GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select for the most up-to-date Resources information.—ED.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Disease characteristics. Canavan disease is characterized by macrocephaly, lack of head control, and developmental delays by the age of three to five months, severe hypotonia, and failure to achieve independent sitting, ambulation, or speech. Hypotonia eventually changes to spasticity. Assistance with feeding becomes necessary. Life expectancy is usually into the teens.
Diagnosis/testing. Diagnosis of Canavan disease in symptomatic individuals relies upon demonstration of very high concentration of N-acetyl aspartic acid (NAA) in the urine. ASPA, the gene encoding the enzyme aspartoacylase, is the only gene known to be associated with Canavan disease. Three common mutations account for about 99% of the disease-causing alleles in Ashkenazi Jewish persons and approximately 50-55% of disease-causing alleles in non-Jewish persons. Molecular genetic testing is clinically available, primarily to persons of Ashkenazi Jewish heritage, for confirmation of the diagnosis, carrier testing, population screening, and prenatal testing.
Management. Treatment for Canavan disease is supportive and directed to providing adequate nutrition and hydration, managing infectious diseases, and protecting the airway. Physical therapy minimizes contractures and maximizes motor abilities and seating posture; special education programs enhance communication skills. Seizures are treated with anti-epileptic drugs. Gastrostomy maintains adequate food intake and hydration when swallowing difficulties exist.
Genetic counseling. Canavan disease is inherited in an autosomal recessive manner. At conception, the sibs of an affected individual have a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Each pregnancy of a couple in which both partners are heterozygous for a disease-causing mutation in the ASPA gene has a 25% chance of resulting in a child with Canavan disease. Prenatal testing for pregnancies at 25% risk is possible when molecular genetic testing has determined the specific ASPA disease-causing allele in both parents. For couples in which one partner is known to be a carrier and the mutation or carrier status of the other is unknown, prenatal testing can be performed by measuring the level of NAA in amniotic fluid at 16-18 weeks.
The triad of hypotonia, macrocephaly, and head lag in an infant after the age of three to five months should raise the suspicion of Canavan disease.
For laboratories offering biochemical testing, see .
N-acetylaspartic acid (NAA)
Urine. The diagnosis of Canavan disease relies upon measurement of the concentration of NAA in the urine using gas chromatography-mass spectrometry (GC-MS). The mean concentration of NAA in the urine in one series was 1440.5 ±873.3 µmol/mmol creatinine in affected individuals and 23.5 ± 16.1 µmol/mmol creatinine in controls.
Note: Some individuals with Canavan disease have lower excretion of NAA, but in these individuals the concentration is nonetheless about fivefold to tenfold what is considered normal [Matalon et al 1993].
Blood and CSF. NAA concentration is also elevated in the blood and cerebrospinal fluid (CSF) of children with Canavan disease, but elevated urine concentration of NAA is sufficient for diagnosis of affected individuals [Matalon et al 1995].
Amniotic fluid. Concentration of NAA, assayed by the stable-isotope dilution method and GC-MS, is elevated in amniotic fluid samples from affected pregnancies at 16-18 weeks' gestation and can therefore be used for prenatal testing in the absence of identified disease-causing mutations [Bennett et al 1993, Elpeleg et al 1994].
Aspartoacylase enzymatic activity
Skin fibroblasts. Deficient aspartoacylase enzymatic activity can be established in affected individuals in cultured skin fibroblasts. Individuals with Canavan disease often have unmeasurable enzymatic activity, whereas carriers have about one-half normal activity [Matalon et al 1993].
White blood cells. Aspartoacylase enzymatic activity is not detectable in white blood cells.
Amniocytes/CVS. Aspartoacylase enzymatic activity is extremely low in normal amniocytes and chorionic villus sampling (CVS) tissue and cannot be used in prenatal testing [Bennett et al 1993].
Gene. ASPA is the only gene known to be associated with Canavan disease.
Molecular genetic testing: Clinical uses
Confirmatory diagnostic testing
Carrier testing for at-risk individuals and individuals of Ashkenazi Jewish heritage
Molecular genetic testing: Clinical methods
Two mutations, E285A and Y231X, account for 98% of disease-causing alleles in the Ashkenazi Jewish population and 3% of alleles in non-Jewish populations [Olsen et al 2002].
One mutation, A305E, accounts for 40-60% of disease-causing alleles in non-Jewish populations and approximately 1% of alleles in the Ashkenazi Jewish population [Kaul, Gao et al 1994, Elpeleg & Shaag 1999].
The 433-2 (A to G) splice site mutation accounts for approximately 1% of disease-causing alleles in the Ashkenazi Jewish population [Kaul, Gao et al 1994].
Deletion/duplication analysis. Deletions are rare in individuals with Canavan disease.
Sequence analysis. Sequence analysis of the ASPA coding region is available on a clinical basis for individuals in whom mutations were not identified by mutation analysis.
Table 1 summarizes molecular genetic testing for this disorder.
Test Method | Mutations Detected | Mutation Dectection Rate | Test Availability | ||
---|---|---|---|---|---|
Jewish | Non-Jewish | ||||
Targeted mutation analysis | ASPA panel 1 | E285A and Y231X | 98% | 3% | Clinical |
A305E | ~1% | 40-60% | |||
433-2A-G | ~1% | – | |||
Deletion/duplication analysis | Large genomic deletions/duplications comprising one or more exons | Unknown <10% | |||
Sequence analysis | ASPA sequence variants | 87% |
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
Diagnosis relies upon demonstration of increased levels of N-acetylaspartic acid (NAA) in the urine.
Molecular genetic testing can be used for confirmation of the diagnosis.
Although three forms of Canavan disease — neonatal, infantile, and late onset — have been reported, a study of 60 affected individuals [Traeger & Rapin 1998] did not find evidence of a distinct juvenile form. Rather, the authors determined that the "classic infantile Canavan disease" starting in infancy is the norm, while the rate of disease progression is highly variable.
Most infants with Canavan disease appear normal early in life. By three to five months of age, macrocephaly, lack of head control, and developmental delays become apparent. Developmental delay becomes more obvious with increasing age. Children with Canavan disease are especially delayed in their motor skills. They learn to interact socially, laugh and smile, reach for objects, and raise their heads in the prone position. They are sometimes irritable and are not able to sit, stand, walk, or talk. As children with Canavan disease get older, the hypotonia gives way to spasticity.
Although optic atrophy is present, the children are not blind and are often able to visually track objects. Hearing is usually not impaired. As they get older, children may experience sleep disturbance, seizures, and feeding difficulties. They may require assisted feeding through a nasogastric tube or by a permanent gastrostomy. The life expectancy is variable; some children die in the first few years of life, while others survive into their teens or beyond, depending on the clinical course of their disease as well as on the medical and nursing care provided.
Atypical Canavan disease. Some individuals who are compound heterozygous for a mild mutation (Y288C) have been reported to have mild elevation of NAA in the urine and mild developmental delay [Surendran et al 2003, Tacke et al 2005]. They may have retinitis pigmentosa (see Retinitis Pigmentosa Overview).
Neuroimaging. CT or MRI performed in infancy may be interpreted as normal [Matalon et al 1990]. Diffuse, symmetrical white matter changes are observed in the subcortical areas and in the cerebral cortex; involvement of the cerebellum and brainstem is less marked [Matalon et al 1995].
Ultrasonography shows white matter echogenicity different from that of normal brain [Breitbach-Faller et al 2003].
In atypical Canavan disease associated with compound heterozygosity for the Y288C mutation, brain MRI does not show sponginess and signal intensities are in the basal ganglia [Surendran et al 2003, Yalcinkaya et al 2005].
Neuropathology. Subcortical spongy degeneration is observed. Electron microscopy (EM) reveals swollen astrocytes and distorted mitochondria.
No strong genotype-phenotype correlations exist in Canavan disease.
Individuals homozygous for the Y231X, 693C>A mutation, who make no enzyme, cannot be clinically distinguished from individuals homozygous for the E285A, 854A>C mutation, who have some residual enzyme activity.
Individuals homozygous for the A305E, 914C>A mutation most common in non-Jews, who have no residual activity, have a clinical course similar to that observed in individuals who are homozygous for the two mutations commonly found in the Jewish population [Matalon & Michals 1998].
Children who share the same genotype may have very different clinical courses, although all eventually succumb to the disease [Traeger & Rapin 1998].
Zeng et al (2002) reported 14 novel mutations among non-Jewish individuals with Canavan disease. Some of the mutations cause a more severe phenotype. As these are individual cases, no clear conclusion can be made.
Zeng et al (2002) reported 14 novel mutations among non-Jewish individuals with Canavan disease. Some of the mutations cause a more severe phenotype. As these are individual cases, no clear conclusion can be made.
While Canavan disease occurs in all ethnic groups, most reported individuals are of Ashkenazi Jewish origin.
Preliminary data from limited population screening of Ashkenazi Jewish individuals using the two common Jewish mutations revealed a carrier rate of 1:40 [Kronn et al 1995, Matalon et al 1995].
Sugarman & Allitto (2001) found a carrier rate of 1:58. Testing for the three most common alleles in the Ashkenazi Jewish population Feigenbaum et al (2004) found a carrier rate of 1:57. Based on these carrier rates, the a priori risk for affected children in the Ashkenazi Jewish population is about 1/6,400 to 1/13,456.
The carrier rate in non-Jews is not known, although it is assumed to be much lower than the carrier rate in the Ashkenazi Jewish population.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Other neurodegenerative disorders presenting in infancy and associated with a normal or large head size include Alexander disease, Tay-Sachs disease, metachromatic leukodystrophy, and glutaricacidemia (see Organic Acidemias Overview). Laboratory testing or molecular genetic testing can be used to distinguish Canavan disease from these disorders.
Spongy degeneration of the brain can be found in viral infections, in mitochondrial disorders, particularly Leigh syndrome (see also Mitochondrial Disorders Overview), and in metabolic disorders such as glycine encephalopathy (nonketotic hyperglycinemia).
Individuals with atypical (mild) Canavan disease may be misdiagnosed as having a mitochondrial disorder (see Mitochondrial Disorders Overview).
Developmental assessment
Nutritional assessment
Treatment for Canavan disease is supportive and directed to providing adequate nutrition and hydration, managing infectious diseases, and protecting the airway.
Children benefit from physical therapy to minimize contractures and to maximize abilities and seating posture, from other therapies to enhance communication skills (especially in those with a more gradual clinical course), and from early intervention and special education programs.
Seizures may be treated with anti-epileptic drugs (AEDs).
A feeding gastrostomy may be performed to maintain adequate intake and hydration in the presence of swallowing difficulties.
A knock-out mouse that has the phenotype of human Canavan disease [Matalon et al 2000] is being used to investigate pathophysiology [Surendran et al 2004] and gene therapy trials [Matalon et al 2003].
Gene transfer to the brains of two children with Canavan disease using a nonviral vector was well tolerated [Leone et al 2000, Janson et al 2002]; some biochemical, radiologic, and clinical changes may have occurred.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Canavan disease is inherited in an autosomal recessive manner.
Parents of a proband
The parents of an affected child are obligate heterozygotes; each therefore carries a single copy of a disease-causing mutation in the ASPA gene.
Heterozygotes are asymptomatic.
Sibs of a proband
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an symptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic.
Offspring of a proband. No affected person has been known to reproduce.
Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.
ASPA DNA mutation analysis can be used to identify carriers among at-risk family members once the mutations are identified in the proband. Carrier detection using biochemical assay is not routinely available because it relies on a complex enzyme assay in cultured skin fibroblasts.
Individuals of Ashkenazi Jewish heritage. Because of the relatively increased carrier rate in Ashkenazi Jews and the availability of genetic counseling and prenatal diagnosis, population screening has been initiated for Jewish individuals of reproductive age in some states and is recommended in published guidelines (American College of Medical Genetics and American College of Obstetricians and Gynecologists) [ACOG Committee on Genetics 2004]. Through this type of screening program, couples in which both partners are carriers can be made aware of their status and risks before having affected children. Then, through genetic counseling and the option of prenatal testing, such families can, if they choose, bring to term only those pregnancies in which the fetus is unaffected. In population screening of people of Jewish heritage, a panel of the two or three common ASPA mutations (E285A, Y231X, and A305E) can be expected to identify 99% of heterozygotes.
Assisted reproductive technologies. Individuals who are pursuing reproductive technologies that involve gamete (egg or sperm) donation and who are at increased risk of being heterozygous for an ASPA mutation because of family history or ethnic background should be offered screening. If the gamete recipient is a carrier, potential gamete donors can be screened to determine carrier status.
Family planning. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.
Molecular genetic testing. Prenatal testing for pregnancies at 25% risk is possible by analysis of DNA extracted from fetal cells obtained by chorionic villus sampling (CVS) at about 10-12 weeks' gestation or by amniocentesis usually performed at about 15-18 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Biochemical genetic testing. For couples in which one partner is known to be a carrier and the mutation or carrier status of the other is unknown, prenatal testing can be performed by measuring the level of NAA in amniotic fluid at 15-18 weeks [Bennett et al 1993, Matalon & Matalon 2002].
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified in an affected family member [Yaron et al 2005]. For laboratories offering PGD, see .
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Gene Symbol | Chromosomal Locus | Protein Name |
---|---|---|
ASPA | 17pter-p13 | Aspartoacylase |
Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
Gene Symbol | Entrez Gene | HGMD |
---|---|---|
ASPA | 443 (MIM No. 608034) | ASPA |
For a description of the genomic databases listed, click here.
Normal allelic variants: The gene is 29 kb with six exons and five introns. The exons vary in size from 94 bp (exon III) to 514 bp (exon VI).
Pathologic allelic variants: The major disease-causing allelic variants are E285A, Y231X, and A305E. (For more information, see Genomic Databases table above.)
Normal gene product: Aspartoacylase is a protein of 313 amino acids, suggesting a molecular weight of 36 kd [Kaul et al 1993]. The 93% homology of the amino acid and nucleotide sequence of human and bovine aspartoacylase suggest a high degree of conservation of this enzyme in mammals [Kaul, Balamurugan et al 1994]. The protein is observed in most tissues.
Abnormal gene product: Aspartoacylase is responsible for hydrolyzing N-acetylaspartic acid (NAA) into aspartic acid and acetate. The abnormal alleles include null mutations, which make no aspartoacylase, and missense mutations, which make less active forms of aspartoacylase. Although aspartoacylase is expressed widely throughout the body, its absence in the CNS leads to the specific build-up of NAA in the brain that leads to demyelinization and other symptoms of the disease.
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select for the most up-to-date Resources information.—ED.
Canavan Foundation
450 West End Avenue, #10C
New York, NY 10024
Phone: 877-4-Canavan (877-422-6282 toll-free); 212-873-4640
Fax: 212-873-7892
Email: info@canavanfoundation.org
www.canavanfoundation.org
National Institute of Neurological Disorders and Stroke
Canavan Disease Information Page
National Library of Medicine Genetics Home Reference
Canavan Disease
Chicago Center for Jewish Genetic Disorders
Ben Gurion Way
One South Franklin Street, Fourth Floor
Chicago, IL 60606
Phone: 312-357-4718
Fax: 312-855-3295
Email: jewishgeneticsctr@juf.org
www.jewishgeneticscenter.org
National Tay-Sachs and Allied Diseases Association, Inc
2001 Beacon Street Suite 204
Brighton MA 02135
Phone: 800-906-8723; 617-277-4463
Fax: 617-277-0134
Email: info@ntsad.org
www.ntsad.org
United Leukodystrophy Foundation (ULF)
2304 Highland Drive
Sycamore IL 60178
Phone: 800-728-5483; 815-895-3211
Fax: 815-895-2432
Email: office@ulf.org
www.ulf.org
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
15 March 2006 (cd) Revision: deletion/duplication analysis clinically available
30 December 2005 (me) Comprehensive update posted to live Web site
7 November 2003 (me) Comprehensive update posted to live Web site
3 October 2001 (me) Comprehensive update posted to live Web site
16 September 1999 (pb) Review posted to live Web site
17 April 1999 (rm) Original submission