Genetic counseling: Canavan Disease: Heterozygote Screening

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

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