- Beyond Batten Disease Foundation - https://beyondbatten.org -

State of the Science



History of Batten disease

Four children with probable Juvenile Batten disease were first described by Otto Christian Stengel, MD, in 1826 (C 1826). He noted that four siblings developed normally until each began to lose their sight around six years old leading to blindness followed by progressive mental decline, loss of speech, seizures and death. The disease, however, is named after Frederick Batten, MA, MD, FRCP, when he reported almost 100 years later on two sisters with vision loss, neurocognitive decline and motor problems separating it from recently discovered Tay-Sachs disease and macular degeneration (FE 1903, FE 1914).


Juvenile Batten disease

Juvenile Batten disease is one of a group of disorders known as neuronal ceroid lipofuscinoses (NCLs). Over 400 different errors (mutations) in 13 segments of DNA (genes) have been attributed to various forms of Batten, which differ from one another primarily by when symptoms first appear (Mole , Mitchison, Lim et al. 2004, Chabrol, Caillaud et al. 2013, Mole SE 2013). These disorders all affect the nervous system with increasing seizures, movement disorders, altered thought processes, and cognitive decline. Childhood NCLs also include vision loss but adult onset Batten typically does not (Boehme, Cottrell et al. 1971, Burneo, Arnold et al. 2003, Sims, Cole et al. 2011). Although Batten disease was originally used to describe only the juvenile form, the term “Batten disease” is widely used to refer to all forms of NCL.


The CLN3 gene

Juvenile Batten disease results from mutations (mistakes) in the CLN3 gene (blueprint) responsible for making CLN3 protein. More than 60 different mutations in the CLN3 gene have been shown to cause juvenile Batten disease (Mole , 2011). However, most children with the disease are missing the same string of 966 DNA building blocks from the CLN3 gene; this mutation is known as the “1kb deletion.” Click here [1]  for more information on the CLN3 gene and its protein.


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 color when viewed under an ultraviolet light microscope. The lipopigments build up in brain cells 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 a more powerful electron microscope. All NCLs form deposits. JNCL deposits which look like fingerprints. Healthy lysosomes regularly dispose of these lipofuscins just as they recycle and get rid of other cellular wastes.


Many cells in the body contain CLN3 protein: skin cells (the cells that are biopsied for diagnosis), muscle cells, kidney cells, liver cells, etc. However, these cells don’t die from having malformed or absent CLN3 protein, and it’s unclear whether they’re affected by all of that material that builds up. So why are neurons so harshly – and uniquely – affected?


Neurons have advanced communication skills. They communicate information through both chemical and electrical signals via specialized structures called axons and dendrites. We aren’t sure why neurons are selectively affected, but we know that these cells are particularly susceptible to damage when their recycling centers fail to work properly, which occurs in many neurodegenerative diseases like JNCL, the other NCLs, and over two-thirds of the 50 lysosomal storage diseases. Although the genetic basis for many of these diseases is clear and some of the biochemistry of missing or affected proteins is well understood, the cellular mechanisms by which deficiencies in these proteins disrupt neuronal viability remain ambiguous. One analogy is to think of neurons as the Lamborghini of cells, capable of providing high performance but delicate.


Research Progress

For over 100 years, researchers have been investigating the cause and mechanism of Juvenile Batten disease. Until 1995 when the genetic culprit, the CLN3 gene, was located, progress was quite slow(1995). By the late 1990s, rapid technological advances in the development of small animal models and molecular biology techniques aided research efforts and helped to add significant knowledge to our understanding of the disease.


We need to capitalize upon new knowledge and advanced technologies being applied to other neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease. We must recruit the best and brightest from our nation’s 173 medical schools and 261 doctoral programs as well as Pharmaceutical Industry experts and scientific thought leaders from around the world. We must provide them with salary support, specialized training, seed money and technological resources that open the door to even great opportunity. We need to build upon the following advances:
























As you can see, even though Juvenile Batten disease has been known to exist for over 100 years, most of the research progress has been made in the last few years. For many families across America and around the world, this is quite literally a race against time. Science provides hope for a cure, but in order to turn this hope into reality, we need to raise enough capital to fund multi-year research programs, drug discovery projects, and clinical trials.

Because Juvenile Batten disease is so rare, affecting several hundred children in the United States, research aimed at finding a cure is also extremely underfunded. Of the $31.3 billion awarded by the U.S. Department of Health and Human Services for medical research in 2016, 1.67 million went to financing research for Juvenile Batten disease. Other rare diseases such as childhood leukemia, which is 8 times more prevalent than juvenile Batten disease, received 100 times more funding than juvenile Batten disease.

While these various avenues of clinical research reflect the progress in our search for a treatment for NCLs, increasingly vulnerable funding sources threaten the ability of these scientists to continue their pursuit for a cure. The best hope we have for a treatment is in empowering investigators to continue their research into the mechanisms of NCLs to identify targets for therapies, work with the pharmaceutical industry to create drugs that match those targets and together, move potential treatments through clinical trials delivering them to children and families suffering from these devastating diseases.[/vc_column_text][vc_column_text]References

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