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.

Dysferlinopathy is caused by over 500 mutations in the gene encoding dysferlin, including close to 300 point mutations. One option to cure the disease is to use a gene therapy to correct these mutations at the root. Prime editing is a technique which can replace the mutated nucleotide with the wild-type nucleotide. In this article, prime editing is used to correct several point mutations in the DYSF gene responsible for dysferlinopathy. In vitro editing of HEK293T cells reaches up to 31%. Notably, editing was more efficient in myoblasts than in patient-derived fibroblasts. The prime editing technique was also used to create a new myoblast clone containing a patient mutation from a healthy myoblast cell line.

Dysferlin (DYSF) has a crucial role in sarcolemmal repair. While DYSF mutations commonly manifest as limb-girdle muscular dystrophy (LGMDR2) or distal Miyoshi myopathy, atypical manifestations, such as asymptomatic hyperCKemia and pseudometabolic myopathy, are rarely reported. We describe clinical, serologic, radiologic, genetic, and muscle pathology findings of three patients with rare dysferlinopathy phenotypes and long-term follow up in one of them. We also review the literature pertinent to uncommon forms of dysferlinopathy presenting with hyperCKemia and pseudometabolic phenotype. Patient 1 is a 51-year-old female with exercise-induced myalgia predominantly affecting calf muscles for 7 years. She had a 22-year history of asymptomatic hyperCKemia (CK 812-2,223 U/L). Neurologic exam showed mild calf enlargement without weakness. CT of the lower limb revealed fatty infiltration of distal peroneal and calf muscles. Genetic testing showed two DYSF variants, c.2163-2A > G (pathogenic) and c.866C > G, p.Ser289Cys (VUS), unknown if heteroallelic. Muscle biopsy demonstrated nuclei internalization and absent dysferlin immunoreactivity. Patient 2 is a 20-year-old male, football player, with an episode of exercise-induced myalgia followed by asymptomatic persistent hyperCKemia (729-2,645 U/L). He had normal strength but mild calf muscle atrophy. Muscle MRI demonstrated subtle T2 hyperintensity in the posterior leg compartment musculature. He has two heteroallelic DYSF variants, c.6008G > A, p.Gly2003Asp (pathogenic) and c.854C > T, p.Thr285Met (VUS). Muscle biopsy showed no myopathic changes but reduced dysferlin immunoreactivity. Patient 3 is a 58-year-old female with incidentally detected asymptomatic hyperCKemia (CK: 249-2,096 U/L) for 2 years. She had normal strength and normal lower limb muscle MRI. She carries two heteroallelic DYSF variants, c.2517del, p.Met840Trpfs*108 (pathogenic) and c.6058C > T, p.Arg2020Cys (VUS). Muscle biopsy showed minimal myopathic changes and attenuated dysferlin immunoreactivity. Reduced dysferlin expression was confirmed by western blot in patients 2 and 3. Needle EMG was normal in all patients. Dysferlinopathy should be considered in the differential diagnosis of metabolic myopathies and asymptomatic hyperCKemia. Patient 1's long history of hyperCKemia without weakness over two decades suggests that CK elevation in dysferlinopathy does not necessarily predict development of weakness. Additionally, the lack of dystrophic changes on muscle biopsy of patients with asymptomatic or minimally symptomatic hyperCKemia should not discourage the search for dysferlin deficiency in muscle, particularly in the setting of DYSF variants.

Popeye domain containing 3 (POPDC3) gene encodes a protein involved in membrane trafficking and is highly expressed in skeletal muscles. POPDC3 pathogenic variants are associated with LGMDR26. Only a few reports of POPDC3 LGMD exist worldwide and none from India. Herein, we describe the first case of POPDC3 LGMD26. This is a case report from a neurology referral center in India. All the clinical, laboratory and electrophysiological data were collected from the medical records. A 34-year-old man born to non-consanguineous parents presented with progressive proximal weakness of lower limbs from 22 years of age. He developed calf muscle pain and recurrent falls on walking for 7 years. He had atrophy of calves (medial gastrocnemius more than lateral) along with weakness of hip extensor, adductors and knee flexors and normal upper limb power, resembling Miyoshi myopathy. Serum creatine kinase ranged from 3524 to 6531 U/L. Muscle MRI showed selective atrophy of gluteus maximus, quadriceps femoris, semimembranosus and gastrocnemius with sparing of rectus femoris, gracilis and sartorius. Muscle biopsy done elsewhere and reported to show dystrophic features and immunohistochemistry showed positive staining for dystrophins and sarcoglycans. Clinically the possibility of LGMDR2/Dysferlinopathy, was considered and whole exome sequencing was done which revealed a novel homozygous pathogenic nonsense premature termination codon (PTC) variant (NM_022361.5) c.316C > T (NP_079130.2:) p.Arg106Ter) in exon 2 of POPDC3 gene. This is the first report of POPDC3- LGMDR26 from India detected among a large cohort (461 genetically confirmed cases). POPDC3 gene variations should be considered in distal onset LGMDs with markedly elevated serum creatine kinase levels.

Miyoshi myopathy is a muscular dystrophy disease characterized by muscle weakness and atrophy generally in distal muscle groups, such as in the legs and arms. Miyoshi myopathy is thought to occur due to genetic mutations in the DYSF gene, which codes for the dysferlin protein, which is critical for muscle cell membrane integrity and muscle fiber adhesiveness. The first symptoms begin in early adulthood and include weakness and atrophy in the calves, gait abnormalities, pain and discomfort in affected muscles, and difficulty jumping or walking on tiptoes. Patients generally are diagnosed by a combination of physical exam findings, genetic testing, muscle biopsy, and elevated creatinine kinase (CK) levels. Management of the disease progression includes physical therapy to strengthen the muscles, nutritional support, occupational therapy, and assisted device education. While not life-threatening, Miyoshi myopathy outlook is generally considered moderate to poor due to significant muscle weakness and eventual loss of mobility usually in 10-20 years after onset. We present a unique case of a 66-year-old male patient complaining of pain in his bilateral calves after having had a series of back surgeries 10 years prior. A diagnosis of Miyoshi myopathy, a rare occurrence in this age group, was made based on CK levels. In this report, we will discuss the pathophysiology, disease progression, and management of Miyoshi myopathy.