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.
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).
|· In Canada, the incidence of CLN3 disease is estimated to be 0.6 per 100,000 live births||MacLeod et al 1976|
|· In Central Europe, the reported incidence of CLN3 disease varies from 0.2-1.5 per 100,000 live births||Claussen et al 1992,
Cardona and Rosati, 1995
|· The incidence of CLN3 disease in Scandinavia varies from 2.0 to 7.0 per 100,000 live births||Uvebrant and Hagberg, 1997|
|· Estimated incidence of CLN3 is 0.7 per 100,000 live births||Mole et al 2011|
|· The number of living CLN3 patients currently registered with the Batten Disease Support and Research Association (BDSRA) is 115 patients in the U.S. in 2015.||Sleat et al 2016|
|· CLN3 disease affects and estimated 200 patients in the US||Gary Clark, personal communication, February 21, 2017|
|· CLN3 disease is the most common type of NCL, but its exact prevalence is unknon; more than 400 cases have been described in the scientific literature.
· All forms of NCL affect an estimated 1 in 100,000 individuals worldwide.
|Genetics Home Reference, 2020;
National Organization for Rare Disorders, 2020
|· In the US, juvenile Batten (CLN3) disease along with the other forms of neuronal ceroid lipofuscinoses, occurs in approximately 3 of 100,000 births.||National Organization for Rare Disorders, 2020|
|· All forms of Batten disease affect an estimated 2 to 4 out of every 100,000 children in the US||National Institute of Neurological Disorders and Stroke, 2020|
- Ballabio A. The Awesome Lysosome. EMBO Mol Med. 2016. Feb;8(2): 73-76.
- Batten Disease Fact Sheet. (n.d.). Retrieved February 5, 202, from https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Batten-Disease-Fact-Sheet.
- Berkovic SF, Staropoli JF, Carpenter S, et al. Diagnosis and misdiagnosis of adult neuronal ceroid lipofuscinosis (Kufs disease). Neurology. 2016;87:579-584.
- Boya P. Lysosomal function and dysfunction: mechanism and disease. Antioxid. Redox Signal. 2012. Sep 1;17(5):766-774.
- Bozorg S, Ramirez-Montealegre D, Chung M, et al. Juvenile neuronal ceroid lipofuscinosis (JNCL) and the eye. Surv Ophthalmol. 2009. Jul-Aug;54(4):463-71.
- Cao Y, Espinola JA, Fossale E, et al. Autophagy is disrupted in a knock-in mouse model of juvenile neuronal ceroid lipofuscinosis. J Biol Chem. 2006. Jul 21;281(29):20483-93.
- Cardona R and E Rosati. Neuronal ceroid-lipofuscinoses in Italy: an epidemiological study. Am J Med Genet. 1995 Jun 5;57(2):142-3.
- Chandrachud U, Walker MW, Simas AM, et al. Unbiased Cell-based Screening in a Neuronal Cell Model of Batten Disease Highlights an Interaction between Ca2+ Homeostasis, Autophagy, and CLN3 Protein Function. J Biol Chem. 2015. 290,14361-14380.
- Claussen M, Heim P, Knispel J, et al. Incidence of neuronal ceroid-lipofuscinoses in West Germany: variation of a method for studying autosomal recessive disorders. Am J Med Genet. 1992. Feb 15;42(4):536-8.
- CLN3 Disease: National Library of Medicine (US). Genetics Home Reference [Internet]. Bethesda (MD): The Library; 2013 Sep 16. CLN3 disease; [reviewed 2017 Jan; cited 2020 Jan]; [about 7 screens]. Available from: https://ghr.nlm.nih.gov/condition/cln3-disease
- Codlin S and SE Mole. S. pombe btn1, the orthologue of the Batten disease gene CLN3, is required for vacuole protein sorting of Cpy1p and Golgi exit of Vps10p. J Cell Sci. 2009. Apr 15;122(Pt 8):1163-73.
- Cotman SL and JF Staropoli. The juvenile Batten Disease protein, CLN3, and its role in regulating anterograde and retrograde post-Golgi trafficking. Clin Lipidol. 2012. Feb;7(1):79-91.
- Fossale E, Wolf P, Espinola JA, et al. Membrane trafficking and mitochondrial abnormalities precede subunit c deposition in a cerebellar cell model of juvenile neuronal ceroid lipofuscinosis. BMC Neurosci. 2004. Dec 10;5:57.
- Gachet Y, Codlin S, Hyams JS, et al. btn1, the Schizosaccharomyces pombe homologue of the human Batten disease gene CLN3, regulates vacuole homeostasis. J Cell Sci. 2005. 118, 5525-5536.
- Genetic and Rare Disease Information Center (GARD ). Adult neuronal ceroid lipofuscinosis. September 1, 2016. Available at: https://rarediseases.info.nih.gov/diseases/10973/adult-neuronal-ceroid-lipofuscinosis Accessed: December 23, 2019.
- Hobert JA and G Dawson. A novel role of the Batten disease gene CLN3: association with BMP synthesis. Biochem Biophys Res Commun. 2007. Jun22;358(1):111-116.
- Kim Y, Ramirez-Montealegre D, Pearce DA. A role in vacuolar arginine transport for yeast Btn1p and for human CLN3, the protein defective in Batten disease. Proc Natl Acad Sci. 2003. 100,15458-15462.
- Kohlschutter A, Schulz A, Bartsch U, et al. Current and Emerging Treatment Strategies from Neuronal Ceroid Lipofuscinoses. CNS Drugs. 2019;33(4):315-325.
- Korolchuk, VI, Saiki S, Lichtenberg M, et al. Lysosomal positioning coordinates cellular nutrient responses. Nat Cell Biol. 2011 April; 13(4):453-460.
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- Luiro K, Yliannala K, Ahtiainen L, et al. Interactions of CLN3, Hook1 and Rab proteins link Batten disease to defects in the endocytic pathway. 2004. Dec 1;13(23):3017-27.
- MacLeod PM, Dolman CL, Chang E, et al. The neuronal ceroid lipofuscinoses in British Columbia: a clinical epidemiologic and ultrastructural study. Birth Defects Orig Artic Ser. 1976;12(6):289-96.
- Metcalf DJ, Calvi AA, Seaman MNj, et al. Loss of the Batten disease gene CLN3 prevents exit from the TGN of the mannose 6-phosphate receptor. Traffic. 2008. Nov;9(11):1905-14.
- Mirza M, Vainshtein A, DiRonza A, et al. The CLN3 gene and protein: What we know. Mol Genet Genomic Med. 2019. Dec;7(12).
- Mole, Sara. The Neuronal Ceroid Lipofuscinoses (Batten Disease): 78 (Contemporary Neurology Series) . OUP Oxford. Kindle Edition.
- National Organization for Rare Disorders (2016, December 16). Juvenile CLN3 Disease. (n.d.). Retrieved February 5, 2020, from https://rarediseases.org/rare-diseases/batten-disease/
- NCL Resource: A Gateway for Batten Disease [Internet]. London: University College London; Available from: http://www.ucl.ac.uk/ncl-disease. Accessed December 23, 2016.
- Ostergaard JR. Juvenile neuronal ceroid lipofuscinosis (Batten disease): current insights. Degener Neurol Neuromuscul Dis. 2016. August 1:6:73-83.
- Padilla-Lopez, S and Pearce DA. Saccharomyces cerevisiae lacking Btn1p modulate vacuolar ATPase activity to regulate pH imbalance in the vacuole. J Biol Chem. 2006. 281,10273-10280.
- Pears MR, Codlin S, Haines RL, et al. Deletion of btn1, an orthologue of CLN3, increases glycolysis and perturbs amino acid metabolism in the fission yeast model of Batten disease. Mol Biosyst. 2010 Jun;6(6):1093-102.
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- Sleat DE, Gedvilaite E, Zhang Y, et al. Analysis of large-scale whole exome sequencing data to determine the prevalence of genetically-distinct forms of neuronal ceroid lipofuscinosis. Gene. 2016. Nov 30;593(2):284-91.
- Uvebrant P and B Hagberg. Neuronal ceroid lipofuscinoses in Scandinavia. Epidemiology and clinical pictures. Neuropediatrics. 1997. Feb;28(1):6-8.
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