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Canavan Disease

Synonyms: ASPA Deficiency, Aspartoacylase Deficiency

, MD, PhD and , PhD, RD.

Author Information
, MD, PhD
Departments of Pediatrics and Biochemistry and Molecular Biology
University of Texas Medical Branch
Galveston, Texas
, PhD, RD
Department of Health and Human Performance
University of Houston
Houston, Texas

Initial Posting: ; Last Update: August 11, 2011.

Summary

Disease characteristics. Neonatal/infantile (severe) Canavan disease is characterized by macrocephaly, lack of head control, and developmental delays usually noted by age three to five months. As children get older hypotonia becomes severe and failure to achieve independent sitting, ambulation, or speech become apparent. Hypotonia eventually changes to spasticity. Assistance with feeding becomes necessary. Life expectancy is usually into the teens. Mild/juvenile Canavan disease is characterized by mild developmental delay that can go unrecognized. Head circumference may be normal.

Diagnosis/testing. The diagnosis of neonatal/infantile Canavan disease relies on demonstration of very high concentration of N-acetylaspartic acid (NAA) in the urine. In mild/juvenile Canavan disease NAA may only be slightly elevated; thus, the diagnosis relies on molecular genetic testing of ASPA, the gene encoding the enzyme aspartoacylase.

Management. Treatment of manifestations: Neonatal/infantile Canavan disease: Treatment 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 antiepileptic drugs. Gastrostomy may be needed to maintain adequate food intake and hydration when swallowing difficulties exist.

Surveillance: Neonatal/infantile Canavan disease: Follow up every six months to evaluate developmental status and evidence of any new problems.

Genetic counseling. Canavan disease is inherited in an autosomal recessive manner. Each pregnancy of a couple in which both partners are heterozygous for a disease-causing mutation in ASPA has a 25% chance of resulting in a child with Canavan disease, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing is available on a population basis for individuals of Ashkenazi Jewish heritage. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible when the disease-causing mutations in the family are known. For couples in which one partner is known to be a carrier and the carrier status of the other is unknown, prenatal testing can be performed by measuring the concentration of NAA in amniotic fluid at 16 to 18 weeks’ gestation.

Diagnosis

Clinical Diagnosis

The triad of hypotonia, macrocephaly, and head lag in an infant after age three to five months raises suspicion of neonatal/infantile (severe) Canavan disease. Neuroimaging studies reveal leukodystrophy.

In individuals with mild/juvenile Canavan disease, neuroimaging may not be helpful.

Testing

N-Acetylaspartic acid (NAA)

  • Urine. The concentration of NAA in the urine can be measured using gas chromatography-mass spectrometry (GC-MS) [Michals & Matalon 2011]. Control values in one series (n=48) were 23.5±16.1 µmol/mmol creatinine.
    • In neonatal/infantile (severe) Canavan disease the mean concentration of NAA (n=117) was 1440.5±873.3 µmol/mmol creatinine.
    • In mild/juvenile Canavan disease, mild elevation of NAA may be found, (n=2) 106 µmol/mmol creatinine.

      Note: Although NAA concentration is also elevated in the blood and CSF of children with neonatal/infantile (severe) Canavan disease, the number of affected individuals evaluated to date is small [Michals & Matalon 2011].
  • Amniotic fluid. The concentration of NAA can be measured in the amniotic fluid by stable-isotope dilution and GC-MS or by liquid chromatography tandem mass spectrometry [Bennett et al 1993, Al Dirbashi et al 2009]. NAA concentration in amniotic fluid was 0.30-2.55 µmol/L in controls and 8.68 µmol/L in an affected pregnancy [Bennett et al 1993].

Aspartoacylase enzyme activity

  • Skin fibroblasts. Although aspartoacylase enzyme activity can be assayed in cultured skin fibroblasts, it may not be reliable because the activity varies with culture conditions.
    • Individuals with severe Canavan disease often have unmeasurable enzyme activity.
    • Carriers of alleles associated with severe Canavan disease have about one-half normal enzyme activity [Matalon et al 1993].
  • White blood cells and thrombocytes. Aspartoacylase enzyme activity is not detectable in white blood cells or platelets.
  • Amniocytes/CVS. Aspartoacylase enzyme activity is extremely low in normal amniocytes and chorionic villus sampling (CVS). Enzyme activity cannot be relied upon for prenatal testing [Bennett et al 1993].

Molecular Genetic Testing

Gene. ASPA is the only gene in which mutations are known to cause with Canavan disease.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Canavan Disease

Gene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1
Ashkenazi JewishNon-Ashkenazi Jewish
ASPATargeted mutation analysisPanel 2p.Glu285Ala, p.Tyr231X98%3%
p.Ala305Glu1%30%-60%
Sequence analysisSequence variants 3NA87%
Deletion / duplication analysis 4Large genomic deletions/duplications comprising one or more exonsNAUnknown (<10%)

NA = not applicable

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. All laboratories use at least a two-allele panel for the Ashkenazi Jewish mutations; many laboratories use a three-allele panel, and a few use a four-allele panel.

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband with:

  • Neonatal/infantile (severe) Canavan disease
    • White matter disease on neuroimaging suggests neonatal/infantile (severe) Canavan disease.
    • Diagnosis relies on measurement of the concentration of N-acetylaspartic acid (NAA) in the urine using gas chromatography-mass spectrometry (GC-MS).

      Note: (1) Although NAA concentration is also elevated in the blood and cerebrospinal fluid (CSF) of children with neonatal/infantile (severe) Canavan disease, elevated urine concentration of NAA is sufficient for diagnosis of affected individuals [Michals & Matalon 2011]. (2) Aspartoacylase enzyme activity may not be reliable in the diagnosis of Canavan disease because enzyme activity fluctuates with culture conditions; therefore, measurement of the urinary concentration of NAA is the preferred diagnostic method [Matalon et al 1993].
    • Molecular genetic testing can be used for confirmation of the diagnosis.
      In individuals of Ashkenazi Jewish ancestry:

      1. Perform targeted mutation analysis for the two or three common ASPA mutations (p.Glu285Ala, p.Tyr231X, and p.Ala305Glu).

      2. If neither or only one mutation in ASPA is identified, perform sequence analysis.

      3. If neither or only one mutation in ASPA is identified on sequence analysis, consider deletion/duplication analysis.

      In individuals of non-Ashkenazi Jewish ancestry:

      1. Perform targeted mutation analysis for the p.Ala305Glu mutation.

      2. If neither or only one mutation in ASPA is identified, perform sequence analysis.

      3. If neither or only one mutation in ASPA is identified on sequence analysis, consider deletion/duplication analysis.
  • Mild/juvenile Canavan disease
    • Neuroimaging usually does not indicate leukodystrophy.
    • Concentration of NAA in the urine is slightly elevated.
    • Diagnosis must be confirmed by ASPA molecular genetic testing in the order described above.

Carrier testing

  • Testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.
  • Population screening for Ashkenazi Jewish individuals of reproductive age is recommended [ACOG Committee on Genetics 2009] and typically includes evaluation for the two mutations common in the Ashkenazi Jewish population.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family. Note: When the family-specific mutations are not known, prenatal diagnosis of Canavan disease can be accomplished by measuring the concentration of NAA in amniotic fluid.

Clinical Description

Natural History

Neonatal/Infantile (Severe) Canavan Disease

Most individuals with Canavan disease have the neonatal/infantile form. Although these infants appear normal early in life, by age three to five months macrocephaly, lack of head control, and developmental delays become apparent. Developmental delay becomes more obvious with increasing age. Children with neonatal/infantile (severe) Canavan disease are especially delayed in their motor skills and are not able to sit, stand, walk, or talk. They learn to interact socially, laugh and smile, reach for objects, and raise their heads in the prone position. They are sometimes irritable. As they get older, hypotonia gives way to spasticity.

Optic atrophy is present in many children with neonatal/infantile (severe) Canavan disease. However, they are still able to visually track objects. Hearing is usually not impaired.

As they get older, children with neonatal/infantile (severe) Canavan disease 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.

Mild/Juvenile Canavan Disease

Children with mild/juvenile Canavan disease may have normal or mildly delayed speech or motor development early in life. If they have a diagnostic work-up for these delays, slightly elevated urinary NAA may be identified and indicate the diagnosis. Generally, these children attend regular school and may benefit from speech therapy or tutoring as needed.

Neuroimaging

Neonatal/infantile (severe) Canavan disease. CT or MRI performed in infancy may be interpreted as normal [Matalon & Michals-Matalon 2000]. Diffuse, symmetric white matter changes are observed in the subcortical areas and in the cerebral cortex; involvement of the cerebellum and brain stem is less marked [Matalon et al 1995].

Ultrasonography shows white matter echogenicity that differs from that of normal brain [Breitbach-Faller et al 2003].

Mild/juvenile Canavan disease. Brain MRI does not show general white matter disease. Brain MRI on many children with Canavan disease demonstrates increased signal intensities in the basal ganglia [Surendran et al 2003, Yalcinkaya et al 2005, Michals & Matalon 2011]. Similar changes are observed on MRI of the brain of individuals with mitochondrial diseases [Surendran et al 2003, Tacke et al 2005, Kurczynski & Victorio 2011, Michals & Matalon 2011].

Neuropathology

In neonatal / infantile Canavan disease subcortical spongy degeneration is observed. Electron microscopy (EM) reveals swollen astrocytes and distorted mitochondria.

Genotype-Phenotype Correlations

Strong genotype-phenotype correlations in Canavan disease have emerged since the measurement of N-acetylaspartic acid (NAA) in the urine and molecular genetic testing of ASPA have become routine.

Neonatal/Infantile (Severe) Canavan Disease

Individuals homozygous for the p.Tyr231X mutation (who have no enzyme activity) cannot be clinically distinguished from individuals homozygous for the p.Glu285Ala mutation (who have some residual enzyme activity).

The clinical phenotype in individuals homozygous for the p.Ala305Glu mutation, most commonly observed in non-Jews (who have no residual enzyme activity), is similar to that observed in individuals homozygous for one of the two mutations commonly found in the Ashkenazi Jewish population [Matalon & Michals-Matalon 1998].

The clinical phenotype in individuals homozygous or compound heterozygous for a large (i.e., multiexonic or whole-gene) deletion is severe.

  • Deletion of both ASPA alleles causes a severe phenotype [Matalon unpublished data].
  • An individual homozygous for a 92-kb deletion had a severe phenotype [Zeng et al 2006].
  • Three individuals who were compound heterozygotes for a large deletion (a whole-gene 92-kb deletion, a multiexonic 56-kb deletion, and a multiexonic 12.3-kb deletion respectively) and a point mutation had severe phenotypes [Zeng et al 2006].

Mild/Juvenile Canavan Disease

Mild/juvenile Canavan disease is associated with at least one “mild” mutation (p.Tyr288Cys, p.Arg71His, or p.Pro257Arg) with residual ASPA enzyme activity. Individuals are usually heterozygous with one mild mutation and one severe mutation [Surendran et al 2003, Yalcinkaya et al 2005, Kurczynski & Victorio 2011, Michals & Matalon 2011].

“Mild” mutations are now more readily recognized by their manifestations of slight increase of NAA in the urine, atypical MRI findings, and associated minor learning difficulties [Surendran et al 2003, Tacke et al 2005, Kurczynski & Victorio 2011, Michals & Matalon 2011].

Nomenclature

Other names for neonatal/infantile (severe) Canavan disease that are no longer in use include:

Prevalence

While Canavan disease occurs in all ethnic groups, most reported individuals are of Ashkenazi Jewish origin.

Carrier frequency has varied depending on the source of samples:

The carrier rate in non-Jews is not known; however, it is assumed to be much lower than the carrier rate in the Ashkenazi Jewish population.

Differential Diagnosis

Other neurodegenerative disorders of infancy that are associated with a normal or large head size include Alexander disease, Tay-Sachs disease, metachromatic leukodystrophy, and glutaricacidemia type 1 (see Organic Acidemias Overview). Laboratory testing or molecular genetic testing can be used to distinguish neonatal/infantile (severe) 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).

Mild/juvenile Canavan disease may be misdiagnosed as a mitochondrial disorder (see Mitochondrial Disorders Overview).

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with neonatal/infantile (severe) Canavan disease, the following evaluations are recommended:

  • Brain MRI
  • Developmental assessment
  • Nutritional assessment

Treatment of Manifestations

Neonatal/infantile Canavan disease

  • Treatment 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 antiepileptic drugs (AEDs).
  • A feeding gastrostomy may be required to maintain adequate intake and hydration in the presence of swallowing difficulties.
  • Diamox® seems to reduce intracranial pressure.
  • Botox® injections may be used to relieve spasticity.

Mild/juvenile Canavan disease. These individuals may require speech therapy or tutoring but require no special medical care.

Prevention of Secondary Complications

Neonatal/infantile Canavan disease

  • Contractures and decubiti need to be prevented by exercise and position changes.
  • Feeding difficulties and seizures increase the risk of aspiration, which can be reduced with use of a G-tube for feeding.

Surveillance

Neonatal/infantile Canavan disease. Follow up at six-month intervals to evaluate developmental status and evidence of any new problems is suggested.

Mild/juvenile Canavan disease. Annual routine follow up is indicated.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Humans

  • 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; however, the children continued to follow the course of those with untreated Canavan disease.
  • In ten children with Canavan disease, multisite injection with AAV2 as the vector for ASPA was well tolerated [McPhee et al 2006]. Three developed AAV2 neutralizing antibodies. No children improved.
  • Lithium citrate may reduce N-acetylaspartic acid (NAA) concentration in the brain. Six persons with Canavan disease given lithium citrate for 60 days were reported to have reduced NAA in the basal ganglia and mild improvement in frontal white matter [Assadi et al 2010]. The clinical significance of use of lithium citrate is not known.
  • The enzyme defect in Canavan disease leads to decreased levels of acetate in the brain. In a clinical trial with glycerol triacetate in two persons with Canavan disease the compound was well tolerated; however, there was no clinical improvement [Madhavarao et al 2009]. It is speculated that higher doses of glycerol triacetate may be needed.

Animal models

  • A knock-out mouse has been created, with a phenotype similar to that of human Canavan disease [Matalon et al 2000]. This model is being used to investigate pathophysiology [Surendran et al 2004] gene therapy and other modes of treatment [Matalon et al 2003].
    • Gene therapy with AAV2 was given to knock-out Canavan disease mice: localized improvement did not spread to the entire brain [Matalon et al 2003].
    • Stem cell therapy in knock-out Canavan disease mice was done in collaboration with Genzyme Corporation: The stem cells produced some oligodendrocytes but not enough to make myelin [Surendran et al 2004].
    • Enzyme replacement therapy using native ASPA and pegylated ASPA (i.e., ASPA in which covalent attachment of polyethylene glycol polymer chains masks the enzyme from the host allowing for longer circulation and less renal clearance) were injected into the peritoneum of Canavan disease mice. Preliminary results show that the enzyme passed the blood brain barrier and there was a decrease of NAA in the brain. These experiments were short term; longitudinal studies are being planned [Zano et al 2011].
  • A mouse that seems to have a Canavan disease phenotype was produced by using the mutagen ethylenenitrosourea (ENU) to change the residue Gln193 to a termination codon in exon 4 (577C>T) [Traka et al 2008].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

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. —ED.

Mode of Inheritance

Canavan disease is inherited in an autosomal recessive manner.

Risk to Family Members

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 ASPA.
  • 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 asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. The phenotype is consistent within families.
  • 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 severely affected person has been known to reproduce. Individuals with mild/juvenile Canavan disease could reproduce; this has not been reported to date.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Molecular genetic testing can be used to identify carriers among at-risk family members once the disease-causing mutations are identified in the family.

Carrier detection using biochemical assay is not routinely possible because it relies on a complex enzyme assay in cultured skin fibroblasts.

Population Screening

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 Ashkenazi Jewish individuals of reproductive age in some states and is recommended in published guidelines (American College of Medical Genetics, American College of Obstetricians and Gynecologists) [ACOG Committee on Genetics 2009]. 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 Ashkenazi Jewish heritage, a panel of the two or three common ASPA mutations (p.Glu285Ala, p.Tyr231X, and p.Ala305Glu) 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.

Related Genetic Counseling Issues

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.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

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.

Prenatal Testing

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 approximately ten to 12 weeks' gestation or by amniocentesis usually performed at approximately 15 to 18 weeks' gestation. Both disease-causing alleles present in the family 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 to 18 weeks’ gestation [Bennett et al 1993, Al-Dirbashi et al 2009].

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified [Yaron et al 2005].

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Canavan Foundation
    450 West End Avenue
    #6A
    New York NY 10024
    Phone: 877-422-6282 (toll free); 212-873-4640
    Fax: 212-873-7892
    Email: info@canavanfoundation.org
  • Jacob's Cure
    PO Box 52
    Rye NY 10580
    Phone: 914-502-4249
    Fax: 914-925-3979
    Email: info@jacobscure.org
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)
  • National Library of Medicine Genetics Home Reference
  • Chicago Center for Jewish Genetic Disorders
    Ben Gurion Way
    30 South Wells Street
    Chicago IL 60606
    Phone: 312-357-4718
    Email: jewishgeneticsctr@juf.org
  • National Tay-Sachs and Allied Diseases Association, Inc. (NTSAD)
    2001 Beacon Street
    Suite 204
    Boston MA 02135
    Phone: 800-906-8723 (toll-free)
    Fax: 617-277-0134
    Email: info@ntsad.org
  • United Leukodystrophy Foundation (ULF)
    2304 Highland Drive
    Sycamore IL 60178
    Phone: 800-728-5483 (toll-free)
    Fax: 815-895-2432
    Email: office@ulf.org
  • Myelin Disorders Bioregistry Project
    Email: myelindisorders@cnmc.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Canavan Disease: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
ASPA17p13​.2AspartoacylaseASPA @ LOVDASPA

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Canavan Disease (View All in OMIM)

271900CANAVAN DISEASE
608034ASPARTOACYLASE; ASPA

Normal allelic variants. The gene comprises 29 kb with six exons and five introns. The exons vary in size from 94 bp (exon 3) to 514 bp (exon 6).

Pathologic allelic variants. See Table 2. The major disease-causing allelic variants are p.Glu285Ala, p.Tyr231X, and p.Ala305Glu. (For more information, see Table A.)

Table 2. Selected ASPA Pathologic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.433-2A>G--NM_000049​.2
NP_000040​.1
c.693C>Ap.Tyr231X
c.854A>Cp.Glu285Ala
c.863A>Gp.Tyr288Cys
c.914C>Ap.Ala305Glu

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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 et al 1994a]. The protein is observed in most tissues.

Recent studies have shown that ASPA is a dimer with zinc at the catalytic site analogous to other carboxypeptidases. Mutations caused conformational changes that affect the activity of the enzyme [Bitto et al 2007].

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 causes demyelinization and other signs of the disease.

References

Published Guidelines/Consensus Statements

  1. American College of Medical Genetics. Position statement on carrier testing for Canavan disease (pdf). Available at www​.acmg.net.1998 Accessed 8-3-11.
  2. ACOG Committee on Genetics; ACOG committee opinion. Screening for Canavan disease. Number 212, November 1998. Committee on Genetics. American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet. 1999;65:91–2. [PubMed: 10390111]

Literature Cited

  1. ACOG Committee on Genetics; ACOG committee opinion. Number 442, October. Prenatal and preconceptional carrier screening for genetic diseases in individuals of Eastern European Jewish descent. Obstet Gynecol. 2009;114:950–3. [PubMed: 19888064]
  2. Al-Dirbashi OY, Kurdi W, Imtiaz F, Ahmad AM, Al-Sayed M, Tulbah M, Al-Nemer M, Rashed MS. Reliable prenatal diagnosis of Canavan disease by measuring N-acetylaspartate in amniotic fluid using liquid chromatography tandem mass spectrometry. Prenat Diagn. 2009;29:477–80. [PubMed: 19235826]
  3. Assadi M, Janson C, Wang DJ, Goldfarb O, Suri N, Bilaniuk L, Leone P. Lithium citrate reduces excessive intra-cerebral N-acetyl aspartate in Canavan disease. Eur J Paediatr Neurol. 2010;14:354–9. [PubMed: 20034825]
  4. Bennett MJ, Gibson KM, Sherwood WG, Divry P, Rolland MO, Elpeleg ON, Rinaldo P, Jakobs C. Reliable prenatal diagnosis of Canavan disease (aspartoacylase deficiency): comparison of enzymatic and metabolite analysis. J Inherit Metab Dis. 1993;16:831–6. [PubMed: 8295397]
  5. Bitto E, Bingman CA, Wesenberg GE, McCoy JG, Phillips GN. Structure of aspartoacylase, the brain enzyme impaired in Canavan disease. Proc Natl Acad Sci U S A. 2007;104:456–61. [PMC free article: PMC1766406] [PubMed: 17194761]
  6. Breitbach-Faller N, Schrader K, Rating D, Wunsch R. Ultrasound findings in follow-up investigations in a case of aspartoacylase deficiency (canavan disease). Neuropediatrics. 2003;34:96–9. [PubMed: 12776232]
  7. Elpeleg ON, Shaag A. The spectrum of mutations of the aspartoacylase gene in Canavan disease in non-Jewish patients. J Inherit Metab Dis. 1999;22:531–4. [PubMed: 10407784]
  8. Fares F, Badarneh K, Abosaleh M, Harari-Shaham A, Diukman R, David M. Carrier frequency of autosomal-recessive disorders in the Ashkenazi Jewish population: should the rationale for mutation choice for screening be reevaluated? Prenat Diagn. 2008;28:236–41. [PubMed: 18264947]
  9. Feigenbaum A, Moore R, Clarke J, Hewson S, Chitayat D, Ray PN, Stockley TL. Canavan disease: carrier-frequency determination in the Ashkenazi Jewish population and development of a novel molecular diagnostic assay. Am J Med Genet A. 2004;124A:142–7. [PubMed: 14699612]
  10. Janson C, McPhee S, Bilaniuk L, Haselgrove J, Testaiuti M, Freese A, Wang DJ, Shera D, Hurh P, Rupin J, Saslow E, Goldfarb O, Goldberg M, Larijani G, Sharrar W, Liouterman L, Camp A, Kolodny E, Samulski J, Leone P. 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;13:1391–412. [PubMed: 12162821]
  11. Kaul R, Balamurugan K, Gao GP, Matalon R. Canavan disease: genomic organization and localization of human ASPA to 17p13-ter and conservation of the ASPA gene during evolution. Genomics. 1994a;21:364–70. [PubMed: 8088831]
  12. Kaul R, Gao GP, Aloya M, Balamurugan K, Petrosky A, Michals K, Matalon R. Canavan disease: mutations among Jewish and non-jewish patients. Am J Hum Genet. 1994b;55:34–41. [PMC free article: PMC1918221] [PubMed: 8023850]
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  17. Leone P, Janson CG, Bilaniuk L, Wang Z, Sorgi F, Huang L, Matalon R, Kaul R, Zeng Z, Freese A, McPhee SW, Mee E, During MJ, Bilianuk L. Aspartoacylase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease. Ann Neurol. 2000;48:27–38. [PubMed: 10894213]
  18. Madhavarao CN, Arun P, Anikster Y, Mog SR, Staretz-Chacham O, Moffett JR, Grunberg NE, Gahl WA, Namboodiri AM. Glyceryl triacetate for Canavan disease: a low-dose trial in infants and evaluation of a higher dose for toxicity in the tremor rat model. J Inherit Metab Dis. 2009;32:640–50. [PubMed: 19685155]
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Suggested Reading

  1. Arun P, Madhavarao CN, Moffett JR, Hamilton K, Grunberg NE, Ariyannur PS, Gahl WA, Anikster Y, Mog S, Hallows WC, Denu JM, Namboodiri AM. Metabolic acetate therapy improves phenotype in the tremor rat model of Canavan disease. J Inherit Metab Dis. 2010;33:195–210. [PMC free article: PMC2877317] [PubMed: 20464498]
  2. Baslow MH, Kitada K, Suckow RF, Hungund BL, Serikawa T. The effects of lithium chloride and other substances on levels of brain N-acetyl-L-aspartic acid in Canavan disease-like rats. Neurochem Res. 2002;27:403–6. [PubMed: 12064356]
  3. Janson CG, Kolodny EH, Zeng BJ, Raghavan S, Pastores G, Torres P, Assadi M, McPhee S, Goldfarb O, Saslow B, Freese A, Wang DJ, Bilaniuk L, Shera D, Leone P. Mild-onset presentation of Canavan's disease associated with novel G212A point mutation in aspartoacylase gene. Ann Neurol. 2006;59:428–31. [PubMed: 16437572]
  4. Kitada K, Akimitsu T, Shigematsu Y, Kondo A, Maihara T, Yokoi N, Kuramoto T, Sasa M, Serikawa T. Accumulation of N-acetyl-L-aspartate in the brain of the tremor rat, a mutant exhibiting absence-like seizure and spongiform degeneration in the central nervous system. J Neurochem. 2000;74:2512–9. [PubMed: 10820213]
  5. Matalon R, Bhatia G, Suzucs S, Michals-Matalon K, Tyring S, Grady J. Aspartoacylase entry to the brain of Canavan mouse with hyaluronidase? J Inherit Metab. Dis. 2008;31:28.

Chapter Notes

Author History

Gita Bhatia, PhD; University of Texas Medical Branch (2009-2011)
Kimberlee Michals-Matalon, PhD, RD (2011-present)
Reuben Matalon, PhD (1999-present)

Revision History

  • 11 August 2011 (me) Comprehensive update posted live
  • 1 October 2009 (me) Comprehensive update posted live
  • 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
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