Limb-girdle muscular dystrophy (LGMD) is a clinico-pathological umbrella used for a group of neuromuscular disorders that have certain clinical and pathological features in common.1 However, it encompasses within it entities that are genetically and clinically quite heterogeneous. Thus, LGMD should not be used as the final diagnosis for a given patient, but efforts need to be made to define the specific genetic entity.
Clinically, LGMD has its onset anytime in life from early childhood to late adult years; however, it does not have a congenital onset, in which case the designation of congenital MD (CMD) is more appropriate.2 In general, muscle weakness starts in the proximal muscle groups, typically in the pelvic girdle, with resulting initial symptoms of difficulties climbing stairs, running, and getting up from the floor, followed by clinically evident weakness in the shoulder girdle some time later. By definition, at least initially, the distal muscles and the muscles of the face are spared, and the extraocular muscles are not involved.
Of essential importance for diagnosing a patient with LGMD is that there is histological evidence of muscular dystrophy in the muscle biopsy. Even more important, however, the biopsy serves to rule out other conditions presenting with a limb-girdle pattern of weakness. Examples include inflammatory muscle disease, metabolic muscle disorders, anterior horn cell disease, and structural myopathies. If a specific genetic diagnosis is entertained on the basis of the clinical features, a biopsy sometimes can be postponed or cancelled if the genetic test confirms the diagnosis. In all other cases, a biopsy becomes necessary.
Thus, both clinical and pathological features are necessary for making a diagnosis of LGMD. A significant elevation of serum CK levels usually helps point towards a dystrophy, but in itself is not specific enough to make a biopsy unnecessary. Both inflammatory and metabolic myopathies can lead to significantly elevated CK levels, and conversely, some dominant forms of LGMD may have only minimally elevated to normal CK levels.
Classification of the Limb-girdle Muscular Dystrophies (LGMD)
Classification of the Limb-girdle Muscular Dystrophies (LGMD)
The following sections outline the more important subtypes of pediatrie LGMD according to their mode of inheritance. The basic genetic nomenclature that has been adopted for classification purposes simply lists the conditions according to their mode of inheritance (LGMDl = autosomal dominant, LGMD2 = autosomal recessive) and in the order they were discovered, giving them continuous letters of the alphabet.
The Table lists all the known entities at the time of this writing, in the order of the genetic classification. While this nomenclature is useful for keeping track of the growing list of conditions subsumed under the label LGMD, there is little clinical or pathophysiological information for the clinician in this list. Thus, in clinical practice, a nomenclature designating the disease after the affected protein is now gaining more acceptance. From a clinical and pathophysiological point of view, Duchenne and Becker MD are part of this group and therefore always part of diagnostic considerations, but for historical reasons, they are kept separate from the other entities within LGMD.
AUTOSOMAL RECESSIVE LGMD
Recessive LGMD (LGMD2) is much more common than dominant LGMD. It also is more prevalent in the pediatrie population, as onset tends to be earlier and the course often more severe compared with the dominant forms of LGMD.7 Therefore, autosomal recessive LGMD is described here not by adhering to genetic numbering but rather by ordering them by age of onset and physiology.
An important group of autosomal recessive LGMD affects proteins that are associated with dystrophin, the protein deficient in Duchenne and Becker MD.8 These proteins are referred to as dystrophin-associated proteins and include the transmembrane sarcoglycan/sarcospan and dystroglycan complexes and the intracellular components syntrophin and dystrobrevin, as well as others (Figure, see page 572).9 Mutations in the sarcoglycan complex in muscle and defective O-linked glycosylation of oc-dystroglycan all lead to autosomal recessive LGMD. Among recessive LGMD, the sarcoglycanopathies and some patients with fukutin-related protein (FKRP) mutations have a tendency for the earliest age of onset.10
Sarcoglycanopathies (LGMD2C, D, E, F)
Mutations causing LGMD have been found in all four sarcoglycans making up the sarcoglycan complex in skeletal muscle (a-, ß-, d- and -y-sarcoglycan).11'15 Age of onset in this group is quite variable and ranges from early childhood to adulthood, but for most patients, onset is in the first decade, around age 6 to 8. 10'16 There is proximal weakness in the pelvic girdle before the shoulder girdle becomes affected, leading initially to difficulties running, climbing stairs, a positive Trendelenburg sign, and a positive Cowers' maneuver. There often is some degree of calf hypertrophy, and CK levels are elevated significantly.
Figure. Highly schematic view of the complex of dystrophin-associated proteins and the adjacent extracellular matrix. Molecules associated with LGMD or LGMD-like pictures are boxed. Not all molecules are discussed in the text and this scheme is far from complete.
The phenotype, in many aspects, resembles Duchenne and Becker MD, although onset often is somewhat later than in Duchenne, and there are no language or cognitive delays. The clinical course is quite variable, even between affected siblings.17'18 In severe cases, loss of ambulation can occur before age IO,19 whereas in very mild cases, there can be minimal muscle weakness, and the only complaint may be muscle cramping. In the majority of cases, however, there is onset in the first decade of life and loss of ambulation by the third decade, but in the second decade of Ufe for childhood-onset cases with Duchenne-like severity.10,16,17,20
A significant subset of patients (about 30%) develop dilated cardiomyopathy by electrocardiogram and echocardiogram criteria.21 Although most of the cardiomyopathy is subclinical, some cases may lead to overt cardiac failure. Thus, cardiac function in the sarcoglycanopathies needs to be monitored on a regular basis.
Analysis of the muscle biopsy by immunohistochemistry with antibodies against the sarcoglycan proteins can reveal deficiencies of the sarcoglycan complex that often gets lost from the membrane as a unit. However, suggestive differences in staining can help guide genetic investigations to the gene with the primary mutation. There is some anecdotal evidence suggesting that steroid treatment may have beneficial effects comparable to those in Duchenne MD,22 but no systematic investigations have yet been published.
Fukutin-related proteinopathy (FKRP, LGMD 21)
Mutations in the gene for Fukutinrelated protein (FKRP) cause an abnormality of the O-mannose linked glycosylation of a-dystroglycan, leading to decreased affinity for its ligands, such as laminin 2 (merosin).23 The spectrum of clinical severities associated with mutations in FKRP is one of the largest known in the field of neuromuscular disorders, including severe congenital MD with abnormalities of brain formation (akin to muscle-eye-brain disease), pure congenital MD with normal brain findings, Duchenne-like MD, juvenile LGMD, and a very late onset form of the disease.24,25
The LGMD presentation of FKRP mutations is very reminiscent of Duchenne or Becker MD as far as the pattern of muscle involvement is concerned.26 It may start in early childhood akin to or even more severe than Duchenne MD, but the onset of the typical LGMD form is in the mid to late teens. Muscle hypertrophy can be prominent in various muscles, including the calves.
There is a tendency for dilated cardiomyopathy, which appears to be even more prevalent than in the sarcoglycanopathies (55.2% in one series; 24% of those patients developed cardiac failure).27 In some patients, cardiomyopathy may be severe enough as to lead to cardiac transplantation even early in the course of the muscle weakenss. Respiratory failure is another conspicuous complication that usually becomes apparent shortly after the loss of independent ambulation.27 Thus, regular cardiac and pulmonary follow up is imperative.
Diagnosis is by muscle biopsy to rule out Duchenne or Becker MD and to identify reduced staining for glycosylated a-dystroglycan. This reduction can be quite variable, however, so the clinical impression should guide the workup. Mutation analysis in the FKRP gene is now offered on a commercial basis. Patients with the typical LGMD phenotype have a recurrent mutation Leu276ne.23,24,25 The potential value of steroid treatment in patients with FKRP mutations has not yet been explored.
Calpainopathy (LGMD 2A)
This MD is different from the previous ones in that it is caused by mutations in the muscle-specific neutral protease calpain 3, a protein that is not associated with the dystropin complex but rather with the sarcomeric protein titin.11 Its functions have not been explored completely. This disorder is of juvenile onset, with a median age of onset around 14 to IS.28'30 It is sufficiently different clinically from the five LGMDs discussed previously that, in a typical patient, it can be recognized clinically with a high degree of sensitivity, although not with the same degree of specificity. Approximately 10% to 20% of patients, however, will have atypical presentations.
Onset is in the lower extremities with proximal weakness, followed by weakness in the upper extremities some years later, but it may also start with weakness in the shoulders. In typical cases, as originally described by Wilhelm Erb in the 19th century,31 there is a striking scapulohumeral distribution to the weakness, resulting in a degree of scapular winging that can resemble facio-scapulo-humeral MD and may even be asymmetric. However, the face is reliably spared.
In contrast to the dystrophin-associated LGMDs, this MD is mostly atrophie, with no significant muscle hypertrophy except for rare transient calf hypertrophy in some patients. Also, in contrast to the dystrophin-associated group, there is no cardiac involvement in calpainopathy. Atypical presentations of calpainopathy can include a Duchenne-like presentation, a contractural presentation with prominent Emery-Dreifuss MDlike contractures, or a pseudometabolic presentation with prominent exercise-induced cramping.29,30
The disease is slowly but steadily progressive, leading to loss of ambulation approximately 20 years after onset, which therefore falls during the fourth decade of life.30 Muscle biopsy is useful to rule out other causes of this pattern of weakness (in particular neurogenic causes) and to rule out abnormalities of the dystrophin complex. Calpain 3 deficiency in muscle can be demonstrated by Western blot analysis, but this is marred by false negative and false positive results.29'30 Genetic testing is now available on a commercial basis.
Dysferlinopathy (LGMD 2B)
Dysferlinopathy is caused by mutations in dysferlin, a membrane-bound protein with a large intracellular domain that likely is crucial for membrane repair events in muscle.32'34 Mutations in the same gene also cause the distal MD type Miyoshi,33 which probably is more common than the LGMD presentation.35
Dysferlinopathy has a relatively narrow age of onset that centers around age 18; patients may even have been athletic onset of the disease.35'37 CK levtend to be excessively elevated.
Even though the main complaints at onset of the disease may be centered the proximal lower extremity there often is a diagnostically helpful early involvement of the muscle, such as an inabilto walk on toes or clear involvement imaging.37 Strikingly, there is less muscle involvement in dysthan in the forms of LGMD previously. There is considervariability in the pattern of muscle in that some patients may a mixed proximal and distal onset. the distal muscles, onset may be the posterior (gastrocnemius) or, rarethe anterior compartments of the leg.
The disease also shows a progressive with wheelchair dependency in years. There have been no reports cardiomyopathy. Diagnosis mostly is immunohistochemistry for dysferlin muscle sections and Western blot on or lymphocytes.38 Mutation analis not yet available commercially.
Recessive LGMD Forms
There are two other genetically deforms of autosomal recessive both of which appear to be rathrare. Telethoninopathy (LGMD2G) is by mutations in the Z-disc protelethonin and may be indicated by drop at onset.39 LGMD2H is caused mutations in TRIM3240 and may also with the morphological picture sarcotubular myopathy.41
AUTOSOMAL DOMINANT LGMD lgmd 12)
Autosomal dominant LGMD is about 10 times less common than the autosomal forms. Although it is milder in onset in childhood is possible.
Myotilinopathy (LGMD IA) is caused mutations in the Z-disc protein myobut appears to be rare; only two with LGMD due to myotilin mutations have been described.42'43 In both families, presentation was mild proximal weakness with some degree of a hypernasal voice in some of the family members. However, myotilin mutations appear to be more common in so-called myofibrillar myopathy, a disease of adult age with characteristic morphological changes in the muscle biopsy.44
Caveolinopathy (LGMD 1 C) is caused by mutations in the oligomeric membrane protein caveolin 3.45 Although this disease may present with LGMD manifesting in childhood, the more characteristic presentation of caveolin 3 mutations is with muscle cramping and pain, hyperCKemia, or both, rather than prominent weakness, which even in the LGMD presentation usually is mild.46'47 Mutations in caveolin 3 also cause rippling muscle disease,48 a disease of intrinsic muscle hyperexcitability in which mechanical stimulation causes a state of local contraction in the muscle. Thus, caveolinopathy should be considered when there is a prominent aspect of cramping/pain (pseudometabolic presentation) in addition to an elevated CK. The diagnosis can be supported using caveolin 3 immunohistochemistry on muscle biopsy sections, followed by genetic mutation analysis. A positive family history is not always required, as de novo mutations clearly occur.
Laminopathy (LGMD IB) is caused by mutations in the nuclear intermediate filament lamin A/C.49 It assumes a special position among the types of LGMD, as it is allelelic with autosomal dominant Emery-Dreifuss MD, with which it can share a number of features.50 Both X-linked Emery-Dreifuss MD, caused by mutations in the inner nuclear membrane protein emerin, and autosomal Emery-Dreifuss MD characteristically present with a scapuloperoneal distribution of initial weakness and show a characteristic pattern of contractures in the spinal extensors (rigid spine), the Achilles tendons, and the elbow joints. In contrast, the LGMD presentation starts in a more purely proximal distribution of weakness.51
Onset of laminopathy (LGMD form) may be in childhood. The disease is only slowly progressive, and contractures may be limited to just the Achilles tendons. From a management point of view, the most important overlap with Emery-Dreifuss MD concerns the cardiac manifestations that may manifest in the teenage years or later. Initial findings are those of conduction disturbances such as atrioventricular block, but later, dilated cardiomyopathy also may develop.52 Many variations of this phenotypic spectrum can occur, including family members presenting with cardiomyopathy only.
Diagnosis is not possible by immunohistochemistry, as there is no reduction of immunoreactivity even in the presence of mutations, so direct genetic analysis has to be performed to confirm the diagnosis (commercially available).
Anumberof other phenotypes are now known to be associated with laminin A/C mutations, including a form of CharcotMarie-Tooth disease, lipodystrophy type Dunnigan, mandibulo-acral dysplasia, and Hutchinson-Guilford and Werner types of progeria.53 A number of overlap phenotypes are now starting to emerge, complicating the clinical picture.54
OTHER MUSCULAR DYSTROPHIES PRESENTING AS LGMD
Some MDs may present as LGMD and yet are not covered in the current classification of LGMD. That is because their major presentation may fall into a different category, most commonly that of congenital MD. An example is congenital MD with primary deficiency of merosin (laminin ot2 mutations),55 a milder form of which may present later in life and thus more correctly be classified as LGMD.56 Analysis of the muscle biopsy shows an incomplete deficiency of the laminin ot2 chain in muscle.
Mutation analysis currently is not readily available. Abnormalities of the white matter on T2-weighted images on brain MRI that are typical for the CMD presentation may also be seen to a lesser degree in the LGMD presentation.56
Mutations in the three genes coding for the extracellular matrix component collagen type VI cause a disease spectrum ranging from a severe congenital presentation known as type Ullrich to a much milder form known as type Bethlem.57 This group of muscle disorders is characterized by a combination of joint hyperlaxity with concomitant development of contractures in addition to weakness. Onset often is at birth, even in the milder cases; however, if onset is delayed and typical contractures are not present, the disease may be very reminiscent of LGMD.58,59
In the LGMD presentation of Bethlem myopathy, progression is very slow, and ambulation often is preserved until late in life.59 CK levels frequently are normal or only slightly elevated. Clinically, it is important to assess the patients for findings suggestive of connective tissue disease, such as an unusual degree of distal joint laxity, contractures, or both, in particular of the deep finger flexors. Clinical assessment for abnormal skin, such as the presence of excessive keloid formation, can also be helpful.
Collagen VI localization can be studied in the muscle biopsy. However, changes are often subtle and are easily missed unless co-staining with markers of the basement membrane is done. Collagen VI expression can also be studied in skin fibroblast cultures by immunohistochemistry. Mutation analysis is not generally available on a commercial basis.60
XL Emery-Dreifuss MD, similar to AD Emery-Dreifuss MD, is caused by mutations in the inner nuclear membrane protein emerin. It rarely can also present with an early LGMD phenotype.61
DIAGNOSTIC APPROACH TO THE SPORADIC PATIENT
The workup of the sporadic patient who presents with childhood-onset proximal weakness is challenging but easier if a few general guidelines are followed.
Onset and Progression
Taking a careful medical history is of particular importance because it helps to determine the onset of the disease and the speed of progression. It is relevant to determine whether prenatal movements were decreased and whether early motor milestones were delayed, suggestive of congenital onset of the weakness and therefore raising the question of a CMD or congenital myopathy.
As noted earlier, the phenotypic spectrum of a number of the LGMDs extends into the CMD range - in particular FKRP, but typically also collagen Vl-related disorders. Expressive language delay in boys may point towards a diagnosis of Duchenne MD. Recognition of the time course and associated complaints is of utmost importance. Relatively recent onset and rapid progression of the weakness, the presence of muscle aches and pains, or a history of skin rashes (which may be absent) should alert the clinician to the possibility of an inflammatory myopathy such as dermatomyositis. CK levels frequently are quite elevated, further confusing the differentiation from LGMD for which dermatomyositis is often mistaken.
The course in dermatomyositis/polymyositis also can be quite protracted, delaying recognition. Whenever suspected, the diagnosis needs to be confirmed without delay and treatment instituted quickly. Diagnostic confirmation in cases that are not clinically obvious can include magnetic resonance imaging with the administration of contrast media, but ultimately a biopsy will become necessary in the maj ority of cases before treatment is started.
Family history helps determine a likely mode of inheritance. Questioning the parents for the presence of subtle signs and symptoms is important to indicate possible autosomal dominant inheritance. X-linked recessive inheritance can be determined by constructing a maternal pedigree, noting all family members at risk and inquiring about their status.
Affected siblings of both sexes or a history of consanguinity would suggest an autosomal recessive pattern of inheritance. However, it is important that, in the sporadic patient, both dominant and recessive modes of inheritance are possible, as de novo mutations can in occur in virtually all of the dominant and Xlinked disorders under consideration. Of course, autosomal recessive disease also may become apparent for the first time in a given patient.
The examination should be focused on the distribution and degree of weakness, as well as diagnostically important associated clinical features. In the very young child, formal strength examination is not possible, and much has to rely on observation. Proximal weakness is well brought out by Cowers' maneuver, but probably the best way to elicit weakness in the hip is to observe the child climbing stairs, which brings out the weakness pushing up the step but also the inability to stabilize the hip (Trendelenburg sign). The initial (truncal) phase of getting up from the floor also is very instructive, as neck flexor weakness and truncal weakness are brought out efficiently. Observation of the gait can reveal signs of distal weakness such as foot drop or an inability to walk on toes. Examination of facial extraocular muscules also should be conducted.
From about age 4 on, confrontational strength testing becomes much more reliable. Attention should also be paid to muscle atrophy and to hypertrophy of selective muscle groups, including the tongue, and signs of denervation such as fasciculations and areflexia should be noted. The physical examination should always include a careful skin examination, for the rash of dermatomyositis, as well as abnormal skin texture and scar formation typical of the collagen Vl-related disorders. In addition, a skeletal examination should look for the presence of contractures, spinal rigidity, scoliosis, kyphosis, and lordosis, and for the presence of excessive joint hyperlaxity. Where suggested by the history, the examination can then be extended to the parents as well.
The first laboratory investigation in all patients usually is determination of CK levels. Very highly elevated levels (more than 30 to 50 times normal) are seen in Duchenne MD, in the sarcoglycanopathies, and in FKRP mutations; at a later age in dysferlinopathy; sometimes in inflammatory myopathies; and intermittently in metabolic myopathies. In boys with a suggestive phenotype and appropriate elevation of the CK levels, testing for deletions in the dystrophin gene can be done directly at this point.
There is limited value for electromyography testing unless a motor nerve disorder is considered in the differential diagnosis. Modalities of muscle imaging (eg, computed tomography, magnetic resonance imaging, ultrasound) can be helpful to ascertain a specific pattern of muscle involvement or to identify an appropriate muscle to biopsy.
Muscle biopsy is next step in the workup. General examination of the biopsy serves to confirm the presence of degeneration and regeneration (hallmarks of MD) and to exclude other conditions, such as inflammatory myopathies, congenital/structural myopathies including nemaline or multi-minicore myopathy, neurogenic disorders, and metabolic myopathies such as mitochondrial disorders. Immunohistochemical examination of the muscle biopsy is instrumental in narrowing the diagnostic possibilities and should include testing for dystrophin, the four sarcoglycans, a-dystroglycan, and merosin, as well as spectrin as a positive control. Assessement of caveolin 3 and dysferlin and calpain 3 by Western blot can be added in the appropriate clinical context.
Genetic testing for the appropriate genes is then pursued on the basis of the combined clinical and morphological information. In some instances, it may be justified to proceed directly to DNA diagnostics; for example, mutation analysis of dystrophin in the right clinical circumstance in a boy, of calpain 3 in patients with a suggestive phenotype, of FKRP in the right clinical circumstance in a girl or in a boy after negative dystrophin deletion analysis, and of lamín A/C in the appropriate clinical context and family history.
In the latter three conditions, muscle biopsy may not be entirely diagnostic except to rule out other conditions. However, when in doubt, a muscle biopsy is always useful to guide diagnostic workup appropriately. It is important not to simply order all possible gene tests in a patient with features suggestive of LGMD, as that may become prohibitively expensive and may also lead to confusion if the mutation data obtained are not unambiguous.
LGMD refers to a class of muscular dystrophies with onset in the proximal muscles. They are genetically heterogeneous, with both autosomal recessive and dominant forms. The autosomal recessive forms are more common and in general follow a more severe course compared to the dominant forms. It is important to reach a specific genetic diagnosis beyond making a group diagnosis of LGMD to provide adequate genetic counseling, to predict risks for the patient such as the development of cardiomyopathy, and to be able to take advantage of specific treatments when they become available. Establishing a specific diagnosis requires knowledge about the individual clinical features, expert analysis of the muscule biopsy, and the guided initiation of appropriate genetic testing.
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Classification of the Limb-girdle Muscular Dystrophies (LGMD)
Classification of the Limb-girdle Muscular Dystrophies (LGMD)