Canavan Disease

[Aspa Deficiency, Aspartoacylase Deficiency]

Clinical Diagnosis

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.

Testing

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 five- 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 enzyme activity

• Skin fibroblasts. Deficient aspartoacylase enzyme activity can be established in affected individuals in cultured skin fibroblasts. Individuals with Canavan disease often have unmeasurable enzyme activity, whereas carriers have about one-half normal activity [Matalon et al 1993].

• White blood cells. Aspartoacylase enzyme activity is not detectable in white blood cells.

• Amniocytes/CVS. Aspartoacylase enzyme activity is extremely low in normal amniocytes and chorionic villus sampling (CVS) tissue and cannot be used in prenatal testing [Bennett et al 1993].

Molecular Genetic Testing

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.

Gene. ASPA is the only gene known to be associated with Canavan disease.

Clinical testing

• Targeted mutation analysis

  • Two mutations, p.Glu285Ala and p.Tyr231X, 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, p.Ala305Glu, accounts for 40%-60% of disease-causing alleles in non-Jewish populations and approximately 1% of alleles in the Ashkenazi Jewish population [Kaul et al 1994b, Elpeleg & Shaag 1999].

  • The c.433-2A>G splice site mutation accounts for approximately 1% of disease-causing alleles in the Ashkenazi Jewish population [Kaul et al 1994b].

• Sequence analysis of the ASPA coding region is available on a clinical basis for individuals in whom mutations were not identified by targeted mutation analysis.

• Deletion/duplication analysis. Exonic or whole-gene deletions are rare in individuals with Canavan disease [Author, personal observation]. The authors encountered two individuals with complete deletion of the ASPA gene and two with partial deletions. Deleted segments of various sizes of cDNA have been reported [Zeng et al 2006, Kaya et al 2008].

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in Canavan Disease

Gene Symbol	Test Method	Mutations Detected		Mutation Detection Frequency by Test Method		Test Availability
				Jewish	Non-Jewish
ASPA	Targeted mutation analysis	Panel 2	p.Glu285Ala and p.Tyr231X	98%	3%	Clinical
			p.Ala305Glu	~1%	40%-60%
			c.433-2A>G	~1%	–
	Sequence analysis	Sequence variants			87%
	Deletion/ duplication analysis	Large genomic deletions/duplications comprising one or more exons			Unknown (<10%)

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 Jewish mutations; many laboratories use a three-allele panel, and a few use a four-allele panel.

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

Testing Strategy

Diagnostic testing in a proband

• 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.

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

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.

Genetically Related (Allelic) Disorders

No other phenotype is associated with mutations in the ASPA gene.

Natural History

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.

Neuroimaging. CT or MRI performed in infancy may be interpreted as normal [Matalon & Michals-Matalon 2000]. Diffuse, symmetrical 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 different from that of normal brain [Breitbach-Faller et al 2003].

In atypical Canavan disease associated with compound heterozygosity for the p.Tyr288Cys 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.

Genotype-Phenotype Correlations

No strong genotype-phenotype correlations exist in Canavan disease.

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

• Individuals homozygous for the p.Ala305Glu mutation most common in non-Jews, who have no residual enzyme 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-Matalon 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 [2006] reported some three deletions associated with a severe phenotype:

  • A 92-kb deletion deleted the entire ASPA gene in one homozygous individual.

  • A 56-kb deletion involved all but exon 1 in a compound heterozygote.

  • A 12.3 kb deletion deleted exons 4 and 5.

Nomenclature

Other names for Canavan disease that are no longer in use include:

• Spongy degeneration of the brain (see also Differential Diagnosis)

• Van Bogaert and Bertrand disease

Prevalence

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 when 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.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Canavan disease, the following evaluations are recommended:

• Developmental assessment

• Nutritional assessment

Treatment of Manifestations

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.

Botox injections may be used to relieve spasticity.

Prevention of Secondary Complications

Contractures and decubuti 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.

Testing of Relatives at Risk

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

Therapies Under Investigation

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 [Matalon et al 2003].

A new Canavan mouse was produced by using a mutagen, Ethylenenitroso urea (ENU) induced changing residue Gln193 to termination, which seems to have a phenotype of Canavan disease [Traka et al 2008].

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.

Early trials in which AAV2 (the vector for ASPA) was injected into the brain of ten children with Canavan disease reported that antibody to AAV2 was well tolerated, but immune response was detected; in three of the ten, the level of reported antibody was low [McPhee et al 2006].

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

Other

Genetics clinics, staffed by genetics professionals, provide 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.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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 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 a 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.

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 available because it relies on a complex enzyme assay in cultured skin fibroblasts.

Population Screening

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. 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 (typically extracted from white blood cells) of affected individuals for possible future use. DNA banking is particularly relevant when molecular genetic testing is available on a research basis only. See for a list of laboratories offering DNA banking.

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 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 to 18 weeks [Matalon & Matalon 2002].

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified [Yaron et al 2005]. For laboratories offering PGD, see .

Literature Cited

Published Statements and Policies Regarding Genetic Testing

Revision History

• 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