Dysferlinopathies are a subset of autosomal recessive muscular dystrophies resulting from pathogenic variants in the dysferlin (DYSF) gene. The prevalence of dysferlinopathies remains inadequately defined. This review aims to elucidate the mutational spectrum of DYSF in Arab populations. A systematic search was conducted in PubMed, ScienceDirect, Scopus, and Web of Science up to September 15, 2025. We identified 48 unique DYSF variants documented in the literature across eight Arab countries, resulting in 49 country-entries due to one variant being reported in two countries. The distribution of reported variants was as follows: Saudi Arabia 32.7% (16/49), Algeria 20.4% (10/49), Egypt 20.4% (10/49), Tunisia 10.2% (5/49), Morocco 6.1% (3/49), Libya 4.1% (2/49), Lebanon 4.1% (2/49), and Oman 2.0% (1/49). Clinical presentations were categorized based on phenotype assignments across variants, totaling 52 assignments as some variants were associated with multiple phenotypes: limb-girdle muscular dystrophy, recessive type 2 (LGMDR2) 50% (26/52), proximodistal 15% (8/52), Miyoshi myopathy 8% (4/52), distal myopathy with anterior tibial onset (DMAT) 4% (2/52), and asymptomatic hyperCKemia 4% (2/52). In terms of molecular consequences (denominator = 48 unique variants), frameshift variants constituted 36% (17/48), missense variants 29% (14/48), nonsense variants 15% (7/48), splice donor variants 6% (3/48), splice acceptor variants 4% (2/48), intronic variants 2% (1/48), and synonymous variants 2% (1/48). Documenting these variants across populations facilitates diagnosis and informs future public health strategies. Notably, no cohort study based in Morocco has focused on the genetics of dysferlinopathy; existing Moroccan data are limited to isolated case reports. Dysferlinopathy includes a spectrum of muscle disease characterized by two major phenotypes: Miyoshi muscular dystrophy (MMD) and limb-girdle muscular dystrophy type 2B (LGMD2B); and two minor phenotypes: asymptomatic hyperCKemia and distal myopathy with anterior tibial onset (DMAT). MMD (median age of onset 19 years) is characterized by muscle weakness and atrophy, most marked in the distal parts of the legs, especially the gastrocnemius and soleus muscles. Over a period of years, the weakness and atrophy spread to the thighs and gluteal muscles. The forearms may become mildly atrophic with decrease in grip strength; the small muscles of the hands are spared. LGMD2B is characterized by early weakness and atrophy of the pelvic and shoulder girdle muscles in adolescence or young adulthood, with slow progression. Other phenotypes in this spectrum are scapuloperoneal syndrome and congenital muscular dystrophy. Asymptomatic hyperCKemia is characterized by marked elevation of serum CK concentration only. DMAT is characterized by early and predominant distal muscle weakness, particularly of the muscles of the anterior compartment of the legs. The diagnosis of dysferlinopathy is established in a proband with suggestive findings and biallelic pathogenic variants in DYSF identified by molecular genetic testing. Treatment of manifestations: There is no approved therapy for dysferlinopathy. Treatment is symptomatic only. Management should be tailored to the individual and the specific subtype. Individualized management may include physical therapy, use of mechanical aids, surgical intervention for orthopedic complications, respiratory aids, and social and emotional support. Surveillance: Annual monitoring of muscle strength, physical function, activities of daily living, joint range of motion, balance, and respiratory function, and for evidence of cardiomyopathy for individuals with cardiac involvement. Agents/circumstances to avoid: Weight control to avoid obesity. Dysferlinopathy is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a DYSF pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the DYSF pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

Antisense-mediated exon skipping and exon inclusion have proven to be powerful tools for treating neuromuscular diseases. The approval of Exondys 51 (eteplirsen) and Spinraza (nusinersen) for the treatment of patients with Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA) was the most noteworthy accomplishment in 2016. Exon skipping uses short DNA-like molecules called antisense oligonucleotides (AONs) to correct the disrupted reading frame, allowing the production of functional quasi-dystrophin proteins, and ameliorate the progression of the disease. Exon inclusion for SMA employs an AON targeting an intronic splice silencer site to include an exon, which is otherwise spliced-out. Recently, these strategies have also been explored in many other genetic disorders, including dysferlin-deficient muscular dystrophy (e.g., Miyoshi myopathy, MM; limb-girdle muscular dystrophy type 2B, LGMD2B; and distal myopathy with anterior tibial onset, DMAT), laminin α2 chain (merosin)-deficient congenital muscular dystrophy (MDC1A), sarcoglycanopathy (e.g., limb-girdle muscular dystrophy type 2C; LGMD2C), and Fukuyama congenital muscular dystrophy (FCMD). A major challenge in exon skipping and exon inclusion is the difficulty in designing effective AONs. The mechanism of mRNA splicing is highly complex, and the efficacy of AONs are often unpredictable. We will discuss the design of effective AONs for exon skipping and exon inclusion in this chapter.

Dysferlinopathies refer to a spectrum of muscular dystrophies that cause progressive muscle weakness and degeneration. They are caused by mutations in the DYSF gene, which encodes the dysferlin protein that is crucial for repairing muscle membranes. This review delves into the clinical spectra of dysferlinopathies, their molecular mechanisms, and the spectrum of emerging therapeutic strategies. We examine the phenotypic heterogeneity of dysferlinopathies, highlighting the incomplete understanding of genotype-phenotype correlations and discussing the implications of various DYSF mutations. In addition, we explore the potential of symptomatic, pharmacological, molecular, and genetic therapies in mitigating the disease's progression. We also consider the roles of diet and metabolism in managing dysferlinopathies, as well as the impact of clinical trials on treatment paradigms. Furthermore, we examine the utility of animal models in elucidating disease mechanisms. By culminating the complexities inherent in dysferlinopathies, this write up emphasizes the need for multidisciplinary approaches, precision medicine, and extensive collaboration in research and clinical trial design to advance our understanding and treatment of these challenging disorders.

Dysferlinopathy is a rare group of hereditary muscular dystrophy with an autosomal recessive mode of inheritance caused by a mutation in the DYSF gene. It encodes for the dysferlin protein, which has a crucial role in multiple cellular processes, including muscle fiber membrane repair. This deficit has heterogeneous clinical presentations. In this study, we collected 20 Tunisian patients with a sex ratio of 1 and a median age of 50.5 years old (Interquartile range (IQR) = [36,5-54,75]). They were followed for periods ranging from 5 to 48 years. The median age at onset was 17 years old (IQR = [16,8-28,4]). Five major phenotypes were identified: Limb-girdle muscular dystrophy (LGMDR2) (35%), a proximodistal phenotype (35%), Miyoshi myopathy (10%),  Distal myopathy with anterior tibial onset (DMAT) (10%), and asymptomatic HyperCKemia (10%). At the last evaluation, more than half of patients (55%) were on wheelchair. Loss of ambulation occurred generally during the fourth decade. After 20 years of disease progression, two patients with a proximodistal phenotype (10%) developed dilated cardiomyopathy and mitral valve regurgitation. Restrictive respiratory syndrome was observed in three patients (DMAT: 1 patient, proximodistal phenotype: 1 patient, LGMDR2: 1 patient). Genetic study disclosed five mutations. We observed clinical heterogeneity between families and even within the same family. Disease progression was mainly slow to intermediate regardless of the phenotype.

Dysferlinopathy covers a spectrum of muscle disorder categorized by two major phenotypes, namely Miyoshi muscular dystrophy type 1 (MMD1, OMIM #254130) and limb-girdle muscular dystrophy autosomal recessive 2 (LGMDR2, OMIM #253601), and two minor symptoms, including asymptomatic hyperCKemia and distal myopathy with anterior tibial onset (DMAT, OMIM #606768). We report the first Korean MMD1 misdiagnosed as Becker muscular dystrophy (BMD), which was caused by a combination of compound heterozygous c.663 + 1G > C and p.Trp992Arg of the DYSF gene. A 70-year-old male previously diagnosed with BMD was admitted for genetic counseling. Since he was clinically suspected to have dysferlinopathy but not BMD, targeted panel sequencing was performed to discover the potential hereditary cause of the suspected muscular dystrophy in the proband. Consequently, two pathogenic single nucleotide variants of the DYSF gene, c.663 + 1G > C (rs398123800) and p.Trp992Arg (rs750028300), associated with dysferlinopathy were identified. These variants were previously reported with variant allele frequencies of 0.000455 (c.663 + 1G > C) and 0.000455 (c.2974T > C; p.Trp992Arg) in the Korean population. This report emphasizes the need for common variant screening in the diagnostic algorithms of certain muscle disorders or gene panels with potential pathogenic effects and high rates of recurrent variants.