Batten disease explained

Batten disease
Field:Endocrinology
Synonyms:Spielmeyer–Vogt–Sjögren–Batten disease, Batten–Mayou disease, Vogt–Spielmeyer disease
Onset:5 to 10 years old
Causes:Genetic
Frequency:2 to 4 per 100,000 births in the US

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 common name for a group of disorders called the neuronal ceroid lipofuscinoses (NCLs).[1]

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).[2] 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 Battenin, the protein encoded by the CLN3 gene.[3] [4] It was first described in 1903.[1]

Signs and symptoms

Signs and symptoms of the disorder usually appear around ages 5–10 years, with gradual onset of vision problems or seizures.[5] 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.[6]

Over time, affected children experience 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.[7] [8]

Females with juvenile Batten disease show first symptoms a year later than males, but on average die a year sooner.[9]

Cause

NCLs are a family of diseases that are inherited in an autosomal recessive manner. Collectively referred to as Batten disease, NCLs are responsible for most paediatric neurodegenerative diseases. The specific type of NCL is characterized by the age of symptomatic onset and genetic mutation involved. Currently, mutations in ten genes are believed to lead to the development of Batten disease; "the incidence is as high as one in 12,500 live births".

NCL diseases

Juvenile NCL: CLN3 mutation

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 frameshift 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.[12]

Diagnosis

Batten disease is rare; misdiagnosis 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 of the disease. Partial or complete loss of vision often develops in patients who have childhood forms of Batten disease, while it is usually preserved in those with adult-onset Batten disease.[13] Children or adults suspected of having Batten disease should initially see 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.[14] Though it is also seen in a variety of other diseases, a loss of ocular cells is 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:

Treatment

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 three years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase-1 (TPP1) deficiency. Human clinical trials of a gene therapy for the CLN5 variant of Batten disease began at the University of Rochester in 2022.[16] Palliative treatment is symptomatic and supportive. One drug, an antisense oligonucleotide, milasen,[17] described in The New England Journal of Medicine,[18] is believed to be the first "custom" treatment for a genetic disease. It is named after Mila Makovec, the only patient who may ever take it.[19]

History

Batten disease is named after the British pediatrician Frederick Batten, who first described it in 1903.[20] Also known as SpielmeyerVogtSjögren–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.[6]

Research

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.[21]

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.[22]

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.[23] By early December, the child had recovered well enough to return home, and some signs of speech returning were reported.[24] 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.[25] [26] The patients' medical, neurological, and neuropsychological conditions, following transplantation, appeared consistent with the normal course of the disease.[26]

In 2010, Cherie and Jim Flores donated $2 million, the biggest gift in Batten disease research history, and the Beyond Batten Disease Foundation contributed $500,000 to establish laboratories for Italian researchers Drs. Ballabio, Sardiello and their colleagues at the Jan and Dan Duncan Neurological Research Institute of Texas Children's Hospital.

During 2011, the first controlled clinical trials began with the University of Rochester for a treatment for Batten Disease. The trial included 30 patients who were experiencing signs of the disease in the hope of slowing its progress.[26] [27]

In November 2013, Weill Medical College of Cornell University began recruiting participants for a safety study of a gene transfer vector, described as a non-randomised safety and efficacy trial.As part of a trial began by University of Rochester in March 2014. Mycophenolate mofetil is being tested to determine its efficacy and safety using a gene transfer vector.[28] [27] [29]

In April 2019, Haney et al. delivered brain soluble lysosomal enzyme TPP1 to treat the disease. Results showed an increased survival rate in late-infantile neruonal ceroid lipofuscinosis (LINCL) mice following treatment. Treatment also showed decreased neuroinflammation, a common side effect that leads to neuronal damage and death, compared to that of mice treated with just saline.[30]

In complex diseases such as Batten, therapies that address multiple aspects of the disease at the same time have the potential for higher impact than those focusing on one aspect. "The use of several treatment strategies might offer additional benefits to patients with neurodegenerative disease, but the benefits of this approach must be weighed carefully against the additional adverse effects that combined treatments might bring," the researchers wrote. The medical team also noted that "over the past two decades, scientists and clinicians within the Batten disease community have worked to ensure that tools are in place to enable progress towards effective treatments at an unprecedented pace. "Recent progress in Batten disease research offers hope that efficient and targeted therapies will be available soon," the researchers said, noting that "the Batten disease research community is becoming a model of how effective, efficient rare disease research can be accomplished by working together."

See also

External links

Notes and References

  1. Web site: Batten Disease Fact Sheet National Institute of Neurological Disorders and Stroke . www.ninds.nih.gov . 30 November 2020.
  2. Hobert JA, Dawson G . Neuronal ceroid lipofuscinoses therapeutic strategies: past, present and future . Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease . 1762 . 10 . 945–53 . October 2006 . 17049436 . 10.1016/j.bbadis.2006.08.004. free .
  3. Rakheja D, Narayan SB, Bennett MJ . Juvenile neuronal ceroid-lipofuscinosis (Batten disease): a brief review and update . Current Molecular Medicine . 7 . 6 . 603–8 . September 2007 . 17896996 . 10.2174/156652407781695729.
  4. Cooper JD . 32126291 . Moving towards therapies for juvenile Batten disease? . Experimental Neurology . 211 . 2 . 329–31 . June 2008 . 18400221 . 10.1016/j.expneurol.2008.02.016.
  5. Book: Basu . Ishita . Perry . Michael . Perry . Michael . Diseases and Injuries to the Head, Face and Neck: A Guide to Diagnosis and Management . 2021 . Springer . Switzerland . 978-3-030-53098-3 . 109 . https://books.google.com/books?id=qKQeEAAAQBAJ&dq=Becker's+sign+graves+aortic&pg=PA109 . en . 2. Initial assessment of the "Head and Neck" patient.
  6. Ostergaard . JR . Juvenile neuronal ceroid lipofuscinosis (Batten disease): current insights. . Degenerative Neurological and Neuromuscular Disease . 2016 . 6 . 73–83 . 10.2147/DNND.S111967 . 30050370. 6053093 . free .
  7. Batten Disease - National Institute of Neurological Disorders and Stroke . www.ninds.nih.gov .
  8. Mole . Sara E. . Williams . Ruth E. . Neuronal Ceroid-Lipofuscinoses – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY . GeneReviews . 1993 . University of Washington, Seattle. 20301601 .
  9. Cialone J, Adams H, Augustine EF . Females experience a more severe disease course in Batten disease . Journal of Inherited Metabolic Disease . 35 . 3 . 549–55 . May 2012 . 22167274 . 3320704 . 10.1007/s10545-011-9421-6. etal.
  10. Jalanko . Anu . Braulke . Thomas . 2009 . Neuronal ceroid lipofuscinoses . Biochimica et Biophysica Acta (BBA) - Molecular Cell Research . 1793 . 4 . 697–709 . 10.1016/j.bbamcr.2008.11.004 . 19084560. free .
  11. Web site: Warren Recognizes Batten Disease Awareness Day . https://ghostarchive.org/varchive/youtube/20211221/tzkeEJzAGgE . 2021-12-21 . live. . June 4, 2018 . May 30, 2020.
  12. 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. 2 . 111–124. 10.1385/nmm:1:2:111. 12025857 . 33921126 .
  13. Simonati . A . Williams . RE . Neuronal Ceroid Lipofuscinosis: The Multifaceted Approach to the Clinical Issues, an Overview. . Frontiers in Neurology . 2022 . 13 . 811686 . 10.3389/fneur.2022.811686 . 35359645. 8961688 . free .
  14. Bozorg . S . Ramirez-Montealegre . D . Chung . M . Pearce . DA . Juvenile neuronal ceroid lipofuscinosis (JNCL) and the eye. . Survey of Ophthalmology . July 2009 . 54 . 4 . 463–71 . 10.1016/j.survophthal.2009.04.007 . 19539834. 4139962 .
  15. Web site: Noah's Hope - Causes and Symptoms of Batten Disease. www.noahshope.com. 2016-11-22. https://web.archive.org/web/20161123053737/http://www.noahshope.com/cause.php. 2016-11-23. dead.
  16. Web site: Biochemistry . Department of . 2022-08-02 . Trial of world-first gene therapy for Batten disease . 2024-04-13 . www.otago.ac.nz . en.
  17. Web site: A Drug Was Made For Just One Child, Raising Hopes About Future Of Tailored Medicine . Chen . Angus . October 15, 2019 . May 30, 2020.
  18. 10.1056/NEJMoa1813279 . 31597037 . Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease . New England Journal of Medicine . 381 . 17 . 1644–1652 . 2019 . Kim . Jinkuk . Hu . Chunguang . Moufawad El Achkar . Christelle . Black . Lauren E. . Douville . Julie . Larson . Austin . Pendergast . Mary K. . Goldkind . Sara F. . Lee . Eunjung A. . Kuniholm . Ashley . Soucy . Aubrie . Vaze . Jai . Belur . Nandkishore R. . Fredriksen . Kristina . Stojkovska . Iva . Tsytsykova . Alla . Armant . Myriam . Didonato . Renata L. . Choi . Jaejoon . Cornelissen . Laura . Pereira . Luis M. . Augustine . Erika F. . Genetti . Casie A. . Dies . Kira . Barton . Brenda . Williams . Lucinda . Goodlett . Benjamin D. . Riley . Bobbie L. . Pasternak . Amy . Berry . Emily R. . 6961983 . 29.
  19. Kim . J . Hu . C . Moufawad El Achkar . C . Black . LE . Douville . J . Larson . A . Pendergast . MK . Goldkind . SF . Lee . EA . Kuniholm . A . Soucy . A . Vaze . J . Belur . NR . Fredriksen . K . Stojkovska . I . Tsytsykova . A . Armant . M . DiDonato . RL . Choi . J . Cornelissen . L . Pereira . LM . Augustine . EF . Genetti . CA . Dies . K . Barton . B . Williams . L . Goodlett . BD . Riley . BL . Pasternak . A . Berry . ER . Pflock . KA . Chu . S . Reed . C . Tyndall . K . Agrawal . PB . Beggs . AH . Grant . PE . Urion . DK . Snyder . RO . Waisbren . SE . Poduri . A . Park . PJ . Patterson . A . Biffi . A . Mazzulli . JR . Bodamer . O . Berde . CB . Yu . TW . Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease. . The New England Journal of Medicine . 24 October 2019 . 381 . 17 . 1644–1652 . 10.1056/NEJMoa1813279 . 31597037. 6961983 . 204030052 .
  20. Batten FE . Cerebral degeneration with symmetrical changes in the maculae in two members of a family . Transactions of the Ophthalmological Societies of the United Kingdom . 1902 . 23 . 386–90.
  21. Worgall S, Sondhi D, Hackett NR . 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 . May 2008 . 18473686 . 10.1089/hum.2008.022. etal. 10.1.1.553.872 .
  22. 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. 10.1016/j.expneurol.2007.09.012. 4418195. 17963751.
  23. "A stem cell first at OHSU " The Portland Tribune, Nov 24, 2006
  24. News: First recipient of new Batten's disease stem cell cure well enough to go home • PET . 22 June 2022 . PET . 9 June 2009.
  25. Web site: A Phase I Study of the Safety and Preliminary Effectiveness of Human CNS Stem Cells (HuCNS-SC) in Patients With Neuronal Ceroid Lipofuscinosis Caused by Palmitoyl Protein Thioesterase 1 (PPT1) or Tripeptidyl Peptidase 1 (TPP-I) Deficiency . clinicaltrials.gov . 13 January 2015.
  26. Selden . NR . Al-Uzri . A . Huhn . SL . Koch . TK . Sikora . DM . Nguyen-Driver . MD . Guillaume . DJ . Koh . JL . Gultekin . SH . Anderson . JC . Vogel . H . Sutcliffe . TL . Jacobs . Y . Steiner . RD . Central nervous system stem cell transplantation for children with neuronal ceroid lipofuscinosis. . Journal of Neurosurgery. Pediatrics . June 2013 . 11 . 6 . 643–52 . 10.3171/2013.3.PEDS12397 . 23581634.
  27. Web site: Augustine . Erika . Phase II, Randomized, Placebo Controlled Trial of the Safety and Tolerability of Mycophenolate in Children With Juvenile Neuronal Ceroid Lipofuscinosis . 7 May 2019 . clinicaltrials.gov.
  28. Augustine . EF . Beck . CA . Adams . HR . Defendorf . S . Vierhile . A . Timm . D . Weimer . JM . Mink . JW . Marshall . FJ . Short-Term Administration of Mycophenolate Is Well-Tolerated in CLN3 Disease (Juvenile Neuronal Ceroid Lipofuscinosis). . JIMD Reports . 2019 . 43 . 117–124 . 10.1007/8904_2018_113 . 29923092. 6323012 . 978-3-662-58613-6 .
  29. Sondhi . Dolan . Kaminsky . Stephen M. . Hackett . Neil R. . Pagovich . Odelya E. . Rosenberg . Jonathan B. . De . Bishnu P. . Chen . Alvin . Van de Graaf . Benjamin . Mezey . Jason G. . Mammen . Grace W. . Mancenido . Denesy . Xu . Fang . Kosofsky . Barry . Yohay . Kaleb . Worgall . Stefan . Kaner . Robert J. . Souwedaine . Mark . Greenwald . Bruce M. . Kaplitt . Michael . Dyke . Jonathan P. . Ballon . Douglas J. . Heier . Linda A. . Kiss . Szilard . Crystal . Ronald G. . Slowing late infantile Batten disease by direct brain parenchymal administration of a rh.10 adeno-associated virus expressing CLN2 . Science Translational Medicine . 2 December 2020 . 12 . 572 . eabb5413 . 10.1126/scitranslmed.abb5413 . 33268510 . 8056991 . en . 1946-6234.
  30. Haney . Matthew J. . Klyachko . Natalia L. . Harrison . Emily B. . Zhao . Yuling . Kabanov . Alexander V. . Batrakova . Elena V. . June 2019 . TPP1 Delivery to Lysosomes with Extracellular Vesicles and their Enhanced Brain Distribution in the Animal Model of Batten Disease . Advanced Healthcare Materials . en . 8 . 11 . 1801271 . 10.1002/adhm.201801271 . 2192-2640 . 6584948 . 30997751.