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

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.