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Dystrophinopathies are progressive hereditary degenerative diseases (often called muscular dystrophies) of skeletal muscles due to an absence or deficiency of the protein dystrophin.

Dystrophin and the associated proteins form a complex system that connects the intracellular cytoskeleton to the extracellular matrix. The normal operation of this system is critical for maintaining the integrity of the delicate, elastic muscle membrane (sarcolemma) and the muscle fiber. The responsible gene is located on the short arm of the X chromosome at locus Xp21. It is an extremely large gene, comprising more than 2.5 million base pairs and 79 exons. The dystrophin gene produces several isoforms (alternative forms of a protein) of dystrophin. Seven distinct promoters have been identified, each driving a tissue-specific dystrophin.

The most common mechanisms of mutation are deletions and duplications largely clustered in the "hot spot," a DNA sequence associated with an abnormally high frequency of mutation or recombination, between exons 44 and 49. Whether the deletion is in the reading frame or out of frame determines whether dystrophin is absent from the muscle or present in a reduced, altered form. This has an important clinical significance because the former is usually associated with the severe Duchenne's variety of the disease (DMD), whereas the latter situation may cause the milder Becker's variant (BMD). Thirty to 40% of DMD/BMD cases are associated with point mutations in the dystrophin gene.

In approximately two-thirds of cases, the dystrophin gene defect is transmitted to affected boys by carrier females following the pattern of Mendelian X-linked recessive inheritance. However, in one-third of cases, the defect arises as a result of a new mutation in the germ cells of parents or during very early embryogenesis.

DMD occurs at a frequency of one per 3,500 live births. The child who appears healthy at birth develops the initial symptoms around age five. Symptoms include clumsy gait, slow running, difficulty in getting up from the floor, difficulty in climbing stairs, and a waddling gait. Mental subnormality, if it occurs, is not progressive and is presumed to be due to the lack of brain dystrophin. The progression of muscle weakness and loss of function for the activities of daily living is relentless. In the typical situation, the child loses the ability to walk independently by age 9-12 years. Despite all therapeutic efforts, most patients die during the third decade. BMD is an allelic variant of DMD in which the mutation of the dystrophin gene produces a reduced amount of truncated dystrophin that is not capable of maintaining the integrity of the sarcolemma. However, the pace of muscle fiber loss is considerably slower than in DMD, which is reflected in a less severe clinical phenotype. The illness usually begins by the end of the first or at the beginning of the second decade. These boys, however, continue to walk independently past the age of 15 years and may not have to use a wheelchair until they are in their twenties or even later. In some people carrying a mutation in the dystrophin gene, no muscular symptoms are present at all

Confirmation of clinical diagnosis of DMD/BMD is largely based on deletion analysis of DNA. In the 30% of patients in whom a deletion is not found, a muscle biopsy is necessary to establish the absence of dystrophin by immunohistochemistry, or Western blotting analysis.

Treatment of dystrophinoptahies is palliative, aimed at managing the symptoms in an effort to optimize the quality of life. Gene therapy which is oriented towards replacement of the defective dystrophin gene with a wild-type one (or a functionally adequate one) or upregulation of the expression of the surrogate molecules such as utrophin is still in the research phase.

Prevention of dystrophinopathies is based on genetic counseling and molecular genetic diagnosis. Female carriers can namely opt for prenatal diagnosis (evaluation in the first trimester of pregnancy of whether the fetus has inherited the mutation) or even preimplantation genetic analysis of the embryo. In the last case, fertilization in vitro is followed by isolation and genetic testing of the single cell from the few-cell-stage embryo. The embryo is implanted into the uterus if no dystrophin gene defect is found.



Barohn, R. J. "Muscular Dystrophies." In L. Goldman, and J.C. Bennett, eds. Cecil Textbook of Medicine, 21st ed. W.B. Saunders Co., 2002.

Brown, Susan C., ed. Dystrophin. Cambridge, UK: Cambridge University Press, 1997.


Muscular Dystrophy Association USA. "Progress in Utrophin Therapy for DMD." Research Updates. (February 7, no. 1 2000).


Muscular Dystrophy Association. 3300 E. Sunrise Drive Tucson, AZ 85718. Tel. (800) 572-1717. <http://www.mdausa.org/>.


National Institutes of Health. National Institute of Neurological Disorders and Stroke. "NINDS Muscular Dystrophy (MD) Information Page" May 29, 2001 [cited February 24, 2003]. <http://www.ninds.nih.gov/health_and_medical/disorders/md.htm>.

Borut Peterlin

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