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Genetic counseling: Duchenne Muscular Dystrophy-1

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Duchenne Muscular Dystrophy

ContractingEdit

  • 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 HistoryEdit

  • 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 InformationEdit

  • 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

DiagnosisEdit

  • 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 then 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 DescriptionEdit

  • 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 DiagnosisEdit

  • 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

InheritanceEdit

  • 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 AssessmentEdit

  • 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 pointsEdit

Elicit final questions and concernsEdit

Ordering the testEdit

  • 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-upEdit

  • 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

ResourcesEdit

  • 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

ReferencesEdit

  • 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

NotesEdit

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.

Heckert GNU white Permission is granted to copy, distribute and/or modify this document under the terms of the GNU Free Documentation License, Version 1.2 or any later version published by the Free Software Foundation; with no Invariant Sections, no Front-Cover Texts, and no Back-Cover Texts. A copy of the license is included in the section entitled "GNU Free Documentation License."

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