# 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

## 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.