extent. effective treatment will depend on determining the cause and principal mechanisms of action of Batten disease and some progress has been made.

Pharmaceuticals: Agents that might slow down brain deterioration need to be investigated and some forms of Batten could respond to chemical chaperone or substrate reduction therapy being used in non-brain-affecting lysosomal storage diseases. Animal models such as mice, dogs and sheep, and even fruit flies, Zebra fish and yeast have been developed to facilitate these studies.

Genetics: The so-called “knock out mouse” models are extremely important to study enzyme and genetic replacement. The use of adeno-associated virus (AAVrh.10) in five CLN2 children has shown it to be non-toxic but whether intravenous, intraventricular or direct brain injections will be successful in restoring enzyme activity remains to be determined.

Enzyme replacement: This has been shown to be effective in other storage diseases not involving the brain and it is within our current expertise to manufacture recombinant tripeptidylpeptidase1 (for CLN2 children). If it can be shown that such enzymes can be delivered to the brain via intraventricular introduction or by direct injection into the cerebral I cortex with subsequent diffusion and uptake by the neurons, then we will have a highly specific therapy.

Neuronal stem cell replacement: This is another possible avenue for specific treatment and a Phase 1 study on four LINCL and two INCL children is in progress.

Neurotrophic factors: These might be used to repair cells already damaged provided no further damage occurs. What is learned from studying Batten disease will apply to the treatment of many different brain diseases such as Alzheimers and Parkinsons.

IMPACT:

What is the impact of Batten disease? Today Batten disease is the most common neurogenetic storage disease of infancy and childhood. The total frequency of all four types may be as high as one in 12,500 births, similar to other common genetic disorders. An inherited disorder. Batten disease is carried as an autosomal recessive gene; this means that if both parents carry the gene, the child has a 25 percent chance of being affected.

Additionally. each child has a 50 percent chance of inheriting the recessive gene from either of his parents and, thus, becoming a carrier. perpetuating the potential for occurrence in subsequent generations.

The emotional and economic impact on the afflicted individuals and their families is overwhelming. Society also bears the burden of the economic costs of this disease Estimates for the supervision and care for one child for one year range from $50,000 to $100,000 Total costs for skilled nursing care and medical care over the childs’ lifetime can reach several million dollars.

Growing interest in Batten disease has resulted in the development of specific research centers at a number of prestigious institutes throughout the world.