Handbook of Genetic Counseling/Becker Muscular Dystrophy

Becker Muscular Dystrophy

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
      • Despite milder skeletal muscle involvement, heart failure from dilated cardiomyopathy is a common cause of morbidity and the most common cause of death
      • Mean age of death is in the mid-40s
• Dystrophin gene
  • Xp21.2
  • Encodes protein dystrophin
  • 85% of males with BMC have deletions or duplications involving exons of this gene
  • Molecular genetic testing is available clinically
• Prevalence
  • 1 in 18,000 live male births

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 BMD have a serum CK concentration >5x normal
    • ~30% of female carriers have a concentration 2-10x normal
      • Some investigations have shown a wide variability in BMD carriers
      • Many have levels within the normal range, so other tests are necessary
      • CPK is not completely reliable
  • Clinical findings
    • Progressive symmetrical muscle weakness and atrophy, proximal greater than distal, often with calf hypertrophy
      • Weakness of quadriceps femoris may be the only sign
    • Activity-induced cramping in some patients
    • Flexion contractus of the elbows may occur late in the course
    • Wheelchari dependency, if present, after 16 years of age
    • Preservation of neck flexor muscle strength in BMD differentiates it from DMD
• Molecular genetic testing
  • Deletions involving one or more exons of the DMD gene
    • ~85% of males with BMD have deletions
    • Testing is done by PCR or southern blot
    • Available on a clinical basis
  • The remaining ~15% have duplications of one or more exons of the DMD gene or other mutations such as small deletions or insertions, single base changes, or splicing mutations
  • 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
  • Characterized by later-onset skeletal muscle weakness (as compared to DMD which presents ~ age 4 years)
    • Patients remain ambulatory into their 20s with BMD
  • Heart failure from dilated cardiomyopathy is a common cause of morbidity and the most common cause of death
  • The mild end of the spectrujm includes men with onset of symptoms after age 30 years who remain ambulatory even into their 60s
  • Cognitive impairment is not as common or as sever as in DMD
• Females
  • Occasionally have clinical features as the result of X chromosome rearrangements involving the DMD locus (Xp21.2)
  • 81% of BMD carriers have no signs or symptoms
  • 14% have mild to moderate muscle weakness
  • 16% have left ventricle dilation
  • 5% have myalgia or cramps
  • No BMD carrier females have been found to have dilated cardiomyopathy
• Genotype-Phenotype Correlations
  • In males, phenotypes are best correlated with the degree of expression of dystrophin, which is largely determine by the reading frame of the spliced messaged obtained from the deleted allele
  • The BMD phenotype occurs when there is some dystrophin, usually resulting from:
    • Deletions or duplications that juxtapose "in-frame" exons
    • Some splicing mutations
    • Most non-truncating single base changes that result in translation of a protein product with intact N or C termini
  • A dystrophin protein that retains partial function produces the milder BMD phenotype
• Management
  • There is no treatment for BMD
  • 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 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 BMD 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

• All daughters of a male affected with BMD are carriers; none of the sons will inherit the mutation

Ordering the test

• Patient must sign consent form for DNA analysis
  • Give the patient a copy
  • Put the original in the chart

Resources

• Muscular Dystrophy Association
  • 800-572-1717
  • [1]

References

• Emery and Rimoin's Principles and Practice of Medical Genetics. Third Edition, 1996. pp 2337-2354
• National Organization for Rare Disorders (NORD)
• Nelson's Textbook of Pediatrics. 15th Edition. pp1745-1748
• Online Mendelian Inheritance in Man (OMIM). BMD#300376
• [www.geneclinics.org] (GeneReviews)

Notes

The information in this outline was last updated in 2002.