Duchenne Muscular Dystrophy: Genetics

Duchenne, Intermediate, and Becker Muscular Dystrophy (DMD/IMD/BMD), collectively, dystrophinopathies, define the severe to mild range of disease caused by alterations in the DMD gene. The DMD gene encodes the dystrophin protein, a membrane-associated contractile protein found in skeletal muscle.

Location and Transmission of the DMD Gene
The DMD gene is located in the Xp21 region of the X chromosome. Therefore, DMD, IMD, and BMD are transmitted as X-linked disorders – males with an altered DMD gene on their single X chromosome will have the disease. Females have two X chromosomes and thus two copies of all its genes. A "normal" (not altered or changed) DMD gene on one of their X chromosomes is sufficient to prevent the disease in most cases. Rare cases of manifesting carriers are increasingly appreciated. Transmission from mother to son occurs in about 2/3 of cases; in about 1/3 of cases, the mutation arises spontaneously.

Genetic Testing
In 95% of cases, standard genetic testing for mutations in the DMD gene, including stepwise evaluation for deletion/duplication mutations followed by sequencing of the full DMD gene, is successful, obviating muscle biopsy in children with clinical findings of DMD (LINK 3296). Testing is also available in asymptomatic females 18 and older to determine if they are a carrier of the DMD gene alteration – important also because carriers are at risk for cardiomyopathy. However, mothers whose testing is negative for the known mutation in their affected son may carry the mutation in a portion of their egg cells. This is called gonadal or germline mosaicism and means a woman's germ cell line (her egg cells) has X chromosomes with the mutation, but her somatic cells do not. This phenomenon is estimated to occur in up to 10% of mothers of affected boys.

Genetic Counseling
Genetic counseling to discuss testing results is important for families as part of the care of a child with DMD/IMD/BMD. Families will gain a better understanding of recurrence risks for current and future generations of the family. Knowledge of the specific mutation in each patient is critical since at least 1 mutation-specific treatment is approved by the FDA (eteplirsen) and several others are in various stages of clinical trial. Parent Project - DMD Prenatal diagnosis and preimplantation testing are available when the mutation in the DMD gene has been identified in the family. With the high cost of newly approved medications, some insurers have approved coverage of preimplantation testing.

Females as Manifesting Carriers
Rarely, females with 1 normal gene and 1 altered DMD gene may have symptoms of muscle weakness, cramping, high creatine kinase, and cardiomyopathy. These females are called "manifesting carriers." These symptoms are thought to be due to nonrandom inactivation of one of the X chromosomes (by the Lyon Hypothesis).

Cardiomyopathy in Carrier Females
Females identified as carriers, even those without any symptoms of systemic muscle weakness, should be screened for cardiomyopathy. [DMD: 2009]

Resources

Helpful Articles

Aartsma-Rus A, Ginjaar IB, Bushby K.
The importance of genetic diagnosis for Duchenne muscular dystrophy.
J Med Genet. 2016;53(3):145-51. PubMed abstract / Full Text

Nallamilli BR, Ankala A, Hegde M.
Molecular diagnosis of Duchenne muscular dystrophy.
Curr Protoc Hum Genet. 2014;83:9.25.1-29. PubMed abstract

Ishizaki M, Kobayashi M, Adachi K, Matsumura T, Kimura E.
Female dystrophinopathy: Review of current literature.
Neuromuscul Disord. 2018. PubMed abstract

Authors & Reviewers

Initial publication: November 2008; last update/revision: January 2020
Current Authors and Reviewers:
Author: Lynne M. Kerr, MD, PhD
Reviewer: Russell Butterfield, MD, Ph.D.
Authoring history
2017: update: Meghan Candee, MDR
2009: update: Karin Dent, MS, CGCR
2008: first version: Lynne M. Kerr, MD, PhDA
AAuthor; CAContributing Author; SASenior Author; RReviewer

Page Bibliography

DMD Care Considerations Working Group.
Diagnosis and management of Duchenne muscular dystrophy, part 1:diagnosis, and pharmacological and psychosocial management.
thelancet.com. 2009:1-17. / Full Text