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Science & Disease
The Three Blind Mice: Life with Juvenile Batten Disease
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.
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.
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.
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|Synonyms||Spielmeyer-Vogt-Sjögren-Batten disease, Batten-Mayou disease, Vogt-Spielmeyer disease|
|Usual onset||5 to 10 years old |
|Frequency||3 per 100,000 births |
Batten disease is a fatal disease of the nervous system that typically begins in childhood.  Onset of symptoms is usually between 5 and 10 years of age.  Often it is autosomal recessive . It is the most common form of a group of disorders called the neuronal ceroid lipofuscinoses (NCLs).
Although Batten disease is usually regarded as the juvenile form of NCL (or “type 3”), some physicians use the term Batten disease to describe all forms of NCL. Historically, the NCLs were classified by age of disease onset as infantile NCL (INCL), late infantile NCL (LINCL), juvenile NCL (JNCL) or adult NCL (ANCL).  At least 20 genes have been identified in association with Batten disease, but juvenile NCL, the most prevalent form of Batten disease, has been linked to mutations in the CLN3 gene.  
It was first described in 1903. 
- 1 Signs and symptoms
- 2 Cause
- 2.1 NCL diseases
- 2.2 Juvenile NCL: CLN3 mutation
- 3 Diagnosis
- 4 Treatment
- 5 History
- 6 Research
- 7 See also
- 8 References
- 9 External links
Signs and symptoms[ edit ]
Early signs and symptoms of the disorder usually appear around ages 2–10, with gradual onset of vision problems or seizures . Early signs may be subtle personality and behavioral changes, slow learning or regression, repetitive speech or echolalia , clumsiness, or stumbling. Slowing head growth in the infantile form, poor circulation in lower extremities (legs and feet), decreased body fat and muscle mass, curvature of the spine, hyperventilation and/or breath-holding spells, teeth grinding, and constipation may occur.
Over time, affected children suffer mental impairment, worsening seizures, and progressive loss of sight, speech, and motor skills. Batten disease is a terminal disease; life expectancy varies depending on the type or variation.
Females with juvenile Batten disease show first symptoms a year later than males, but on average die a year sooner. 
Cause[ edit ]
NCLs are a family of diseases which are inherited in an autosomal recessive manner. Collectively referred to as Batten disease, NCLs are responsible for the majority of neurodegenerative diseases that affect children. Specifically, the frequency of this disease is about one per 12,500 individuals. The specific type of NCL is characterized by the age of symptomatic onset and genetic mutation involved. Currently, mutations in 10 genes lead to the development of Batten disease. 
Batten disease has an autosomal recessive pattern of inheritance .
NCL diseases[ edit ]
- Infantile neuronal ceroid (INCL): CLN1 encodes for the protein PPT1 which functions as a lysosomal enzyme. 
- Late infantile NCL (LINCL): CLN2 encodes for the protein TPP1 which serves as a lysosomal enzyme.  Life expectancy is between eight and twelve years of age. 
- Juvenile NCL (JNCL): CLN3 encodes for CLN3 , a lysosomal transmembrane protein. 
- Adult NCL: CLN4 has no known associated protein. 
- Finnish variant of late infantile NCL (fLINCL): CLN5 encodes for CLN5 , a soluble lysosomal protein. 
- Variant of the late infantile NCL: CLN6 encodes for the protein CLN6 , which serves as a transmembrane protein of the endoplasmic reticulum. 
- Turkish variant of late infantile NCL: CLN7 or MFSD8, encodes for MFSD8 , which functions as a lysosomal transmembrane protein. 
- Northern epilepsy: CLN8 encodes for CLN8 , a transmembrane protein of the endoplasmic reticulum. 
- Late infantile NCL: CLN10 or CTSD encodes for CTSD , which is a lysosomal protein which a variety of functions. 
- Infantile osteopetrosis: CLCN7 encodes for CLCN7 . 
Juvenile NCL: CLN3 mutation[ edit ]
The CLN3 gene is located on the short arm of chromosome 16 at gene position 12.1 (16p12.1), and mutations within this gene are the major cause of juvenile NCL. More specifically, 73% of Batten disease cases are due to a 1.02-kb deletion within this gene, CLN3, which causes a frame shift which produces a truncated mutant gene product of only 181 amino acids in length when compared to the wild-type gene product of 438 amino acids in length. Normal-functioning CLN3 encodes for a hydrophobic transmembrane protein that is mainly localized to the lysosome; however, the 181 amino acid mutant gene product was instead found to primarily localize to the endoplasmic reticulum and Golgi apparatus. The precise function of the CLN3 gene product remains unknown. 
Diagnosis[ edit ]
Batten disease is rare, so may result in misdiagnosis, which in turn may lead to
increased medical expenses, family stress, and the chance of using incorrect forms of treatment, which may exacerbate the patient’s condition. Nevertheless, Batten disease can be diagnosed if properly detected. Vision impairment is the most common observable symptom to detect the disease. Children are more prevalent, and should be suspected more for juvenile Batten disease.  Children or someone suspected to have Batten disease should initially be seen by an optometrist or ophthalmologist. A fundus eye examination that aids in the detection of common vision impairment abnormalities, such as granularity of the retinal pigment epithelium in the central macula will be performed.  Though it is also seen in a variety of other diseases, a loss of ocular cells should be a warning sign of Batten disease. If Batten disease is the suspected diagnosis, a variety of tests is conducted to help accurately confirm the diagnosis, including:
- Blood or urine tests can help detect abnormalities that may indicate Batten disease. For example, elevated levels of dolichol in urine have been found in many individuals with NCL. The presence of vacuolated lymphocytes—white blood cells that contain holes or cavities (observed by microscopic analysis of blood smears)—when combined with other findings that indicate NCL, is suggestive for the juvenile form caused by CLN3 mutations. 
- Skin or tissue sampling is performed by extracting a small piece of tissue, which then is examined under an electron microscope. This can allow physicians to detect typical NCL deposits. These deposits are common in tissues such as skin, muscle, conjunctiva, and rectum.  This diagnostic technique is useful, but other invasive tests are more reliable for diagnosing Batten disease.
- Electroencephalogram (EEG) is a technique that uses special probes attached on to the individual’s scalp. It records electrical currents/signals, which allow medical experts to analylze electrical pattern activity in the brain. EEG assists in observing if the patient has seizures. 
- Electrical studies of the eyes are used, because as mentioned, vision loss is the most common characteristic of Batten disease. Visual-evoked responses and electroretinograms are effective tests for detecting various eye conditions common in childhood NCLs.
- Computed tomography (CT) or magnetic resonance imaging (MRI) are diagnostic imaging tests which allow physicians to better visualize the appearance of the brain. MRI imaging test uses magnetic fields and radio waves to help create images of the brain. CT scan uses x-rays and computers to create a detailed image of the brain’s tissues and structures. Both diagnostic imaging test can help reveal brain areas that are decaying, or atrophic, in persons with NCL. 
- Measurement of enzyme activity specific to Batten disease may help confirm certain diagnoses caused by different mutations. Elevated levels of palmitoyl-protein thioesterase is involved in CLN1. Acid protease is involved in CLN2. Cathepsin D is involved in CLN10. 
- DNA analysis can be used to help confirm the diagnosis of Batten disease. When the mutation is known, DNA analysis can also be used to detect unaffected carriers of this condition for genetic counseling. If a family mutation has not previously been identified or if the common mutations are not present, recent molecular advances have made it possible to sequence all of the known NCL genes, increasing the chances of finding the responsible mutation(s). 
Treatment[ edit ]
Batten disease is a terminal illness; the FDA has approved Brineura ( cerliponase alfa ) as a treatment for a specific form of Batten disease. Brineura is the first FDA-approved treatment to slow loss of walking ability (ambulation) in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase-1 (TPP1) deficiency. Palliative treatment is symptomatic and supportive.
History[ edit ]
Batten disease is named after the British pediatrician Frederick Batten , who first described it in 1903.   Also known as Spielmeyer – Vogt – Sjögren -Batten disease, it is the most common form of a group of disorders called neuronal ceroid lipofuscinosis (NCL). Although Batten disease is usually regarded as the juvenile form of NCL, some physicians use the term Batten disease to describe all forms of NCL.
Research[ edit ]
Memorial sculpture in Progress Frenchman’s Bay East Park, Pickering , Ontario, Canada, dedicated to the children who have lost or will lose their lives to Batten disease
In June 1987, a phase-I clinical trial was launched at Weill Cornell Medical College of Cornell University to study a gene therapy method for treatment of the signs and symptoms of LINCL. The experimental drug works by delivering a gene transfer vector called AAV2CUhCLN2 to the brain.  Although the trial is not matched, randomized, or blinded and lacked a contemporaneous placebo/sham control group, assessment of the primary outcome variable suggests a slowing of progression of LINCL in the treated children. 
Researchers believe the neurological deficits common in JNCL could be due to overactive AMPA receptors in the cerebellum. To test this hypothesis, researchers administered AMPA antagonist drugs into affected mice. The motor skills of the affected mice showed significant improvement after the antagonist treatment, which supported the hypothesis that the neurological deficits in JNCL are due to overactive AMPA receptors. This research could eventually help to alleviate neurological deficits of JNCL in humans. 
In November 2006, after receiving FDA clearance, neurosurgeon Nathan Selden, pediatrician Bob Steiner, and colleagues at Doernbecher Children’s Hospital at Oregon Health and Science University began a clinical study in which purified neural stem cells were injected into the brain of Daniel Kerner, a six-year-old child with Batten disease, who had lost the ability to walk and talk. This patient was the first of six to receive the injection of a stem cell product from StemCells Inc., a Palo Alto biotech company. These are believed to be the first-ever transplants of fetal stem cells into the human brain.  By early December, the child had recovered well enough to return home, and some signs of speech returning were reported.  Daniel Kerner died on August 20th, 2009.  The main goal of phase-I clinical trials, however, was to investigate the safety of transplantation. Overall, the phase-I data demonstrated that high doses of human neural stem cells, delivered by a direct transplantation procedure into multiple sites within the brain, followed by 12 months of immunosuppression, were well tolerated by all six patients enrolled in the trial. The patients’ medical, neurological, and neuropsychological conditions, following transplantation, appeared consistent with the normal course of the disease.
Mycophenolate mofetil is being tested to determine its ability to safely slow or halt neurodegeneration. A non-randomised safety and efficacy trial of a gene transfer vector is underway.
See also[ edit ]
- Lysosomal storage diseases
References[ edit ]
- ^ a b c d e f “Batten Disease Fact Sheet” . National Institute of Neurological Disorders and Stroke. Retrieved 9 November 2017.
- ^ Hobert JA, Dawson G (October 2006). “Neuronal ceroid lipofuscinoses therapeutic strategies: past, present and future”. Biochimica et Biophysica Acta. 1762 (10): 945–53. doi : 10.1016/j.bbadis.2006.08.004 . PMID 17049436 .
- ^ Rakheja D, Narayan SB, Bennett MJ (September 2007). “Juvenile neuronal ceroid-lipofuscinosis (Batten disease): a brief review and update”. Current Molecular Medicine. 7 (6): 603–8. doi : 10.2174/156652407781695729 . PMID 17896996 .
- ^ Cooper JD (June 2008). “Moving towards therapies for juvenile Batten disease?”. Experimental Neurology. 211 (2): 329–31. doi : 10.1016/j.expneurol.2008.02.016 . PMID 18400221 .
- ^ Cialone J, Adams H, Augustine EF, et al. (May 2012). “Females experience a more severe disease course in Batten disease” . Journal of Inherited Metabolic Disease. 35 (3): 549–55. doi : 10.1007/s10545-011-9421-6 . PMC 3320704 . PMID 22167274 .
- ^ a b Jill M. Weimer; Elizabeth Kriscenski-Perry; Yasser Elshatory; David A. Pearce (2002). “The Neuronal Ceroid Lipofuscinoses: Mutations in Different Proteins Result in Similar Disease”. NeuroMolecular Medicine. 1: 111–124. doi : 10.1385/nmm:1:2:111 .
- ^ a b c d e f g h i j Jalanko Anu, Braulke Thomas (2009). “Neuronal ceroid lipofuscinoses” . Biochimica et Biophysica Acta (BBA) – Molecular Cell Research. 1793: 697–709. doi : 10.1016/j.bbamcr.2008.11.004 .
- ^ https://www.youtube.com/watch?v=tzkeEJzAGgE
- ^ a b Ostergaard, John R (2016-08-01). “Juvenile neuronal ceroid lipofuscinosis (Batten disease): current insights” . Degenerative Neurological and Neuromuscular Disease. 6. doi : 10.2147/DNND.S111967 .
- ^ a b c d e f “Noah’s Hope – Causes and Symptoms of Batten Disease” . www.noahshope.com. Archived from the original on 2016-11-23. Retrieved 2016-11-22.
- ^ synd/7 at Who Named It?
- ^ Batten FE (1902). “Cerebral degeneration with symmetrical changes in the maculae in two members of a family”. Transactions of the Ophthalmological Societies of the United Kingdom. 23: 386–90.
- ^ Clinical trial number NCT00151216 for “Safety Study of a Gene Transfer Vector for Children With Late Infantile Neuronal Ceroid Lipofuscinosis” at ClinicalTrials.gov
- ^ Worgall S, Sondhi D, Hackett NR, et al. (May 2008). “Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA”. Human Gene Therapy. 19 (5): 463–74. doi : 10.1089/hum.2008.022 . PMID 18473686 .
- ^ Kovács, Attila D.; Pearce, David A. (2008-01-01). “Attenuation of AMPA receptor activity improves motor skills in a mouse model of juvenile Batten disease” . Experimental Neurology. The Role of α-synuclein in the Pathogenesis of Parkinson’s Disease / Gene Therapy for Parkinson’s. 209 (1): 288–291. doi : 10.1016/j.expneurol.2007.09.012 . PMC 4418195 . PMID 17963751 .
- ^ ” A stem cell first at OHSU ” The Portland Tribune , Nov 24, 2006
- ^ http://www.technologyreview.com/read_article.aspx?id=17888&ch=biotech [ full citation needed ]
- ^ “Archived copy” . Archived from the original on 2015-10-24. Retrieved 2015-09-21.
External links[ edit ]
|Wikimedia Commons has media related to Batten disease .|
- Batten disease at NINDS
- GeneReviews/NCBI/NIH/UW entry on Neuronal Ceroid-Lipofuscinosis
- NCL resource – Batten disease at University College London
- Batten Disease Support and Research Association (bdsra.org)
- Batten FE, Mayou MS (1915). “Family Cerebral Degeneration with Macular Changes” . Proceedings of the Royal Society of Medicine. 8 (Sect Ophthalmol): 70–90. PMC 2003604 . PMID 19978990 .
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