NORD gratefully acknowledges Reuben Matalon, MD, PhD, Professor of Pediatrics, Professor of Biochemistry and Molecular Biology, University of Texas Medical Branch, for assistance in the preparation of this report.
Canavan disease is rare genetic neurological disorder characterized by the spongy degeneration of the white matter in the brain. Affected infants may appear normal at birth, but usually develop symptoms between 3-6 months of age. Symptoms may include an abnormally large head (macrocephaly), lack of head control, severely diminished muscle tone resulting in "floppiness," and delays in reaching developmental milestones such as independent sitting and walking. Most affected children develop life-threatening complications by 10 years of age. Canavan disease occurs because of mutations in the aspartoacylase (ASPA) gene that affects the breakdown (metabolism) of the N-acetylaspartic acid (NNA). It is inherited as an autosomal recessive condition.
Canavan disease belongs to a group of disorders known as the leukodystrophies. The leukodystrophies are a group of rare, progressive, metabolic, genetic disorders that can affect the brain, spinal cord and often the nerves outside the central nervous system (peripheral nerves). Each type of leukodystrophy is caused by an abnormality affecting a specific gene that results in abnormal development of one of at least 10 different chemicals that make up the white matter of the brain. The white matter is tissue composed of nerve fibers. Many of these nerve fibers are covered by a collection of fats (lipids) and proteins known as myelin. Myelin, which collectively may be referred to as the myelin sheath, protects the nerve fibers, acts as an insulator and increases the speed of transmission of nerve signals. Each type of leukodystrophy affects a different part of the myelin sheath, leading a range of different neurological problems.
The symptoms and progression of Canavan disease varies from case to case. The disorder usually becomes apparent between 3 and 6 months of age and the initial symptoms usually include extremely poor head control, an abnormally large head (macrocepahly), and severely diminished muscle tone (hypotonia) resulting in “floppiness.” Affected infants may be generally unresponsive (apathetic), lethargic or irritable. Some infants may experience difficulty swallowing (dysphagia), which contributes to feeding difficulties.
Affected infants also show delays in reaching developmental milestones (e.g., sitting or standing unassisted) and most never walk independently. The progressive loss of abilities requiring the coordination of mental and muscular activity (psychomotor regression) and mental retardation also become apparent during infancy. Most affected infants do learn to smile, laugh, raise their heads and interact socially.
Additional symptoms that affect children with Canavan disease include seizures, sleep disorders, feeding difficulties, nasal regurgitation, backflow of acid from the stomach to the esophagus (reflux) sometimes associated with vomiting, and 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). Optic atrophy may cause reduced visual responsiveness. In most case, hearing is unaffected, but hearing loss can occur.
As affected infants age, hypotonia may eventually develop into spasticity, a condition characterized by involuntary muscle spasms that result in slow, stiff movements of the legs. Affected individuals may eventually exhibit uncontrolled rigid extensions and rotations of the arms, legs, fingers, and toes (decerebrate rigidity) or paralysis. Canavan disease eventually progresses to cause life-threatening complications; however, the severity and progression of the disease varies. Some individuals develop life-threatening complications in infancy; others live beyond their teen-age years.
In the last few years, a mild form of Canavan disease has been recognized, with characteristic mutations of the ASPA gene and only slightly increased NAA in the urine. These children may be only slightly delayed, can learn and go to school. The head may be somewhat enlarged, but the typical white matter changes associated with Canavan may be absent. The prognosis is certainly much better.
Canavan disease is caused by disruptions or changes (mutations) to the aspartoacylase (ASPA) gene. This mutation 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 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.
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, “chromosome 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The ASPA contains instructions for developing (encoding) aspartoacylase, an enzyme that breaks down (metabolizes) N-acetylaspartic acid (NAA). NAA is a compound that researchers believe plays a vital role in maintaining the brain’s white matter. Deficient or inactive aspartoacylase results in the accumulation of NAA in brain tissue. The symptoms of Canavan disease result from damage to the white matter from the abnormally high levels of NAA.
Canavan disease affects males and females in equal numbers. It affects all ethnic groups, but occurs with greater frequency in individuals of Ashkenazi Jewish descent. In this population, the carrier frequency is estimated to be as high as one in 40-58 people. The risk for an affected child born to Ashkenazi Jewish parents is between 1 and 6,400 and 1 in 13,456. The carrier frequency in other populations is not known, but most likely far lower. The overall incidence of Canavan disease in the general population is unknown.
A diagnosis of Canavan disease may be suspected in infants with the characteristic findings of the disorder (e.g., poor head control, macrocephaly, etc.). A diagnosis may be confirmed by a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests. Such tests may include may include gas chromatography-mass spectrometry, a device that can detect elevated levels of NAA in the urine. Elevated levels of NAA can also be detected in the blood and cerebrospinal fluid (CSF). Examination of certain connective tissue cells from the skin (cultured fibroblasts) can reveal deficiency of the enzyme aspartoacylase. Aspartoacylase activity is also absent in white blood cells.
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 (CVS) in which a sample of placental cells is removed at 10-12 weeks gestation for mutation analysis.
The treatment of Canavan disease is directed toward the specific symptoms that are apparent in each individual. Supportive care may alleviate some discomfort. Physical therapy and early intervention may help to improve posture and communication skills, respectively. If swallowing difficulties occur, feeding tubes may be useful to ensure proper nutrition and hydration. Seizures may be treated with anti-seizure (anti-convulsant) medications.
Genetic counseling and carrier testing will benefit families in which this disease occurs.
Researchers are studying gene therapy for the treatment of children with Canavan disease. In gene therapy, healthy copies of the defective ASPA gene are inserted into the brains of affected children. These genes then produce the enzyme aspartoacylase required to breakdown NAA. Children treated with gene therapy have shown marked improvement of symptoms. More research is necessary to determine the long-term safety and effectiveness of gene therapy as a potential treatment for individuals with Canavan disease.
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 web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
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For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Contact for additional information about Canavan disease:
Reuben Matalon, MD, PhD
Professor of Pediatrics
Professor of Biochemistry and Molecular Biology
Director Biochemical & Molecular Genetics
University of Texas Medical Branch
301 University Blvd, Galveston, Texas 77555-0359
van Passel-Clark L, Pearl PL. Leukodystrophy (Canavan Disease). NORD Guide to Rare Disorders. Philadelphia, PA: Lippincott Williams & Wilkins; 2003: 550-1.
Rowland LP. Ed. Merritt’s Neurology. 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2000:555-6.
Janson CG, McPhee SW, Francis J, et al., Natural history of Canavan disease revealed by proton magnetic resonance spectroscopy (1H-MRS) and diffusion-weighted MRI. Neuropediatrics. 2006;37:209-21.
Surendran S, Michals-Matalon K, Quast MJ, et al. Canavan disease: a monogenic trait with complex genomic interaction. Mol Genet Metab. 2003;80:74-80.
Olsen TR, Tranebjaerg L, Kvittingen EA, et al., Two novel aspartoacylase gene (ASPA) missense mutations specific to Norwegian and Swedish patients with Canavan disease. J Med Genet. 2002;39:55-8.
Janson C, McPhee S, Bilaniuk L, et al. Clinical protocol. Gene therapy of Canavan disease: AAV-2 vector for neurosurgical delivery of aspartoacylase gene (ASPA) to the human brain. Hum Gene Ther. 2002;20:1391-412.
Matalon R, 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.
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.
Traeger EC, 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.
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, Michals-Matalon K. Canavan Disease. 1999 Sep 16 [Updated 2011 Aug 11]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1234/ Accessed May 12, 2015.
National Institute of Neurological Disorders and Stoke. NINDS Canavan Disease Information Page. http://www.ninds.nih.gov/disorders/canavan/canavan.htm Last Updated June 13, 2013. Accessed May 12, 2015.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Canavan Disease. Entry No: 271900. Last Edited May 13, 2008. Available at: http://omim.org/entry/271900 Accessed May 12, 2015.
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