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Canavan Disease

Synonyms: ASPA Deficiency, Aspartoacylase Deficiency

, MD, PhD, , BS, and , PhD, RD.

Author Information

Initial Posting: ; Last Update: September 13, 2018.

Estimated reading time: 16 minutes

Summary

Clinical characteristics.

Most individuals with Canavan disease have the neonatal/infantile form. Although such infants appear normal early in life, by age three to five months, hypotonia, head lag, macrocephaly, and developmental delays become apparent. With age, children with neonatal/infantile-onset Canavan disease often become irritable and experience sleep disturbance, seizures, and feeding difficulties. Swallowing deteriorates, and some children require nasogastric feeding or permanent feeding gastrostomies. Joint stiffness increases, so that these children resemble individuals with cerebral palsy. Children with mild/juvenile Canavan disease may have normal or mildly delayed speech or motor development early in life without regression. In spite of developmental delay most of these children can be educated in typical classroom settings and may benefit from speech therapy or tutoring as needed. Most children with mild forms of Canavan disease have normal head size, although macrocephaly, retinitis pigmentosa, and seizures have been reported in a few individuals.

Diagnosis/testing.

The diagnosis of Canavan disease is established in a proband with typical clinical findings and elevated N-acetylaspartic acid (NAA) in urine and/or with biallelic pathogenic variants in ASPA identified by molecular genetic testing.

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. Hospice care is a resource used by the families of the individuals affected by the disease. 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.
  • Mild/juvenile Canavan disease. May require speech therapy or tutoring but no special medical care.

Surveillance:

  • Neonatal/infantile Canavan disease. Follow up every six months to evaluate developmental status and evidence of any new problems.
  • Mild/juvenile Canavan disease. Annual routine follow up by a pediatric neurologist or a developmental pediatrician is indicated.

Genetic counseling.

Canavan disease is inherited in an autosomal recessive manner. Each pregnancy of a couple in which both partners are heterozygous for a pathogenic variant in ASPA has a 25% chance of resulting in a child with Canavan disease, a 50% chance of resulting in a child who is an asymptomatic carrier, and a 25% chance of resulting in a child who is 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, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible when the pathogenic variants in the family are known.

Diagnosis

Suggestive Findings

Canavan disease should be suspected in individuals with

  • The triad of hypotonia, head lag, and macrocephaly after age three to five months
  • Poor visual following and difficulties with suck and swallow
  • Developmental delays (with regression in infantile form and without regression in mild/juvenile form)
  • Leukodystrophy on neuroimaging (generalized in infantile form and localized to basal ganglia in mild/juvenile form)
  • Elevated N-acetylaspartic acid (NAA) in urine using gas chromatography-mass spectrometry (GC-MS)

Establishing the Diagnosis

The diagnosis of Canavan disease is established in a proband with typical clinical findings and elevated N-acetylaspartic acid (NAA) in urine using gas chromatography-mass spectrometry (see Note) and/or biallelic pathogenic variants in ASPA identified by molecular genetic testing (see Table 1).

Note: (1) Although NAA concentration is also elevated in the blood and cerebrospinal fluid (CSF) of children with neonatal/infantile (severe) Canavan disease, elevated concentration of NAA in urine is sufficient for diagnosis of affected individuals [Michals & Matalon 2011]. (2) Canavan disease is associated with decreased aspartoacylase enzyme activity; individuals with severe Canavan disease may have unmeasurable enzyme activity, and carriers (heterozygotes) may have enzyme activity ~50% of normal. 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 approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Canavan disease is broad, infants with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a mild/juvenile Canavan disease phenotype indistinguishable from many other inherited disorders with developmental delay are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of Canavan disease, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.

Single-gene testing. Sequence analysis of ASPA detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If only one or no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.

Targeted analysis for the pathogenic variants p.Glu285Ala, p.Tyr231Ter, and p.Ala305Glu can be performed first in individuals of Ashkenazi Jewish ancestry.

Targeted analysis for the pathogenic variant p.Ala305Glu can be performed first in individuals of non-Ashkenazi Jewish ancestry.

Note: This targeted testing is most appropriate when (1) biochemical testing indicates a diagnosis of Canavan disease or (2) the individual is of Ashkenazi Jewish ancestry.

A multigene panel that includes ASPA and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Note: Follow-up urinary NAA or enzyme testing may help to interpret sequencing results if a variant of unknown significance is identified.

Option 2

When the phenotype is indistinguishable from many other inherited disorders characterized by developmental delay, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

Exome array (when clinically available) may be considered if exome sequencing is non-diagnostic.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Canavan Disease

Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method
ASPATargeted
testing 3
p.Glu285Ala, p.Tyr231TerAshkenazi Jewish: 98% 4
Non-Ashkenazi Jewish: 3% 4
p.Ala305GluAshkenazi Jewish: 1% 5
Non-Ashkenazi Jewish: 30%-60% 5
Sequence analysis 6~99% 7
Gene-targeted deletion/duplication analysis 89 reported 9
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Various molecular methods may be used to detect targeted variants.

4.
5.
6.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

7.
8.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

9.

Clinical Characteristics

Clinical Description

Canavan disease is a neurodegenerative disorder associated with spongy degeneration of the white matter of the brain. Typical presentation is in the first several months of life, although a later presentation is also recognized.

Neonatal/Infantile (Severe) Canavan Disease

Presentation. Most individuals with Canavan disease have the neonatal/infantile form. Such infants appear normal early in life, but by age three to five months, hypotonia, head lag, macrocephaly, and developmental delays become apparent.

Hypotonia is an early finding associated with poor head control.

  • Inability to support the head is a constant feature of this disorder.
  • With age, hypotonia gives way to spasticity.

Macrocephaly. In early infancy the head circumference may be normal or in some cases remain at the upper limit of normal. However, in the majority of individuals, the head circumference increases after age six months and by the first year is above the 90th percentile.

Developmental delay becomes more obvious with increasing age:

  • Children 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.

Vision and hearing. Early in life there is a decreased ability to fix and follow. Optic atrophy usually develops in the second year of life. Hearing is usually not impaired.

Progression. With age, children with neonatal/infantile-onset Canavan disease often become irritable and experience sleep disturbance, seizures, and feeding difficulties. Swallowing deteriorates, and some of the children require nasogastric feeding or permanent feeding gastrostomies. Joint stiffness increases, so that these children resemble individuals with cerebral palsy.

Prognosis. Most individuals with Canavan disease die in the first decade of life. However, with improved medical and nursing care a larger number of children survive beyond the first decade.

Mild/Juvenile Canavan Disease

Presentation. Children with mild/juvenile Canavan disease may have normal or mildly delayed speech or motor development early in life without regression. In spite of developmental delay most of these children can be educated in typical classroom settings and may benefit from speech therapy or tutoring as needed [Matalon & Michals Matalon 2015]. Most of the children with mild forms of Canavan disease have normal head size, although macrocephaly, retinitis pigmentosa, and seizures have been reported in a few individuals [Tacke et al 2005, Delaney et al 2015].

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].

Magnetic resonance spectrometry (MRS) to detect N-acetylaspartic acid has been reported as the best method for the diagnosis of Canavan disease in infants, even with normal serum and urine N-acetylaspartic acid levels [Karimzadeh et al 2014].

Mild/juvenile Canavan disease. Brain MRI does not show general white matter changes, although increased signal intensities in the basal ganglia have been reported [Surendran et al 2003, Yalcinkaya et al 2005, 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

Neonatal/infantile (severe) Canavan disease is associated with complete loss of ASPA enzyme activity. The common p.Tyr231Ter, p.Glu285Ala, and p.Ala305Glu pathogenic variants in the homozygous or compound heterozygous (with each other) state are associated with neonatal/infantile disease [Matalon & Michals-Matalon 1998].

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

Nomenclature

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

Prevalence

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

Carrier frequency has varied from 1:40 to 1:82 in the Ashkenazi Jewish population depending on the source of samples [Kronn et al 1995, Matalon et al 1995, Fares et al 2008].

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

Table 2.

Disorders to Consider in the Differential Diagnosis of Canavan Disease

DisorderGene(s)MOIClinical Features of This Disorder
Overlapping w/Canavan diseaseDistinguishing from Canavan disease
Alexander diseaseGFAPAD
  • Neurodegenerative disorder of infancy
  • Normal or large head
  • Marked frontal predominance of white matter changes
  • Rostrocaudal progression of myelin loss on serial imaging studies
Tay-Sachs diseaseHEXAAR
  • Neurodegenerative disorder of infancy
  • Normal or large head
  • Increased startle response
  • Cherry-red spot of the macula of the retina
Metachromatic leukodystrophyARSAAR
  • Neurodegenerative disorder of infancy
  • Normal or large head
Late-infantile onset (age <30 mos) after a period of apparently normal development
Glutaric acidemia type 1GCDHAR
  • Neurodegenerative disorder of infancy
  • Normal or large head
Progressive movement disorder
Leigh syndrome
(see also Mitochondrial Disorders Overview)
mtDNAmt
AR
Spongy degeneration of the brainDecompensation (often w/elevated lactate levels in blood &/or CSF) during an intercurrent illness is typically associated w/psychomotor retardation or regression.
Glycine encephalopathy (nonketotic hyperglycinemia)AMT
GCSH
GLDC
ARSpongy degeneration of the brain
  • Neonatal form manifests in 1st hrs/days of life w/progressive lethargy, hypotonia, & myoclonic jerks.
  • Apnea
  • Profound intellectual disability
  • Intractable seizures
Viral encephalitisNANASpongy degeneration of the brainHistory of viral infection in a previously typical individual

AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; mt = mitochondrial; NA = not applicable; XL = X-linked

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

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Canavan disease, the following evaluations are recommended if they have not already been completed.

Neonatal/infantile (severe) form

  • Brain MRI and MRI spectroscopy
  • Neurologic evaluation
  • Developmental assessment
  • Ophthalmologic assessment
  • Nutritional assessment

Juvenile/mild form

  • Neurologic evaluation
  • Developmental assessment
  • Ophthalmologic assessment

All Canavan disease. Consultation with a clinical geneticist and/or genetic counselor

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.
  • Hospice care is a resource used by the families of the individuals affected by the disease.
  • Children benefit from:
    • Physical therapy to minimize contractures and optimize abilities and seating posture,
    • Other therapies to enhance communication skills (especially in those with a more gradual clinical course), and
    • Early intervention and special education programs.
  • Seizures may be treated with antiepileptic drugs.
  • A feeding gastrostomy may be required to maintain adequate intake and hydration in the presence of swallowing difficulties.
  • Botox® injections may be used to relieve spasticity.

Mild/juvenile Canavan disease. 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 by a pediatric neurologist to evaluate developmental status and evidence of any new problems is suggested.

Mild/juvenile Canavan disease. Annual routine follow up by a pediatric neurologist (or a developmental pediatrician) 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

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

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 (i.e., carriers of one ASPA pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

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.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

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. Each sib of the proband's parents is at a 50% risk of being a carrier of an ASPA pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the ASPA pathogenic variants in the family.

Carrier detection using biochemical assay is not routinely possible because it relies on a complex enzyme assay in cultured skin fibroblasts and enzyme activity fluctuates with culture conditions.

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 [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 pathogenic variants (p.Glu285Ala, p.Tyr231Ter, 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 pathogenic variant 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the ASPA pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

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
  • 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
  • Center for Jewish Genetics
    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)
    224 North Second Street
    Suite 2
    DeKalb IL 60115
    Phone: 800-728-5483 (toll-free); 815-748-3211
    Fax: 815-748-0844
    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

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
ASPA17p13​.2AspartoacylaseASPA @ LOVDASPAASPA

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Canavan Disease (View All in OMIM)

271900CANAVAN DISEASE
608034ASPARTOACYLASE; ASPA

Gene structure. 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). For a detailed summary of gene and protein information, see, Table A, Gene.

Pathogenic variants. See Table 3. The major pathogenic variants are p.Glu285Ala, p.Tyr231Ter, and p.Ala305Glu. (For more information, see Table A.)

Two pathogenic variants, p.Glu285Ala and p.Tyr231Ter, account for 98% of pathogenic variants in the Ashkenazi Jewish population and 3% of pathogenic variants in non-Ashkenazi Jewish populations [Michals & Matalon 2011].

One pathogenic variant, p.Ala305Glu, accounts for 30%-60% of pathogenic variants in non-Ashkenazi Jewish populations and approximately 1% of pathogenic variants in the Ashkenazi Jewish population [Kaul et al 1994b, Elpeleg & Shaag 1999].

Note that a c.433-2A>G splice site variant – not a typical Ashkenazi Jewish variant – has been found in a single Ashkenazi Jewish family; more than 70 additional pathogenic variants have been reported in non-Ashkenazi Jewish populations [Kaul et al 1994b, Elpeleg & Shaag 1999, Olsen et al 2002, Zeng et al 2002, Michals & Matalon 2011]. Large deletions have also been reported [Zeng et al 2006, Kaya et al 2008]. The authors encountered two individuals with complete deletion of ASPA and two with partial deletions [Matalon, unpublished data].

Table 3.

Selected ASPA Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.212G>Ap.Arg71HisNM_000049​.2
NP_000040​.1
c.433-2A>G--
c.693C>Ap.Tyr231Ter
c.770C>Gp.Pro257Arg
c.854A>Cp.Glu285Ala
c.863A>Gp.Tyr288Cys
c.914C>Ap.Ala305Glu

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

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

Normal gene product. ASPA encodes aspartoacylase, a protein of 313 amino acids, suggesting a molecular weight of 36 kd [Kaul et al 1993]. Aspartoacylase catalyzes the conversion of N-acetyl_L-aspartic acid (NAA) to aspartate and acetate. The protein has a high degree of conservation across mammals [Kaul et al 1994a].

Aspartoacylase is observed in most tissues. NAA is abundant in the brain, where hydrolysis by aspartoacylase is thought to help maintain white matter. This protein is an NAA scavenger in other tissues.

The protein forms a dimer with zinc at the catalytic site analogous to other carboxypeptidases. Aspartoacylase is responsible for hydrolyzing N-acetylaspartic acid (NAA) into aspartic acid and acetate.

Abnormal gene product. Loss or reduction of aspartoacylase activity causes Canavan disease. Some pathogenic variants caused conformational changes that affect the activity of the enzyme [Bitto et al 2007]. Although aspartoacylase is expressed widely throughout the body, its absence in the CNS leads to the specific buildup of NAA in the brain that causes demyelinization and other signs of the disease.

References

Published Guidelines / Consensus Statements

  • American College of Medical Genetics. Position statement on carrier testing for Canavan disease. 1998.
  • 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

  • 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]
  • Bitto E, Bingman CA, Wesenberg GE, McCoy JG, Phillips GN Jr. 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]
  • Caliebe A, Vater I, Plendl H, Gesk S, Siebert R, Cremer FW, Klein-Hitpass L. A. 439 kb-sized homozygous deletion in 17p13.3 leading to biallelic loss of the ASPA as cause of Canavan disease detected by SNP-array analysis. Mol Genet Metab. 2010;99:184–5. [PubMed: 19932039]
  • Cozzolino M, Augello B, Carella M, Palumbo O, Tavazzi B, Amorini AM, Lazzarino G, Merla G, Brunetti-Pierri N. Chromosomal 17p13.3 microdeletion unmasking recessive Canavan disease mutation. Mol Genet Metab. 2011;104:706–7. [PubMed: 22019069]
  • Delaney KE, Kralik SF, Hainline BE, Golomb MR. An atypical case of Canavan disease with stroke-like presentation. Pediatr Neurol. 2015;52:218–21. [PubMed: 25497124]
  • 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]
  • 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]
  • Karimzadeh P, Jafari N, Nejad Biglari H, et al. The clinical features and diagnosis of Canavan’s disease: A case series of Iranian patients. Iran J Child Neurol. 2014;8:66–71. [PMC free article: PMC4307371] [PubMed: 25657773]
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  • 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]
  • Kaul R, Gao GP, Balamurugan K, Matalon R. Cloning of the human aspartoacylase cDNA and a common missense mutation in Canavan disease. Nat Genet. 1993;5:118–23. [PubMed: 8252036]
  • Kaya N, Imtiaz F, Colak D, Al-Sayed M, Al-Odaib A, Al-Zahrani F, Al-Mubarak BR, Al-Owain M, Al-Dhalaan H, Chedrawi A, Al-Hassnan Z, Coskun S, Sakati N, Ozand P, Meyer BF. Genome-wide gene expression profiling and mutation analysis of Saudi patients with Canavan disease. Genet Med. 2008;10:675–84. [PubMed: 18978679]
  • Kronn D, Oddoux C, Phillips J, Ostrer H. Prevalence of Canavan disease heterozygotes in the New York metropolitan Ashkenazi Jewish population. Am J Hum Genet. 1995;57:1250–2. [letter] [PMC free article: PMC1801394] [PubMed: 7485179]
  • Kurczynski TW, Victorio MC. Atypical Canavan disease associated with a p.A305E mutation and a p.P257R novel variant in the aspartoacylase gene. Abstract 312. Vancouver, Canada: American College of Medical Genetics Annual Clinical Genetics Meeting; 2011.
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  • Matalon R, Michals K, Kaul R. Canavan disease: from spongy degeneration to molecular analysis. J Pediatr. 1995;127:511–7. [PubMed: 7562269]
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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)
Lisvania Delgado, BS (2018-present)

Revision History

  • 13 September 2018 (ha) Comprehensive update posted live
  • 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 live
  • 7 November 2003 (me) Comprehensive update posted live
  • 3 October 2001 (me) Comprehensive update posted live
  • 16 September 1999 (pb) Review posted live
  • 17 April 1999 (rm) Original submission
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