doi: 10.1053/ejpn.2000.0426 available online at http://www.idealibrary.com on Ill~i" European Journal of Paediatric Neurology 2001 ; 5(Suppl. A): 3-5

R E V I E W A R T I C L E

Batten disease r e s e a r c h - where we were - where we a r e - where we are going

J ALFRED RIDER, DEAN L RIDER Children's Brain Diseases Foundation, San Francisco, California, USA

The modem era of Batten disease research began in 1968 with the creation of the Children's Brain Diseases Foundation, whose goal was to discover the cause and cure of Batten disease. The first steps were to create local, national and international awareness for this condition and to sort out the various theories as to the cause; such as, viral diseases, toxicity, disorders in lipid metabolism, abnormalities in peroxide metabolism and genetic defects. At that time, there was no definitive clinical diagnostic test, and it was by no means clear that this was a genetic disease. In the ensuing years, by providing seed money to various inves- tigators and finally, with the enlistment of the support of the National Institute of Neurological Disorders and Stroke (NINDS), significant advances have been made. It is now clear that Batten disease or neuronal ceroid lipofuscinosis (NCL) is the most common recessive neurogenetic disease in children and may occur as frequently as one in 12 500 births depending upon ethnicity. There are three major types in children; infantile (CLN1); late infantile (CLN2); and juvenile (CLN3) with a number of variants. The disease is characterized by an accu- mulation of a yellow fluorescent pigment in the brain cells, which probably is the result of metabolic derangements and marks the progres- sive deterioration in brain function. Progressive changes in personality and behaviour and a decline in learning ability; clumsiness, stumbling and failing vision soon follow. As the child deteriorates progressively, motor co-ordination is lost, blind- ness develops, mental changes become severe and seizures become more frequent.

These changes are particularly devastating in young children who have just begun to experience

life; their declines are often quite precipitous and most die within a few years. In general, the earlier the onset of the disease, the quicker the demise. Although in rare instances, death may not occur until the patient is well into the forties. Unfortunately, at the present time, there is no definitive treatment for Batten disease.

In 1995, a group in Finland, working with other researches at the University of Texas Southwestern medical centre, isolated the gene defect; mutations in the palmitoyl-protein thioesterase gene localized on chromosome lp32, were causing the infantile form of Batten disease) The International Batten Disease Consortium, in 1995, isolated the genetic defect in the juvenile form of Batten disease and found it to be on chromosome 16p12.1. 2

Researches in England, headed by Doctor Mark Gardiner, in 1996, identified the area that contains the gene for the classical late infantile form of Batten disease. 3 It lies on chromosome 11p15 and the gene for a variant form of the late infantile lies on chromosome 15q21-23.

Doctor Peter Lobel and his group at the Center for Advanced Biotechnology and Medicine in New Jersey, in 1997, using a unique approach, looking at lysosomal enzymes, instead of concentrating on which of the 100000 genes are defective, discovered the molecular basis for the late infantile form of Batten disease by identifying the single protein that is absent in the late infantile Batten disease which appeared to be a pepstatin-insensitive lysomal peptidase. 4 Since then, Junaid et al. (2000) have purified the pepstatin proteinase, s

At the present time, at least eight forms of Batten disease have been recognized. However,

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4 Review article: J A Rider, D L Rider

the specific gene defect has not been identified in several of these and furthermore, there are some families with clinical pathological features of Batten disease who cannot be classified with these eight forms.

It is now possible to prevent disease by appro- priate use of genetic counselling, identification of carriers and where appropriate, use of amnio- centesis or chorionic biopsies in the course of a pregnancy. Families who are at high risk can be readily identified.

Numerous test animals, dogs, sheep and mice, have been identified who have diseases similar to some of the forms of Batten disease. These have facilitated research.

The future is now here, and the gates have been swung wide open.

Prevention

As with any disease, prevention is always better than treatment. It is recommended that all pro- spective parents be tested for the various forms of Batten d isease- especially, if there is any family history. All newborn infants should be tested in a similar manner, so that when definitive treatment becomes available, it can be started before irrever- sible brain damage takes place.

Treatment

Pharmaceuticals

Pharmaceuticals that might slow down the brain deterioration need to be further investigated such as, gentamicin, chloroquine and carnitine. Animal models are essential to implement these studies.

Genetics

The so-called 'knockout' mouse models are extre- mely important for the study of enzymes and genetic replacement. The use of adeno-associated virus may play a significant role as a carrier for a specific gene for replacement. Whether intra- venous, intraventricular or direct brain injections will be successful remains to be determined.

recombinant enzymes. If it can be shown that enzymes can be delivered to the brain via intraventricular introduction or by direct injection into the cerebral cortex with subsequent diffusion and uptake by the neurons, we will have a highly specific therapy.

Neuronal stem cell replacement is another possible avenue for specific treatment as there are suggestions that it can be successful in treatment of neurodegenerative diseases.

Neurotrophic factors might be used to repair cells already damaged provided no further damage occurs.

Finally, it is obvious that without research funds research cannot proceed. Private foundations such as the Children's Brain Diseases Foundation and the Batten Disease Support and Research Associa- tion are essential to raise money and support the initial or early research studies. Seed money is extremely important to enable research to begin and continue until significant results are obtained. The major long-term funding in the USA, however, must come from the National Institutes of Health (NIH), NINDS. In the last several congressional appropriations bills, the NIH has been criticized for the slow pace of Batten disease research. For example, in the 2000-2001 appropriation budget, the following wording appears:

The Committee is disappointed with the pace of research in Batten disease. The Committee believes that the Institute should actively solicit grant applications for Batten disease and also take aggressive steps to assure that a vigorous research program be established. In recent years, funding for this disease has decreased. The Committee requests that NINDS be prepared to discuss the funding history and steps taken to increase research in this area. The Committee strongly urges that increased funding be provided to combat this devastating disease.

With this pressure to provide funds and stimu- late research, we can expect to see an expanded increase in research activity - leading to definitive treatment.

In summary, we have come a long way since 1968. We are on the verge of feasible specific therapy. Prevention, however, remains a corner stone in the overall picture.

Enzyme replacement

This may be an extremely important treatment. It is within our current expertise to manufacture

References

1 Vessa J, Hellsten E, Verkruyse LA. Mutations in the palmitoyl protein thioesterase gene causing infantile

Review article: Batten disease research 5

neuronal ceroid lipofuscinosis. Nature 1995; 376: 584-587. The International Batten Disease Consortium. Isola- tion of a novel gene underlying Batten disease, CLN3. Cell 1995; 82: 949-967. Sharp JD, Wheeler RB, Lake BD et al. Loci for classical and a variant late infantile neuronal ceroid lipofusci- nosis map to chromosomes 11p15 and 15Q21-23. Hum Mol Genet 1997; 6: 591-595.

4 Sleat DE, Donnelly RJ, Lackland H et al. Association of mutations in a lysomal protein with classical late- infantile neuronal ceroid lipofuscinosis. Science 1997; 277: 1802-1804.

5 Junaid MA, Wu G, Pullarkat RK. Purification and characterization of bovine brain lysomal pepstatin- insensitive proteinase, the gene product deficient in the human late-infantile neuronal ceroid lipofuscino- sis. J Neurochem 2000; 66: 287-294.