Dystrophinopathy, caused by mutations in the
Duchenne muscular dystrophy (DMD) is a recessive X-linked form of muscular dystrophy. The milder form of this disease is called Becker muscular dystrophy(BMD).1) The disorder is also called dystrophinopathy because it caused by mutations in the
Duchenne’s description of DMD was published in 1861. He referred to the disease as “hypertrophic paraplegia of infancy due to a cerebral cause”.5) However, in 1868, he performed muscle biopsies and recognized that it was of muscular origin. He proposed the criteria for diagnosing this disease and reported the results of muscle biopsy which showed replacement of muscle by fat and connective tissue.6) Gowers, in 1886, noted that cases always occurred on the mother’s side of the family.7) Depending on the advancement of molecular genetics, mapping of the gene responsible for DMD was available to band p21 of the short arm of the X chromosome (Xp21).8-11) Subsequently, Kunkel’s group identified the muscle protein dystrophin which is encoded by the
Random inactivation of one of the two X chromosomes occurs during early embryonic development, leaving active 50% of the maternally derived chromosomes and 50% of the paternally derived ones.14) Non-random X-chromosome inactivation induce fewer than 50% of the nuclei which may have the normal dystrophin gene, resulting in clinical manifesting female carriers.15) Some reports described cases of X-autosomal translocations with breakpoints at Xp21 resulting in preferential inactivation of the normal chromosome.8, 11) If the X chromosome of turner syndrome patient (karyotype XO) carries a mutated dystrophin gene, her daughter can be symptomatic.
DMD is the most common form of childhood muscular dystrophy, with an incidence of approximately 1 in 3,600- 6,000 live male births and a prevalence of approximately 3 per 100,000.16, 17) The symptoms of DMD female carriers range from mild muscle weakness to severe gait problems. Although manifesting girls usually show much milder symptoms than boys, a few cases have disease severity similar to that seen in affected boys.3, 18, 19) The most commonly presented symptom is mild proximal muscle weakness, which is often asymmetric and progressive. There are variable clinical patterns from BMD-like to severe DMD-like phenotype.20) The prevalence of manifesting female carriers of DMD is slightly different in each study. Recent study reported 22% of female carriers manifested the symptoms, with 19% demonstrating muscle weakness measured by manual muscle testing and 8% presenting with dilated cardiomyopathy.21) A similar prevalence of females with symptoms was observed by other group, with 12% presenting with muscle weakness and 7% displaying cardiomyopathies.22) Some manifesting carriers only present myalgia or cramps without limb weakness.23) In addition, unusual cases such as isolated cardiomyopathy without skeletal muscle weakness24-26) and developmental delay in childhood have been reported.23) Also, there have been reports of manifesting carriers of DMD who initially presented with camptocormia which is forward flexion of the thoracolumbar spine that abates in the supine position.27)
Serum creatine kinase levels are commonly elevated in manifesting carriers of DMD.28) Magnetic resonance imaging (MRI) is performed for more comprehensive assessment of muscles. There was a report about elevation of reported proton spin lattice relaxation time (T1) in female carriers elevated in the gluteals, vastus lateralis, and gastrocnemius compared with the control group and correlation with the distribution of muscle edema.29) Elevated spin-spin or tranverse relaxation time (T2) in DMD carriers was also observed following muscle damage and inflammation/edema.30, 31) Quantitative MRI measures were used to evaluate muscle composition.32) In female carriers of DMD, there was considerable heterogeneity among lipid fraction measures compared with the control groups during 21 months of a longitudinal study.32) Although specific findings of imaging evaluation in female carriers of DMD has not yet been established, depending on the advance of neuroradiology, these invasive techniques could be strong tools for evaluation of carrier status.
Muscle biopsy is used for diagnosis in cases of clinically suspicious of dystrophinopathy. It can provide information about the amount and molecular size if the protein is present. Muscle biopsy is usually not necessary when genetic testing is positive. However, pathological evidence is helpful for patients with a family history of DMD, but no family mutation is known.18) Dystrophin labeling of muscle biopsies from manifesting carriers shows a mosaic pattern, with reduced or absent dystrophin.33, 34) Immunohistochemistry findings are concordant with western blot analysis for dystrophin.34) No association is seen between the pattern of distribution of dystrophin and clinical severity of manifesting carriers.35) However, a few cases revealed that the absence of dystrophin expression and unstained fiber presumably affected the more severe phenotype.20) Moreover, dystrophin expression can vary in different muscle groups of DMD carriers.36)
The dystrophin gene have majority of deletion mutation, approximately 61.9-73% in western, northerm and Asian populations.37-39) The frequency of deletions of the DMD gene is greater in affected males resulting from a female gametic mutation (75%) than in those resulting from a male genetic mutation (56%).40)
Dystrophin mutation is able to be detected by Multiplex PCR42) and multiplex ligation-dependent probe amplification (MLPA).43) Multiplex PCR is a common technique to identify mutations of the
Furthermore, dystrophin gene sequencing is used to analyze single-condition amplification/internal primers and multiplex amplifiable probe hybridization for detecting point mutations or small deletions/insertions if deletion/ duplication testing is negative.48, 49)
Full characterisation of the mutation (deletion endpoints or exact position of any point mutation) is helpful to investigate the clinical variability of dystrophinopathy50, 51) and recent trials about mutation-specific treatment.52-54)
Symptomatic carriers of DMD without chromosomal rearrangements have been explained by skewed X-chromosome inactivation related to preferential expression of the mutant allele.36, 55, 56) The nonrandom X-inactivation pattern of manifesting carriers of DMD showed derivative X remaining active as a saving mechanism against disease-expression.11, 57) Therefore, the extent of X-chromosome inactivation skewing is correlated with clinical phenotype.58) Nevertheless, some studies reported no significant association between X-chromosome inactivation pattern and clinical severity.59) Prognostic value of X-chromosome inactivation is also controversial.58, 60, 61)
Female carriers of DMD are not less common, and they have an important role in male DMD. Comprehension of characterization of female carriers of DMD is helpful for establishment of diagnostic approaches in patients who may have in the past been diagnosed as having autosomal recessive limb-girdle muscular dystrophy or unknown myopathy with a negative family history.