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Canavan Disease: Heterozygote Screening (2002)


  • What do you know about Canavan Disease?
  • What are your concerns? What do you hope to learn?

Etiology and Natural HistoryEdit

  • Also called aspartoacylase deficiency or spongy degeneration of the brain
  • Caused by deficiency of aspartoacylase enzyme
    • Encoded by the gene ASPA
    • Found at chromosomal locus 17p13
    • Responsible for hydrolyzing N-acetylaspartic acid (NAA) into aspartic acid and acetate
    • Expressed throughout body but mainly causes problems in central nervous system
      • Build-up of NAA in brain
      • Causes demyelinization leading to evidence of clinical symptoms
  • ASPA mutations
    • Over 30 different mutations have been identified
    • Three common mutations
      • Account for 99% of disease causing alleles in Ashkenazi Jewish population and 55% of disease causing alleles in other populations
      • Includes E285A, Y231X, and A305E
      • Null mutations make no aspartoacylase, missense mutations make less active forms
    • No strong genotype-phenotype correlation but missense mutations not as severe as null mutations
  • Autosomal recessive inheritance
    • If both partners heterozygous for a mutation, each pregnancy has a 25% risk of resulting in a child with Canavan disease
    • Explanation of autosomal recessive inheritance

Incidence and Carrier FrequencyEdit

  • Most reported cases are individuals of Ashkenazi Jewish descent
    • Carrier frequency about 1 in 40 to 1 in 60
    • Incidence is about 1/6400 to 1/13,456
  • Carrier frequency in general population is not known but assumed to be much lower than 1 in 40 (Maybe 1 in 300?)

Clinical FeaturesEdit

  • Infants appear normal early in life
  • Developmental delay apparent at 3-5 months of age
    • Particularly delayed in motor skill development
      • Can laugh and smile, reach for objects, and raise their head but may lose those skills
      • Hypotonia, seizures, and poor eye contact develop by sixth month
      • May not learn to sit, stand, walk, or talk
    • Can learn to interact socially but are sometimes irritable
    • Sleep disturbance and feeding difficulties begin as they get older
    • Macrocephaly
  • Life expectancy is variable
    • Varies from few years to the teens or beyond
    • Depends on clinical course of disease and medical care
  • Some studies have reported three forms
    • Neonatal, infantile, and late-onset
    • More recent studies show that disease usually begins in infancy with highly variable rate of disease progression
  • Neuropathology
    • CT or MRI in infancy may be normal
    • Later studies will show diffuse, symmetrical white matter changes and possible involvement of cerebellum and brainstem
    • Subcortical spongy degeneration
    • Distorted mitochondria


  • Diagnostic testing
    • Increased levels of N-acetylaspartic acid (NAA) in urine
      • Measure using gas chromatography-mass spectrometry
      • Can also find elevated levels in blood and cerebrospinal fluid of older children
    • Aspartoacylase enzymatic activity
      • Can be measured in cultured skin fibroblasts
        • Affected patients have unmeasurable activity
        • Carriers have about ½ normal activity
      • Not detectable in white blood cells
      • Cannot be used for prenatal diagnosis because normal enzyme levels very low in amniocytes and CVS tissue
    • Can do molecular testing to confirm diagnosis
  • Molecular testing
    • Primarily used for:
      • Identify specific mutation in affected individuals
      • Carrier testing of individuals of Ashenazi Jewish heritage
      • Carrier testing for individuals with affected family members and their spouses
      • Prenatal testing for at-risk pregnancies
    • Most labs use a two allele panel for testing
      • Some labs use three allele panel
        • Detects 99% of mutations in Ashkenazi Jewish population
        • Detects only about 55% of mutations in other populations
      • Testing for remaining mutations is on research basis only
    • Population Screening
      • Initiated for Jewish individuals of reproductive age recommended by American College of Medical Genetics and American College of Obstetricians and Gynecologists
      • Couples and partners who are carriers can be made aware of risks and status before having children
    • In the US and Canada, 27 labs offer testing
      • Genetics and IVF Institute - Fairfax, Virginia
        • Ashkenazi Jewish Recessive Disease panel
          • Blood samples only (5-10 cc in lavender topped tube)
          • Ship at room temperature
          • Package to screen for most common mutations causing Tay-Sachs, Gaucher Disease, Canavan Disease, and Cystic Fibrosis
          • Screens for 3 most common Canavan mutations
          • No prenatal diagnosis
          • Turn around time is 10-14 days
        • Canavan Disease testing
          • Blood samples same as above
          • Amniotic fluid:
            • <15 weeks send 2 confluent T25 flasks
            • >15 weeks send 5 ml unspun fluid and keep backup cultures at our facility
          • CVS send 5 mg cleaned CV tissue and maintain backup cultures
          • Ship at ambient temperature
          • Turn around time 7-10 days
          • If carrier status of parents determined at another lab, must also send parental blood specimens as controls
      • Laboratory Corporation of America - Research Triangle Park, NC
        • Have primary testing and distribution center in Cincinnati
        • Canavan Disease
          • Blood sample (7 ml in lavender topped tube)
          • Screens for only 2 mutations
          • Send specimens at room temperature
        • Jewish Heritage Profile 1
          • Blood sample (8 ml in lavender topped tube)
          • Screens for mutations causing Canavan Disease, Cystic Fibrosis, Niemann-Pick, and Tay-Sachs
          • Ship at room temperature
          • Medicare and other carriers may not recognize this procedure as covered health care
        • Jewish Heritage Profile II
          • Blood sample same as above
          • Screens for mutations causing Canavan Disease, Cystic Fibrosis, Fanconi Anemi (Type C), Gaucher, Niemann-Pick, and Tay-Sachs Disease
          • Medicare and other carriers may not cover this test
          • Not appropriate for non-Ashkenazi Jewish individuals
      • Genzyme Genetics - Framingham, MA
        • Ashkenazi Jewish Panal
          • Blood sample (20 cc in purple topped tube)
          • Tests for Cystic Fibrosis, Tay-Sachs, and Canavan and Gaucher Disease can be ordered in addition
          • $375 for 3diseases, $480 for all 4 diseases
          • Tests for 4 mutations in aspartoacylase gene
          • Can also order each test individually, although very expensive
          • Ship at room temperature via FedEx
          • Turn around time approximately 10 days

-Genzyme forms are in the red crate in the student room

    • Prenatal testing
      • Molecular testing if specific ASPA mutation has been identified in both parents
      • If one partner is a known carrier but status of the other partner is unknown, measure the level of NAA in amniotic fluid at 16-18 weeks
    • Research testing
      • Supposedly available for mutations not tested for by clinical studies
      • Duke University Medical Center does NOT offer research testing
      • NYU School of Medicine may offer research testing
      • Haemek Medical Center in Afula, Israel


  • No cure
  • Treatment focuses on support, nutrition, hydration, management of infectious diseases, and protection of the airway
    • Feeding tube if swallowing difficulties
    • Seizures treated with anticonvulsants
  • Physical therapy
    • Minimizes contractures
    • Maximize abilities and seating posture
  • Other therapies to enhance communication skills
  • Gene therapy
    • Studies with a mouse model are being used in gene therapy trials
    • Gene transfer to brain of two children with Canavan Disease
      • Using non-viral vector
      • Procedure well tolerated and some biochemical, radiological, and clinical changes may have been seen

Differential DiagnosisEdit

  • Alexander's Disease, Tay-Sachs disease, metachromatic leukodystrophy, and glutaric acidemia may have similar clinical symptoms
  • Laboratory or molecular genetic testing can be used to distinguish from these diseases
  • Spongy degeneration of the brain found in some viral disorders can also be distinguished by testing

Psychosocial IssuesEdit

  • Past experiences with family members with Canavan Disease
  • DNA banking, particularly if an individual is diagnosed based on elevated NAA levels but molecular testing does not identify a mutation
  • Feelings about preimplantation genetic diagnosis and termination
  • Daily management of an affected family member
  • Financial pressures
  • Lifestyle changes necessary to care for an affected child
  • Guilt, depression


  • Canavan Foundation
110 Riverside Drive #4F
New York, NY 10024
Phone: 877-4-Canavan
  • National Foundation for Jewish Genetic Diseases, Inc
250 Park Ave, Ste 1000
New York, NY 10177
Phone: 212-371-1030


  • Genetics and IVF Institute. (2002). [1]
  • GeneReviews. "Canavan Disease" (2002). [2]
  • GeneTests. "Canavan Disease" (2002). [3]
  • Genzyme Genetics. "Ashkenazi Jewish Panel" Patient literature.
  • Laboratory Corporation of America. (2002). [4]
  • Online Mendelian Inheritance in Man. "Canavan Disease" (2002). [5]
  • Scriver, CR, ed. The Metabolic and Molecular Bases of Inherited Disease. "Aspartoacylase Deficiency (Canavan Disease)" (2001):5799-580**


The information in this outline was last updated in 2002.

Material obtained under GFDL Licence from

Heckert GNU white Permission is granted to copy, distribute and/or modify this document under the terms of the GNU Free Documentation License, Version 1.2 or any later version published by the Free Software Foundation; with no Invariant Sections, no Front-Cover Texts, and no Back-Cover Texts. A copy of the license is included in the section entitled "GNU Free Documentation License."

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