Handbook of Genetic Counseling/Duchenne Muscular Dystrophy-2

Duchenne's Muscular Dystrophy Introduction Contracting Family Hx Medical hx Have you ever had muscle weakness Difficulty going up/down stairs? Muscle cramps easily? Ever had your heart monitored by EKG? Result? Ever had a CPK test (blood test) Ever had a muscle biopsy? Muscle weakness? Difficulty going up and down stairs? Muscle cramps easily? Ever had a heart EKG? Result? Ever had a CPK test? Ever had a muscle biopsy test? Why we are talking about this stuff? DMD - the basics What do you know about DMD? Prevalence = 1/5600 Characteristics Delays in motor milestones (sitting, standing, walking 20%) Progressive symmetrical muscle weakness (proximal greater than distal) Calf hypertrophy Onset before age of 5 (dx age is usually 4 years 10 months) Wheelchair dependency by 13 Serum CK levels are >10X the normal range Cardiomyopathy 100% by age 18 Death by 30's by respiratory/cardiomyopathy Cause Change in a gene (DMD) Xp21.3-p21.2 that produces dystrophin, which is a protein in muscle cells, and neurons and holds them in the right place to do their functions. Without it, or with decreased levels of it, the muscle complex is not properly formed. Based on family hx (assuming no other affected in upper generations), obligate carrier , germline mutation or germline mosaicism in Pam's mother Inheritance - what it means for you!!! X linked recessive means that since her brothers were affected, we know that Pam has a 50% risk of being a carrier. Means that if Pam is a carrier, Sarah has a 50% risk of being a carrier. If Sarah is a carrier, she has a 50% chance of passing it on = an affected son or carrier daughter. So, what do we do when we suspect a person has DMD/is a carrier? = Testing options Ideally we would test an affected individuals (Pam's brothers) Clinical exam Family hx CPK test muscle biopsy DNA test 70% of males with DMD can be diagnosed by running PCR looking for deletions of the exons in the DMD gene. (will find 98% of the deletions identifiable by cDNA hybridization) - clinical Small changes in the gene can only be found on research basis only. Testing carriers Serum creatine phosphokinase concentration levels noninvasive blood test CK is an enzyme that is present in muscle cells and helps to give our body energy. When muscle degeneration occurs, muscle cells burst open and the CK is released into the blood. So, the test looks at the blood serum (without cells) and measures the levels of CK present. the more there is, the more likely muscle is being broken down. 50% of female DMD carriers are found to have 2-10 X normal levels Normal range is 22-198 U/L (units per liter) Hints: do not exercise 24 hours before the test. Muscle biopsy Invasive test of removing a piece of skeletal muscle. Results of carriers will show a mosaic pattern of normal levels of dystrophin and non-normal levels. Using linkage studies when affected individuals are willing to participate in testing. Linkage - If we had access to both boy's tissue blocks we could run an informative test. Direct DNA testing difficult technically because of the presence of two x chromosomes. 600-700 dollars (billed to insurance) We do testing at Baylor Medical Center turn around time = 2-3 weeks (say about 4 weeks) Prenatal testing CVS/amniocentesis to determine the sex of the baby if a boy, there is a 50% chance he is affected If familial mutation is identified, they can determine the presence of the gene. Muscle biopsy for fetus VERY specialized - could not be done in Cincinnati Questions to consider before testing Why is this information important to you? What will you do if the result is uninformative? How will knowing you are a carrier affect you? THIS IS AN OPTION!!! NOT A REQUIREMENT!!! Have you considered how this may affect your reproductive decisions? There are a variety of ways to be tested and different levels of complexity, invasiveness and accuracy. DNA testing can bring up issues of paternity revelation Consent the test is >99% accurate but there may be error in the lab We will be testing only for those mutations that are recognized as important based on family history DNA may be used for research purposes. How do you want your results given to you? Important management for DMD carriers Although 76% of carriers show no signs at all 8% have a risk of dilated cardiomyopathy and should be worked up at least once if carrier status is suspected or proven 19% left ventricle dilation. Resources for parents Muscular Dystrophy Association - USA National headquarters 3300 E. Sunset Drive Tucson, AZ 85718 (800) 572-1717 http://www.mdausa.org Other issues preconceptional health folic acid CF Notes The information in this outline was last updated in 2000.