Handbook of 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 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: http://www.genzymegenetics.com/Our-Services/Reproductive-Testing/aj-carrier-test.aspx Ashkenazi Jewish Panel Specimen Requirements: 1. Blood: ACD-A (yellow-top) or EDTA (lavender-top) tube. Adult: 10 ml whole blood for one test, 30ml whole blood if ordering multiple tests. Turnaround Time: 10-14 days 2. Mouthwash: Please Note: Patient should not eat, drink, smoke or chew gum for at least one hour prior to collection (see specimen kit for detailed instructions). Mouthwash samples can be sent when ordering up to two tests. When ordering more than two tests, blood samples are required. Mouthwash cannot be used for Tay-Sachs disease carrier screening as Tay-Sachs enzyme analysis requires a blood sample. 10 ml of Scope® mouthwash that has been swished vigorously for at least one minute. Collect in orange-top 50 ml polypropylene tube. Turnaround Time: 10-14 days Tests for Bloom syndrome, Canavan disease, Cystic fibrosis, Dihydrolipoamide dehydrogenase deficiency, Familial dysautonomia, Familial hyperinsulinism, Fanconi anemia group C, Gaucher disease, Glycogen storage disease type 1a, Maple syrup urine disease, Mucolipidosis type IV, Nemaline myopathy, Niemann-Pick disease type A, Tay-Sachs disease, Usher syndrome type III , Usher syndrome type IF Can also order each test individually, although very expensive Ship at room temperature via FedEx -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] Jacob's Cure: A Fight Against Canavan Disease PO Box 52 Rye, NY 10580 Phone: 914-502-4249 Email: info@jacobscure.org [Web: www.jacobscure.org] References Genetics and IVF Institute. (2002). GeneReviews. "Canavan Disease" (2002). GeneTests. "Canavan Disease" (2002). Genzyme Genetics "Ashkenazi Jewish Panel" - http://www.genzymegenetics.com/Our-Services/Reproductive-Testing/aj-carrier-test.aspx Laboratory Corporation of America. (2002). Online Mendelian Inheritance in Man. "Canavan Disease" (2002). 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.