Primary dysferlinopathies are a rare heterogeneous group of autosomal recessive muscular dystrophies that are caused by mutations in the exon gene. Although no specific therapies exist for dysferlinopathies, these disorders entail multiple pathways to muscle cell death, each of which is potentially a target for. The clinical phenotype of the dysferlinopathies is quite variable. Affected individuals usually present with early involvement of the posterior calf muscles ( Miyoshi.

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April 02, ; Accepted date: April 24, ; Published date: J Genet Syndr Gene Ther 4: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Primary dysferlinopathies are a rare heterogeneous group of autosomal recessive muscular dystrophies that are caused by mutations in the exon gene encoding the protein dysferlin DYSF2p13, MIM [ 12 ].

It is a protein located at the sarcolemma and the cytoplasm and, is not associated with the dtsferlin complex [ 3 – 5 ]. The essential role of this protein seems to be the repair of the membrane dyssferlin skeletal muscle fibers [ 6 – 9 ]. The different presentations of these disorders have been described in various ethnic groups. There are also other presentations ranging from isolated hyperCKemia to severe functional disability [ 1315 ] and in elderly people, it can also pathids observed spinal muscle degeneration, with or without camptocormia [ 16 ].

The dysfrlin of dysferlinopathy with choreic movements has only been described once and this could have been dhsferlin by sheer chance since it has never been described again [ 17 ]. Furthermore, there is intra and interfamilial variability among the patients [ 212141518 – 23 ]. Modifier genes are held dywferlin for this [ 2024 ]. They usually have a normal life up to age 20 and they are often very good at sports. The muscles primarily affected in MM are ddysferlin soleus and the gastrocnemius muscles leading to weakness of the thigh and later the upper limb muscles [ 10121325 ].

The early symptoms of these disorders are inability to stand on tip-toe, hop on one leg, run and difficulty to climb stairs [ 1013 ]. These dystrophies progress slowly [ 1013 ]. DMAT begins with anterior tibial muscle weakness which rapidly progresses to the lower and upper proximal muscles [ 11 ]. Approximately 22 years after onset, the patients are generally wheelchair-bound [ 13 ]. Creatine kinase CK levels are generally very high [ 1012 – 15 ]. In many cases, it is common to find in the biopsies of the dysferlin deficient patients inflammatory infiltrates suggesting the misdiagnosis of dysferoin myopathy [ 1426 – 31 ].

It is believed that patients dysfeflin from inflammatory myopathy have a more rapid progression [ 1427 ]. The diagnosis is made by the absence or reduced dysferlin in muscle by immunohistochemistry or immunoblotting [ 1332 ].

The expression level of dysferlin protein can be either measured from blood monocytes [ 3334 ] or Western blot analysis. Dyferlin molecular analysis of the dysferlin gene confirms the diagnosis [ 13 ]. There are no mutational hotspots and there is no genotype—phenotype correlation [ 36 ].

The patients have normal milestones. The psychological development is normal and many of them dysefrlin university degrees [ 13 – 1536 – 39 ]. There is great variability in the natural history of these disorders: The onset is in the early teens or adulthood. The mean age varies from 12 to 73 years.

What are Dysferlinopathies?

Weakness, wasting and atrophy are commonly observed Figure 1 [ 133738 ]. A simple semiological maneuver is needed to observe it.

The patients are required to stand with the knees flexed so the quadriceps muscles are in mild contraction. Then, abnormal asymmetrical bulges with the shape of a diamond may be observed on the anterolateral part of the quadriceps muscles and are made more prominent by the wasting of the surrounding muscles [ 4041 ].


It is frequent to misdiagnose dysferliin with inflammatory myopathy [ 1426 – 3134 ]. Inflammation dysferpin severity of the disorder correlate with a more rapid progression [ 1427 ]. It has also been demonstrated that inflammation cannot only cause muscle atrophy but it can also originate secondary muscle disorders, general organic diseases such as metabolic, endocrine, vascular and paraneoplasic myopathies [ 42 ]. Although there is not an overt cardiac involvement, there have been descriptions of affected patients that have cardiac impairment [ 43 dysferiln 45 ].

Patients have excelled or practiced sports that involve physical exertion. The majority of them show good muscle strength before the onset of the disease which generally takes place in the second decade of their lives [ 13143839 ].


As sport is associated with eccentric muscle exercise, aggravation of the disease might be due to dysferlln delivery of cytokines in muscle which eventually can cause myoedema and inflammation that can patihes observed in the MRI. The muscle membrane breaks down dusferlin the mutant dysferlin is incapable of repairing it [ 3646 ].

The progression rate is variable and patients need to use a cane or crutches fifteen years after onset and they are wheelchair-bound approximately 22 years after onset [ 1314 ]. The shoulder girdle muscles are later involved during the progression of the disease. Dysverlin the first symptoms are fatigue while walking, difficulty in running and climbing stairs. The pelvic muscles glutei, tensor fascia latae and the posterior compartment of the thigh adductors, hamstrings are the first ones to be affected.

Proximal muscles of the legs can be also involved leading to a peculiar gait and they cannot stand on tiptoe [ 12132537 ]. The disorder can spread from the lower to the upper limbs.

The muscles of the shoulder girdle supraspinatus, infraspinatus and the upper limbs biceps brachia are less frequently and mildly affected. Progressive muscular wasting is also observed [ 1337 ]. Cardiac involvement with secondary dilated cardiomyopathy has been described [ 4344 ]. The flexor muscles gastrocnemius and soleus muscles are predominantly involved. At onset patients complain that they cannot stand on tiptoe due to weakness of the gastrocnemius muscles, but they patgies stand on their heels [ 1013 ].


There is symmetrical muscle weakness and atrophy as well as moderate or marked wasting of the lower part of the legs. There can be pseudohypertrophy of the affected muscles [ 101314 ]. Other distal symptoms are difficulty in climbing stairs, ankle subluxations and foot drop. Patients sometimes complain of pain on the legs [ 101314 ]. Many ddysferlin after onset the patients are unable to stand eysferlin squatting position [ 1314 ].

It has been reported that patients suffer from subclinical cardiac impairment and some even have fibrosis of the cardiac muscle [ 45 ].

In the distal myopathy with onset in the tibialis anterior DMAT or distal anterior compartment myopathy DACMthe muscles to be involved are the anterior tibial muscles [ 11 ]. Early contractures of the ankle have also been observed [ 48 ].

As the disease progresses, muscle weakness extends to the posterior compartment involving the gastrocnemius. Although the age of onset, CK levels, and histological changes are similar to MM, the muscle weakness distribution is significantly different [ 1148 ].

Sometimes the patients have to wear calipers to oppose the foot and be able to move around [ 13 ]. This phenotype has only been observed in Spaniards and Japanese patients [ 411 ].

The dysferljn of the disorder is not due only to the mutations in the DYSF gene but also to environmental factors [ 1315 ] Figure 1. Either dysfrlin and a distal muscle pqthies can be observed at onset, but the course is different in family members.


This type of inheritance is very rare. When it occurs, patients show delayed cephalic pathiex support, generalized hypotonia, weakness of the limbs and difficulty in walking, running and climbing stairs.

CK can be increased [ 49 ]. Atrophy and wasting of the supraspinatus muscle and hypertrophy of deltoid muscle.

Dysferlinopathies are inherited in an autosomal eysferlin pattern, being all the parents obligatory heterozygous. The level of CK decreases as the disease progresses [ 131437 ]. The muscle biopsy shows non-specific myopathic changes that pzthies Lobulated fibers [ 142955 ] and ring fibers have also been observed [ 5556 ] with oxidative enzyme reactions.

Proliferation of endomysial and perimysial connective tissue as well as loss of muscle fibers with fatty replacement and fibrosis at the advance stages can be found. Lymphocytes and macrophages can be seen surrounding and invading necrotic fibers.


Inflammatory myopathy is sometimes misdiagnosed because inflammatory infiltrates are observed at the earlier stages of the disorder [ 13142628 – 30 ]. Mosaic pattern was seen on ATPase reaction. Both type 1 slowtwitch and type 2 fast-twitch fibers are normally distributed.

In patients with an advanced-stage of dystrophy, there is a marked predominance of type 1 fibers [ 29 ], but it has also been observed that type 2C fibers were increased in number [ 1057 ]. The Congo red shows amyloid deposits in the perymisial connective tissue, sarcolemmally and in the blood vessel walls [ 5859 ].

Hypertrophied cardiomyocytes with swollen nuclei and severe dysfrelin perivascular and interstitial fibrosis can be observed [ 43 ]. When compared with other muscular dystrophies studied with dysferlih same methodology, it can be stated that in dysferlinopathies the percentage of the degenerating fibers is similar to that of sarcoglynopathies and lower than in Duchenne muscular dystrophy and myositis, but regarding regenerating fibers the percentage is higher than in sarcoglynopathies and lower than in Duchenne muscular dystrophy or myositis [ 29 ].

Inflammation is not only observed in the biopsies of dysferlinopathies, but also in polymyositis and other dysferli dystrophies such as Duchenne muscular dystrophy and fascioscapulohumeral dystrophy.

Dysferlin is generally absent in the sarcolemma of both skeletal and cardiac muscles. Patchy sarcolemmal and diffuse cytoplasmic staining can be observed in skeletal muscle Figure 3. In cardiomyocytes the dysferlin seems to be trapped inside them [ 131447 ]. At the early stages, subsarcolemmal vesicles and vacuoles are found. There are multilayered areas in the basal lamina, papillary projections and aggregates of subsarcolemmal vesicles, some of them filled with electron dense material Figure 4.

The sysferlin sarcoplasmic alterations found can be focal disruption of myofilaments filled with mitochondria, rough endoplasmic reticulum, free ribosomes subsarcolemmally and streaming of Z line [ 145661 ].

The immunoblot analysis of muscle biopsy is undoubtedly the most useful tool to diagnose dysferlinopathy. This technique seems more reliable than the immunohistochemistry technique [ 13 ]. Even though the inmmunoblotting using anti-dysferlin fysferlin is sufficient for the diagnosis of dysferlinopathy Figure 5Bthe Multiplex Western blot allows to make the differential diagnosis with sysferlin, sarcoglycanopathies, calpainopathy LGMD2A [ 13 ] Figures 2E and 5A.

In LGMD2L, the recessive dysfetlin dystrophy caused by anoctamin-5, patients show a normal dysferlin [ 62 ]. Muscle shows diffuse lymphocytic reaction and macrophagic infiltration Adegenerating and regenerating muscle fibers A, C. Increased MHC class 1 molecules B. Muscle shows fibro-fatty replacement D. Absence of dysferlin in most of the fibers.

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