Dystrophinopathies: Duchenne Muscular Dystrophy

MANIFESTING DMD/BMD CARRIER FEMALES

The vast majority of DMD/BMD carriers, 76% and 81%, respectively, are usually free of symptoms. Mild calf hypertrophy may be seen. However, approximately 8% to 19% of carriers present with mild-to-moderate and, occasionally, severe muscle weakness of the limb-girdle type or even with DMD/BMD.

GENETICS

DMD Gene. The DMD gene is the largest gene yet identified in humans, spanning approximately 2.3 megabases on the short arm of the X chromosome at Xp21. The protein product dystrophin is identified on Western blots of human skeletal muscle proteins using anti-dystrophin antibodies. The dystrophin-associated protein (DAP) complex also contains many other proteins that are tightly associated. The DAP complex appears to be stabilized and protected from degradation by dystrophin in normal cells; the complex becomes unstable when dystrophin is absent. The muscle tissue of patients with DMD usually shows secondary reduction in the amount of other proteins of the DAP complex.

DMD Gene Mutations. Most DMD gene mutations identified so far are deletions (about 5%-20%). Patients without detectable deletions or duplications are identified as having small insertions/deletions, point mutations, or splicing errors.

No apparent correlation has yet been found between the size of DMD gene deletions and the severity and progression of the DMD/BMD phenotype. In most patients, the molecular differentiation of Duchenne versus Becker muscular dystrophy appears related to the disruption or preservation of the amino acid reading frame by deletion or duplication mutations. The latter either disrupt (DMD) or preserve (BMD) the reading frame in most cases (in-frame, out-of-frame hypothesis).

Dystrophin. In greater than 99% of DMD patients, skeletal muscle biopsy specimens display complete or almost complete absence of dystrophin (0-5% of normal). The intermediate phenotype (mild DMD or severe BMD) appears to develop in patients with dystrophin levels between 5% to 20% of normal, regardless of protein size. Patients with mild-to-moderate BMD usually have dystrophin levels greater than 20% of either normal or abnormal molecular weight. In contrast, patients with neuromuscular diseases other than DMD/BMD have normal dystrophin concentrations.

DIAGNOSIS

Creatine kinase (CK) values varying between 1,000 to 50,000 IU/L are not unusual in DMD/BMD. If serum CK concentration is less than that, the diagnosis should be questioned. From birth through 3 years, serum CK concentration in a child with DMD is always more than 10 times the upper limit of normal (ULN), and in a child with BMD is usually more than 5 times the ULN. However, CK values do not differentiate reliably between the two types of dystrophy. Serum CK may be mildly increased in manifest carriers.

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