What is Batten?

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What is Batten disease?

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. ¹⁸These disorders all affect the nervous system with increasing seizures, movement disorders, altered thought processes, and cognitive decline. Childhood NCLs include vision loss but adult onset forms of the disease typically do not. ^3,15 Although Batten disease was originally used to describe only the juvenile or CLN3 form, the term “Batten disease” is widely used in the US and UK to refer to all forms of NCL.

The CLN3 form of Batten disease

CLN3, often called juvenile Batten disease, is an ultra-rare, fatal, inherited disorder that primarily affects the nervous system and left untreated, is fatal. Children with CLN3 disease develop normally, even excelling in school until ages 5–6 years, when progressive vision loss becomes noticeable.⁵ Shortly thereafter, parents report personality changes and behavioral issues. Typically, within 2–3 years after symptom onset, total vision loss occurs, and seizures begin. This is followed by declining speech and the progressive loss of motor coordination. Eventually, children become wheelchair-bound, bed-ridden, and die in their late teens to late twenties. Some children display heart arrhythmias in their late teens requiring pacemakers. Psychosis, hallucinations and/or dementia can appear anytime during the disease.^18,28 While this is the general order of symptoms as they appear, affected children and young adults can vary significantly in the time it takes to develop the next symptom and not every child experiences every symptom listed.

What causes CLN3 disease?

CLN3 disease results from mutations (mistakes) in the CLN3 gene (blueprint) responsible for making CLN3 protein. For a quick explanation of how mistakes in the genes of healthy parents can create CLN3 disease, take a look at this short video. More than Sixty-seven (67) different mutations in the CLN3 gene have been shown to cause juvenile Batten disease (NCL Resource).²⁷ However, 74% of children with the disease are missing the same string of 966 DNA building blocks in one or both of their mutated CLN3 genes. This is known as the “～1kb deletion.”²⁴ Researchers believe that children with these deletions make a shortened version of the normal protein which gets stuck on a cellular highway before it gets to its work sites.²³

Where is CLN3 protein?

All of us are made up of cells, each with the basic biological equipment needed to keep that cell alive. The nucleus acts as a command center storing DNA blueprints. Ribosomes make proteins from those instructions. The Golgi Apparatus (golgi) sorts and addresses proteins (cellular workhorses) for distribution to their work sites. The Rough Endoplasmic Reticulum (RER) provides transportation. Mitochondria act as batteries to create energy for these processes. Vacuoles store food, water and sometimes waste. Lysosomes, filled with caustic enzymes, digest waste. CLN3 protein is found in the walls of all of these compartments.

What is it doing there?

So what is CLN3 protein doing in all of these places? The short answer is that we don’t know. For many years, researchers have been trying to understand the CLN3 protein by working backwards. Just like accident reconstructionists work backwards from multicar pileups to determine whether and to what degree excessive speed, poor visibility, and driver errors contribute to the cause or severity of an accident, CLN3 disease researchers have been working to determine which abnormalities (i.e. problems with intracellular movement of amino acids, changes in metabolism, failed calcium homeostasis, lysosomal pH, vacuolar maturation, vacuolar protein sorting, endocytosis, vesicular trafficking, lipid transport, etc) happen because CLN3 protein is missing, are further down the pathological chain reaction, or contribute to disease. ^{6,8,11-14,16,17,21,23,29,30,32} How, what, where, why and when is critically important to the creation of new medicines. The first or the most devastating events represent the most plausible drug.

Lysosomal CLN3

The most intense focus of investigation has been CLN3 protein’s potential role in the lysosome as its absence clearly results in the impaired degradation of cellular material, and the subsequent accumulation of ceroid lipopigment (fat and protein). Studies in the laboratory of Thomas Braulke demonstrate that CLN3 deficient cells show reduced quantities, 28 of 60 protein-degrading enzymes and 11 lipid-degrading enzymes when compared with healthy lysosomes.³³The most simplistic conclusion from these findings is that CLN3 protein is somehow responsible for helping these enzymes move from ribosomes, golgi and RER to their lysosomal worksites. This would explain why CLN3 is found in these sites as well as lysosomes. However, this does not explain why CLN3 would be in the nuclear envelope, the plasma membrane surrounding the cell, or mitochondria. Recent studies suggest that lysosomes are not just degradation centers. Lysosomes are also important for nutrient sensing, energy metabolism, immune responses, cellular repair and signaling between organelles.^1,4,19,20,31 Therefore, just like the lysosome itself, CLN3’s job may be complex. As for what CLN3 is doing in all of those other places, it could be doing the same job, a different job, or both.

For more details the CLN3 gene and the CLN3 protein, click here for access to, “The CLN3 gene and protein: What we know” published in the Journal of Molecular Genetics and Genomic Medicine December 7, 2019. Led by BBDF, 10 members of 9 laboratories in the US and Europe, along with BBDF scientists, reviewed 1,729 research reports, conducted 13 patent searches, pored over 14 US federally-funded scientific databases, and searched 3 international scientific funding/results portals. Investigators then traced back each finding to its original source and compiled the information on the CLN3 gene and protein into a reference manual to provide researchers with quick access to original reports on regulation, structure, tissue distribution, and pathological responses to its deficiency. Compiling pertinent information into a single source document for quick access is one of the ways BBDF supports existing and incoming researchers.

For information on diagnosing CLN3 disease click here.

How common is juvenile Batten disease?

While a worldwide incidence rate is difficult to confirm, individual studies in various countries suggest rates range from 0.2 – 7 per 100,000 live births (see below).

References

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