Making the diagnosis of a particular type of limb girdle muscular dystrophy (LGMD) can appear challenging. In fact, various clues from the way the patient presents, and the results of simple investigations such as creatine kinase levels, can be extremely helpful in sorting out the various disease entities within this group of patients. The results of more specialised testing of the muscle biopsy and DNA sequencing offer the prospect of a clear answer in around 75% of cases. As more is understood about the clinical features of the different types of LGMD, targeted management is increasingly possible, especially focusing on those patients at high risk of cardiac and respiratory complications.
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Diagnosing the various disorders within the “limb girdle muscular dystrophies” (LGMD) requires information from the clinical presentation and the results of various investigations, such as serum creatine kinase (CK), muscle biopsy and genetic testing (fig 1).1 2 3 4 These investigations can help to make a definitive diagnosis for the various disorders included in the LGMD classification (table 1). Despite the overall “LGMD” designation implying predominant involvement of the limb girdle musculature, there may be considerable clinical heterogeneity, especially for the autosomal dominant group of LGMD; among these there are many new dominant mutations, so that a high level of diagnostic suspicion needs to be maintained, even without a clear family history.
The specific features for each of the LGMD types, together with their particular differential diagnoses, are outlined below. It is of course important to be aware that in most populations any form of LGMD is relatively rare. It follows that before considering the diagnosis of LGMD, other perhaps more likely diagnoses need to be excluded. In particular, there may be some diagnostic confusion with conditions such as facioscapulohumeral muscular dystrophy and the dystrophinopathies (Duchenne muscular dystrophy, Becker muscular dystrophy and manifesting carriers of dystrophin mutations); this is usually now resolved with DNA analysis.
In a patient presenting with suspected LGMD, the first things to note in the pathway to reaching a precise diagnosis are the mode of presentation, in particular the pattern of muscle involvement, any additional clinical features, the CK level and any informative family history. Next, the muscle biopsy may be partially informative at the level of histology (eg, by suggesting an alternative disorder such as Pompe’s disease, an inflammatory myopathy or a neurogenic problem). Then, with immunohistochemistry or immunoblotting for the specific proteins involved in the various forms of LGMD, the biopsy may suggest a particular disorder. Nowadays, however, for most LGMD diagnostic groups, the gold standard is detecting the causative mutation with DNA analysis (table 2).
With appropriate testing it should be possible to reach a precise diagnosis in around 75% of the LGMD patients with all of the advantages this brings in terms of precision of genetic counselling and management advice. Ultimately of course this may also lead to specific therapies.5 6
As our knowledge of LGMD grows, there is an increasing awareness of the complications which may accompany the various types, in particular those affecting the cardiac and respiratory systems. Appreciating the risk of arrhythmias, cardiomyopathy and important respiratory compromise and then instituting appropriate management is crucial to improving quality of life and longevity.1 2 3 4
Specific types of limb girdle muscular dystrophy
Dominant forms of limb girdle muscular dystrophy
LGMD1A was described in rare families with proximal muscular dystrophy combined with dysarthria and modestly raised serum CK. This form of LGMD is due to mutations in the myotilin gene.7 8 As the diagnostic spectrum of myotilin mutations has been better defined, it is now clear that an “LGMD” presentation is probably a rare form of myotilinopathy (its more common presentation is with a distal myopathy). Presentation tends to be in middle to late adult life. This form of LGMD therefore overlaps with the myofibrillar myopathies, a group of diseases where the affected muscles may be distal, proximal or a mixture, with typically moderately raised serum CK (approximately five times the upper limit of normal) and characteristic histological features including vacuoles and accumulation of myofibrillar proteins such as desmin and myotilin. This histological appearance should prompt the search for mutations in the various genes responsible for the myofibrillar myopathies: desmin, myotilin, ZASP, alpha-beta crystallin and filamin C.9 10 11 12 There are similar pathological features in patients with valosin containing protein mutations where the clinical phenotype may include frontotemporal dementia and Paget’s disease of bone.
Importantly, in the management of myofibrillar myopathy patients, cardiac, respiratory and other complications such as cataracts are relatively common, and of course the dominant inheritance pattern is crucial for genetic counselling. In fact, the pattern of complications between the different genetic groups may be somewhat different, and the myotilin mutation patients have a lower risk of complications. Nonetheless, a high index of suspicion of associated problems is necessary in these dominant and rather clinically variable conditions.13
As for myotilin/LGMD1A, a pure LGMD presentation is just one (relatively uncommon) form of a variety of presentations in patients with mutations in the lamin A/C gene.14 15 16 17 18 Only approximately 60% of presentations involve skeletal and cardiac muscle. Importantly though, where there is skeletal muscle involvement with laminopathy, there is a very high risk of significant cardiomyopathy giving rise not only to progressive and malignant arrhythmias necessitating defibrillator implantation but also a progressive cardiomyopathy.
The skeletal muscle presentation of lamin A/C mutations is also broad. The “typical” presentation is as an Emery–Dreifuss muscular dystrophy in childhood, with a prominent contractual phenotype involving the Achilles tendons, elbows and spine predominantly, together with humeroperoneal muscle weakness (fig 2). On the other hand, contractures may be less prominent and muscle weakness more proximal, or patients may present with a mixed phenotype. A pure cardiac presentation is seen in some families. In some rare cases there may be an overlapping phenotype with the other laminopathy presentations such as partial lipodystrophy, progeria, mandibuloacral dysplasia and neuropathy.
Presentation with laminopathy has been described at any age, including a congenital phenotype with dropped head as a typical feature. Often there are new dominant mutations in the lamin A/C gene so it is not uncommon to make this diagnosis without a family history.
For the patient presenting with a contractural myopathy in the absence of the additional features above, there are various important differential diagnoses. Although “classical” Emery–Dreifuss muscular dystrophy was described as an X linked disease, it is now known that lamin mutations are a more common cause of this phenotype than emerin mutations. For most patients with emerin mutations there is no emerin in muscle or skin biopsies making these a useful first screen in this situation. By contrast, for patients with lamin A/C mutations, no lamin abnormalities are typically seen on muscle biopsy, except in the rare autosomal recessive cases. Other genes involved in an Emery–Dreifuss presentation with contractures and a high risk of cardiac arrhythmia include FHL1 and nesprin.19 20
A very similar pattern of contractures, without primary cardiac involvement, can be seen in Bethlem myopathy due to mutations in the collagen VI genes.21 22 Here the pattern of muscle weakness is more typically proximal than the humeroperoneal involvement seen in the various types of Emery–Dreifuss muscular dystrophy. In both Emery–Dreifuss and Bethlem myopathies, serum CK is typically normal or only slightly raised. Contractures may also be a prominent feature of LGMD2A due to calpain 3 mutations (fig 3). As specific MRI patterns of muscle involvement can be recognised for many of these disorders, including laminopathy, Bethlem myopathy and LGMD2A, imaging can be an important part of the diagnostic pathway.23 24
LGMD1C is due to mutations in the caveolin 3 gene. Again, there is a variety of phenotypes. These include a proximal LGMD presentation, a distal myopathy, rippling muscle disease, myalgia and hyperCKaemia.25 26 27 28 29 In some patients, the phenotype may evolve over time with different manifestations of the disease at different ages. When patients present they may in fact have very good muscle power and muscle hypertrophy, with muscle weakness evolving slowly. Here rippling muscles or the induction of percussion-induced repetitive contractures may be important clues to the diagnosis. Relatively few patients with caveolin 3 mutations have had long term follow-up; those that have may show gradual progression of weakness with time.30
There is as yet no clear association of cardiomyopathy or respiratory failure with caveolin 3 associated muscular dystrophy. Patients with caveolin mutations typically have a serum CK of around 10 times the upper limit of normal or more. On muscle biopsy, there is reduced caveolin 3 on immunolabelling.
For patients with a rippling muscle phenotype, an important differential diagnosis is autoimmune rippling muscle disease, where a mosaic pattern of caveolin loss may be seen in the muscle but without caveolin 3 mutations.
Other forms of autosomal dominant LGMD
Other forms of autosomal dominant LGMD do not yet have a known genetic cause. Careful characterisation of autosomal dominant families and exclusion of known genes is important. As cardiac and respiratory complications are typically important in the known forms of dominant LGMD, the families should have appropriate screening, even in the absence of a molecular diagnosis.
Autosomal recessive forms of LGMD
LGMD2A is the most common form of LGMD in most populations. It is due to mutations in the calpain 3 gene. The clinical presentation is fairly characteristic. Most patients present between the age of 8 and 15 years, although there are outliers at both ends of the spectrum. There is proximal muscle weakness, especially in the posterior muscles of the lower limb, together with involvement of the shoulder girdle leading to scapular winging.31 32 33 34 35 36 37 38 39 40 41 The key discriminators between LGMD2A and other forms of autosomal recessive LGMD are preservation of respiratory muscle strength, as measured by forced vital capacity, scapular winging and early Achilles tendon (and sometimes other) contractures (fig 3). CK levels are typically over 10 times the upper limit of normal.
Diagnostic testing may be challenging. Protein analysis on muscle biopsy is difficult to interpret and the results of protein immunoblotting are also complex, with several different calpain 3 bands detected, all susceptible to degradation. Nonetheless, different patterns of protein loss that are highly predictive of LGMD2A can be determined. The detection of mutations in the calpain 3 gene confirms the diagnosis, although again there may be a level of complexity because in around 23% of cases only one mutation in the gene is found by the commonly used mutation technologies.
LGMD2A is not often associated with cardiac or respiratory complications and is compatible with a normal lifespan. Inability to walk is typically 10–20 years after disease onset.
LGMD2B is due to mutations in the dysferlin gene. Dysferlin mutations may also present with a distal myopathy affecting predominantly the gastrocnemius (Miyoshi myopathy) or more rarely as a distal myopathy with involvement of the anterior tibialis (DMAT).42 43 44 45 46 With any mode of presentation, eventually the other muscle groups become involved so that inability to stand on tiptoe is a common feature in LGMD2B even when presentation has been predominantly proximal. Upper limb involvement is typically not seen early in the course of the disease (fig 4).
Whatever the mode of presentation, the age at presentation of dysferlinopathy is usually within a fairly tight window, around 17–25 years, although rare outliers have been described. Patients often have had a period of good muscle prowess such as high level sporting achievement before presentation, which is rare with muscular dystrophy patients.
CK is often massively raised, even up to 100 times the upper limit of normal, with an acute presentation which, together with a frequent inflammatory infiltrate in the muscle biopsy, can lead to misdiagnosis of polymyositis (not surprisingly unresponsive to steroids). Immunoanalysis of the muscle biopsy characteristically shows loss of dysferlin, which can be confirmed by mutation testing.
Patients with dysferlinopathy have a variable progression with increasing weakness over time. Cardiac and respiratory complications are not common.
LGMD2C–F types of limb girdle muscular dystrophy are due to mutations in the various genes which encode proteins of the sarcoglycan complex (alpha, beta, gamma and delta sarcoglycan). These proteins are in the sarcolemma in a complex with dystrophin, the protein involved in Duchenne and Becker muscular dystrophies. The phenotypes of the sarcoglycanopathies overlap with the dystrophinopathies, with the important distinction that the learning difficulty which may be seen with Duchenne in particular is not seen and scapular winging may be more frequent (fig 5).37 39 47 48 49 50 51
These patients may present at any age with a spectrum of disease severity as in dystrophinopathy, from a childhood muscular dystrophy (which is probably the most common presentation of sarcoglycanopathy) to an adult presentation. Muscle hypertrophy is common and serum CK is more than 10 times the upper limit of normal. Along with the progressive muscle weakness comes impairment of the respiratory muscles and cardiomyopathy so surveillance and treatment for these complications is indicated along the same lines as recommended for dystrophinopathy.
While the precise protein involved cannot be pinpointed by protein testing because all members of the complex are usually reduced in the presence of a mutation in the gene encoding one member, involvement of the sarcoglycan complex as a whole can be determined by muscle immunohistochemistry and immunoblotting, with subsequent mutation analysis in the different genes to pinpoint the diagnosis.
LGMD2G is a relatively mild and rare form of LGMD caused by mutations in telethonin in patients from Brazil and ethnic Chinese.52 53 The age of onset is typically 9–15 years with loss of walking ability after the fourth decade. There is frequent cardiac involvement and raised serum CK to 3–30 times the upper limit of normal. Suggestive muscle biopsy findings may include rimmed vacuoles as well as loss of telethonin labelling which needs to be confirmed by mutation testing.
LGMD2H was identified in the Hutterite population of Canada and is caused by mutations in the E3 ubiquitin ligase TRIM32 gene.54 55 Age at onset is typically from the mid twenties although it may be earlier in some cases. Progression is slow and any cardiac involvement is subclinical. CK levels are typically 5 times the upper limit of normal. No pathogenomic changes in the muscle biopsy have yet been described.
LGMD2I and other types of LGMD caused by proteins altering alpha dystroglycan.
LGMD2I is an important and frequent type of LGMD, especially in Northern Europe, where a common mutation accounts for most cases. The presentation ranges from a severe childhood muscular dystrophy to a much milder adult disease (fig 6). Clinical clues to the diagnosis include calf and other muscle hypertrophy, as well as frequent involvement of the diaphragm leading to the requirement for respiratory support in many patients (which may supervene when the patient is still walking) and frequently a cardiomyopathy.56 57 58 59 60 61
LGMD2I belongs to a family of disorders with abnormal alpha dystroglycans labelling on muscle biopsy, caused by mutations in genes encoding proteins important in the glycosylation of alpha dystroglycan.16 62 63 All cause an important spectrum of disease from a congenital muscular dystrophy to a limb girdle muscular dystrophy; apart from LGMD2I where the limb girdle presentation is more common, the congenital presentation tends to predominate.
If abnormal alpha dystroglycan is detected in a patient with an LGMD presentation, and FKRP mutations are not found, then it is logical to screen the other alpha dystroglycan altering genes for mutations. It is important to note that there are still a large proportion of cases with abnormal alpha dystroglycan where the causative mutation cannot be identified.
LGMD2J is a rare form of autosomal recessive LGMD resulting from homozygous mutations in the titin gene. It has been reported only in a large Finnish family where the heterozygous state of the gene mutation causes a distal myopathy. LGMD2J patients have severe progressive proximal muscle weakness with onset between the first and third decade.64 Cardiac or respiratory impairment has not been reported. CK levels are massively raised. There is severe reduction or absence of calpain 3 as a reflection of the interaction of titin and calpain 3.
LGMD2L was localised to chromosome 11p in French Canadian families with a broad range of age at onset from 11 to 50 years. Most patients had myalgia and there was prominent weakness and atrophy of the quadriceps muscles. CK was variably raised.65 The gene involved has not yet been definitively identified.
The molecular characterisation of so many forms of LGMD has provided new diagnostic tools as well as a much clearer understanding of the different disorders within this group of patients (tables 1, 2). Diagnostic expertise is frequently concentrated in specialised centres where the multidisciplinary approach to diagnosis can be fully exploited. One model for this kind of concentration of expertise can be seen in the UK where our National Specialist Commissioning Group allows access to specialised testing for patients from across the UK. Details can be found at http://www.ncl.ac.uk/ihg/services/miu.
Future possibilities include gene based therapies for the specific forms of LGMD as well as new gene sequencing technology driving the development of high throughput gene based screening for LGMD. These developments will change the algorithm for testing LGMD patients and further increase the impetus for reaching a precise diagnosis.
LGMD is relatively rare: consider more likely diagnoses first, especially dystrophinopathy.
A firm diagnosis should be achievable in around 75% of patients with LGMD.
Muscle biopsy immunoanalysis can suggest the diagnosis in at least two-thirds of the genetically defined types of LGMD.
Mutation testing is now the gold standard for diagnosis.
A firm diagnosis provides management guidance, including the need for cardiac and respiratory surveillance which is particularly important in LGMD1B, LGMD2C-F and LGMD2I.
Recognising the potential complications of arrhythmias, cardiomyopathy and respiratory failure facilitates appropriate management.
The limb girdle diagnostic service is funded by the NHS National Commissioning Group. This article was reviewed by David Hilton-Jones, Oxford. KB is very grateful to helpful discussion with Fiona Norwood, Volker Straub, Hanns Lochmulter and other colleagues in informing this review.
Competing interests None.
Funding The Newcastle Muscle Centre is funded by the Muscular Dystrophy Campaign, the Medical Research Council and the European Union (TREAT-NMD contract number EC 036825).
Detail has been removed from these case illustrations to ensure anonymity. The editor and reviewer have seen the detailed information available and are satisfied that the information backs up the case the author is making.
Provenance and peer review: Commissioned; externally peer reviewed.