Dysferlinopathies

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] Neurology India | July-September 2008 | Vol 56 | Issue 3 289 Urtizberea et al.: Dysferlinopathies 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

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