The Three Blind Mice: Life with Juvenile Batten Disease

The Three Blind Mice: Life with Juvenile Batten Disease

“It is important to understand the epidemiology and etiology of juvenile Batten disease so that we can develop treatments to help people like the Chappell family, preventing others from meeting the same sombre fate.”

Years and years of suffering, capped off by three deaths in three days. A parent should never have to describe their children’s lives in this way. Unfortunately, this is the reality for the Chappell family.1 With three children, Christopher, Elizabeth, and James, all suffering from juvenile Batten disease, their lives were never easy. In September of 2017, the family decided to take their children off life support, putting an end to their suffering from this fatal yet rare genetic disease. Known affectionately as the three blind mice, the siblings developed vision problems and seizures early on in life.1 Eventually, the disease progressed to the point where they all lost the ability to swallow, leading their parents to make the heartbreaking decision to take them off life support rather than tube-feeding them for the rest of their lives. It is important to understand the epidemiology and etiology of juvenile Batten disease so that we can develop treatments to help people like the Chappell family, preventing others from meeting the same sombre fate.

The disease that Christopher, Elizabeth, and James suffered from is one of a group of genetic disorders, known as the neuronal ceroid-lipofuscinoses (NCLs). NCLs are a set of autosomal recessive neurodegenerative disorders that affect about one in 100,000 people.2 NCLs are more common in Scandinavian countries, with prevalence rates as high as nine in 100,000. Juvenile Batten disease is the most common of the NCLs. The disease is characterized by the buildup of lipopigments, which are composed of fats and proteins, in nerve cells.3 These lipopigments are easily recognized as they are naturally fluorescent and often appear as distinctive crescent shapes under the microscope.

In 1826, Dr. Otto Christian Stengle observed four siblings of apparently healthy parents who began to lose their eyesight around age six.3 This was the first described case of what is now known as juvenile Batten disease. Characteristically, juvenile Batten disease presents as gradual visual failure between the ages of four to nine, eventually progressing to blindness.4 The oldest Chappell child, Christopher, had trouble seeing since the young age of three; his parents recall that he would stand too close to the television while watching cartoons.1 Vision failure is typically followed by cognitive and motor decline, and generalized epileptic seizures.4,5 The brain also undergoes some physical changes.4 Namely, brain weight decreases due to degeneration in both grey and white matter. By the third decade of life, patients become unable to walk, and death often occurs shortly after.4,5 In the more unfortunate cases, like those of the Chappell siblings, death can come earlier. James, the youngest of the three children, was just 15 years old at the time of death.1

Juvenile Batten disease is caused by mutations in a gene called CLN3.6 To date, 67 of these mutations have been discovered.7 However, most cases of the disease have the same mutation: a missing string of DNA known as the 1-kb deletion. CLN3 is found in many places throughout the body, including grey matter, peripheral nerves, and pancreatic islet cells.4 The CLN3 gene produces the CLN3 protein (CLN3P), which is found in cells. Overall, the specific function of CLN3P is unknown. However, through research on animal models, CLN3P has been implicated in various important cellular functions, including neurotransmission,8 Golgi trafficking,9 and pH maintenance.10

As previously mentioned, juvenile Batten disease is characterized by the buildup of fatty lipopigments in nerve cells. Healthy cells can dispose of these lipopigments using a cellular structure called lysosomes, which are organelles primarily responsible for cellular recycling and waste removal.11 They also play a role in other processes, like cell-cell communication, membrane repair, protein transport, and cell nutrient status.12 They carry out these functions with the help of various lysosome-associated proteins. In 1998, researchers made the connection between juvenile Batten disease and lysosomes, as CLN3P is found in lysosomes.13 Thus, a mutation in the CLN3 gene will cause the formation of a defective lysosomal protein, meaning lysosomes can no longer effectively dispose of lipopigments. Lipopigments will build up in the lysosomes, eventually causing neuron degradation and death.13 Notably, defective lysosomal function is linked to other neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, which is why there are similar symptoms present between all these diseases.12 Therefore, to help those like the Chappell family, we need to capitalize on knowledge and technologies being applied to these other neurodegenerative diseases.

Currently, there is no cure for juvenile Batten disease. Patients have access to drugs that manage seizures and other symptoms, but nothing that stops the relentless progress of the disease as a whole.14 However, since the discovery of the CLN3 gene and its connection to lysosomes, many promising treatments are being developed. One possible treatment involves transcription factor EB (TFEB), which is known as the lysosome’s master regulator.15 TFEB is responsible for controlling lysosomal proliferation, expression of degradative enzymes, autophagy, and lysosomal exocytosis, among other functions. By applying trehalose, a sugar, to mouse models with juvenile Batten disease, researchers found that the lysosomes were better able to recycle lipopigments, increasing survival rates overall.15 The treatment is effective because trehalose increases the activity of TFEB, allowing for greater lysosomal function. Treatments like these give promise to those affected by juvenile Batten disease, and will hopefully extend their lifespans.


“The struggle of juvenile Batten disease is something that no child should have to experience.”

Juvenile Batten disease is an autosomal recessive neurodegenerative disorder that is a part of the group of diseases known as the NCLs. The disease has a detrimental effect on patients’ lives, shown by the struggle that the Chappell family had to face through the losses of Christopher, Elizabeth, and James. Unfortunately, the Chappell siblings have a younger brother, 10-year-old Samuel, who has also been diagnosed with the disease.1 The struggle of juvenile Batten disease is something that no child should have to experience. Therefore, we must continue to research this disease and its possible treatments to help provide hope for these suffering children. Even though we have come a long way in understanding the disease, there is still a long way to go.


Works Cited:

1. Bever L. Three goodbyes in three days: Why these parents watched their children die at home. The Washington Post. September 26, 2017. https://www.washingtonpost.com/news/morning-mix/wp/2017/09/26/three-goodbyes-in-three-days/?utm_term=.5110a8b29435.

2. Simpson NA, Wheeler ED, Pearce DA. Screening, diagnosis and epidemiology of Batten disease. Expert Opin Orphan Drugs. 2014; 2(9): 903-910. doi: 10.1517/21678707.2014.935762.

3. Haltia M. The neuronal ceroid-lipofuscinoses: From past to present. Biochim Biophys Acta - Mol Basis Dis. 2006; 1762(10): 850-856. doi: 10.1016/j.bbadis.2006.06.010.

4. Rakheja D, Narayan SB, Bennett MJ. Juvenile Neuronal Ceroid-Lipofuscinosis (Batten Disease): A Brief Review and Update. Curr Mol Med. 2007; 7(6): 603-608. doi: 10.2174/156652407781695729.

5. Hofmann, S., Peltonen, L. The Neuronal Ceroid Lipofuscinoses. In: Scriver, CR, Beaudet, AL, Sly, WS and Valle, D, eds, The Molecular and Metabolic Database of Inherited Disease. New York, NY: McGraw-Hill; 2001.

6. Mole SE, Williams RE. Neuronal Ceroid-Lipofuscinoses. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews. Seattle, WA: University of Washington, Seattle; 1993.

7. CLN3 Mutation Table. NCL Resource - A Gateway for Batten Disease. MRC Laboratory for Molecular Cell Biology Web site. http://www.ucl.ac.uk/ncl/CLN3mutationtable.htm. Updated November 13, 2017.

8. Luiro K, Kopra O, Lehtovirta M, Jalanko A. CLN3 protein is targeted to neuronal synapses but excluded from synaptic vesicles: new clues to Batten disease. Hum Mol Genet. 2001; 10(19): 2123-2131. doi: 10.1093/hmg/10.19.2123.

9. Persaud-Sawin D-A, Mousallem T, Wang C, Zucker A, Kominami E, Boustany R-MN. Neuronal Ceroid Lipofuscinosis: A Common Pathway? Pediatr Res. 2007; 61(2): 146-152. doi: 10.1203/pdr.0b013e31802d8a4a.

10. Golabek AA, Kida E, Walus M, Kaczmarski W, Michalewski M, Wisniewski KE. CLN3 Protein Regulates Lysosomal pH and Alters Intracellular Processing of Alzheimer’s Amyloid-β Protein Precursor and Cathepsin D in Human Cells. Mol Genet Metab. 2000; 70(3): 203-213. doi: 10.1006/mgme.2000.3006.

11. Maxfield FR, Willard JM, Lu S. Lysosomes: Biology, Diseases, and Therapeutics. Hoboken, NJ: John Wiley & Sons; 2016.

12. Appelqvist H, Wäster P, Kågedal K, Öllinger K. The lysosome: from waste bag to potential therapeutic target. J Mol Cell Biol. 2013; 5(4): 214-226. doi: 10.1093/jmcb/mjt022.

13. Järvelä I, Sainio M, Rantamäki T, et al. Biosynthesis and Intracellular Targeting of the CLN3 Protein Defective in Batten Disease. Hum Mol Genet. 1998; 7(1): 85-90. Available at: https://www.ncbi.nlm.nih.gov/pubmed/9384607.

14. Cooper JD. Moving towards therapies for Juvenile Batten disease? Exp Neurol. 2008; 211(2): 329-331. doi: 10.1016/j.expneurol.2008.02.016.

15. Palmieri M, Pal R, Nelvagal HR, et al. mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases. Nat Commun. 2017; 8: 14338. doi: 10.1038/ncomms14338.


Cite This Article:

Sharpe I., Chan G., Zhang B., Palczewski K., Lewis K., Ho J. The Three Blind Mice: Life with Juvenile Batten Disease. Illustrated by C. Scavuzzo. Rare Disease Review. June 2018. DOI:10.13140/RG.2.2.29892.53125.

Pulling the Plug on Orphan Drug Policy

Pulling the Plug on Orphan Drug Policy

Repeal of the Orphan Drug Tax Credit: A Step Backwards

Repeal of the Orphan Drug Tax Credit: A Step Backwards