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Saad, F.A.; Siciliano, G.; Angelini, C. Dystrophinopathy Diagnosis and Therapy. Encyclopedia. Available online: https://encyclopedia.pub/entry/48895 (accessed on 23 December 2024).
Saad FA, Siciliano G, Angelini C. Dystrophinopathy Diagnosis and Therapy. Encyclopedia. Available at: https://encyclopedia.pub/entry/48895. Accessed December 23, 2024.
Saad, Fawzy A., Gabriele Siciliano, Corrado Angelini. "Dystrophinopathy Diagnosis and Therapy" Encyclopedia, https://encyclopedia.pub/entry/48895 (accessed December 23, 2024).
Saad, F.A., Siciliano, G., & Angelini, C. (2023, September 07). Dystrophinopathy Diagnosis and Therapy. In Encyclopedia. https://encyclopedia.pub/entry/48895
Saad, Fawzy A., et al. "Dystrophinopathy Diagnosis and Therapy." Encyclopedia. Web. 07 September, 2023.
Dystrophinopathy Diagnosis and Therapy
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This entry is adapted from the peer-reviewed paper 10.3390/biom13091319

Dystrophinopathies are x-linked muscular disorders that emerge from mutations in the Dystrophin gene, including Duchenne and Becker muscular dystrophy, and dilated cardiomyopathy. However, Duchenne muscular dystrophy interconnects with bone loss and osteoporosis, which are exacerbated by glucocorticoid therapy. Appropriate choice of steroids and regimen is crucial. Creatine kinase (CK) has a 71% potential of detecting female carriers that are increased by multiplex ligation-dependent probe amplification (MLPA) or dystrophin study in biopsy. Clinical neurologists need to relate to patients and families of patients with neurocognitive problems since mental retardation might be part of Duchenne's picture.

dystrophinopathies Duchenne muscular dystrophy Becker muscular dystrophy steroid carriers mental retardation

1. Introduction

Molecular cloning of the Dystrophin gene in 1985 [1][2] has revealed that its 14 kilobase messenger RNA comprises 79 exons extending over 2.4 megabases (2.4 centimorgans) of the human chromosome X [3][4]. The dystrophin protein contains four domains [5]: the amino-terminal, the rod, the cysteine-rich, and the carboxy-terminal domains.
Dystrophin and utrophin are muscle cytoskeletal proteins with similar molecular masses of 420 and 395 kDa, respectively. Furthermore, utrophin shares 80% homology with the dystrophin carboxy-terminal domain [6][7].
Approximately 75% of Dystrophin gene mutations are intragenic deletions (65%) or duplications (10%), while the remaining 25% are nucleotide variants, including nonsense and missense mutations, small insertions/deletions (indels), or splicing alterations [8][9]. Out-of-frame exon deletions/duplications and nonsense mutations generate transcripts with premature stop codons which would be degraded through a nonsense-mediated mRNA decay pathway [10][11].
The absence or deficiency of dystrophin due to mutations in the Dystrophin gene leads to a spectrum of dystrophinopathies including Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and dilated cardiomyopathy (DCM) in humans and animal models [12][13]. Cardiomyopathy is a common feature of DMD patients and influences the prognosis of the disease [14]. The prevalence of dilated cardiomyopathy in DMD patients rises from 59% to 90% depending on the age of the patients [15], and may reach 61% in BMD patients [16]. However, carriers of Dystrophin gene mutations may represent a rare distinct form of dilated cardiomyopathy without skeletal muscle abnormalities [17].
Dystrophinopathies are associated with elevated levels of serum creatine kinase (CK) beyond the background of metabolic myopathies [18][19][20]. DMD is the most severe phenotype, which usually manifests in childhood with a sequence of muscle degeneration leading to a loss of mobility before the teenage years. Conversely, BMD is a late-onset entity, therefore, patients with a mild BMD spectrum display symptoms after the age of 30 and stay mobile even into their 60s. However, left ventricular dilation and congestive heart failure are common causes of morbidity and a prevalent cause of death for BMD patients, which may occur early in their 40s. Melacini and colleagues illustrated that the deletion of exon 49 from the Dystrophin gene is associated with cardiac manifestation, which is characterized in BMD patients by early right ventricular involvement related or not to left ventricular weakening [21].
Dystrophinopathies are inherited in a sex-linked recessive manner, mainly affecting boys due to their single copy of chromosome X. As carrier girls have two copies of chromosome X, they are at increased risk for dilated cardiomyopathy. Although DMD and BMD are the common types of dystrophinopathies in boys, isolated dilated cardiomyopathy, myalgia, cramps, rhabdomyolysis, hypercKemia (elevated serum creatine kinase), are less common manifestations in carrier girls [22]. However, about 8–18% of carrier girls present with dilated cardiomyopathy, which could vary to a certain degree depending on whether the carrier girl manifests a DMD or BMD phenotype [20][23][24][25][26][27].

2. Diagnosis Technology

Prior to the molecular diagnosis era, diagnosis of muscular dystrophy patients and their carrier mothers has mainly relied on elevations of serum creatine kinase [28], and to a lesser degree on muscle histopathology [29] and haplotype (pedigree) analysis of the Dystrophin gene using restriction fragment length polymorphisms [30] or short tandem repeat polymorphisms [31].

2.1. Serum Creatine Kinase Assay

More than six decades ago, investigative studies provided evidence that serum creatine kinase (CK) is superior to other enzymes like aldolase, lactic dehydrogenase, glutamic oxalacetic transaminase, glutamic pyruvic transaminase, and phosphohexoseisomerase for the biochemical diagnosis of muscular dystrophy patients and their carrier mothers [28][32][33][34][35], allowing for the detection of preclinical cases of muscular dystrophy and disease prediction in infancy. Since then, the elevation of serum creatine kinase (CK) has been the prominent preclinical diagnostic tool and is still in use in the molecular diagnosis era [36].
Duchenne muscular dystrophy is always coupled with high levels of serum creatine kinase [20]. Yasmineh and colleagues have reported that serum creatine kinase in DMD patients reached around 867 U/L compared to 28 U/L of the healthy control group, which is thirty-one-fold higher than healthy subjects [37]. However, serum creatine kinase assay has the potential to diagnose up to 71% of DMD carriers [33]. In fact, normal serum creatine kinase levels in two DMD carriers with muscle histological abnormalities have been reported [38].
The molecular diagnosis era started with the cloning of the Dystrophin gene in 1985 [1][2]. Since then, the diagnosis of muscular dystrophy patients and their carrier mothers have relied on haplotype analysis, Southern blot analysis, immunological analysis, multiplex polymerase chain reaction (PCR), multiplex ligation-dependent probe amplification, Sanger DNA sequencing, and next-generation DNA sequencing.

2.2. Haplotype and Southern Blot Analyses

Molecular diagnosis of DMD was initiated four decades ago with haplotype (pedigree) analysis, using restriction fragment length polymorphisms (RFLP) related to the Dystrophin gene [39][40]. Furthermore, the use of Southern blotting and complementary DNA (cDNA) probe hybridization has detected several intragenic deletions and duplications in the Dystrophin gene [41][42][43][44][45][46][47][48][49].

2.3. Diagnostic Methods on Muscle Tissue

Immunohistochemical analysis of muscle biopsy cryosections reveals that human dystrophin antibodies react with an antigen in skeletal muscle sarcolemma. This immunoreactivity is faint or absent in the muscle fibers of DMD patients compared to the muscle fibers of healthy subjects. On immunoblots, dystrophin antibodies react with 400 kDa protein extracts of normal human muscle [50][51][52]. Protein truncation tests revealed that about 73% (19 out of 26) of BMD patients show a truncated dystrophin of abnormal molecular weight [52][53][54], leading to the presence of normal and shorter dystrophins in the muscle fibers of BMD asymptomatic carriers. However, in case of duplication, BMD patients show longer and normal dystrophins [44]. Also, a screening of 62 Becker muscular dystrophy patients revealed that 35 of them had dystrophin abnormalities [55]. Currently, there are six anti-human dystrophin antibodies for Western blotting that recognize the different domains of dystrophin; one is polyclonal and five are rabbit monoclonal antibodies available from various commercial sources. RNA sequencing (RNA-seq) is a valuable approach for dystrophin mutation detection [56][57][58][59].

2.4. Multiplex Ligation-Dependent Probe Amplification

Multiplex ligation-dependent probe amplification (MLPA) is widely employed to examine exonic duplications/deletions (dupdels) within the 79 exons of the Dystrophin gene [60][61][62][63][64][65][66][67], detecting up to 70% of exonic alterations. However, genetic diagnosis of the remaining 30% of DMD/BMD patients requires point mutation screening and DNA sequencing. Sanger DNA sequencing of the entire Dystrophin gene obtained from the analysis of reverse transcription (RT-PCR) from muscle Dystrophin mRNA (cDNA) is a powerful approach for detecting nucleotide alterations within the transcript of the Dystrophin gene [56][57].

2.5. Multiplex PCR

For more than a decade, the standard clinical diagnosis relied on the conventional multiplex PCR for a selected number of Dystrophin exons within the proximal (exons 3–9), and the distal (exons 45–55) deletion hotspots [68]; nonetheless, this multiplex PCR platform holds the power to confirm the presence of exonic deletions in about 98% of DMD/BMD boys [69][70]. Although effective and economical, this multiplex PCR platform was imperfect; because it did not include all the 79 exons of the Dystrophin gene, leaving the deletions border undefined and the reading frame ambiguous in many patients [71].
Soon after, semiquantitative multiplex PCR was able to detect intragenic duplications in DMD patients and girls carrying intragenic deletions within the Dystrophin gene [72][73]. About two decades later, semiquantitative fluorescent multiplex PCR for deletions and duplication detection was achieved [57]. The high-density single-strand PCR-based comparative genomic hybridization (CGH) array represents an effective high-throughput tool (DMD-CGH array) to detect Dystrophin gene exon deletions/duplications [74][75].

2.6. Point Mutations Screening

If the results of multiplex PCR and MLPA analyses do not reveal intragenic alterations (single or multiple exon deletions or duplications—dupdels), the next step is to screen PCR products for nucleotide alterations (point mutations) including nucleotide substitutions, deletions, or insertions using denaturing gradient gel electrophoresis [76][77], single strand conformation polymorphism analysis [78][79], double strand confirmation analysis [80][81], or DNA fingerprinting [82][83][84].
If the point mutations screening shows electrophoretic mobility alterations of certain PCR products (amplicons), the next step is to sequence these amplicons to identify nucleotide alterations. Furthermore, rapid direct sequencing of Dystrophin gene exons and flanking intronic regions, which is necessary to detect mutations affecting splice sites, became available in 2003 [16][85].

2.7. Next Generation DNA Sequencing

The next-generation DNA sequencing (NGS) platform is a valuable tool for the molecular diagnosis of dystrophinopathies [86][87][88][89][90][91]. The NGS platform combines a DNA sequencing apparatus (NovaSeq 6000, sequencer) and results analysis gear (SeqNext software, version number is 3.5.0). The NGS platform is able to simultaneously detect intragenic and nucleotide alterations of libraries obtained with the DMD MASTR kit (Agilent Technologies, Cheadle, UK).
The combination of MLPA and NGS is a valuable approach for detecting mutations in the Dystrophin gene in Peruvian patients suspected of muscular dystrophies [92]. Moreover, a comprehensive NGS assay for sequencing the entire 2.2 Mb Dystrophin gene holds the power to detect all copy number and sequence variants in both patients and carrier females [93].

3. Pharmacological Therapy

Since the first description of Duchenne muscular dystrophy in 1867 [94], various pharmacological efforts have failed to alter the natural course of the disease [95][96]. Recent updates of the pharmacological therapy for Duchenne muscular dystrophy are reported elsewhere [97].

3.1. Skeletal Muscle Care

The mainstay therapy of DMD patients is glucocorticoids (prednisone, prednisolone, and deflazacort), which target the glucocorticoid receptor to exert anti-inflammation effects by suppressing the NF-κB signaling pathway [98][99][100]. Glucocorticoids are usually administered in daily or intermittent doses; however, glucocorticoids have different efficacy and remarkable side effects [99][101][102], including weight gain, osteoporosis, cataracts, hypertension, and stunted bone growth [103][104][105][106][107]. Bonifati and colleagues suggest that the 1220 A to G (Asn363Ser—N363S) polymorphism in the Glucocorticoid receptor (GR) gene has a definite modulating effect on steroid response in DMD patients by inducing a long-term sensitivity to glucocorticoids [108].
In a randomized double-blind controlled trial, 28 DMD patients were treated with either deflazacort 2.0 mg/kg or placebo on alternate days. After 6 months of therapy, the deflazacort group showed significant progress in climbing stairs, rising from a chair, Gower’s maneuver, and walking. Moreover, these motor outcomes continued to meliorate during a two-year follow-up period. Additionally, the loss of ambulation of the deflazacort group was delayed for 12.7 months compared to placebo—33.2 versus 20.5 months, respectively [109]. Wissing and colleagues suggest that the cyclophilin inhibitor (Debio-025) is more effective than prednisone in reducing skeletal muscle pathology in the DMD mouse model [110], which is due to its ability to desensitize mitochondrial permeability pore and successive cellular necrosis. This observation suggests a latent mitochondrial dysfunction in DMD myoblasts [111].
Currently, vamorolone (VBP15), an innovative steroid, is being investigated as a potential alternative to corticosteroids (glucocorticoids and mineralocorticoids), aiming at maintaining the corticosteroids’ efficacy profile while diminishing their side effects [112][113][114]. Ataluren is approved in several countries for DMD therapy. Ataluren (Translarna—PTC124) is a disease-modifying molecule for stop codon read-through therapy, which could help up to 10–15% of the DMD patients carrying nonsense mutations plus those carrying out of frame mutations [20][115][116][117][118]. However, there is no pharmacological drug that can compensate for the lack of dystrophin in muscle fibers [96][97].
Corticosteroids (prednisone, prednisolone, and deflazacort) stabilize muscle strength for some time [106]. Although corticosteroid therapy improves muscle strength and function for DMD boys aged 5 to 15 years, their therapeutic efficacy in BMD is less obvious. Moreover, intermittent glucocorticoids combined with continuous oral steroid therapy significantly improve myocardial function in DMD, but not in BMD patients [119]. Merlini and colleagues reported that early corticosteroid treatment increases quadriceps muscle strength and prolongs the mobility of DMD boys [120]. Barp and colleagues identified a putative predictive value of the LTBP4 rs10880 genotype for delaying the onset of dilated cardiomyopathy with steroid therapy, which could help in deciding whether and how long to preserve therapy in non-ambulatory patients [121].

3.2. Cardiologic Care

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and β-blockers are the first-line cardioprotective prescriptions to prevent DMD cardiac manifestations [121][122][123][124]. While ACE inhibitors are used with or without beta blockers for cardiomyopathy in muscular dystrophy patients, congestive heart failure is treated with diuretics and oxygen. Nevertheless, cardiac transplantations are usually offered to DMD patients and symptomatic carriers with severe dilated cardiomyopathy [13][125][126]. Angiotensin II is involved in the fibrotic process of skeletal muscle and heart [127]. The ACE inhibitor perindopril is associated with lower mortality in young DMD patients with cardiomyopathy [128].

4. Standard Multidisciplinary Care

Duchenne muscular dystrophy affects multiple organs, thus, besides physiotherapy, a multidisciplinary approach for pulmonary, cardiac, and orthopedic care will be adopted.. Clinical neurologists need to relate to patients and families with neurologic problems since mental retardation might be part of Duchenne's picture. Duchenne muscular dystrophy patients suffer from skeletal muscle degeneration as well as lung and heart function limitations. However, advances in pulmonary care have significantly reduced respiratory complications [129]. The combination of yoga and early-age physiotherapy intervention improves pulmonary function in children with DMD [130]. Also, home exercise plays an important role in preventing early complications in patients with muscular dystrophy [131] and may increase their bone mass [132]. There is some general dietary advice such as on the consumption of micronutrients (multivitamins, calcium, vitamin D, high protein diet with low fat and carbohydrates) which should be part of a good dietary practice. However, DMD patients should always consult with their physicians for their nutrient requirements [129].

5. Gene Therapy

Duchenne muscular dystrophy gene therapy strategies are comprehensively reported elsewhere [95][97]. Eteplirsen, an antisense-oligonucleotide drug for exon 51 skipping from the Dystrophin gene, is available on the market after FDA approval in 2017 [133], however, there are reservations about its efficacy. Other FDA-approved exon-skipping drugs include ExonDys-51 for exon 51, VyonDys-53 and Viltolarsen for exon 53, and AmonDys-45 for exon 45 skipping [134]. Exon 51 skipping offers gene therapy for up to 14% of DMD patients [133]. Other antisense oligonucleotide drugs in the pipeline include casimersen for exon 45, golodirsen for exon 53, and suvodirsen for exon 51 skipping [135].
Prime gene editing alone is able to correct up to 89% of the genetic mutations causing genetic diseases [136]. Dystrophin restoration therapies have been developed using synthetic antisense oligonucleotides drugs (genetic medicine, genetic drugs, or gene drugs) to restore the reading frame by exon skipping or exon reframing for individuals with specific pathogenic variants in the Dystrophin gene [137][138][139]. Bello and colleagues conclude that patients with deletions ending at exon 51 (del X-51) or an exon 48 isolated deletion (del 48) have mild or asymptomatic BMD, while deletions starting at exon 45 (del 45-X) cause relatively severe weakness [16]. Similar to the deletion of exons 45–55 [140], the deletion of exons 10–25, 10–29, and 11–30 show dystrophin quantities similar to control [16], providing models for exon skipping of deletions within these exonic intervals.

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Fawzy A. Saad
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Gabriele Siciliano
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Corrado Angelini
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