Handbook of Genetic Counseling/Duchenne Muscular Dystrophy-1

Duchenne Muscular Dystrophy

Contracting

 * Discuss the reason for referral
 * Express sympathy for the recent loss of son and brother
 * Who is the referring physician?
 * Obtain written consent to use son/brother's records for session and for testing
 * From mother
 * Tell me about your son/brother
 * Elicit prior knowledge about MD carrier testing
 * CK testing ever done? = creatine phosphokinase
 * Did anyone else ever address carrier status with them?
 * What is the perceived risk of being a carrier?
 * Assess concerns
 * What will she do with the information?
 * Discuss pros and cons of knowing carrier status
 * Reproductive decisions, planning for the future, prenatal diagnosis options
 * Stress, anxiety, fear
 * Set goals for the session
 * Provide overview of topics for counseling session
 * Review personal and family history
 * Discuss inheritance pattern
 * Risk of being a carrier
 * Testing process and delivery of results
 * Decide if you would like testing today
 * Emphasize that it is VOLUNTARY

Intake & Family History

 * Pedigree
 * Any other affected family members?
 * Psychosocial assessment
 * Who have you told about the appointment?
 * Who will you tell about the results?
 * Do you have a serious boyfriend?
 * How would the results affect your future reproductive plans?
 * What was it like growing up with a brother who had DMD?

General Information

 * Dystrophinopathies
 * Characterized by a spectrum of muscle disease that ranges from mild to severe
 * Duchenne/Becker muscular dystrophy is severe
 * Skeletal muscle is primarily affected in both
 * DMD is rapidly progressive and presents in early childhood.
 * Patients are often wheelchair-bound by age 12
 * Becker is characterized by later-onset skeletal muscle weakness
 * Patients remain ambulatory into their 20s
 * Dystrophin gene
 * Xp21.2
 * Encodes protein dystrophin
 * Often deletions or duplications involving exons of this gene
 * Molecular genetic testing is available clinically
 * Prevalence
 * 1 in 5,600 live male births
 * 1/3 of patients are new mutations and the mother is not a carrier

Diagnosis

 * Clinical
 * Family history
 * Compatible with X-linked recessive inheritance
 * Creatine Phosphokinase (CK) concentration
 * Evaluated by blood test
 * Elevated serum CK concentration results from progressive elimination of dystrophic muscle fibers.
 * Can also result from strenuous exercise
 * CK concentration gradually decreases with advancing age due to the progressive elimination of these muscle fibers.
 * 100% of males with DMD have a serum CK concentration >10x normal
 * ~50% of female carriers have a concentration 2-10x normal
 * Some investigations have shown a wide variability in DMD carriers
 * Many have levels within the normal range, so other tests are necessary
 * CPK is not completely reliable
 * Muscle biopsy
 * Histology
 * Shows non-specific dystrophic changes
 * Western blot and immunohistochemistry
 * Dystrophin protein is often completely or almost completely absent
 * Clinical findings
 * Progressive symmetrical muscle weakness, proximal greater than distal
 * Symptoms before age 5 years
 * Wheelchair dependency before age 13 years
 * Molecular genetic testing
 * Deletions involving one or more exons of the DMD gene
 * ~65% of males with DMD have deletions
 * Most deletions occur in two hotspots clustered around the first 20 exons and around exons 45 to 55.
 * Testing is done by PCR or southern blot
 * Available on a clinical basis
 * Duplications of one or more exons of the DMD gene
 * ~6% of males with DMD have a duplication
 * Testing is done by southern blot or quantitative PCR
 * Available on a clinical basis
 * Other mutations in the DMD gene
 * ~30% of males with DMD have other mutations including small deletions or insertions, single base changes, or splicing mutations
 * Analysis is available on a research basis only
 * Carrier testing may be performed but requires quantitative analysis for gene dosage which can be difficult to perform and interpret
 * Prenatal testing is available

Clinical Description

 * Males
 * DMD usually presents in early childhood with delayed milestones
 * This included delays in sitting and standing
 * First symptoms are typically:
 * General motor delay
 * Gait problems including persistent toe-walking and flat-footedness
 * Delay in walking
 * Mean age of walking is about 18 months
 * Learning difficulties
 * Speech problems
 * Mean age of diagnosis without a family history is about 4 years
 * Range of diagnosis is 16 months to 8 years
 * DMD is rapidly progressive
 * Proximal weakness causes a waddling gait and difficulty climbing
 * Boys use the Gower maneuver to rise from a supine position, using the arms to supplement weak pelvic girdle muscles
 * The calf muscles are hypertrophic and firm to palpation
 * Occasionally there is calf pain
 * Affected children are wheelchair-bound by age 12
 * Mean age of death is 17 or 18 years of age
 * Cardiomyopathy
 * Incidence increases steadily in the teenage years
 * 1/3 of patients are affected by age 14
 * ½ by age 18
 * All patients are affected after age 18
 * Few affected males survive beyond the third decade
 * Respiratory complications and cardiomyopathy are common causes of death
 * Cognitive impairment
 * Some degree of nonprogressive impairment is common
 * Affects the verbal ability more than nonverbal performance
 * Phenotype correlates with the degree of expression of dystrophin
 * Expression is largely determine by the reading frame of the spliced message
 * Females
 * Occasionally have DMD clinical features as the result of X chromosome rearrangements involving the DMD locus (Xp21.2)
 * Carriers can have DMD because of Turner syndrome of nonrandom X chromosome inactivation
 * 76% of DMD carriers have no signs or symptoms
 * Management
 * There is no treatment for DMD
 * Prednisone therapy is controversial due to side effects
 * Some report improvement in strength and function which begins within 10 days and plateaus after 3 months
 * Long term benefit has not been demonstrated
 * Appropriate management can prolong survival and improve quality of life
 * Physical therapy to promote mobility
 * Range-of-motion exercises
 * Braces to delay the onset of contractures
 * Monitoring and surgical intervention for orthopedic complications
 * Scoliosis, kyphosis, or lordosis
 * Routine monitoring for evidence of cardiomyopathy
 * All carriers should have a complete cardiac evaluation at least once

Differential Diagnosis

 * Limb-girdle muscular dystrophy
 * A group of disorders clinically similar to DMD
 * Occurs in both sexes
 * Caused by mutations in genes that encode sarcoglycans and other proteins that interact with dystrophin
 * Emery-Dreifuss muscular dystrophy
 * Associated with limb contractures and cardiac arrhythmia
 * X-linked recessive, autosomal dominant, and autosomal recessive forms
 * Caused by mutations in the LMNA gene
 * Spinal muscular atrophy
 * Caused by mutations in the SMN gene
 * Characterized by:
 * Poor muscle tone
 * Symmetric muscle weakness that spares the face and ocular muscles
 * Evidence of anterior horn cell involvement
 * Includes fasciculations of the tongue and absence of deep tendon reflexes
 * Dilated cardiomyopathy
 * Can be sporadic or familial
 * No other phenotypes are associated with mutations in the DMD gene

Inheritance

 * X-linked recessive
 * Carrier females have a 50% chance of transmitting the DMD mutation in each pregnancy
 * With each pregnancy, a carrier has a 25% chance of having an affected child
 * Risk to family members
 * A woman with an affected son and one other affected relative in the maternal line is an obligate heterozygote
 * A woman with more than one affected son and no other family history can have:
 * A germline mutation
 * DMD disease-causing mutation present in every cell
 * Germline mosaicism
 * Mosaicism for a DMD disease-causing mutation which includes the germline
 * The frequency of germline mosaicism in DMD is estimated at 12% to 20%
 * If proband is only affected family member, must determine if mother and other females are carriers
 * The proband may have a de novo DMD disease-causing mutation
 * The mutation could have occurred in the egg at the time of conception
 * The mutation could have occurred after conception and therefore is present in some but not all cells of the proband's body.
 * The likelihood that the mother is a carrier is low
 * The proband's mother may have a de novo mutation
 * 2/3 of mothers of sporadically occurring males with DMD are carriers
 * Could have occurred if:
 * Mutation occurred in the egg or sperm at the time of her conception and is present in every cell of her body (germline mutation)
 * Mutation is present in some but not all cells of her body (somatic mosaicism)
 * Mutation is present only in her egg cells (germline mosaicism) and is not detected in a blood sample.
 * The proband's mother may have inherited a DMD mutation from her mother who is a carrier, her mother or father who has somatic mosaicism, or her mother or father who has germline mosaicism.

Risk Assessment

 * Sporadic versus inherited
 * If inherited, sister has 50% chance of being a carrier
 * Bayes analysis takes into account 3 unaffected male siblings
 * Sister has a 1/18 or 5.5% chance of being a carrier
 * 1/3 of cases are due to sporadic mutation

Ordering the test

 * Patient must sign consent form for DNA analysis
 * Use blue ink so it is obvious which is the original
 * Give the patient a copy
 * Put the original in the chart
 * Use special specimen processing request form
 * Make a copy for the chart
 * Give a copy to Lori Martineek at E352
 * Blood is drawn at Test Referral Center
 * Pt must have consent form, 2-ply specimen processing request form, and DNA analysis requisition
 * Tell pt to make sure her name is on the tube of blood
 * TRC will FedEx to Dr. Prior's lab
 * Contact Dr. Thomas W. Prior to inform him that you are sending the sample
 * Prior-1@medctr.osu.edu
 * Give him clinical history and lab report # from prior testing

Arrange for Follow-up

 * How do you want to receive the test results?
 * Results may take 2-3 weeks
 * We will only be able to give the results to the person tested, not to mother
 * Give potential risk figures if positive and emphasize that she can come back for more information at any time
 * Some people may wait for years until they are thinking of starting a family
 * Send a clinic letter after the results are back

Resources

 * Muscular Dystrophy Association
 * 800-572-1717
 * www.mdausa.org
 * Gale Encyclopedia of Medicine
 * Muscular Dystrophy by Richard Robinson (1999)
 * From the CHMC Health Reference Center