Review Article

Dysferlinopathies

Urtizberea J. Andoni, Bassez Guillaume1, Leturcq France2, Nguyen Karine3, Krahn Martin3, Lévy Nicolas3 Assistance Publique Hopitaux de Paris, Hopital Marin, BP40139, 64700 Hendaye – France, 1Assistance Publique Hopitaux de Paris, CHU Henri-Mondor, Department of Histology, 94000 CRETEIL – France, 2Department of Genetic Biochemistry, CHU Cochin, 75014 PARIS – France, 3Department of Genetics, CHU La Timone, 13000 MARSEILLE – France.

Dysferlinopathies encompass a large variety of neuromuscular significantly elevated creatine Kinase (CK) levels. This diseases characterized by the absence of dysferlin in skeletal phenotype was called Miyoshi myopathy (MM). Long muscle and an autosomal recessive mode of inheritance. thought to be confined to Japan, the disease was soon So far, three main phenotypes have been reported: Miyoshi reported in Europe and elsewhere thereafter. In 1995, myopathy (MM), limb girdle muscular dystrophy type 2B Bejaoui, from the Boston group, mapped the MM locus (LGMD 2B), and distal myopathy with anterior tibial onset to chromosome 2p14-p12 by studying 12 informative [4] (DMAT). A growing number of clinical variants have recently families, five of which were consanguineous. In been described with a much wider range of symptoms and 1996, Weiler et al., reported the coexistence, in a large onset. Although rare, dysferlinopathies can account for Canadian aboriginal family, of MM on the one hand and [5] up to 30% of progressive recessive muscular dystrophies of a condition mimicking LGMD on the other. Similar in certain geographical areas, notably in the Middle East findings had been reported earlier by Mahjneh in a large [6] and the Indian subcontinent. Dysferlin is a large protein kindred from Palestine. involved in membrane repair and vesicle trafÞ cking and Limb girdle muscular dystrophy is the generic name interacts probably with important immunological pathways. for a heterogeneous group of neuromuscular disorders New insights in its pathophysiology may result in innovative inherited either dominantly of recessively. They are therapies in the near future. characterized by muscle wasting and atrophy mostly in the shoulder and pelvic girdle but with a quite variable Key words: Distal myopathy with anterior tibial onset, degree of severity and disease course. The vast majority dysferlinopathies, dysferlin, limb girdle muscular dystrophy, of LMGDs are recessively inherited. In 1994, the first LGMD 2B, Miyoshi myopathy, muscular dystrophy, gene to be cloned in a recessive LGMD was unraveled mini-dysferlin 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 Historical Landmarks that another group of LGMD families, one of which was located in Palestine, was particularly informative The term ‘dysferlinopathy’ was coined in 1999 by for linkage studies[6] and actually mapped to another Bushby after Miyoshi myopathy (MM) and limb girdle locus, on chromosome 2p.[8] The LGMD international muscular dystrophy type 2B (LGMD 2B) were found to consortium agreed in Naarden in 1995 to name the be allelic disorders.[1] Nowadays, it corresponds to the different LGMD loci based on chronological order and various clinical phenotypes related to a complete or mode of inheritance. As a result, calpain deficiency was partial absence of dysferlin. termed LGMD 2A and the other locus became LGMD Historically, the first phenotype of dysferlinopathy 2B (the suffix “2” is meant to point out the recessive to be described was the one reported by Miyoshi, forms). a Japanese physician, in 1967 and subsequently in In 1998, after several successful attempts to refine the 1986.[2,3] In Miyoshi’s original publication, four interval of the MM/LGMD2B locus to the 2p13 region, patients from two consanguineous families presented two independent laboratories (located in Newcastle with recessively inherited late-onset distal myopathy and Boston respectively) cloned the dysferlin gene and associated with clear-cut muscular dystrophy and clearly demonstrated that the two disorders (MM and

J. Andoni Urtizberea Assistance Publique Hopitaux de Paris, Hopital Marin, BP40139, 64700 Hendaye – France. E-mail: [email protected]

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LGMD 2B) were allelic and caused by the same gene to the pelvic muscles and to the upper limbs, more defect (DYSF).[9,10] distally. Partial atrophy of the biceps brachialis muscle sometimes results in the phenomenon of the ‘boule du Clinical Phenotypes biceps’ as described by Fardeau earlier.[11] Similarly, one author suggests that certain muscle body shapes in the Miyoshi myopathy (OMIM # 254310) shoulder and in the quadriceps might be indicative of [12,13] Miyoshi myopathy is the most recognizable, at dysferlinopathy. Scapular winging is rather least in theory, subtype of dysferlinopathies. It is also uncommon in MM. Cardiac and respiratory the commonest form of autosomal recessive distal complications are not part of the mainstream form of myopathy. Miyoshi myopathy is characterized by dysferlinopathy either. Disease progression is generally weakness, initially affecting the gastrocnemius muscle slow, over decades, but 10-20% of MM patients from the late teens or early adulthood. In the early nevertheless become wheelchair dependent. stage of the disease, serum levels of muscle enzymes (creatine kinase, lactic dehydrogenase (LDH), aldolase) Limb girdle muscular dystrophy type 2B (OMIM are massively elevated and the pattern of myopathic #253601) changes in muscle is clearly dystrophic with numerous In LGMD 2B, the clinical phenotype shares a great deal inflammatory foci. At first, patients complain of of similarities with MM. Age of onset is also in the late impaired tiptoe-standing, thus corroborating the primary teens, and progression is usually slow. Distribution of involvement of the gastrocnemius muscle. Other distal muscle weakness, although selective, is predominant in symptoms include difficulties in getting downstairs, the proximal pelvic muscles while the shoulder girdle is episodes of ankle subluxations and even foot drop when more mildly involved over time. Distal involvement in the leg anterior compartment becomes affected after the lower legs can occur, after years of progression, and some time. Patients occasionally complain of painful can result in foot drop.[14] In some instances, the initial legs, sometimes unilaterally, with concomitant calf presentation is a proximo-distal muscle weakness. This swelling but without any myoglobinuria. The onset of distal involvement is a key clue. symptoms, in the late teens or in early adulthood, is delayed as opposed to Duchenne muscular dystrophy Distal myopathy with onset in tibialis anterior (DMD) or to other forms of LGMD (calpain deficiency (OMIM # 606768) or sarcoglycanopathies, notably). Most patients do Distal myopathy with onset in the tibialis anterior not show any signs of muscle weakness in childhood (DMAT) (also referred to as DACM for distal anterior and a significant number of them are even excellent at compartment myopathy) is a new entity coined by sports and physical activities, something quite unusual Illa.[15] An extended Spanish consanguineous family was in muscular dystrophy in general. On examination, shown to carry one homozygous mutation in the DYSF the most striking feature is the wasting of both calves gene but with an atypical clinical presentation. If age of [Figure 1]. Over time, muscle weakness can extend 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.[16-19] 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

Figure 1: The shape of the calf (with marked atrophy) is suggestive of indicative of dysferlinopathy. Miyoshi myopathy In other instances, the disease manifests as a

290 Neurology India | July-September 2008 | Vol 56 | Issue 3 Urtizberea et al.: Dysferlinopathies pseudometabolic disorder with exercise intolerance, Differential Diagnosis myalgias and cramps, but without myoglobinuria. Isolated and long-lasting hyperCKemia has also been Misdiagnosis is commonplace in patients with primary reported. Elevated CK levels and minimal clinical dysferlinopathy. Worse, it can lead to unnecessary and manifestations have also been anecdotally described potentially hazardous therapeutic interventions such [20] in a few heterozygotes. as long-term oral administration of corticosteroids Interestingly, many authors reported that onset of or immunosuppressors. In a couple of retrospective disease can be quite asymmetrical, unilateral, with or studies, close to 25% of LGMD 2B/MM patients had without transient calf myalgia and swelling. In some initially been diagnosed with polymyositis, one of the unusual cases, it inappropriately led to the diagnosis most common dysimmune inflammatory myopathy in of thrombophlebitis. A case of dysferlinopathy with adults. In dysferlinopathy, inflammatory changes in choreic movements has been described only once and muscle are sometimes so florid that they can mislead [21] may just be coincidental. In elderly people, spinal the pathologist as well as the clinician. Moreover, CK muscle degeneration, with or without camptocormia levels are equally elevated in both conditions, a finding can also be a presenting symptom.[22] which also adds to the confusion. When faced with Several comprehensive surveys have stressed the similar challenges, it is best to systematically perform importance of these clinical variants and advocate for a additional immunostains in order to differentiate the broader view as far as the spectrum of dysferlinopathies two conditions. In dysferlinopathies, the HLA-Class is concerned.[18,23,24] For instance, age at onset is more I complex is not over-expressed.[33] In any event, variable than originally thought, with some patients the most critical clue will be generated by dysferlin remaining asymptomatic till 60 or 70 years of age, and immunocytochemistry and immunoblotting as conversely, patients becoming symptomatic in their mentioned earlier. early teens. When CK levels are less informative (at end- The association between dysferlinopathy and stages of disease, for instance), alternative forms cardiomyopathy is still a debated issue.[25] Some authors argue for its anecdotal nature while others, putting of distal myopathy may need to be differentiated. forward the evidence accumulated from the murine Dysferlinopathy remains by far the most frequent cause [34-35] animal model of dysferlinopathy (SJL mouse), think of autosomal recessive distal myopathy. Nonaka that this cardiac complication might be overlooked in distal myopathy is sometimes an option, especially patients.[26,27] Recently, a group from Berlin, Germany, if onset is in the anterior compartment of the lower reported two out of six LGMD/MM unrelated patients, leg. Age of onset and disease progression can overlap who developed overt cardiac disease without any with MM. However, the presence of numerous rimmed correlation with the severity of their skeletal muscle vacuoles in muscle is a distinctive feature; even though phenotype. This combination may exist in other such vacuoles have occasionally been reported in patients but this has not been fully investigated so far. primary dysferlinopathy. Such a working hypothesis fully justifies prospective Except in large inbred kindred where pseudo- heart studies in patients with genotypically proven dominance can be observed and in sporadic cases dysferlinopathy. of MM, the autosomal dominant forms of distal myopathy (Welander myopathy, Udd-Markesbery- Distribution of Phenotypes Griggs myopathy, Laing myopathy) are much less relevant to the differential diagnosis. By taking into account the topography of the predominantly affected While DMAT remains rather uncommon and was muscles (in the upper limbs in Welander disease) or reported mainly in Spain and Japan,[15,28] MM and LGMD the age at onset (in childhood in Laing myopathy, in 2B seem to be equally frequent in the overall patient rather late adulthood in Markesbery-Griggs myopathy), population with dysferlinopathy (personal data). Other a definite diagnosis is often reached. But once again, clinical variants may account for 20-30% of the total, based on the different available worldwide studies. immunostaining of dysferlin in muscle or monocytes is More importantly, at least two, more rarely three essential in that context and will be quite discriminating. or more, phenotypes (MM, LGMD 2B, DMAT, others) With the exception of Welander myopathy, genetic can coexist within the same family or pedigree as markers are now available for most of these variants of reported on several occasions, first in Canada[5] and distal myopathies (GNE mutations in Nonaka myopathy, elsewhere.[18,29-32] So far, no satisfactory explanation titin mutations in Udd myopathy, ZASP mutations in has been given to account for this unusual occurrence. Markesbery-Griggs myopathy and MYH7 mutations in Modifier genes or environmental factors are likely to Laing distal myopathy respectively). be involved. When dysferlinopathy presents as LGMD, the two

Neurology India | July-September 2008 | Vol 56 | Issue 3 291 Urtizberea et al.: Dysferlinopathies alternate diagnoses are LGMD 2A and LGMD 1C, Creatine Kinase (CK) levels precisely because both entities can result in secondary Elevated CK levels are not specific in themselves. dysferlinopathy with significant signal reduction In early stages of dysferlinopathy, they are usually either of calpain or of caveolin-3. Other forms markedly elevated, up to 50-100 times over normal (sarcoglycanopathies and FKRP-deficiencies) are easier values. In the context of a patient presenting with to rule out. distal motor symptoms, this massive increase is quite Charcot-Marie-Tooth disease and other neurogenic suggestive of MM and therefore of dysferlinopathy. conditions also form a differential diagnosis. Sparing of Over time, CK levels tend to decline and lose their the extensor digitorum brevis muscle in dysferlinopathy informative value. is usually a distinctive feature. The muscle tends to be affected in most neurogenic conditions. Electromyographic (EMG) studies EMG studies are actually useful to rule out alternative Epidemiology diagnoses like Charcot-Marie-Tooth disease. This is particularly relevant when the patient presents with In the absence of a comprehensive international patients’ foot drop like in DMAT. In most dysferlinopathies, registry, the overall prevalence of dysferlinopathies is one notes myogenic changes, and nerve conduction still hard to estimate. Additionally, figures vary from velocities are normal. Neurogenic changes have one place to another. As recessive disorders, MM and occasionally been reported, especially at late stages of LGMD 2B are commonly reported in communities or muscle degeneration. geographical areas in which endogamy is high. It is true notably in Maghreb, Israel, Saudi Arabia, Iran and the Muscle imaging Indian subcontinent where cases with dysferlinopathy Whatever the subtype of dysferlinopathy, muscle are many. In these areas, dysferlinopathies are now imaging is often of great interest, especially in the emerging as the second most common cause of early phases of disease. Magnetic resonance imaging autosomal recessive LGMD in adults after calpain (MRI) studies or computerized tomography (CT)-scan deficiency (LGMD 2A). In less consanguineous areas, imaging of the lower limbs provide the clinician with valuable clues and are therefore warranted as first-line such as the USA, they can still account for 15% of investigations. Marked wasting of both calves points to autosomal recessive LGMD.[36] MM while predominance in the pelvic girdle muscles Population-specific mutations and founder effects is more indicative of LGMD 2B. Muscle atrophy of the have been described in communities such as the Libyan calves often extends to the posterior compartment of the Jews and more recently in the so-called Mountain Jews thigh over time, long before its perception at the clinical originating from the Caucasus region.[37-38] Similarly, level. Heterogeneity in the gastrocnemius appearance recurrent mutations in supposedly unrelated families often precedes onset of clinical symptoms [Figure 2]. have been picked in Japan, Italy and Spain.[32,39] A Muscle imaging of the upper limbs may also be founder effect is also likely in a cluster of Acadian/Cajun valuable but is technically more challenging to perform patients with proven dysferlinopathy settled both in and interpret. Nova-Scotia and in Louisiana (personal unpublished In DMAT, muscle wasting is initially noted in the data). tibialis anterior muscle but extends to the gastrocnemius 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

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 Figure 2: CT-scan image at the calf level: early involvement of the approaches should be considered. gastrocnemius muscle

292 Neurology India | July-September 2008 | Vol 56 | Issue 3 Urtizberea et al.: Dysferlinopathies over time, generally in a couple of years. blood sampling and shipping to an appropriate laboratory within 48 h. The sensitivity and sensibility Muscle histology of both tests are quite acceptable. The blood-based The most striking feature of dysferlinopathies is assay on monocytes is commercially available through the overt necrotizing process found in muscle. At an Athena Diagnostics. early stage, though, the dystrophic changes can be minimal with simple fiber splitting, centralized nuclei Primary versus secondary dysferlinopathies and limited degeneration of muscle fibers. Lesions Cumulative data have established the existence are best observed in affected muscles and the site of secondary dysferlinopathies. Given the location of the biopsy therefore matters. Muscle imaging is of dysferlin, close to the muscle membrane, and its instrumental in achieving this targeting. At advanced interactions with other proteins, it is not very surprising. stages of disease, fatty replacement is the rule. Rimmed The commonest ‘mistake’ is made with primary calpain vacuoles are never a prominent feature. Initially deficiency (LGMD 2A) and caveolin-3 deficiency regarded as exclusion criteria, they have nonetheless (LGMD 1C). In both conditions, occasional weak signals been reported as an occasional but nonspecific finding. of dysferlin have been reported but never a complete Similarly, amyloid deposits have recently been seen absence. A re-appraisal of the general clinical picture in three German patients with dysferlinopathy.[40] In is recommended before embarking on genetic studies contrast, inflammatory infiltrates are quite common of alternative genes (CAPN-3, CAV). in dysferlinopathy, above all at disease onset[33] and they immunologically and cytologically differ from DNA studies those classically evidenced in polymyositis (PM) In theory, DNA analysis is the ultimate way to confirm (macrophages are twice as many, while CD8+ T cells the diagnosis of primary dysferlinopathy. In practice, are, by contrast, less numerous that in PM). however, it remains challenging given the numerous Dysferlin is recognized at the sarcolemma by hurdles met by molecular geneticists in detecting at least two commercially available monoclonal mutations in the DYSF gene. The DYSF gene is huge, antibodies (Hamlet-1 and Hamlet-2 antibodies are indeed, and composed of 55 exons. It spans 150 kb of directed against two far-apart epitopes of dysferlin). genomic DNA and generates a 6.9 kb-wide transcript. In muscle, such antibodies detect the vast majority More than 300 different mutations have been detected of dysferlin deficiencies.[18,23,41] It is noteworthy that including some at the intronic level. Most are single- they equally work nowadays with peroxydase and in nucleotide changes (for a review, Leiden Muscular immunofluorescence. There is a wide range of stain Dystrophy database: www.dmd.nl/md.html).[18,23,45] intensities between a complete absence of signal and a The currently available techniques fail to pick up large mere weak immunostain. The interpretation of the weak rearrangements (big deletions) as opposed to micro- or slightly reduced immunostains remains challenging deletions/duplications or point mutations which are as secondary dysferlinopathies have been described in easier to detect. A second challenge lies in the difficulty other muscular dystrophies. in detecting compound heterozygotes at the molecular At the ultrastructural level, alterations of the membrane level. It is not uncommon to only find out one of the are present such as small tears and accumulation two expected mutations of the DYSF gene. In addition, of subsarcolemmal vesicles and vacuoles, but such the DYSF gene is full of many non-pathogenic variants anomalies are not routinely investigated.[42] (polymorphisms). When faced with an MM phenotype without any Western blotting pathogenic mutations in the DYSF gene, the hypothesis Immunoblotting or Western blotting (WB) is a of a genetic heterogeneity in MM may arise. As a matter semi-quantitative technique aimed at assessing the of fact, a few families with a true Miyoshi phenotype do amount and molecular weight of a given protein. In not exhibit any dysferlin deficiency as reported earlier[46] the context of dysferlinopathy, the protein of interest and do not map to chromosome 2p. Some of them have is thus evaluated both in muscle specimens and also even been mapped to another locus (Chromosome in monocytes.[43,44] In muscle, the current trend is to 10).[47] In a couple of these non-dysferlin patients, a perform a multiplex WB by analyzing simultaneously comparable defect in membrane repair mechanisms on the same gel, other key proteins involved in DMD and has also been documented.[48] LGMD such as dystrophin, sarcoglycans and calpain-3. Western blotting in muscle seems more reliable than Genetic Counseling direct immunocytochemistry on muscle sections. A complementary assay consists of measuring the By definition, all cases of dysferlinopathies are dysferlin content in an enriched pool of monocytes transmitted following an autosomal recessive mode called CD-14+. The test is robust and simply requires of inheritance. A pseudo-dominant transmission is

Neurology India | July-September 2008 | Vol 56 | Issue 3 293 Urtizberea et al.: Dysferlinopathies occasionally observed in very endogamic communities sarcolemmal repair.[52-55] Dysferlin-containing vesicles with multiple consanguineous loops. fuse to form a “membrane patch”. The patch would then The risk of recurrence among sibships is usually of 25%. be added to the membrane disruption site for resealing. Consanguinity does not raise the figure per se but increases Dysferlin belongs to the larger family of ‘ferlins’ that the probability of two heterozygotes (healthy carriers) include myoferlin, otoferlin and others (FER1L4, FER1L5, belonging to the same inbred community marrying and and FER1L6). Dysferlin may also play a role in the central therefore giveing birth to an affected child. nervous system, notably at the level of the blood-brain Given the relative mildness observed in the majority barrier.[56] of dysferlinopathies, prenatal testing is seldom offered Two naturally-occurring mouse mutants are used to even if the gene defects are accurately known in a given study the putative functions of dysferlin and the natural patient. course of disease. The SJL/J mice carry a spontaneous Carrier testing can be considered in inbred populations splice-site mutation resulting in a 171-bp in-frame as long as a founder mutation has been found. Such deletion removing 57 amino acids in the C2-E domain preventive measures have been proposed already in of the dysferlin protein.[57] Interestingly, SJL/J mice have Libyan and Caucasian Jews living in Israel. been used extensively as a model for auto-immune Genetic counseling sometimes turns out to be complex disease. Another mouse, the A/J mouse, has a unique ETn due to the fact that the different phenotypes, with variable retrotransposon insertion within intron 4 of the DYSF disease progression, can coexist in the same sibship. At gene. Other transgenic mice are in preparation to further this point, it is impossible to predict whether the patient understand the role of the different parts of the protein will develop as an MM or as an LGMD. in muscle physiology. Detailed interactions of dysferlin with other proteins Diagnostic Algorithm are under investigation. While dysferlin co-localizes with annexin A1 and A2 at the sarcolemma, it The preliminary clinical ascertainment is crucial and also interacts with caveolin-3, affixin and AHNAK generally provides relevant clues to the diagnosis of nucleoprotein.[58-60] dysferlinopathy. As mentioned above, a ‘distal touch’ In parallel, it has been shown that dysferlin also in the clinical picture is quite suggestive and is often results in downregulation of the complement-protection confirmed by calf muscle imaging. A total absence molecule CD-55. These immunological findings coupled of dysferlin in monocytes and/or in muscle is a key with the high degree of inflammation observed in early element for the positive diagnosis. Even better is to dysferlinopathy is an interesting avenue to explore. detect a homozygous mutation in the DYSF gene. This Indeed, macrophages (the circulating version of is seen in most consanguineous pedigrees. The fact of monocytes) exhibit an overaggressive activity in muscle not finding out a second heterozygous mutation in the fibers and may therefore contribute significantly to DYSF gene is not enough in itself to reject the diagnosis disease onset and progression.[61] of dysferlinopathy. On the other hand, when the dysferlin immunostain Genotype-Phenotype Correlations shows some remnants of the protein, one has to be cautious, especially if the mutation screening turns out So far, the relationship between phenotype and to be negative. A secondary dysferlinopathy is therefore a genotype in dysferlinopathy has remained extremely working hypothesis and this should prompt re-appraisal loose. Different mutations in DYSF have varying effects of the clinical and histological data. on protein expression.[18,62,63] As a result, the type of mutation does not correlate with phenotypic severity, Pathophysiology and the same mutation has been found to be associated with a wide inter- and intra-familial variation in clinical Dysferlin is a large protein (230 kDa), composed of phenotype. The best example is given by the concomitant 2080 amino-acids with a C-terminal transmembrane observation of three or more clinical phenotypes (MM, domain and six calcium-binding C2 domains. Dysferlin is LGMD, DMAT) within the same sibship or kindred. Even, located mainly at the muscle membrane in adult muscle the amount of residual dysferlin, if any, in muscle rarely and at the T-tubule system in early development.[49-51] correlates to the disease severity. It is obvious now that Dysferlin is widely expressed not only in skeletal muscle other modifying factors, or genetic and environmental and cardiomyocytes, but also in non-myofibers such as nature, interfere. monocytes (in CD14+ T cells, in particular). Dysferlin is a sarcolemmal protein sharing homology Dysferlinopathy in the Indian Context with the sperm vesicle fusion protein FER-1 that mediates fusion of intracellular vesicles with the spermatid plasma Dysferlinopathies are definitely ubiquitous membrane. Dysferlin has been shown to be involved in conditions.[18,23,35,64,65] They have been observed

294 Neurology India | July-September 2008 | Vol 56 | Issue 3 Urtizberea et al.: Dysferlinopathies in all ethnic groups, but have some propensity to something valuable even if such complications remain occur in endogamic communities. Whether or not an exception in dysferlinopathies. this group of disorders is more prevalent in India Surgical procedures are rarely needed in dysferlin than in the Western world remains to be proved, deficiencies. Surgical release of the Achilles tendons is but it seems highly plausible. A growing number of sometimes useful in early stages of LGMD 2B in order to Indian teams have reported series of patients with prolong ambulation but it is not a rule. In DMAT, ankle dysferlinopathy.[12,13,66,67] Immunocytochemistry for arhrodesis may also help in case of advanced foot drop dysferlin has only been introduced in India recently, with major functional impairment. most exclusively in academic centers dedicated to Pharmacological medications have not proved to myology (via Hamlet and Hamlet-2 antibodies marketed be of any benefit in dysferlinopathy. Anecdotal data by Novacastra). Muscle Western blotting, though, is still suggest dantrolene could be beneficial to CK levels but at a preliminary stage and mastered only by a couple of without any impact at the clinical level.[68] The impact laboratories across the country. The dysferlin assay on of corticosteroids is still subject to many discussions. monocytes had been available for some time in Mumbai Many patients misdiagnosed with PM erroneously but service has stopped recently. The detection of gene received corticosteroids, sometimes for long duration, defects in DYSF still remains a bottleneck since no but none reported any dramatic clinical improvement. Indian laboratory has ever embarked on this lengthy, One randomized clinical trial is in progress in Germany time-consuming, costly task. Indian clinicians are to document this point in more detail. Other clinicians therefore dependent on the goodwill of foreign molecular also work along the immune pathway to counteract the geneticists to confirm the diagnosis of their patients initiation of inflammation. Intravenous immunoglobulins at the molecular level. Hopefully, an international (Iv-IG) and other immunosuppressive agents (some initiative put forward and financially supported by the of them being more specific to certain lymphocyte Jain Foundation (www.jain-foundation.org) enables the populations) are also under consideration in therapeutic mutation detection of numerous patients worldwide. trials to come. The Jain Foundation website gathers information on Gene-based therapies are still far away from any clinical dysferlinopathy, patients and professionals can freely application in dysferlinopathy but they represent a register in order to get more information and news, as great hope. Such therapeutic avenues are currently well as to get prepared for further clinical trials. taking advantage from advances and technological breakthroughs made in other muscular dystrophies, Therapeutic Perspectives especially in DMD. Besides, DMD and dysferlinopathy share many traits such as the critical size of the gene, Palliative treatment is so far the only available option in the wide range of mutations and the comparable severity dysferlinopathy. Daily management, based on medical or of the necrotizing process (even though DMD starts surgical interventions, is largely supportive but definitely earlier and cardiomyopathy is not a part of the cardinal more efficient than any innovative therapy whatever its symptoms in dysferlinopathy). great appeal and its potential impact in the long run. One good example of these promising techniques has A customized therapeutic approach is always preferable recently been given by the Marseilles’ group which for each patient and must take into account the natural demonstrated that shortened versions of the DYSF gene history of disease. Patients either with MM, LGMD 2B or could still be functional, a finding long established in DMAT have specific needs. The vast majority of patients DMD (the various so-called mini-dystrophins). This with MM remain ambulatory throughout their life. Limb important discovery was based on the observation girdle muscular type 2B, conversely, often confines the of a minimally affected 41-year-old patient with patient to a wheelchair after two or three decades of dysferlinopathy harboring a large DYSF deletion. The disease progression, sometimes less. The DMAT patients so-called mini-dysferlin derived from this patient has require the use of callipers to oppose foot drop more been able to rescue faulty processes of membrane repair efficiently. in vitro.[69] A multidisciplinary approach is always better and should Many other therapeutic avenues, such as exon- combine the expertise of at least an adult neurologist, a skipping, viral gene therapy and stem cell therapies are rehabilitation specialist, and paramedics (occupational also being investigated. therapist, physiotherapist and social workers). It is of the utmost importance to follow up the patient regularly References (once a year is a good tempo in most cases), even in the absence of curative medications. Not only to evaluate the 1. Bushby KM. Making sense of the limb-girdle muscular dystrophies. disease progression and intervene accordingly but also Brain 1999;122:1403–20. to keep track of the patient in the perspective of clinical 2. Miyoshi K, Saijo K, Kuryu Y, Tada Y, Otsuka Y, Oshima Y, et al. Four cases trials. Monitoring of cardio-respiratory functions is also of distal myopathy in two families. Jpn J Hum Genet 1967;12:113.

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