Advances in Dystrophinopathy Diagnosis and Therapy

Abstract

Dystrophinopathies are x-linked muscular disorders which 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 glucocorticoids therapy. Procedures for diagnosing dystrophinopathies include creatine kinase assay, haplotype analysis, Southern blot analysis, immunological analysis, multiplex PCR, multiplex ligation-dependent probe amplification, Sanger DNA sequencing, and next generation DNA sequencing. Pharmacological therapy for dystrophinopathies comprises glucocorticoids (prednisone, prednisolone, and deflazacort), vamorolone, and ataluren. However, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and β-blockers are the first-line to prevent dilated cardiomyopathy in dystrophinopathy patients. Duchenne muscular dystrophy gene therapy strategies involve gene transfer, exon skipping, exon reframing, and CRISPR gene editing. Eteplirsen, an antisense-oligonucleotide drug for skipping exon 51 from the Dystrophin gene, is available on the market, which may help up to 14% of Duchenne muscular dystrophy patients. There are various FDA-approved exon skipping drugs including ExonDys-51 for exon 51, VyonDys-53 and Viltolarsen for exon 53 and AmonDys-45 for exon 45 skipping. Other antisense oligonucleotide drugs in the pipeline include casimersen for exon 45, suvodirsen for exon 51, and golodirsen for exon 53 skipping. Advances in the diagnosis and therapy of dystrophinopathies offer new perspectives for their early discovery and care.

Gene-based therapies for neuromuscular disorders

“… 81 DMD mutations are intragenic deletions affecting one or more exons (60-65%), duplications of one or more exons (10%), and nucleotide variants (around 20-25%), including missense and nonsense variants, small insertions/deletions, or splicing alterations. 82 Mutations in DMD that do not disrupt the reading frame, leading to the expression of a truncated yet functional dystrophin cause the milder phenotype of Becker muscular dystrophy. 83 …”

Mechanisms and effects of metformin on skeletal muscle disorders

“…Mutations in the Dystrophin gene result in dystrophinopathies, such as DMD, Becker muscular dystrophy, and others. Approximately 75% of Dystrophin gene mutations are intragene deletions (65%) or duplications (10%), with the remaining 25% being nucleotide variants ( 97 ). One of the most severe phenotypes is DMD, an X-linked recessive neuromuscular disorder.…”

“…One of the most severe phenotypes is DMD, an X-linked recessive neuromuscular disorder. About 1 in 5,000 people suffer from DMD ( 97 ). Muscle fiber cells rely on dystrophin to maintain their functionality by linking the intracellular cytoskeleton with the transmembrane components of the dystrophin-glycoprotein complex ( 98 ).…”

“…The gene therapy strategies for DMD include gene transfer, exon reframing, exon skipping, exon reconstruction, and CRISPR gene editing. The latter three as personalized treatment options are beneficial for only a small number of patients ( 97 ).…”

A novel splicing mutation identified in a DMD patient: a case report

“…Approximately 60%–70% of mutations observed in DMD are deletions or duplications in single or multiple exons ( 7 , 8 ). The remaining genetic changes are mainly related to small mutations, which include nonsense, missense, splice site variations, or small rearrangements like insertion/deletion, and small inversions ( 9 – 12 ). Splicing mutations, which can lead to disruption of existing splicing regulatory sequences, alterations in the open reading frame and inappropriate intron removal during splicing process, and ultimately the production of a defective protein ( 13 ), constitute approximately 3% of total mutations of DMD , and has been thought to an important causes for undiagnosed DMD ( 11 , 14 ).…”