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Last updated:
October 27, 2016
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NORD gratefully acknowledges Sara E. Mole, PhD, of the MRC Laboratory for Molecular Cell Biology, University College London, for assistance in the preparation of this report.
Summary
Juvenile CLN3 disease, a rare genetic disorder, belongs to a group of progressive degenerative neurometabolic disorders known as the neuronal ceroid lipofuscinoses. These disorders share certain similar symptoms and are distinguished in part by the age at which such symptoms appear. Juvenile CLN3 disease was previously called juvenile neuronal ceroid lipofuscinoses (NCLs). The NCLs are characterized by abnormal accumulation of certain fatty, granular substances (i.e., pigmented lipids [lipopigments] ceroid and lipofuscin) within nerve cells (neurons) of the brain as well as other tissues of the body that may result in progressive deterioration (atrophy) of certain areas of the brain, neurological impairment, and other characteristic symptoms and physical findings.
The symptoms of juvenile CLN3 disease usually become apparent between 5 and 15 years of age when progressive loss of vision, seizures, and progressive neurological degeneration develop. In some individuals, initial symptoms may be less obvious and include clumsiness, balance problems and behavioral or personality changes. Juvenile CLN3 disease is caused by changes (mutations) of the CLN3 gene and is inherited as an autosomal recessive trait. It is the most common form of NCL, is found worldwide, and is found particularly in families of Northern European or Scandinavian ancestry.
Introduction
For many years, the term Batten disease was used to describe the classic juvenile form of NCL (JNCL). Other terms in Scandinavian countries included Vogt-Spielmeyer-Sjogren disease. Recently, families, clinicians and researchers have begun to prefer the use of the term Batten disease to collectively describe all types of neuronal ceroid lipofuscinoses.
The symptoms of juvenile CLN3 disease usually become apparent between 5 and 15 years of age, usually with visual abnormalities that progresses rapidly. Affected children also suffer from problems with their speech, cognitive decline, behavioral changes, and motor decline.
An early finding in juvenile CLN3 disease is the progressive loss of vision characterized by macular degeneration, deterioration of the nerves of the eyes (optic nerves) that transmit impulses from the nerve-rich membrane lining the eyes (retina) to the brain (optic atrophy), and abnormal accumulation of colored (pigmented) material on the retinas (retinitis pigmentosa). Retinitis pigmentosa eventually causes degeneration of the retina leading to progressive loss of vision, and may be the first initial diagnosis. Children with juvenile CLN3 disease often lose their sight by the age of 10.
In some children, the first signs of juvenile CLN3 disease are episodes of uncontrolled electrical disturbances in the brain (seizures) and the loss of previously acquired physical and mental abilities (developmental regression). As affected individuals age, seizures worsen, signs of dementia become apparent, and motor abnormalities similar to those seen in Parkinson’s disease develop. During this period, behavioral and personality changes often occur including mood disturbances, anxiety, psychotic states (such as explosive, unprovoked laughing and/or crying), and hallucinations. Speech disturbances such as stuttering may also occur.
Eventually, usually during the late teens or twenties, additional abnormalities develop including sudden involuntary muscle contractions (myoclonus), muscle spasms (spasticity) that result in slow, stiff movements of the legs, weakness or paralysis of all four limbs (quadriparesis), and sleep disturbances. In most cases, progressive neurological and mental degeneration leaves affected individuals bedridden and unable to communicate easily and eventually results in life-threatening complications by the twenties or thirties.
Juvenile CLN3 disease occurs because of disruptions or changes (mutations) of the CLN3 gene located on the short arm (p) of chromosome 16 (16p12.1). The function of the protein encoded by this gene is not yet understood.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 16p12.1” refers to band 12.1 on the short arm of chromosome 16. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Researchers suspect that juvenile CLN3 disease is caused by alterations within the cell so that the body is unable to break down and recycle substances such as fats, and their associated sugars and proteins in the normal way. Some of these fats, sugars, and proteins then appear to form the lipopigments that accumulate in nerve and other tissue alongside the symptoms associated with this disorder. Although these substances accumulate in most cells, brain cells are affected first.
Juvenile CLN3 disease is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Juvenile CLN3 disease affects males and females in equal numbers. In the United States, juvenile CLN3 disease along with the other forms of neuronal ceroid lipofuscinoses, occurs in approximately three in 100,000 births. It can occur with greater frequency in families of Northern European Scandinavian ancestry; in particular, those of Swedish heritage. It is thought to occur in one in 25,000 infants in northern Europe. Juvenile CLN3 disease is one of the most common neurodegenerative disorders affecting children.
A diagnosis of juvenile CLN3 disease may be made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic physical findings, and a variety of specialized tests including the microscopic examination (i.e., electron microscopy) and study of the chemical components (histochemical examination) of samples of tissue (biopsy), usually from the skin. The study of such tissue samples reveals abnormal accumulations of deposits (i.e., pigmented lipids [lipopigments] ceroid and lipofuscin) in membrane-bound cavities within the body (cytoplasm) of cells (inclusion bodies). In juvenile CLN3 disease these have a characteristic appearance rather like fingerprints. Similar deposits may also be present in other tissues and cells of the body (e.g., certain white blood cells [lymphocytes].
In addition, in children with juvenile CLN3 disease, electroretinography (ERG), a special instrument that measures the retina’s electrical response to light stimulation, may reveal lack of response when the eye is stimulated by light (visually evoked potential [VEP]), confirming progressive retinal pigmentary degeneration and/or optic nerve abnormalities (e.g., optic atrophy). Unique to this type of NCL is the presence of vacuoles in lymphocytes, easily visible at the trailing edges of blood films.
Almost all children affected with juvenile CLN3 disease carry a 1 kb intragenic deletion in the CLN3 gene that can be detected using a simple DNA-based test.
Other forms of NCL such as CLN10, CLN5, CLN6, CLN7, CLN8 diseases may also present at the same age as classic juvenile CLN3 disease. CLN1, CLN2 and CLN10 diseases, regardless of age of onset, can be distinguished by testing for activity of the underlying genes which encode enzymes, providing a firm diagnosis. The other types can be distinguished by comparing the DNA sequence of the respective genes.
Treatment
The treatment of juvenile CLN3 disease is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who diagnose and treat neurological disorders (neurologists), eye specialists (ophthalmologists), physical therapists, psychiatrists, and/or other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.
Specific therapies for juvenile CLN3 disease are symptomatic and supportive. In some cases, treatment with anticonvulsant drugs such as valproate and lamotrigine may help prevent, reduce, or control various types of seizures associated with the condition. Medications may also be used to help psychiatric symptoms such as hallucinations.
Early intervention is important to ensure that children with juvenile CLN3 disease reach their potential. Special services that may be beneficial to affected children may include special remedial education, special social support, and other medical, social, and/or vocational services.
Genetic counseling is recommended for affected individuals and their families.
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TEXTBOOKS
Mole SE, Williams RE, Goebel HH. The neuronal ceroid lipofuscinoses (Batten disease). 2nd edition. Oxford University Press. 2011. pp444.
Behrman RE, Kliegman RM, Jenson HB, eds. Nelson Textbook of Pediatrics. 17th ed. Elsevier Saunders. Philadelphia, PA; 2005:2032.
Dyken PR. Batten Disease. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:516-7.
JOURNAL ARTICLES
Nita DA, Mole SE, Minassian BA. Neuronal ceroid lipofuscinoses. Epileptic Disord. 2016;18:73-88. https://www.ncbi.nlm.nih.gov/pubmed/27629553
Augustine EF, Mink JW. Juvenile NCL (CLN3 disease): emerging disease-modifying therapeutic strategies. Pediatr Endocrinol Rev. 2016;13 Suppl 1:655-662. https://www.ncbi.nlm.nih.gov/pubmed/27491213
Ouseph MM, Kleinman ME, Wang OJ. Vision loss in juvenile neuronal ceroid lipofuscinosis (CLN3 disease). Ann NY Acad Sci. 2016;137:55-67. https://www.ncbi.nlm.nih.gov/pubmed/26748992
Mole SE, Cotman SL. Genetics of neuronal ceroid lipofuscinoses (Batten disease). Biochim Biophys Acta. 2015;1852:2237-2241. https://www.ncbi.nlm.nih.gov/pubmed/26026925
Neverman NJ, Best HL, Hofmann SL, Hughes SM. Experimental therapies in the neuronal ceroid lipofuscinoses. Biochim Biophys Acta. 2015;1852:2292-2300. https://www.ncbi.nlm.nih.gov/pubmed/25957554
Williams R. Juvenile neuronal ceroid lipofuscinoses (CLN3 Batten disease): what kind of epilepsy? Dev Med Child Neurol. 2015;57:312. https://www.ncbi.nlm.nih.gov/pubmed/25523638
Mole SE. Development of new treatments for Batten disease. Lancet Neurol. 2014;13:749-751. https://www.ncbi.nlm.nih.gov/pubmed/24997881
Mole SE, Williams RE, Goebel HH. Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses. Neurogenetics. 2005;6:107-26.
https://www.ncbi.nlm.nih.gov/pubmed/15965709
Mole SE, Mitchison HM, Munroe PB. Molecular basis of the neuronal ceroid lipofuscinoses: mutations in CLN1, CLN2, CLN3, and CLN5. Hum Mutat. 1999;14:199-215. https://www.ncbi.nlm.nih.gov/pubmed/10477428
Boustany RM. Neurology of the neuronal ceroid-lipofuscinoses: late infantile and juvenile types. Am J Med Genet. 1992;533-5. https://onlinelibrary.wiley.com/doi/10.1002/ajmg.1320420421/abstract
Gardiner M, Sanford A, Deadman M, et al. Batten disease (Spielmeyer-Sjogren disease, juvenile onset neuronal ceroid-lipofuscinosis) gene (CLN3) maps to human chromosome 16. Genomics. 1990;8:387-90. https://www.ncbi.nlm.nih.gov/pubmed/2249854
Eiberg H, Gardiner RM, Mohr J. Batten disease (Spielmeyer-Sjogren disease) and haptoglobins (HP): indication of linkage and assignment to chromosome 16. Clin Genet. 1989;36:217-8. https://www.ncbi.nlm.nih.gov/pubmed/2805379
INTERNET
Mole SE. NCL Resource Site–A Gateway for Batten Disease. Available at: https://www.ucl.ac.uk/ncl . Accessed October 26, 2016.
Chang CH. Neuronal Ceroid Lipofuscinoses. Medscape. December 14, 2015. Available at: https://www.emedicine.com/neuro/topic498.htm Accessed October 26, 2016.
Mole SE, Williams RE. Neuronal Ceroid-Lipofuscinoses. 2001 Oct 10 [Updated 2013 Aug 1]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1428/ Accessed October 26, 2016.
National Institute of Neurological Disorders and Stroke. Batten Disease Fact Sheet. May 2011. Available at:https://www.ninds.nih.gov/disorders/batten/detail_batten.htm Accessed On: October 26, 2016.
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:204200; Last Update:010/14/2016. Available from: https://omim.org/entry/204200 Accessed October 26, 2016.
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