Information on the following diseases can be found in the Related Disorders section of this report:

• Adrenoleukodystrophy
• Metachromatic Leukodystrophy (MLD)
• Krabbe's Leukodystrophy
• Alexander's Disease
• Balo Disease
• Tay-Sachs Disease

Children with Canavan disease are usually healthy and develop normally until the age of approximately 3-5 months. Symptoms begin with the loss of previously acquired mental and physical skills (developmental regression) or are first noted when children fail to achieve early milestones. Affected children never develop good head control or the ability to roll over. Other early symptoms may include general unresponsiveness (apathy), severe lack of muscle tone (hypotonia), and/or loss of motor skills. Affected children are sometimes irritable early on and are not able to sit, stand, walk or talk. As the disease progresses, affected infants may have involuntary muscle contractions in the arms and legs (spasticity), exaggerated reflex responses (hyperreflexia), weakness of the neck muscles (atonicity) that support the head, and/or paralysis. Older children may have sleep disturbances, seizures, and feeding problems. Other symptoms may include excessive thirst, episodes of sweating, paleness, fever, and/or vomiting. The head typically becomes progressively enlarged as the brain swells (hydrocephaly) and the bones of the skull usually fail to fuse normally.

When the muscles of the chest become weak, children with Canavan disease may be susceptible to repeated respiratory infections. Degeneration of the optic nerve fibers (optic atrophy) can lead to visual impairment. Hearing is usually not impaired. Life-threatening complications may occur in the first few years of life or later on, and life expectancy is often into the teens.
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Canavan disease is caused by an abnormality in the ASPA gene that leads to a deficiency of the enzyme aspartoacylase. Canavan disease is inherited as an autosomal recessive genetic 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 the same abnormal gene for the same trait from each parent. If an individual receives 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 defective gene and, therefore, 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 and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

Symptoms associated with the progressive degeneration of the central nervous system develop due to the insufficient levels of the active enzyme asparatoacylase. This enzyme breaks down (metabolizes) N-acetylaspartic acid, which is present in high levels in the brain. Breakdown of this acid may act to trigger certain chemical reactions which are required for proper brain function (e.g., formation of the coverings on nerve cells [myelination]). It is also possible that excessively high levels of N-acetylaspartic acid may damage the brain directly.

The defective gene responsible for Canavan disease has been mapped to chromosome 17 (17pter-p13). 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, "chromosome17pter-p13" refers to band 13 to the end of the short arm of chromosome 17. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
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Canavan disease is a rare disorder that affects males and females in equal numbers. This disease tends to affect families of Eastern European Jewish ancestry more frequently than individuals of other ethnic groups. In this population, the carrier frequency may be as high as one in 40-58 people; therefore, the risk for an affected child born to Ashkenazi Jewish parents is between 1/6,400 and 1/13,456. The carrier frequency in non-Jews has not been determined but is thought to be much lower.
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Symptoms of the following disorders can be similar to those of Canavan disease. Comparisons may be useful for a differential diagnosis:

There are many other types of leukodystrophy that may have similar symptoms caused by demyelination of nerve fibers. Adrenoleukodystrophy is a rare inherited metabolic disorder characterized by the loss of the fatty covering (myelin sheath) around nerve fibers in the brain (cerebral demyelination) and the progressive degeneration of the adrenal gland. The symptoms of this disorder may include generalized muscle weakness (hypotonia), exaggerated reflex responses (hyperreflexia), impaired ability to coordinate movement (ataxia), spastic partial paralysis, and/or tingling or burning sensations in the arms or legs. (For more information on this disorder, choose "adrenoleukodystrophy" as your search term in the Rare Disease Database.)

Metachromatic leukodystrophy (MLD) is a rare inherited leukodystrophy characterized by the abnormal accumulation of a fatty-like substance known as sulfatide in the tissues of the nervous system and other organs. This results in the loss of the coverings on nerve fibers (myelin sheath). Symptoms may include blindness, convulsions, muscle rigidity (hypertonia) and/or motor disturbances that may lead to paralysis and dementia. (For more information on this disorder, choose "metachromatic leukodystrophy" as your search term in the Rare Disease Database.)

Krabbe's leukodystrophy is a rare inherited metabolic disorder characterized by the abnormal accumulation of a fatty substance (ceremide galactoside) in the brain. Symptoms develop due to a deficiency of the enzyme galactoside beta-galactosidase. These may include irritability, vomiting, episodes of partial unconsciousness, and/or seizures. There may also be spastic contractions of the legs, difficulty swallowing, and mental deterioration. (For more information on this disorder, choose "Krabbe" as your search term in the Rare Disease Database.)

Alexander's disease is an extremely rare inherited, progressive metabolic disorder. It is one of the subtypes of leukodystrophy. Alexander's disease is characterized by the loss of fatty layers that cover nerve fibers (demyelination) and the formation of abnormal fibers (Rosenthal) in the brain. The symptoms may include muscle spasms, mental impairment, and/or growth delays. Most infants with Alexander's disease have an abnormally large head (macrocephaly), failure to thrive, and seizures. (For more information on this disorder, choose "Alexander" as your search term in the Rare Disease Database.)

Balo disease is a rare neurological disorder characterized by the rapid, progressive loss of the fatty covering (myelin sheath) around nerve fibers in the brain (demyelination). This disease typically affects children, although some cases have been reported in adults. Children with Balo disease experience a gradual onset of muscle spasms and paralysis. Other neurological symptoms develop depending on the areas of the brain that are affected and may include intellectual impairment and/or physiological abnormalities. (For more information on this disorder, choose "Balo" as your search term in the Rare Disease Database.)

Tay-Sachs disease is a rare inherited disorder that results in the progressive destruction of the central nervous system. The body in unable to properly metabolize certain fats (lipid) due to the absence of the enzyme hexosaminidase A. Individuals of eastern European Jewish ancestry have a higher risk to carry the gene for Tay-Sachs disease than do other ethnic groups, but affected children are born to couples of many different ethnic backgrounds. Infants with Tay-Sachs disease usually develop normally until the age of 6 or 9 months, when symptoms may become obvious. Symptoms may include an abnormal startle response (reflex), muscle weakness (hypotonia), restlessness, and/or abnormal eye movements. Eventually a child with Tay-Sachs disease experiences a loss of cognitive skills. (For more information on this disorder, choose "Tay-Sachs" as your search term in the Rare Disease Database.)
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Diagnosis
The diagnosis of Canavan disease may be made based on high levels of N- acetylaspartic acid (NAA) in urine using gas chromatograph-mass spectrometry (GC-MS). NAA levels are also elevated in blood and spinal fluid from affected infants, but urine testing is sufficient for diagnosis. Mutation analysis of the ASPA gene is available to confirm the diagnosis. Over 30 different disease-causing mutations have been identified in the ASPA gene. Three specific gene mutations are responsible for 99% of the cases of Canavan disease in the Ashkenazi Jewish population. These three gene mutations account for 50-55% of the cases in non-Jews.

Prenatal diagnosis of Canavan disease is available through amniocentesis by measuring the level of NAA in the fluid that surrounds the developing fetus (amniotic fluid) at 16-18 weeks of gestation. If both parents have known ASPA gene mutations, prenatal diagnosis is available using chorionic villus sampling in which a sample of placental cells is removed at 10-12 weeks gestation for mutation analysis.

Treatment
Treatment of Canavan disease is symptomatic and supportive. Supportive care may alleviate some discomfort. Physical therapy and early intervention may help to improve posture and communication skills, respectively. Feeding tubes may be useful if swallowing difficulties occur. Genetic counseling and carrier testing will benefit families in which this disease occurs.
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Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

A gene therapy trial is underway in which normal ASPA genes are being introduced into the brains of children affected with Canavan disease in an attempt to increase aspartocyclase levels. For more information about this trial contact:

Paola Leone, Ph.D.
Associate Professor
University of Medicine and Dentistry of New Jersey/RWJ Medical School
Director, Cell and Gene Therapy Center
401 Haddon Ave. Room 390
Camden, N.J. 08103
Phone: 856-757-7744: Fax: 856-757-9647
Leonepa@umdnj.edu

Another therapy being explored for Canavan disease is the introduction of normal neuronal stem cells into the brains of affected children in an effort to increase the number of neurons that produce aspartoacyclase. Drugs are being studied to determine if it is possible to reduce fluid and/or decrease the NAA enzyme in the brains of affected children. For more information about these studies contact:

National Tay Sachs and Allied Diseases Association
2001 Beacon St., Suite 204
Boston, MA 02135
Phone: 617-277-4463; Fax: 617-277-0134
http://www.ntsad.org
info@ntsad.org

Two children with Canavan disease were treated with topiramate, an antiepileptic drug. The children experienced a decrease in rate of head growth (megalencephaly) that is associated with Canavan disease. The relationship between topiramate and the decrease in head growth rate is unknown. More research is necessary to determine the long-term safety and effectiveness of this potential symptomatic treatment for Canavan disease.

Passel-Clark L and Pearl P. Leukodystrophy (Canavan Disease). In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003:550-551.

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore, MD: The Johns Hopkins University; Entry No. 271900 Last Update: 9/23/03.

Matalon R. (Updated 10/3/01). Canavan Disease. In: GeneReviews at Genetests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2003. Available at http://www.genetests.org (accessed 10/03).

Topcu M, Yalnizoglu D, Saatci I, et al. Effect of topiramate on enlargement of the head in Canavan disease: a new option for treatment of megalencephaly. Turk J Pediatr. 2004;46:67-71.

Kaul R, Gao GP, Balamurugan K, et al. Spectrum of Canavan mutations among Jewish and non-Jewish patients. Am J Hum Genet. 1994;55:A212.

Matalon R and Matalon KM. Canavan disease prenatal diagnosis and genetic counseling. Obstet Gynecol Clin North Am 2002:29:297-304.

Sugarman EA Allitto BA. Carrier testing for seven diseases common in the ashkenazi jewish population: implications for counseling and testing. Obstet Gynecol 2001;97:S38-S39.

Traeger EC and Rapin I. The clinical course of Canavan disease. Pediatr Neurol 1998;18:207-12.

Matalon R. Canavan disease:diagnosis and molecular analysis. Genet test 1997;1:21-25.

Gordon N. Canavan disease:a review of recent developments Eur J Paediatr Neurol 2001;5:65-69.

Leone P, Janson CG Bilaniuk L, et al. Aspartoacyclase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease. Ann Neurol 2000;48-9-10.