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
 *