# 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.