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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
- Histology
- Clinical findings
- Progressive symmetrical muscle weakness, proximal greater then distal
- Symptoms before age 5 years
- Wheelchair dependency before age 13 years
- Family history
- 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
- Deletions involving one or more exons of the DMD gene
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
- Incidence increases steadily in the teenage years
- 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
- DMD usually presents in early childhood with delayed milestones
- 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
- Prednisone therapy is controversial due to side effects
- 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
- Physical therapy to promote mobility
- All carriers should have a complete cardiac evaluation at least once
- There is no treatment for DMD
Differential Diagnosis[]
- Limb-girdle muscular dystrophy
- A group of disorders clinically similar to DMD
- Occurs in both sexes
- Caused by mutations I 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%
- A germline mutation
- 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.
- The proband may have a de novo DMD disease-causing mutation
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
Review and summarize major points[]
Elicit final questions and concerns[]
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
References[]
- About Muscular Dystrophy. A booklet sponsored by the Muscular Dystrophy Association. 1981.
- www.mdausa.org (Muscular Dystrophy Association)
- www.geneclinics.org (GeneClinics)
- Emery and Rimoin's Principles and Practice of Medical Genetics. Third Edition, 1996. pp 2337-2354
- Nelson's Textbook of Pediatrics. 15th Edition. pp1745-1748
- Online Mendelian Inheritance in Man (OMIM). DMD#310200, Dystrophin#300377
Notes[]
The information in this outline was last updated in 2002.
This material has been imported fom the wikibook "Genetic counseling"[ http://en.wikibooks.org/wiki/Genetic_counseling] under the GNU Free Documentation License.
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