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.