Genetic counseling: Canavan Disease: Heterozygote Screening

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Canavan Disease: Heterozygote Screening (2002)

Contracting

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

Etiology and Natural History

• 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 Frequency

Carrier frequency in general population is not known but assumed to be much lower than 1 in 40 (Maybe 1 in 300?)

Clinical Features

• 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

Testing

• 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

Management

• 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 Diagnosis

• 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 Issues

• 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

Resources

• Canavan Foundation

110 Riverside Drive #4F

New York, NY 10024

Phone: 877-4-Canavan

Email: canavandisease@aol.com

[Web: www.canavanfoundation.org]

• National Foundation for Jewish Genetic Diseases, Inc

250 Park Ave, Ste 1000

New York, NY 10177

Phone: 212-371-1030

Email: NFJGD@aol.com

[Web: www.nfjgd.org]

References

• 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**

Notes

The information in this outline was last updated in 2002.

Material obtained under GFDL Licence from http://en.wikibooks.org/wiki/Handbook_of_Genetic_Counseling

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