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

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.