Neurology India
menu-bar5 Open access journal indexed with Index Medicus
  Users online: 2748  
 Home | Login 
About Editorial board Articlesmenu-bullet NSI Publicationsmenu-bullet Search Instructions Online Submission Subscribe Videos Etcetera Contact
  Navigate Here 
  » Next article
  » Previous article 
  » Table of Contents
 Resource Links
  »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
  »  Article in PDF (198 KB)
  »  Citation Manager
  »  Access Statistics
  »  Reader Comments
  »  Email Alert *
  »  Add to My List *
* Registration required (free)  

  In this Article
 »  Abstract
 »  Historical Landmarks
 »  Clinical Phenotypes
 »  Distribution of ...
 »  Differential Dia...
 »  Epidemiology
 »  Diagnosis
 »  Genetic Counseling
 »  Diagnostic Algorithm
 »  Pathophysiology
 »  Genotype-Phenoty...
 »  Dysferlinopathy ...
 »  Therapeutic Pers...
 »  References
 »  Article Figures

 Article Access Statistics
    PDF Downloaded746    
    Comments [Add]    
    Cited by others 55    

Recommend this journal


Year : 2008  |  Volume : 56  |  Issue : 3  |  Page : 289-297


1 Assistance Publique Hopitaux de Paris, Hopital Marin, BP40139, 64700 Hendaye, France
2 Assistance Publique Hopitaux de Paris, CHU Henri-Mondor, Department of Histology, 94000 CRETEIL, France
3 Department of Genetic Biochemistry, CHU Cochin, 75014 PARIS, France
4 Department of Genetics, CHU La Timone, 13000 MARSEILLE, France

Date of Acceptance08-Aug-2008

Correspondence Address:
J Andoni Urtizberea
Assistance Publique Hopitaux de Paris, Hopital Marin, BP40139, 64700 Hendaye
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.43447

Rights and Permissions

 » Abstract 

Dysferlinopathies encompass a large variety of neuromuscular diseases characterized by the absence of dysferlin in skeletal muscle and an autosomal recessive mode of inheritance. So far, three main phenotypes have been reported: Miyoshi myopathy (MM), limb girdle muscular dystrophy type 2B (LGMD 2B), and distal myopathy with anterior tibial onset (DMAT). A growing number of clinical variants have recently been described with a much wider range of symptoms and onset. Although rare, dysferlinopathies can account for up to 30% of progressive recessive muscular dystrophies in certain geographical areas, notably in the Middle East and the Indian subcontinent. Dysferlin is a large protein involved in membrane repair and vesicle trafficking and interacts probably with important immunological pathways. New insights in its pathophysiology may result in innovative therapies in the near future.

Keywords: Distal myopathy with anterior tibial onset, dysferlinopathies, dysferlin, limb girdle muscular dystrophy, LGMD 2B, Miyoshi myopathy, muscular dystrophy, mini-dysferlin

How to cite this article:
Urtizberea J A, Bassez G, Leturcq F, Nguyen K, Krahn M, Levy N. Dysferlinopathies. Neurol India 2008;56:289-97

How to cite this URL:
Urtizberea J A, Bassez G, Leturcq F, Nguyen K, Krahn M, Levy N. Dysferlinopathies. Neurol India [serial online] 2008 [cited 2022 Dec 7];56:289-97. Available from: https://www.neurologyindia.com/text.asp?2008/56/3/289/43447

 » Historical Landmarks Top

The term 'dysferlinopathy' was coined in 1999 by Bushby after Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD 2B) were found to be allelic disorders. [1] Nowadays, it corresponds to the various clinical phenotypes related to a complete or partial absence of dysferlin.

Historically, the first phenotype of dysferlinopathy to be described was the one reported by Miyoshi, a Japanese physician, in 1967 and subsequently in 1986. [2],[3] In Miyoshi's original publication, four patients from two consanguineous families presented with recessively inherited late-onset distal myopathy associated with clear-cut muscular dystrophy and significantly elevated creatine Kinase (CK) levels. This phenotype was called Miyoshi myopathy (MM). Long thought to be confined to Japan, the disease was soon reported in Europe and elsewhere thereafter. In 1995, Bejaoui, from the Boston group, mapped the MM locus to chromosome 2p14-p12 by studying 12 informative families, five of which were consanguineous. [4] In 1996, Weiler et al., reported the coexistence, in a large Canadian aboriginal family, of MM on the one hand and of a condition mimicking LGMD on the other. [5] Similar findings had been reported earlier by Mahjneh in a large kindred from Palestine. [6]

Limb girdle muscular dystrophy is the generic name for a heterogeneous group of neuromuscular disorders inherited either dominantly of recessively. They are characterized by muscle wasting and atrophy mostly in the shoulder and pelvic girdle but with a quite variable degree of severity and disease course. The vast majority of LMGDs are recessively inherited. In 1994, the first gene to be cloned in a recessive LGMD was unraveled by Richard. [7] It rapidly became obvious that many other recessive genes were involved in that group of patients. The same year, the Newcastle team showed that another group of LGMD families, one of which was located in Palestine, was particularly informative for linkage studies [6] and actually mapped to another locus, on chromosome 2p. [8] The LGMD international consortium agreed in Naarden in 1995 to name the different LGMD loci based on chronological order and mode of inheritance. As a result, calpain deficiency was termed LGMD 2A and the other locus became LGMD 2B (the suffix "2" is meant to point out the recessive forms).

In 1998, after several successful attempts to refine the interval of the MM/LGMD2B locus to the 2p13 region, two independent laboratories (located in Newcastle and Boston respectively) cloned the dysferlin gene and clearly demonstrated that the two disorders (MM and LGMD 2B) were allelic and caused by the same gene defect (DYSF). [9],[10]

 » Clinical Phenotypes Top

Miyoshi myopathy (OMIM # 254310)

Miyoshi myopathy is the most recognizable, at least in theory, subtype of dysferlinopathies. It is also the commonest form of autosomal recessive distal myopathy. Miyoshi myopathy is characterized by weakness, initially affecting the gastrocnemius muscle from the late teens or early adulthood. In the early stage of the disease, serum levels of muscle enzymes (creatine kinase, lactic dehydrogenase (LDH), aldolase) are massively elevated and the pattern of myopathic changes in muscle is clearly dystrophic with numerous inflammatory foci. At first, patients complain of impaired tiptoe-standing, thus corroborating the primary involvement of the gastrocnemius muscle. Other distal symptoms include difficulties in getting downstairs, episodes of ankle subluxations and even foot drop when the leg anterior compartment becomes affected after some time. Patients occasionally complain of painful legs, sometimes unilaterally, with concomitant calf swelling but without any myoglobinuria. The onset of symptoms, in the late teens or in early adulthood, is delayed as opposed to Duchenne muscular dystrophy (DMD) or to other forms of LGMD (calpain deficiency or sarcoglycanopathies, notably). Most patients do not show any signs of muscle weakness in childhood and a significant number of them are even excellent at sports and physical activities, something quite unusual in muscular dystrophy in general. On examination, the most striking feature is the wasting of both calves [Figure 1]. Over time, muscle weakness can extend to the pelvic muscles and to the upper limbs, more distally. Partial atrophy of the biceps brachialis muscle sometimes results in the phenomenon of the 'boule du biceps' as described by Fardeau earlier. [11] Similarly, one author suggests that certain muscle body shapes in the shoulder and in the quadriceps might be indicative of dysferlinopathy. [12],[13] Scapular winging is rather uncommon in MM. Cardiac and respiratory complications are not part of the mainstream form of dysferlinopathy either. Disease progression is generally slow, over decades, but 10-20% of MM patients nevertheless become wheelchair dependent.

Limb girdle muscular dystrophy type 2B (OMIM #253601)

In LGMD 2B, the clinical phenotype shares a great deal of similarities with MM. Age of onset is also in the late teens, and progression is usually slow. Distribution of muscle weakness, although selective, is predominant in the proximal pelvic muscles while the shoulder girdle is more mildly involved over time. Distal involvement in the lower legs can occur, after years of progression, and can result in foot drop. [14] In some instances, the initial presentation is a proximo-distal muscle weakness. This distal involvement is a key clue.

Distal myopathy with onset in tibialis anterior (OMIM # 606768)

Distal myopathy with onset in the tibialis anterior (DMAT) (also referred to as DACM for distal anterior compartment myopathy) is a new entity coined by Illa. [15] An extended Spanish consanguineous family was shown to carry one homozygous mutation in the DYSF gene but with an atypical clinical presentation. If age of onset, CK levels, and histological changes were indeed comparable to MM, the muscle weakness distribution was significantly different: the anterior tibial muscles being the first muscle group to be involved. As disease progresses, muscle weakness also extends to the posterior compartment.

Other clinical variants

Because dysferlin deficiency is nowadays being diagnosed more readily by routine muscle immunocytochemistry, a growing number of clinical variants have been reported in the literature. [16],[17],[18],[19] Amongst them, the so-called 'proximo-distal' (PD), or 'distal-proximal' presentation tends to be an entity of growing prevalence. This phenotype results either from MM after extension of disease to more proximal muscles, or from LGMD 2B descending to the lower part of the lower limb. Besides, it is noteworthy that a 'distal touch' in the clinical context of LGMD is strongly indicative of dysferlinopathy.

In other instances, the disease manifests as a pseudometabolic disorder with exercise intolerance, myalgias and cramps, but without myoglobinuria. Isolated and long-lasting hyperCKemia has also been reported. Elevated CK levels and minimal clinical manifestations have also been anecdotally described in a few heterozygotes. [20]

Interestingly, many authors reported that onset of disease can be quite asymmetrical, unilateral, with or without transient calf myalgia and swelling. In some unusual cases, it inappropriately led to the diagnosis of thrombophlebitis. A case of dysferlinopathy with choreic movements has been described only once and may just be coincidental. [21] In elderly people, spinal muscle degeneration, with or without camptocormia can also be a presenting symptom. [22]

Several comprehensive surveys have stressed the importance of these clinical variants and advocate for a broader view as far as the spectrum of dysferlinopathies is concerned. [18],[23],[24] For instance, age at onset is more variable than originally thought, with some patients remaining asymptomatic till 60 or 70 years of age, and conversely, patients becoming symptomatic in their early teens.

The association between dysferlinopathy and cardiomyopathy is still a debated issue. [25] Some authors argue for its anecdotal nature while others, putting forward the evidence accumulated from the murine animal model of dysferlinopathy (SJL mouse), think that this cardiac complication might be overlooked in patients. [26],[27] Recently, a group from Berlin, Germany, reported two out of six LGMD/MM unrelated patients, who developed overt cardiac disease without any correlation with the severity of their skeletal muscle phenotype. This combination may exist in other patients but this has not been fully investigated so far. Such a working hypothesis fully justifies prospective heart studies in patients with genotypically proven dysferlinopathy.

 » Distribution of Phenotypes Top

While DMAT remains rather uncommon and was reported mainly in Spain and Japan, [15],[28] MM and LGMD 2B seem to be equally frequent in the overall patient population with dysferlinopathy (personal data). Other clinical variants may account for 20-30% of the total, based on the different available worldwide studies.

More importantly, at least two, more rarely three or more, phenotypes (MM, LGMD 2B, DMAT, others) can coexist within the same family or pedigree as reported on several occasions, first in Canada [5] and elsewhere. [18],[29],[30],[31],[32] So far, no satisfactory explanation has been given to account for this unusual occurrence. Modifier genes or environmental factors are likely to be involved.

 » Differential Diagnosis Top

Misdiagnosis is commonplace in patients with primary dysferlinopathy. Worse, it can lead to unnecessary and potentially hazardous therapeutic interventions such as long-term oral administration of corticosteroids or immunosuppressors. In a couple of retrospective studies, close to 25% of LGMD 2B/MM patients had initially been diagnosed with polymyositis, one of the most common dysimmune inflammatory myopathy in adults. In dysferlinopathy, inflammatory changes in muscle are sometimes so florid that they can mislead the pathologist as well as the clinician. Moreover, CK levels are equally elevated in both conditions, a finding which also adds to the confusion. When faced with similar challenges, it is best to systematically perform additional immunostains in order to differentiate the two conditions. In dysferlinopathies, the HLA-Class I complex is not over-expressed. [33] In any event, the most critical clue will be generated by dysferlin immunocytochemistry and immunoblotting as mentioned earlier.

When CK levels are less informative (at end-stages of disease, for instance), alternative forms of distal myopathy may need to be differentiated. Dysferlinopathy remains by far the most frequent cause of autosomal recessive distal myopathy. [34],[35] Nonaka distal myopathy is sometimes an option, especially if onset is in the anterior compartment of the lower leg. Age of onset and disease progression can overlap with MM. However, the presence of numerous rimmed vacuoles in muscle is a distinctive feature; even though such vacuoles have occasionally been reported in primary dysferlinopathy.

Except in large inbred kindred where pseudo-dominance can be observed and in sporadic cases of MM, the autosomal dominant forms of distal myopathy (Welander myopathy, Udd-Markesbery-Griggs myopathy, Laing myopathy) are much less relevant to the differential diagnosis. By taking into account the topography of the predominantly affected muscles (in the upper limbs in Welander disease) or the age at onset (in childhood in Laing myopathy, in rather late adulthood in Markesbery-Griggs myopathy), a definite diagnosis is often reached. But once again, immunostaining of dysferlin in muscle or monocytes is essential in that context and will be quite discriminating. With the exception of Welander myopathy, genetic markers are now available for most of these variants of distal myopathies (GNE mutations in Nonaka myopathy, titin mutations in Udd myopathy, ZASP mutations in Markesbery-Griggs myopathy and MYH7 mutations in Laing distal myopathy respectively).

When dysferlinopathy presents as LGMD, the two alternate diagnoses are LGMD 2A and LGMD 1C, precisely because both entities can result in secondary dysferlinopathy with significant signal reduction either of calpain or of caveolin-3. Other forms (sarcoglycanopathies and FKRP-deficiencies) are easier to rule out.

 Charcot-Marie-Tooth disease More Details and other neurogenic conditions also form a differential diagnosis. Sparing of the extensor digitorum brevis muscle in dysferlinopathy is usually a distinctive feature. The muscle tends to be affected in most neurogenic conditions.

 » Epidemiology Top

In the absence of a comprehensive international patients' registry, the overall prevalence of dysferlinopathies is still hard to estimate. Additionally, figures vary from one place to another. As recessive disorders, MM and LGMD 2B are commonly reported in communities or geographical areas in which endogamy is high. It is true notably in Maghreb, Israel, Saudi Arabia, Iran and the Indian subcontinent where cases with dysferlinopathy are many. In these areas, dysferlinopathies are now emerging as the second most common cause of autosomal recessive LGMD in adults after calpain deficiency (LGMD 2A). In less consanguineous areas, such as the USA, they can still account for 15% of autosomal recessive LGMD. [36]

Population-specific mutations and founder effects have been described in communities such as the Libyan Jews and more recently in the so-called Mountain Jews originating from the Caucasus region. [37],[38] Similarly, recurrent mutations in supposedly unrelated families have been picked in Japan, Italy and Spain. [32],[39] A founder effect is also likely in a cluster of Acadian/Cajun patients with proven dysferlinopathy settled both in Nova-Scotia and in Louisiana (personal unpublished data).

It is somewhat difficult to distinguish a recurrent mutation in a large extended pedigree from a genuine founder effect within a strongly inbred community. Interestingly, no such mutational hotspots have been reported as yet in any of the three Maghrebian countries (Morocco, Algeria, and Tunisia) despite the equally high prevalence of primary dysferlinopathy in this area. The ongoing registration of all patients worldwide would certainly help clarify this point.

 » Diagnosis Top

With the advent of routine immunocytochemistry and targeted molecular genetics, diagnosing dysferlinopathy has become an easier task than before. However, a number of pitfalls exist for which several complementary approaches should be considered.

Creatine Kinase (CK) levels

Elevated CK levels are not specific in themselves. In early stages of dysferlinopathy, they are usually markedly elevated, up to 50-100 times over normal values. In the context of a patient presenting with distal motor symptoms, this massive increase is quite suggestive of MM and therefore of dysferlinopathy. Over time, CK levels tend to decline and lose their informative value.

Electromyographic (EMG) studies

EMG studies are actually useful to rule out alternative diagnoses like Charcot-Marie-Tooth disease. This is particularly relevant when the patient presents with foot drop like in DMAT. In most dysferlinopathies, one notes myogenic changes, and nerve conduction velocities are normal. Neurogenic changes have occasionally been reported, especially at late stages of muscle degeneration.

Muscle imaging

Whatever the subtype of dysferlinopathy, muscle imaging is often of great interest, especially in the early phases of disease. Magnetic resonance imaging (MRI) studies or computerized tomography (CT)-scan imaging of the lower limbs provide the clinician with valuable clues and are therefore warranted as first-line investigations. Marked wasting of both calves points to MM while predominance in the pelvic girdle muscles is more indicative of LGMD 2B. Muscle atrophy of the calves often extends to the posterior compartment of the thigh over time, long before its perception at the clinical level. Heterogeneity in the gastrocnemius appearance often precedes onset of clinical symptoms [Figure 2].

Muscle imaging of the upper limbs may also be valuable but is technically more challenging to perform and interpret.

In DMAT, muscle wasting is initially noted in the tibialis anterior muscle but extends to the gastrocnemius over time, generally in a couple of years.

Muscle histology

The most striking feature of dysferlinopathies is the overt necrotizing process found in muscle. At an early stage, though, the dystrophic changes can be minimal with simple fiber splitting, centralized nuclei and limited degeneration of muscle fibers. Lesions are best observed in affected muscles and the site of the biopsy therefore matters. Muscle imaging is instrumental in achieving this targeting. At advanced stages of disease, fatty replacement is the rule. Rimmed vacuoles are never a prominent feature. Initially regarded as exclusion criteria, they have nonetheless been reported as an occasional but nonspecific finding. Similarly, amyloid deposits have recently been seen in three German patients with dysferlinopathy. [40] In contrast, inflammatory infiltrates are quite common in dysferlinopathy, above all at disease onset [33] and they immunologically and cytologically differ from those classically evidenced in polymyositis (PM) (macrophages are twice as many, while CD8+ T cells are, by contrast, less numerous that in PM).

Dysferlin is recognized at the sarcolemma by at least two commercially available monoclonal antibodies (Hamlet-1 and Hamlet-2 antibodies are directed against two far-apart epitopes of dysferlin). In muscle, such antibodies detect the vast majority of dysferlin deficiencies. [18],[23],[41] It is noteworthy that they equally work nowadays with peroxydase and in immunofluorescence. There is a wide range of stain intensities between a complete absence of signal and a mere weak immunostain. The interpretation of the weak or slightly reduced immunostains remains challenging as secondary dysferlinopathies have been described in other muscular dystrophies.

At the ultrastructural level, alterations of the membrane are present such as small tears and accumulation of subsarcolemmal vesicles and vacuoles, but such anomalies are not routinely investigated. [42]

Western blotting

Immunoblotting or Western blotting (WB) is a semi-quantitative technique aimed at assessing the amount and molecular weight of a given protein. In the context of dysferlinopathy, the protein of interest is thus evaluated both in muscle specimens and also in monocytes. [43],[44] In muscle, the current trend is to perform a multiplex WB by analyzing simultaneously on the same gel, other key proteins involved in DMD and LGMD such as dystrophin, sarcoglycans and calpain-3. Western blotting in muscle seems more reliable than direct immunocytochemistry on muscle sections.

A complementary assay consists of measuring the dysferlin content in an enriched pool of monocytes called CD-14+. The test is robust and simply requires blood sampling and shipping to an appropriate laboratory within 48 h. The sensitivity and sensibility of both tests are quite acceptable. The blood-based assay on monocytes is commercially available through Athena Diagnostics.

Primary versus secondary dysferlinopathies

Cumulative data have established the existence of secondary dysferlinopathies. Given the location of dysferlin, close to the muscle membrane, and its interactions with other proteins, it is not very surprising. The commonest 'mistake' is made with primary calpain deficiency (LGMD 2A) and caveolin-3 deficiency (LGMD 1C). In both conditions, occasional weak signals of dysferlin have been reported but never a complete absence. A re-appraisal of the general clinical picture is recommended before embarking on genetic studies of alternative genes (CAPN-3, CAV).

DNA studies

In theory, DNA analysis is the ultimate way to confirm the diagnosis of primary dysferlinopathy. In practice, however, it remains challenging given the numerous hurdles met by molecular geneticists in detecting mutations in the DYSF gene. The DYSF gene is huge, indeed, and composed of 55 exons. It spans 150 kb of genomic DNA and generates a 6.9 kb-wide transcript. More than 300 different mutations have been detected including some at the intronic level. Most are single-nucleotide changes (for a review, Leiden Muscular Dystrophy database: www.dmd.nl/md.html). [18],[23],[45] The currently available techniques fail to pick up large rearrangements (big deletions) as opposed to micro-deletions/duplications or point mutations which are easier to detect. A second challenge lies in the difficulty in detecting compound heterozygotes at the molecular level. It is not uncommon to only find out one of the two expected mutations of the DYSF gene. In addition, the DYSF gene is full of many non-pathogenic variants (polymorphisms).

When faced with an MM phenotype without any pathogenic mutations in the DYSF gene, the hypothesis of a genetic heterogeneity in MM may arise. As a matter of fact, a few families with a true Miyoshi phenotype do not exhibit any dysferlin deficiency as reported earlier [46] and do not map to chromosome 2p. Some of them have even been mapped to another locus (Chromosome 10). [47] In a couple of these non-dysferlin patients, a comparable defect in membrane repair mechanisms has also been documented. [48]

 » Genetic Counseling Top

By definition, all cases of dysferlinopathies are transmitted following an autosomal recessive mode of inheritance. A pseudo-dominant transmission is occasionally observed in very endogamic communities with multiple consanguineous loops.

The risk of recurrence among sibships is usually of 25%. Consanguinity does not raise the figure per se but increases the probability of two heterozygotes (healthy carriers) belonging to the same inbred community marrying and therefore giveing birth to an affected child.

Given the relative mildness observed in the majority of dysferlinopathies, prenatal testing is seldom offered even if the gene defects are accurately known in a given patient.

Carrier testing can be considered in inbred populations as long as a founder mutation has been found. Such preventive measures have been proposed already in Libyan and Caucasian Jews living in Israel.

Genetic counseling sometimes turns out to be complex due to the fact that the different phenotypes, with variable disease progression, can coexist in the same sibship. At this point, it is impossible to predict whether the patient will develop as an MM or as an LGMD.

 » Diagnostic Algorithm Top

The preliminary clinical ascertainment is crucial and generally provides relevant clues to the diagnosis of dysferlinopathy. As mentioned above, a 'distal touch' in the clinical picture is quite suggestive and is often confirmed by calf muscle imaging. A total absence of dysferlin in monocytes and/or in muscle is a key element for the positive diagnosis. Even better is to detect a homozygous mutation in the DYSF gene. This is seen in most consanguineous pedigrees. The fact of not finding out a second heterozygous mutation in the DYSF gene is not enough in itself to reject the diagnosis of dysferlinopathy.

On the other hand, when the dysferlin immunostain shows some remnants of the protein, one has to be cautious, especially if the mutation screening turns out to be negative. A secondary dysferlinopathy is therefore a working hypothesis and this should prompt re-appraisal of the clinical and histological data.

 » Pathophysiology Top

Dysferlin is a large protein (230 kDa), composed of 2080 amino-acids with a C-terminal transmembrane domain and six calcium-binding C2 domains. Dysferlin is located mainly at the muscle membrane in adult muscle and at the T-tubule system in early development. [49],[50],[51] Dysferlin is widely expressed not only in skeletal muscle and cardiomyocytes, but also in non-myofibers such as monocytes (in CD14+ T cells, in particular).

Dysferlin is a sarcolemmal protein sharing homology with the sperm vesicle fusion protein FER-1 that mediates fusion of intracellular vesicles with the spermatid plasma membrane. Dysferlin has been shown to be involved in sarcolemmal repair. [52],[53],[54],[55] Dysferlin-containing vesicles fuse to form a "membrane patch". The patch would then be added to the membrane disruption site for resealing. Dysferlin belongs to the larger family of 'ferlins' that include myoferlin, otoferlin and others (FER1L4, FER1L5, and FER1L6). Dysferlin may also play a role in the central nervous system, notably at the level of the blood-brain barrier. [56]

Two naturally-occurring mouse mutants are used to study the putative functions of dysferlin and the natural course of disease. The SJL/J mice carry a spontaneous splice-site mutation resulting in a 171-bp in-frame deletion removing 57 amino acids in the C2-E domain of the dysferlin protein. [57] Interestingly, SJL/J mice have been used extensively as a model for auto-immune disease. Another mouse, the A/J mouse, has a unique ETn retrotransposon insertion within intron 4 of the DYSF gene. Other transgenic mice are in preparation to further understand the role of the different parts of the protein in muscle physiology.

Detailed interactions of dysferlin with other proteins are under investigation. While dysferlin co-localizes with annexin A1 and A2 at the sarcolemma, it also interacts with caveolin-3, affixin and AHNAK nucleoprotein. [58],[59],[60]

In parallel, it has been shown that dysferlin also results in downregulation of the complement-protection molecule CD-55. These immunological findings coupled with the high degree of inflammation observed in early dysferlinopathy is an interesting avenue to explore. Indeed, macrophages (the circulating version of monocytes) exhibit an overaggressive activity in muscle fibers and may therefore contribute significantly to disease onset and progression. [61]

 » Genotype-Phenotype Correlations Top

So far, the relationship between phenotype and genotype in dysferlinopathy has remained extremely loose. Different mutations in DYSF have varying effects on protein expression. [18],[62],[63] As a result, the type of mutation does not correlate with phenotypic severity, and the same mutation has been found to be associated with a wide inter- and intra-familial variation in clinical phenotype. The best example is given by the concomitant observation of three or more clinical phenotypes (MM, LGMD, DMAT) within the same sibship or kindred. Even, the amount of residual dysferlin, if any, in muscle rarely correlates to the disease severity. It is obvious now that other modifying factors, or genetic and environmental nature, interfere.

 » Dysferlinopathy in the Indian Context Top

Dysferlinopathies are definitely ubiquitous conditions. [18],[23],[35],[64],[65] They have been observed in all ethnic groups, but have some propensity to occur in endogamic communities. Whether or not this group of disorders is more prevalent in India than in the Western world remains to be proved, but it seems highly plausible. A growing number of Indian teams have reported series of patients with dysferlinopathy. [12],[13],[66],[67] Immunocytochemistry for dysferlin has only been introduced in India recently, most exclusively in academic centers dedicated to myology (via Hamlet and Hamlet-2 antibodies marketed by Novacastra). Muscle Western blotting, though, is still at a preliminary stage and mastered only by a couple of laboratories across the country. The dysferlin assay on monocytes had been available for some time in Mumbai but service has stopped recently. The detection of gene defects in DYSF still remains a bottleneck since no Indian laboratory has ever embarked on this lengthy, time-consuming, costly task. Indian clinicians are therefore dependent on the goodwill of foreign molecular geneticists to confirm the diagnosis of their patients at the molecular level. Hopefully, an international initiative put forward and financially supported by the Jain Foundation ( www.jain-foundation.org ) enables the mutation detection of numerous patients worldwide. The Jain Foundation website gathers information on dysferlinopathy, patients and professionals can freely register in order to get more information and news, as well as to get prepared for further clinical trials.

 » Therapeutic Perspectives Top

Palliative treatment is so far the only available option in dysferlinopathy. Daily management, based on medical or surgical interventions, is largely supportive but definitely more efficient than any innovative therapy whatever its great appeal and its potential impact in the long run.

A customized therapeutic approach is always preferable for each patient and must take into account the natural history of disease. Patients either with MM, LGMD 2B or DMAT have specific needs. The vast majority of patients with MM remain ambulatory throughout their life. Limb girdle muscular type 2B, conversely, often confines the patient to a wheelchair after two or three decades of disease progression, sometimes less. The DMAT patients require the use of callipers to oppose foot drop more efficiently.

A multidisciplinary approach is always better and should combine the expertise of at least an adult neurologist, a rehabilitation specialist, and paramedics (occupational therapist, physiotherapist and social workers). It is of the utmost importance to follow up the patient regularly (once a year is a good tempo in most cases), even in the absence of curative medications. Not only to evaluate the disease progression and intervene accordingly but also to keep track of the patient in the perspective of clinical trials. Monitoring of cardio-respiratory functions is also something valuable even if such complications remain an exception in dysferlinopathies.

Surgical procedures are rarely needed in dysferlin deficiencies. Surgical release of the Achilles tendons is sometimes useful in early stages of LGMD 2B in order to prolong ambulation but it is not a rule. In DMAT, ankle arhrodesis may also help in case of advanced foot drop with major functional impairment.

Pharmacological medications have not proved to be of any benefit in dysferlinopathy. Anecdotal data suggest dantrolene could be beneficial to CK levels but without any impact at the clinical level. [68] The impact of corticosteroids is still subject to many discussions. Many patients misdiagnosed with PM erroneously received corticosteroids, sometimes for long duration, but none reported any dramatic clinical improvement. One randomized clinical trial is in progress in Germany to document this point in more detail. Other clinicians also work along the immune pathway to counteract the initiation of inflammation. Intravenous immunoglobulins (Iv-IG) and other immunosuppressive agents (some of them being more specific to certain lymphocyte populations) are also under consideration in therapeutic trials to come.

Gene-based therapies are still far away from any clinical application in dysferlinopathy but they represent a great hope. Such therapeutic avenues are currently taking advantage from advances and technological breakthroughs made in other muscular dystrophies, especially in DMD. Besides, DMD and dysferlinopathy share many traits such as the critical size of the gene, the wide range of mutations and the comparable severity of the necrotizing process (even though DMD starts earlier and cardiomyopathy is not a part of the cardinal symptoms in dysferlinopathy).

One good example of these promising techniques has recently been given by the Marseilles' group which demonstrated that shortened versions of the DYSF gene could still be functional, a finding long established in DMD (the various so-called mini-dystrophins). This important discovery was based on the observation of a minimally affected 41-year-old patient with dysferlinopathy harboring a large DYSF deletion. The so-called mini-dysferlin derived from this patient has been able to rescue faulty processes of membrane repair in vitro. [69]

Many other therapeutic avenues, such as exon-skipping, viral gene therapy and stem cell therapies are also being investigated.

 » References Top

1.Bushby KM. Making sense of the limb-girdle muscular dystrophies. Brain 1999;122:1403-20.  Back to cited text no. 1  [PUBMED]  [FULLTEXT]
2.Miyoshi K, Saijo K, Kuryu Y, Tada Y, Otsuka Y, Oshima Y, et al. Four cases of distal myopathy in two families. Jpn J Hum Genet 1967;12:113.   Back to cited text no. 2    
3.Miyoshi K, Kawai H, Iwasa M, Kusaka K, Nishino H. Autosomal recessive distal muscular dystrophy as a new type of progressive muscular dystrophy: Seventeen cases in eight families including an autopsied case. Brain 1986;109:31-54.   Back to cited text no. 3  [PUBMED]  [FULLTEXT]
4.Bejaoui K, Hirabayashi K, Hentati F, Haines JL, Ben Hamida C, Belal S, et al. Linkage of Miyoshi myopathy (distal autosomal recessive muscular dystrophy) locus to chromosome 2p12-14. Neurology 1995;45:768-72.  Back to cited text no. 4  [PUBMED]  
5.Weiler T, Greenberg CR, Nylen E, Halliday W, Morgan K, Eggertson D, et al. Limb-girdle muscular dystrophy and Miyoshi myopathy in an aboriginal Canadian kindred map to LGMD2B and segregate with the same haplotype. Am J Hum Genet 1996;59:872-8.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]
6.Mahjneh I, Vannelli G, Bushby K, Marconi GP. A large inbred Palestinian family with two forms of muscular dystrophy. Neuromuscul Disord 1992;2:277-83.  Back to cited text no. 6  [PUBMED]  
7.Richard I, Broux O, Allamand V, Fougerousse F, Chiannikulchai N, Bourg N, et al. Mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A. Cell 1995;81:27-40.  Back to cited text no. 7    
8.Bashir R, Strachan T, Keers S, Stephenson A, Mahjneh I, Marconi G, et al. A gene for autosomal recessive limb-girdle muscular dystrophy maps to chromosome 2p. Hum Mol Genet 1994;3:455-7.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]
9.Liu J, Aoki M, Illa I, Wu C, Fardeau M, Angelini C, et al. Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy. Nat Genet 1998;20:31-6.   Back to cited text no. 9  [PUBMED]  [FULLTEXT]
10.Bashir R, Britton S, Strachan T, Keers S, Vafiadaki E, Lako M, et al. A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B. Nat Genet 1998;20:37-42.   Back to cited text no. 10  [PUBMED]  [FULLTEXT]
11.Eymard B, Laforet P, Tome FM, Collin H, Leroy JP, Hauw JJ, et al. Miyoshi distal myopathy: Specific signs and incidence. Rev Neurol (Paris) 2000;156:161-8.  Back to cited text no. 11    
12.Pradhan S. Calf-head sign in Miyoshi myopathy. Arch Neurol 2006;63:1414-7.  Back to cited text no. 12  [PUBMED]  [FULLTEXT]
13.Pradhan S. Diamond on quadriceps: A frequent sign in dysferlinopathy. Neurology 2008;70:322.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]
14.Mahjneh I, Marconi G, Bushby K, Anderson LV, Tolvanen-Mahjneh H, Somer H. Dysferlinopathy (LGMD2B): A 23-year follow-up study of 10 patients homozygous for the same frameshifting dysferlin mutations. Neuromuscul Disord 2001;11:20-6.  Back to cited text no. 14  [PUBMED]  [FULLTEXT]
15.Illa I, Serrano-Munuera C, Gallardo E, Lasa A, Rojas-Garcia R, Palmer J, et al. Distal anterior compartment myopathy: A dysferlin mutation causing a new muscular dystrophy phenotype. Ann Neurol 2001;49:130-4.   Back to cited text no. 15    
16.Ueyama H, Kumamoto T, Horinouchi H, Fujimoto S, Aono H, Tsuda T. Clinical heterogeneity in dysferlinopathy. Intern Med 2002;41:532-6.  Back to cited text no. 16  [PUBMED]  [FULLTEXT]
17.Nguyen K, Bassez G, Bernard R, Krahn M, Labelle V, Figarella-Branger D, et al. Dysferlin mutations in LGMD2B, Miyoshi myopathy, and atypical dysferlinopathies. Hum Mutat 2005;26:165.  Back to cited text no. 17  [PUBMED]  [FULLTEXT]
18.Guglieri M, Magri F, D'Angelo MG, Prelle A, Morandi L, Rodolico C, et al. Clinical, molecular, and protein correlations in a large sample of genetically diagnosed Italian limb girdle muscular dystrophy patients. Hum Mutat 2008;29:258-66.  Back to cited text no. 18  [PUBMED]  [FULLTEXT]
19.Okahashi S, Ogawa G, Suzuki M, Ogata K, Nishino I, Kawai M. Asymptomatic sporadic dysferlinopathy presenting with elevation of serum creatine kinase: Typical distribution of muscle involvement shown by MRI but not by CT. Intern Med 2008;47:305-7.  Back to cited text no. 19  [PUBMED]  [FULLTEXT]
20.Illa I, De Luna N, Domνnguez-Perles R, Rojas-Garcνa R, Paradas C, Palmer J, et al. Symptomatic dysferlin gene mutation carriers: Characterization of two cases. Neurology 2007;68:1284-9.  Back to cited text no. 20    
21.Takahashi T, Aoki M, Imai T, Yoshioka M, Konno H, Higano S, et al. A case of dysferlinopathy presenting choreic movements. Mov Disord 2006;21:1513-5.  Back to cited text no. 21  [PUBMED]  [FULLTEXT]
22.Seror P, Krahn M, Laforet P, Leturcq F, Maisonobe T. Complete fatty degeneration of lumbar erector spinae muscles caused by a primary dysferlinopathy. Muscle Nerve 2008;37:410-4.  Back to cited text no. 22  [PUBMED]  [FULLTEXT]
23.Nguyen K, Bassez G, Krahn M, Bernard R, Laforκt P, Labelle V, et al. Phenotypic study in 40 patients with dysferlin gene mutations: High frequency of atypical phenotypes. Arch Neurol 2007;64:1176-82.  Back to cited text no. 23    
24.Klinge L, Dean AF, Kress W, Dixon P, Charlton R, Müller JS, et al. Late onset in dysferlinopathy widens the clinical spectrum. Neuromuscul Disord 2008;18:288-90.  Back to cited text no. 24    
25.Luft FC. Dysferlin, dystrophy, and dilatative cardiomyopathy. J Mol Med 2007;85:1157-9.  Back to cited text no. 25  [PUBMED]  [FULLTEXT]
26.Han R, Bansal D, Miyake K, Muniz VP, Weiss RM, McNeil PL, et al. Dysferlin-mediated membrane repair protects the heart from stress-induced left ventricular injury. J Clin Invest 2007;117:1805-13.  Back to cited text no. 26    
27.Wenzel K, Geier C, Qadri F, Hubner N, Schulz H, Erdmann B, et al. Dysfunction of dysferlin-deficient hearts. J Mol Med 2007;85:1203-14.   Back to cited text no. 27  [PUBMED]  [FULLTEXT]
28.Saito H, Suzuki N, Ishiguro H, Hirota K, Itoyama Y, Takahashi T, et al. Distal anterior compartment myopathy with early ankle contractures. Muscle Nerve 2007;36:525-7.  Back to cited text no. 28  [PUBMED]  [FULLTEXT]
29.Illarioshkin SN, Ivanova-Smolenskaya IA, Greenberg CR, Nylen E, Sukhorukov VS, Poleshchuk VV, et al. Identical dysferlin mutation in limb-girdle muscular dystrophy type 2B and distal myopathy. Neurology 2000;55:1931-3.  Back to cited text no. 29  [PUBMED]  [FULLTEXT]
30.Nakagawa M, Matsuzaki T, Suehara M, Kanzato N, Takashima H, Higuchi I, et al. Phenotypic variation in a large Japanese family with Miyoshi myopathy with nonsense mutation in exon 19 of dysferlin gene. J Neurol Sci 2001;184:15-9.  Back to cited text no. 30  [PUBMED]  [FULLTEXT]
31.Ueyama H, Kumamoto T, Nagao S, Masuda T, Horinouchi H, Fujimoto S, et al. A new dysferlin gene mutation in two Japanese families with limb-girdle muscular dystrophy 2B and Miyoshi myopathy. Neuromuscul Disord 2001;11:139-45.  Back to cited text no. 31  [PUBMED]  [FULLTEXT]
32.Vilchez JJ, Gallano P, Gallardo E, Lasa A, Rojas-Garcia R, Freixas A, et al. Identification of a novel founder mutation in the DYSF gene causing clinical variability in the Spanish population. Arch Neurol 2005;62:1256-9.  Back to cited text no. 32    
33.Gallardo E, Rojas-Garcia R, de Luna N, Pou A, Brown RH Jr, Illa I. Inflammation in dysferlin myopathy: Immunohistochemical characterization of 13 patients. Neurology 2001;57:2136-8.   Back to cited text no. 33    
34.Barohn RJ, Amato AA, Griggs RC. Overview of distal myopathies: From the clinical to the molecular. Neuromuscul Disord 1998;8:309-16.  Back to cited text no. 34  [PUBMED]  [FULLTEXT]
35.Udd B, Griggs R. Distal myopathies. Curr Opin Neurol 2001;14:561-6.  Back to cited text no. 35  [PUBMED]  [FULLTEXT]
36.Moore SA, Shilling CJ, Westra S, Wall C, Wicklund MP, Stolle C, et al. Limb-girdle muscular dystrophy in the United States. J Neuropathol Exp Neurol 2006;65:995-1003.  Back to cited text no. 36  [PUBMED]  [FULLTEXT]
37.Argov Z, Sadeh M, Mazor K, Soffer D, Kahana E, Eisenberg I, et al. Muscular dystrophy due to dysferlin deficiency in Libyan Jews: Clinical and genetic features. Brain 2000;123:1229-37.   Back to cited text no. 37  [PUBMED]  [FULLTEXT]
38.Leshinsky-Silver E, Argov Z, Rozenboim L, Cohen S, Tzofi Z, Cohen Y, et al. Dysferlinopathy in the Jews of the Caucasus: A frequent mutation in the dysferlin gene. Neuromuscul Disord 2007;17:950-4.  Back to cited text no. 38  [PUBMED]  [FULLTEXT]
39.Cagliani R, Fortunato F, Giorda R, Rodolico C, Bonaglia MC, Sironi M, et al. Molecular analysis of LGMD-2B and MM patients: Identification of novel DYSF mutations and possible founder effect in the Italian population. Neuromuscul Disord 2003;13:788-95.  Back to cited text no. 39  [PUBMED]  [FULLTEXT]
40.Spuler S, Carl M, Zabojszcza J, Straub V, Bushby K, Moore SA, et al. Dysferlin-deficient muscular dystrophy features amyloidosis. Ann Neurol 2008;63:323-8.  Back to cited text no. 40  [PUBMED]  [FULLTEXT]
41.Fanin M, Angelini C. Muscle pathology in dysferlin deficiency. Neuropathol Appl Neurobiol 2002;28:461-70.  Back to cited text no. 41  [PUBMED]  [FULLTEXT]
42.Cenacchi G, Fanin M, De Giorgi LB, Angelini C. Ultrastructural changes in dysferlinopathy support defective membrane repair mechanism. J Clin Pathol 2005;58:190-5.  Back to cited text no. 42  [PUBMED]  [FULLTEXT]
43.Ho M, Gallardo E, McKenna-Yasek D, De Luna N, Illa I, Brown RH Jr. A novel, blood-based diagnostic assay for limb girdle muscular dystrophy 2B and Miyoshi myopathy. Ann Neurol 2002;51:129-33.  Back to cited text no. 43    
44.De Luna N, Freixas A, Gallano P, Caselles L, Rojas-Garcνa R, Paradas C, et al. Dysferlin expression in monocytes: A source of mRNA for mutation analysis. Neuromuscul Disord 2007;17:69-76.   Back to cited text no. 44    
45.Aoki M, Liu J, Richard I, Bashir R, Britton S, Keers SM, et al. Genomic organization of the dysferlin gene and novel mutations in Miyoshi myopathy. Neurology 2001;57:271-8.   Back to cited text no. 45  [PUBMED]  [FULLTEXT]
46.Linssen WH, Notermans NC, Van der Graaf Y, Wokke JH, Van Doorn PA, Howeler CJ, et al. Miyoshi-type distal muscular dystrophy. Clinical spectrum in 24 Dutch patients. Brain 1997;120:1989-96.  Back to cited text no. 46    
47.Linssen WH, de Visser M, Notermans NC, Vreyling JP, Van Doorn PA, Wokke JH, et al. Genetic heterogeneity in Miyoshi-type distal muscular dystrophy. Neuromuscul Disord 1998;8:317-20.  Back to cited text no. 47  [PUBMED]  [FULLTEXT]
48.Jaiswal JK, Marlow G, Summerill G, Mahjneh I, Mueller S, Hill M, et al. Patients with a non-dysferlin Miyoshi myopathy have a novel membrane repair defect. Traffic 2007;8:77-88.  Back to cited text no. 48  [PUBMED]  [FULLTEXT]
49.Anderson LV, Davison K, Moss JA, Young C, Cullen MJ, Walsh J, et al. Dysferlin is a plasma membrane protein and is expressed early in human development. Hum Mol Genet 1999;8:855-61.  Back to cited text no. 49  [PUBMED]  [FULLTEXT]
50.Matsuda C, Aoki M, Hayashi YK, Ho MF, Arahata K, Brown RH Jr. Dysferlin is a surface membrane associated protein that is absent in Miyoshi myopathy. Neurology 1999;53:1119-22.   Back to cited text no. 50  [PUBMED]  [FULLTEXT]
51.Piccolo F, Moore SA, Ford GC, Campbell KP. Intracellular accumulation and reduced sarcolemmal expression of dysferlin in limb-girdle muscular dystrophies. Ann Neurol 2000;48:902-12.  Back to cited text no. 51  [PUBMED]  
52.Lennon NJ, Kho A, Bacskai BJ, Perlmutter SL, Hyman BT, Brown RH Jr. Dysferlin interacts with annexins A1 and A2 and mediates sarcolemmal wound-healing. J Biol Chem 2003;278:504466-73.  Back to cited text no. 52    
53.Bansal D, Miyake K, Vogel SS, Groh S, Chen CC, Williamson R, et al. Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature 2003;423:168-72.  Back to cited text no. 53  [PUBMED]  [FULLTEXT]
54.Bansal D, Campbell KP. Dysferlin and the plasma membrane repair in muscular dystrophy. Trends Cell Biol 2004;14:206-13.   Back to cited text no. 54  [PUBMED]  [FULLTEXT]
55.Han R, Campbell KP. Dysferlin and muscle membrane repair. Curr Opin Cell Biol 2007;19:409-16.   Back to cited text no. 55  [PUBMED]  [FULLTEXT]
56.Hochmeister S, Grundtner R, Bauer J, Engelhardt B, Lyck R, Gordon G, et al. Dysferlin is a new marker for leaky brain blood vessels in multiple sclerosis. J Neuropathol Exp Neurol 2006;65:855-65.  Back to cited text no. 56  [PUBMED]  [FULLTEXT]
57.Nemoto H, Konno S, Nakazora H, Miura H, Kurihara T. Histological and immunohistological changes of the skeletal muscles in older SJL/J mice. Eur Neurol 2007;57:19-25.  Back to cited text no. 57  [PUBMED]  [FULLTEXT]
58.Cagliani R, Magri F, Toscano A, Merlini L, Fortunato F, Lamperti C, et al. Mutation finding in patients with dysferlin deficiency and role of the dysferlin interacting proteins annexin A1 and A2 in muscular dystrophies. Hum Mutat 2005;26:283.   Back to cited text no. 58  [PUBMED]  [FULLTEXT]
59.Matsuda C, Hayashi YK, Ogawa M, Aoki M, Murayama K, Nishino I, et al. The sarcolemmal proteins dysferlin and caveolin-3 interact in skeletal muscle. Hum Mol Genet 2001;10:1761-66.  Back to cited text no. 59  [PUBMED]  [FULLTEXT]
60.Matsuda C, Kameyama K, Tagawa K, Ogawa M, Suzuki A, Yamaji S, et al. Dysferlin interacts with affixin (beta-parvin) at the sarcolemma. J Neuropathol Exp Neurol 2005;64:334-40.  Back to cited text no. 60  [PUBMED]  [FULLTEXT]
61.Nagaraju K, Rawat R, Veszelovszky E, Thapliyal R, Kesari A, Sparks S, et al. Dysferlin deficiency enhances monocyte phagocytosis: A model for the inflammatory onset of limb-girdle muscular dystrophy 2B. Am J Pathol 2008;172:774-85.  Back to cited text no. 61  [PUBMED]  [FULLTEXT]
62.Tagawa K, Ogawa M, Kawabe K, Yamanaka G, Matsumura T, Goto K, et al. Protein and gene analyses of dysferlinopathy in a large group of Japanese muscular dystrophy patients. J Neurol Sci 2003;211:23-8.   Back to cited text no. 62  [PUBMED]  [FULLTEXT]
63.Takahashi T, Aoki M, Tateyama M, Kondo E, Mizuno T, Onodera Y, et al. Dysferlin mutations in Japanese Miyoshi myopathy: Relationship to phenotype. Neurology 2003;60:1799-804.  Back to cited text no. 63  [PUBMED]  [FULLTEXT]
64.Ren SC, Yan CZ, Li MX, Liu SP, Wu JL, Zhao YY, et al. Dysferlin expression in limb-girdle muscular dystrophy and Miyoshi myopathy: Analysis of 45 cases. Zhonghua Yi Xue Za Zhi 2007;87:1486-90.  Back to cited text no. 64  [PUBMED]  
65.Rosas-Vargas H, Gómez-Dνaz B, Ruano-Calderón L, Fernαndez-Valverde F, Roque-Ramνrez B, Portillo-Bobadilla T, et al. Dysferlin homozygous mutation G1418D causes limb-girdle type 2B in a Mexican family. Genet Test 2007;11:391-6.   Back to cited text no. 65    
66.Khadilkar SV, Singh RK, Kulkarni KS, Chitale AR. A study of clinical and laboratory features of 14 Indian patients with dysferlinopathy. J Clin Neuromusc Dis 2004;6:1-8.  Back to cited text no. 66    
67.Nalini A, Gayathri N. Dysferlinopathy: A clinical and histopathological study of 28 patients from India. Neurol India 2008;58:384-390.  Back to cited text no. 67    
68.Hattori H, Nagata E, Oya Y, Takahashi T, Aoki M, Ito D, et al. A novel compound heterozygous dysferlin mutation in Miyoshi myopathy siblings responding to dantrolene. Eur J Neurol 2007;14:1288-91.   Back to cited text no. 68  [PUBMED]  [FULLTEXT]
69.Krahn M, Wein N, Nguyen K, Vial C, Courrier S, Lostal W, et al. Functional evaluation of a putative mini-dysferlin identified in a patient with moderate Miyoshi myopathy phenotype. Neuromusc Dis 2008;17:790.  Back to cited text no. 69    


  [Figure 1], [Figure 2]

This article has been cited by
1 Causative variants linked with limb girdle muscular dystrophy in an Iranian population: 6 novel variants
Hamidreza Mianesaz, Safoura Ghalamkari, Mansoor Salehi, Mahdiyeh Behnam, Majid Hosseinzadeh, Keivan Basiri, Majid Ghasemi, Maryam Sedghi, Behnaz Ansari
Molecular Genetics & Genomic Medicine. 2022;
[Pubmed] | [DOI]
2 Dysferlinopathies: Clinical and genetic variability
Alisa Ivanova, Svetlana Smirnikhina, Alexander Lavrov
Clinical Genetics. 2022;
[Pubmed] | [DOI]
3 The C2 domains of dysferlin: roles in membrane localization, Ca 2+ signalling and sarcolemmal repair
Joaquin Muriel, Valeriy Lukyanenko, Tom Kwiatkowski, Sayak Bhattacharya, Daniel Garman, Noah Weisleder, Robert J. Bloch
The Journal of Physiology. 2022;
[Pubmed] | [DOI]
4 Key biomarkers and latent pathways of dysferlinopathy: Bioinformatics analysis and in vivo validation
Yan Xie, Ying-hui Li, Kai Chen, Chun-yan Zhu, Jia-ying Bai, Feng Xiao, Song Tan, Li Zeng
Frontiers in Neurology. 2022; 13
[Pubmed] | [DOI]
5 Clinical, Neurophysiological, Radiological, Pathological, and Genetic Features of Dysferlinopathy in Saudi Arabia
Norah Alharbi, Rawan Matar, Edward Cupler, Hindi Al-Hindi, Hatem Murad, Iftteah Alhomud, Dorota Monies, Ali Alshehri, Mossaed Alyahya, Brian Meyer, Saeed Bohlega
Frontiers in Neuroscience. 2022; 16
[Pubmed] | [DOI]
6 Elevated Ca2+ at the triad junction underlies dysregulation of Ca2+ signaling in dysferlin-null skeletal muscle
Valeriy Lukyanenko, Joaquin Muriel, Daniel Garman, Leonid Breydo, Robert J. Bloch
Frontiers in Physiology. 2022; 13
[Pubmed] | [DOI]
7 A Novel Homozygous Variant in DYSF Gene Is Associated with Autosomal Recessive Limb Girdle Muscular Dystrophy R2/2B
Patrizia Spadafora, Antonio Qualtieri, Francesca Cavalcanti, Gemma Di Palma, Olivier Gallo, Selene De Benedittis, Annamaria Cerantonio, Luigi Citrigno
International Journal of Molecular Sciences. 2022; 23(16): 8932
[Pubmed] | [DOI]
8 Myositis mimics
Sujata Ganguly, Rudrarpan Chatterjee, Abhishek Zanwar, Latika Gupta
Indian Journal of Rheumatology. 2021; 16(4): 427
[Pubmed] | [DOI]
9 Subclinical Cardiomyopathy in Miyoshi Myopathy Detected by Late Gadolinium Enhancement Cardiac Magnetic Resonance Imaging
Sarah Ming Li Tan, Ching Ching Ong, Kong Bing Tan, Hui-Lin Chin, Prakash R Paliwal, Kay Wei Ping Ng, Weiqin Lin
International Heart Journal. 2021; 62(1): 186
[Pubmed] | [DOI]
10 Prospects for the Etiotropic Treatment of Dysferlinopathy
Alisa V. Ivanova, Svetlana A. Smirnikhina, Alexander V. Lavrov
Annals of the Russian academy of medical sciences. 2021; 76(3): 307
[Pubmed] | [DOI]
11 Deep phenotyping of an international series of patients with late-onset dysferlinopathy
Gorka Fernández-Eulate, Giorgia Querin, Ursula Moore, Anthony Behin, Marion Masingue, Guillaume Bassez, Sarah Leonard-Louis, Pascal Laforêt, Thierry Maisonobe, Philippe-Edouard Merle, Marco Spinazzi, Guilhem Solé, Thierry Kuntzer, Anne-Laure Bedat-Millet, Emmanuelle Salort-Campana, Shahram Attarian, Yann Péréon, Leonard Feasson, Julie Graveleau, Aleksandra Nadaj-Pakleza, France Leturcq, Svetlana Gorokhova, Martin Krahn, Bruno Eymard, Volker Straub, Teresinha Evangelista, Tanya Stojkovic
European Journal of Neurology. 2021; 28(6): 2092
[Pubmed] | [DOI]
12 A novel dysferlin gene mutation in a Filipino male with Miyoshi myopathy
Karen Joy Adiao, Mario B. Prado, Mina Astejada
Clinical Neurology and Neurosurgery. 2021; 201: 106433
[Pubmed] | [DOI]
13 Early pathological signs in young dysf mice are improved by halofuginone
Hila Barzilai-Tutsch, Olga Genin, Mark Pines, Orna Halevy
Neuromuscular Disorders. 2020; 30(6): 472
[Pubmed] | [DOI]
14 The effects of concentric and eccentric training in murine models of dysferlin-associated muscular dystrophy
Morium Begam, Renuka Roche, Joshua J. Hass, Chantel A. Basel, Jacob M. Blackmer, Jasmine T. Konja, Amber L. Samojedny, Alyssa F. Collier, Sujay S. Galen, Joseph A. Roche
Muscle & Nerve. 2020; 62(3): 393
[Pubmed] | [DOI]
15 Myofibers deficient in connexins 43 and 45 expression protect mice from skeletal muscle and systemic dysfunction promoted by a dysferlin mutation
Gabriela Fernández, Guisselle Arias-Bravo, Jorge A. Bevilacqua, Mario Castillo-Ruiz, Pablo Caviedes, Juan C. Sáez, Luis A. Cea
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 2020; 1866(8): 165800
[Pubmed] | [DOI]
16 Clinical and Genomic Evaluation of 207 Genetic Myopathies in the Indian Subcontinent
Samya Chakravorty, Babi Ramesh Reddy Nallamilli, Satish Vasant Khadilkar, Madhu Bala Singla, Ashish Bhutada, Rashna Dastur, Pradnya Satish Gaitonde, Laura E Rufibach, Logan Gloster, Madhuri Hegde
Frontiers in Neurology. 2020; 11
[Pubmed] | [DOI]
17 Functions of Vertebrate Ferlins
Anna V. Bulankina, Sven Thoms
Cells. 2020; 9(3): 534
[Pubmed] | [DOI]
18 Increased nonHDL cholesterol levels cause muscle wasting and ambulatory dysfunction in the mouse model of LGMD2B
Stephanie L. Sellers,Nadia Milad,Zoe White,Chris Pascoe,Rayleigh Chan,Geoffrey W. Payne,Chun Seow,Fabio Rossi,Michael A. Seidman,Pascal Bernatchez
Journal of Lipid Research. 2018; 59(2): 261
[Pubmed] | [DOI]
19 Limb-Girdle Muscular Dystrophy 2B and Miyoshi Presentations of Dysferlinopathy
Nirupa J. Patel,Kenneth W. Van Dyke,Luis R. Espinoza
The American Journal of the Medical Sciences. 2017; 353(5): 484
[Pubmed] | [DOI]
20 Dysferlin function in skeletal muscle: Possible pathological mechanisms and therapeutical targets in dysferlinopathies
Ana M. Cárdenas,Arlek M. González-Jamett,Luis A. Cea,Jorge A. Bevilacqua,Pablo Caviedes
Experimental Neurology. 2016; 283: 246
[Pubmed] | [DOI]
21 Respiratory and cardiac function in japanese patients with dysferlinopathy
Atsuko Nishikawa,Madoka Mori-Yoshimura,Kazuhiko Segawa,Yukiko K. Hayashi,Toshiaki Takahashi,Yuko Saito,Ikuya Nonaka,Martin Krahn,Nicolas Levy,Jun Shimizu,Jun Mitsui,En Kimura,Jun Goto,Naohiro Yonemoto,Masashi Aoki,Ichizo Nishino,Yasushi Oya,Miho Murata
Muscle & Nerve. 2016; 53(3): 394
[Pubmed] | [DOI]
22 Progress and challenges in diagnosis of dysferlinopathy
Marina Fanin,Corrado Angelini
Muscle & Nerve. 2016; 54(5): 821
[Pubmed] | [DOI]
23 The absence of dysferlin induces the expression of functional connexin-based hemichannels in human myotubes
Luis A. Cea,Jorge A. Bevilacqua,Christian Arriagada,Ana María Cárdenas,Anne Bigot,Vincent Mouly,Juan C. Sáez,Pablo Caviedes
BMC Cell Biology. 2016; 17(S1)
[Pubmed] | [DOI]
24 Myofiber Damage Precedes Macrophage Infiltration after in Vivo Injury in Dysferlin-Deficient A/J Mouse Skeletal Muscle
Joseph A. Roche,Mohan E. Tulapurkar,Amber L. Mueller,Nico van Rooijen,Jeffrey D. Hasday,Richard M. Lovering,Robert J. Bloch
The American Journal of Pathology. 2015; 185(6): 1686
[Pubmed] | [DOI]
25 AAV.Dysferlin Overlap Vectors Restore Function in Dysferlinopathy Animal Models
Patricia C. Sondergaard,Danielle A. Griffin,Eric R. Pozsgai,Ryan W. Johnson,William E. Grose,Kristin N. Heller,Kim M. Shontz,Chrystal L. Montgomery,Joseph Liu,Kelly Reed Clark,Zarife Sahenk,Jerry R. Mendell,Louise R. Rodino-Klapac
Annals of Clinical and Translational Neurology. 2015; 2(3): 256
[Pubmed] | [DOI]
26 Diagnostic overview of blood-based dysferlin protein assay for dysferlinopathies
Arunkanth Ankala,Babi R Nallamilli,Laura E. Rufibach,Esther Hwang,Madhuri R. Hegde
Muscle & Nerve. 2014; : n/a
[Pubmed] | [DOI]
27 Improved immunoblotting methods provide critical insights into phenotypic differences between two murine dysferlinopathy models
Amber L. Mueller,Patrick F. Desmond,Ru-ching Hsia,Joseph A. Roche
Muscle & Nerve. 2014; 50(2): 286
[Pubmed] | [DOI]
28 Exome sequencing as a second-tier diagnostic approach for clinically suspected dysferlinopathy patients
Marc Bartoli,Jean-Pierre Desvignes,Jean-Pierre BSc,Levy Nicolas,Krahn Martin
Muscle & Nerve. 2014; : n/a
[Pubmed] | [DOI]
29 Lipid Accumulation in Dysferlin-Deficient Muscles
Miranda D. Grounds,Jessica R. Terrill,Hannah G. Radley-Crabb,Terry Robertson,John Papadimitriou,Simone Spuler,Tea Shavlakadze
The American Journal of Pathology. 2014; 184(6): 1668
[Pubmed] | [DOI]
30 New developments in exon skipping and splice modulation therapies for neuromuscular diseases
Aleksander Touznik,Joshua JA Lee,Toshifumi Yokota
Expert Opinion on Biological Therapy. 2014; 14(6): 809
[Pubmed] | [DOI]
31 Dysferlin aggregation in limb-girdle muscular dystrophy type 2B/myoshi myopathy necessitates mutational screen for diagnosis
Mats I. Nilsson,Marissa L. Laureano,Munim Saeed,Mark A. Tarnopolsky
Muscle & Nerve. 2013; 47(5): 740
[Pubmed] | [DOI]
32 Dysferlin aggregation in limb-girdle muscular dystrophy type 2B/myoshi myopathy necessitates mutational screen for diagnosis
Nilsson, M.I. and Laureano, M.L. and Saeed, M. and Tarnopolsky, M.A.
Muscle and Nerve. 2013; 47(5): 740-747
33 Inhibition of muscle fibrosis and improvement of muscle histopathology in dysferlin knock-out mice treated with halofuginone
Halevy, O. and Genin, O. and Barzilai-Tutsch, H. and Pima, Y. and Levi, O. and Moshe, I. and Pines, M.
Histology and Histopathology. 2013; 28(2): 211-226
34 A regional panorama of dysferlinopathies [Disferlinopatilerin bölgesel panoramasi{dotless
Diniz, G. and Eryaşar, G. and Türe, S. and Akçay, A. and Ortaç, R. and Tekgül, H. and Akhan, G.
Turk Patoloji Dergisi/Turkish Journal of Pathology. 2012; 28(3): 259-265
35 Generation of skeletal muscle cells from embryonic and induced pluripotent stem cells as an in vitro model and for therapy of muscular dystrophies
Salani, S. and Donadoni, C. and Rizzo, F. and Bresolin, N. and Comi, G.P. and Corti, S.
Journal of Cellular and Molecular Medicine. 2012; 16(7): 1353-1364
36 Generation of skeletal muscle cells from embryonic and induced pluripotent stem cells as anin vitromodel and for therapy of muscular dystrophies
Sabrina Salani,Chiara Donadoni,Federica Rizzo,Nereo Bresolin,Giacomo P. Comi,Stefania Corti
Journal of Cellular and Molecular Medicine. 2012; 16(7): 1353
[Pubmed] | [DOI]
37 Unmasking Potential Intracellular Roles For Dysferlin through Improved Immunolabeling Methods
Joseph A. Roche,Lisa W. Ru,Andrea M. O’Neill,Wendy G. Resneck,Richard M. Lovering,Robert J. Bloch
Journal of Histochemistry & Cytochemistry. 2011; 59(11): 964
[Pubmed] | [DOI]
38 Comparison of Dysferlin Expression in Human Skeletal Muscle with That in Monocytes for the Diagnosis of Dysferlin Myopathy
Eduard Gallardo,Noemi de Luna,Jordi Diaz-Manera,Ricardo Rojas-García,Lidia Gonzalez-Quereda,Bàrbara Flix,Antoine de Morrée,Silvère van der Maarel,Isabel Illa,Markus Schuelke
PLoS ONE. 2011; 6(12): e29061
[Pubmed] | [DOI]
39 UMD-DYSF, a novel locus specific database for the compilation and interactive analysis of mutations in the dysferlin gene
Dalil Hamroun, Brad Williams, Nilah Monnier, Laura E. Rufibach, Jon Andoni Urtizberea, Gaelle Blandin, Christophe Beroud, Veronique Labelle, Karine Nguyen, Nicolas Wein
Human Mutation. 2011; : n/a
[VIEW] | [DOI]
40 Comparison of dysferlin expression in human skeletal muscle with that in monocytes for the diagnosis of dysferlin myopathy
Gallardo, E. and de Luna, N. and Diaz-Manera, J. and Rojas-García, R. and Gonzalez-Quereda, L. and Flix, B. and de Morrée, A. and van der Maarel, S. and Illa, I.
PLoS ONE. 2011; 6(12)
41 Unmasking Potential Intracellular Roles For Dysferlin through Improved Immunolabeling Methods
Roche, J.A. and Ru, L.W. and OæNeill, A.M. and Resneck, W.G. and Lovering, R.M. and Bloch, R.J.
Journal of Histochemistry and Cytochemistry. 2011; 59(11): 964-975
42 Ferlin proteins in myoblast fusion and muscle growth
Posey Jr., A.D. and Demonbreun, A. and McNally, E.M.
Current Topics in Developmental Biology. 2011; 96: 203-230
43 Dysferlinopathy: Spectrum of pathological changes in skeletal muscle tissue
Gayathri, N. and Alefia, R. and Nalini, A. and Yasha, T.C. and Anita, M. and Santosh, V. and Shankar, S.K.
Indian Journal of Pathology and Microbiology. 2011; 54(2): 350-354
44 Novel ancestral Dysferlin splicing mutation which migrated from the Iberian peninsula to South America
Neuromuscular Disorders. 2011; 21(5): 328
[VIEW] | [DOI]
45 Muscular dystrophy with marked Dysferlin deficiency is consistently caused by primary dysferlin gene mutations
European Journal of Human Genetics. 2011;
[VIEW] | [DOI]
46 Exclusion of Mutations in the Dysferlin Alternative Exons 1 ofDYSF-v1, 5a, and 40a in a Cohort of 26 Patients
Martin Krahn,Véronique Labelle,Ana Borges,Marc Bartoli,Nicolas Lévy
Genetic Testing and Molecular Biomarkers. 2010; 14(1): 153
[Pubmed] | [DOI]
47 Diversification of muscle types: Recent insights from Drosophila
Vanessa Tixier,Laetitia Bataillé,Krzysztof Jagla
Experimental Cell Research. 2010; 316(18): 3019
[Pubmed] | [DOI]
48 Recessive Mutations in the Putative Calcium-Activated Chloride Channel Anoctamin 5 Cause Proximal LGMD2L and Distal MMD3 Muscular Dystrophies
Véronique Bolduc,Gareth Marlow,Kym M. Boycott,Khalil Saleki,Hiroshi Inoue,Johan Kroon,Mitsuo Itakura,Yves Robitaille,Lucie Parent,Frank Baas,Kuniko Mizuta,Nobuyuki Kamata,Isabelle Richard,Wim H.J.P. Linssen,Ibrahim Mahjneh,Marianne de Visser,Rumaisa Bashir,Bernard Brais
The American Journal of Human Genetics. 2010; 86(2): 213
[Pubmed] | [DOI]
49 Diversification of muscle types: Recent insights from Drosophila
Tixier, V. and Bataillé, L. and Jagla, K.
Experimental Cell Research. 2010; 316(18): 3019-3027
50 Autosomal recessive limb-girdle muscular dystrophy [Distrofias musculares de cinturas autosómicas recesivas]
Hernández-Caballero, M.E. and Miranda-Duarte, A. and Escobar-Cedillo, R.E. and Villegas-Castrejón, H.
Revista de Neurologia. 2010; 51(8): 489-496
51 Recessive Mutations in the Putative Calcium-Activated Chloride Channel Anoctamin 5 Cause Proximal LGMD2L and Distal MMD3 Muscular Dystrophies
Bolduc, V., Marlow, G., Boycott, K.M., Saleki, K., Inoue, H., Kroon, J., Itakura, M., Brais, B.
American Journal of Human Genetics. 2010; 86(2): 213-221
52 Diaphragm displays early and progressive functional deficits in dysferlin-deficient mice
Elisabeth R. Barton, Bing Jing Wang, Becky K. Brisson, H. Lee Sweeney
Muscle & Nerve. 2010; 42(1): 22
[VIEW] | [DOI]
53 Exclusion of mutations in the dysferlin alternative exons 1 of DYSF-v1, 5a, and 40a in a cohort of 26 patients
Krahn, M., Labelle, V., Borges, A., Bartoli, M., Lévy, N.
Genetic Testing and Molecular Biomarkers. 2010; 14(1): 153-154
54 Efficient bypass of mutations in dysferlin deficient patient cells by antisense-induced exon skipping
Anthony Behin, Gillian Butler-Browne, Vincent Mouly, Martin Krahn, Nicolas Wein, Aurélie Avril, Marc Bartoli, Cyriaque Beley, Soraya Chaouch, Pascal Laforet
Human Mutation. 2010; 31(2): 136-142
[Pubmed] | [DOI]
55 Clinical and pathological analysis of limb-girdle muscular dystrophy type 2B misdiagnosed as polymyositis
Li, N. and Liu, Y.-L. and Li, Q.-X. and Yuan, J.-H. and Zhao, Z. and Shen, H.-R. and Hu, J.
Chinese Journal of Neurology. 2009; 42(9): 596-599


Print this article  Email this article
Previous article Next article
Online since 20th March '04
Published by Wolters Kluwer - Medknow