Authors

A.J. van der Kooi, M.D., Ph.D.
M. de Visser, M.D., Ph.D., Professor of Neuromuscular Diseases

Clinical features

Autosomal recessive LGMD
The clinical picture of autosomal recessive LGMD closely resembles that of Duchenne/Becker type of muscular dystrophy (DMD/BMD). There is a variable age of onset although in most families the first symptoms occur in the first or second decade. Weakness of the limb-girdle muscles is first manifesting in the pelvic girdle, and is progressive. Involvement of the shoulder girdle muscles occurs about 2-10 years later. Some forms have a course similar to DMD, in which the ability to walk is lost around the age of 10 years. Other forms have a less rapid course, sometimes even without losing ambulance. Calf enlargement is frequently seen, especially in sarcoglycanopathies. Facial involvement is unusual, although it may occur in late stages of the disease. Distal muscle involvement usually occurs in late stages, and is less prominent than proximal weakness, however in LGMD2G footdrop is a rather early observation, and in 2J wasting of the anterior tibial muscle. The knee and biceps jerks often disappear first, whereas the ankle jerks are relatively spared. Achilles-tendon contractures are frequently observed but more extensive contractures are only encountered in severely disabled patients. Intellectual functions are usually preserved. Pulmonary function decreases with deterioration of muscle strength, sometimes leading to premature death. Cardiac involvement occurs in about 20% in any type of sarcoglycanopathy (LGMD2C-F). LGMD2I due to mutations in the FKRP gene appears to have a frequent assocition with cardiomyopathy . There is no clear evidence for cardiac involvement in calpainopathy (LGMD2A) or dysferlinopathy (LGMD2B). LGMD2H (TRIM 32), LGMD2G (telethinopathy) and LGMD2J (titin) have only rarely been described, and have as yet not been associated with cardiac abnormalities.

Autosomal dominant limb girdle muscular dystrophy
There are several reports of families with evidence of autosomal dominant limb girdle dystrophy. Onset may range from childhood to the fourth decade. The course is usually relatively mild. Calf enlargement is sometimes seen. In an occasional family dysarthria and facial weakness were distinctive features of the disease, this family has been linked to chromosome 5, and mutations in the myotilin gene have been found. Distal involvement has been described in late stages of the disease, always less pronounced than proximal weakness. In a small proportion of the autosomal dominant families contractures of elbows, and plantar flexion of the ankles are conspicuous features early in the course of the disease. Pulmonary involvement seems to be related to the severity of the skeletal muscle weakness, and is therefore uncommon. AV conduction disturbances necessitating pacemaker implantation are a key feature in LGMD1B. Because of the risk of sudden cardiac death despite pacemaker implantation, the necessity of intracardiac defibrillator implantation is now in analysis.  LGMD1A (myotilin) and LGMD1C (caveolin) have not been associated with cardiac problems. 

Epidemiology

In 1991, a world survey of population frequencies of inherited neuromuscular diseases was undertaken by Emery. The prevalence and incidence rates for mainly adult onset cases of limb girdle muscular dystrophy lie between 20-40 x 10^-6. Autosomal recessive (Duchenne-like) muscular dystrophy of childhood appeared to be a rare disorder with a prevalence of less than 5 x 10^-6. It is, however, commoner in certain Arabic communities in North Africa, in Switzerland, in certain inbred communities in North America originating from Switzerland, and in Brazil. It has been estimated that around 3-12% of isolated males diagnosed as having X-linked Duchenne muscular dystrophy may in fact have this clinically similar autosomal recessive disorder.

There were always some reservations in accepting these figures because until recently diagnostic criteria were too imprecise for a reliable epidemiological survey. As shown above, LGMD can be mimicked by a number of clinically similar neurogenic and myogenic conditions and therefore it has become clear that these data were artificially inflated. In the Netherlands, using strict diagnostic criteria, a prevalence of 8.1 x 10^-6 for all cases, and 5.7 x 10^-6 for autosomal recessive and sporadic cases was calculated.

The frequency of sarcoglycanopathies among cases of autosomal recessive LGMD varies in the literature from 0-35%. The overall prevalence of primary sarcoglycanopathies in North east Italy, was estimated to be 5.6 x 10^-6. Investigations in Brazilian families suggest that 33% of the LGMD families are caused by mutations in the 15q gene, 33% in the 2p gene, 17% by mutations in the adhalin gene, and less than 10% can be ascribed to mutations at the 13q locus. LGMD2I seems to account for a large proportion of patients who have previously been excluded from other LGMD disease loci .

Differential diagnosis

It remains very important to exclude all other possible causes of a limb girdle syndrome. In a detailed survey it became evident that 25% percent of patients had been misdiagnosed.

Duchenne and Becker dystrophy and manifesting carriers of these X-linked dystrophies usually present with a limb girdle syndrome. These disorders are identified by dystrophin analysis in the skeletal muscle and DNA-Xp21 screening, which gives an accurate diagnosis in 90% of the cases. The karyogram should always be checked in female persons in order to rule out Turner syndrome, structurally abnormal X-chromosomes or X-autosome translocations. In some families restricted fragment length polymorphism analysis with probes within the dystrophin gene may be useful.

Facioscapulohumeral (FSH) dystrophy is inherited as an autosomal dominant trait. Facial muscles, although characteristically involved early in the disease, can be normal. This observation, and the fact that some cases may show limb girdle weakness at onset rather than a FSH distribution of weakness, may give rise to diagnostic confusion. Most families are linked to chromosome 4q, in 95% of patients deletions can be found . As yet no gene has been identified.

Some of the congenital myopathies may seemingly become manifest only in childhood or adult life and therefore confusion with LGMD may arise. The distinction is made by a meticulous history (early onset and floppiness) and muscle biopsy, showing characteristic structural changes of the muscle fibers.

Congenital muscular dystrophies often show hypotonia or generalized muscle weakness with multiple joint contractures at birth or in the first year of life, and a non-progressive or slowly progressive course ^{. In merosin negative congenital muscular dystrophy linked to chromosome 6, the children are never able to walk and MRI of the brain shows prominent white matter changes, whereas intelligence is normal. Merosin deficient muscular dystrophy rarely also presents as a late-onset limb girdle syndrome} . Equally rare are limb girdle muscular dystrophy and Duchenne muscular dystrophy presenting at birth . Another form of congenital muscular dystrophy is caused by mutations in the fukutin-related protein gene (FKRP), whereas mutations in the same gene cause the more benign LGMD2I.

In Bethlem myopathy molecular genetics disclosed mutations in two genes encoding for collagen type VI on chromosomes 21q22.3 and linkage to chromosome 2q3715;16. It is a slowly progressive autosomal dominantly inherited myopathy manifesting with skeletal muscle weakness and contractures. The clinical onset is variable: prenatal with decreased foetal movements, neonatal with hypotonia and/or contractures, more frequently in early childhood with proximal weakness of the legs, but also in adulthood and as late as the 6th decade with predominant limb girdle weakness.

Miyoshi type muscular dystrophy characteristically presents with calf muscle weakness and highly elevated (>10x) serum CK activities. In the course of the disease weakness spreads to the thigh, pelvic girdle, biceps brachii, and deltoid muscles, respectively. In later stages distinction with LGMD might therefore be difficult. The disease has been linked to the LGMD2B locus on chromosome 2p, mutations have been found in the dysferlin gene. Now it is evident that both LGMD2B and Miyoshi myopathy are different phenotypes of the same genotype .

Scapuloperoneal syndromes may be either neurogenic or myogenic by nature and present with the distinctive clinical picture of proximal upper extremity weakness accompanied by involvement of the peroneal muscles. One family has been linked to chromosome 12.

Emery-Dreifuss muscular dystrophy (EDMD) can present as an X-linked, autosomal dominant, or autosomal recessive disorder. The disorder is characterized by early onset of elbow, Achilles tendons, and spine contractures, and presents with humero-peroneal weakness. Cardiac conduction abnormalities with dilated cardiomyopathy are characteristic features of this disease. LGMD1B is characterized by identical cardiac involvement in combination with limb girdle weakness, without early contractures. The diagnosis of X-linked EDMD can be confirmed immunocytochemically, or more reliably by identifying mutations in the emerin gene. Both autosomal dominant and recessive EDMD and LGMD1B are caused by mutations in the lamin A/C gene.

Metabolic myopathies, including glycogen storage diseases, disorders of lipid metabolism, and mitochondrial myopathies, often manifest with a limb girdle syndrome. These disorders should be differentiated readily from LGMD by assessment of enzyme activities in the appropriate tissue, McArdle ischaemic forearm test, and histological, enzyme-histochemical and biochemical investigation of a muscle biopsy specimen, and ultimately by mutation analysis.

Chronic autosomal recessive spinal muscular atrophy (types III and IV) is more difficult to distinguish from LGMD. The diagnosis is usually established by the histopathological examination of biopsied muscle and electromyography. The discovery of the SMN gene on chromosome 5 allows DNA analysis in 95% of the patients.

Proximal myotonic myopathy (PROMM), caused by an enlarged CCTG expansion in intron 1 of the zinc finger protein gene on chromsome 3, also presents with slowly progressive weakness in a limb girdle distribution, with onset in the third or fourth decade. A detailed family history might reveal autosomal dominant inheritance, with cataract, cardiac death, and pacemaker implantation. Myotonia is clinically present in 55 % of patients, during electromyographic examination it can be demonstrated in an additional 25% of patients.

Therapeutically very important disorders to differentiate are polymyositis and dermatomyositis. The more rapid evolution of weakness, often reported myalgias and common involvement of pharyngeal muscles in both polymyositis and dermatomyositis and the characteristic rash in the latter are discriminating features. Excellent response to treatment with corticosteroids favours a diagnosis of poly- and dermatomyositis. Diagnostic confusion sometimes arises since LGMD may show extensive mononuclear cell infiltrates in muscle, and half of the polymyositis patients does not respond to therapy.

Other differential diagnostic possibilities include vitamin deficiency, carcinoma, sarcoidosis, weakness following rhabdomyolysis, neuromuscular transmission disorders, non idiopathic inflammatory myopathies, toxic and endocrine myopathies.

Ancillary investigations

Serum CK activity can be markedly elevated (up to 188 times the normal value), especially in the severe Duchenne-like forms. CK can be markedly raised in preclinical stages and it shows a tendency to decrease with the duration of the disease. In the dominant forms serum CK activity is usually only mildly elevated.

Electromyography demonstrates a myopathic pattern in most cases of LGMD, consisting of small amplitude, short duration motor unit action potentials (MUAPs) and an increased percentage of polyphasic potentials. Sometimes an excessive recruitment pattern can be seen because of recruitment of a disproportional large number of MUAPs recruited for the relatively small amount of muscle power generated. Late in the disease the severe loss of muscle fibers produces an apparent decrease in the number of MUAPs recruited and thus a decreased interference pattern. In addition muscle fibrosis may result in increased mechanical resistance to insertion of the needle electrode and decreased insertional activity. Fibrillation potentials and positive sharp waves may occur and are ascribed to functional denervation due to segmental necrosis of muscle fibers.

Muscle imaging shows a decrease in muscle density due to replacement of muscle by connective tissue and fat . Extensive decrease in muscle density can be seen without apparent atrophy. In LGMD symmetrically distributed areas of lower attenuation were seen in quadriceps, semimembranosus and semitendinosus muscles. Paravertebral and gluteal muscles, the soleus muscle and the caput mediale of the gastrocnemius muscles were also often affected. Psoas and ventral lower leg muscles are usually spared. Hypertrophy of the gracilis, sartorius and semitendinosus muscles was frequently seen .CT- or MRI scanning often reveals unexpected abnormalities in clinically not affected muscles.

Muscle biopsy in LGMD shows myopathic changes, including variation in muscle fiber diameter with an increase in internal nuclei, and an increase in adipose and connective tissue. Degenerating fibers and also isolated or clustered basophilic fibers with vesicular nuclei and prominent nucleoli were frequently seen. Other reported features were hypertrophic fibers, predominance of type I fibers, moth eaten fibers, and (rimmed) vacuoles. Cellular infiltrates were described in 10% of autosomal dominant and 25% of autosomal recessive and sporadic patients.

Genetics

Genes involved in limb girdle muscular dystrophy:
DYSF - Dysferlin
SGCA - Sarcoglycan-alpha
SGCB - Sarcoglycan-beta
SGCG - Sarcoglycan-gamma
SGCD - Sarcoglycan-delta
CAV3 - Caveolin
CAPN3 - Calpain 3
FKRP - Fukutin-Related protein
LMNA - Laminin A/C
TTID - Titin immunoglobulin domain protein
TCAP - Telethonin
TRIM32 - Tripartite motif-containing protein 32

Therapy

No specific therapy is known. Patients should be counseled about the inheritance pattern and the course of this disorder. Many patients receive physical therapy to prevent worsening of contractures although its efficacy has not been evaluated. In the majority of patients, progressive weakness leads to disability necessitating additional aids and adjustments, like a cane, home alterations, and wheelchair. In this stage of the disease referral to a rehabilitation physician should be considered. If patients become wheelchair-bound, involvement of the respiratory muscles must be monitored. The recommendations for cardiac surveillance in this group depend very much on the type of LGMD.

Genetic counselling is useful. Limb girdle muscular dystrophy is inherited in either an autosomal recessive or dominant manner. In case of autosomal dominant inheritance each affected individual is at 50% risk of transmitting the disorder to each of his children, whatever gender. In autosomal recessive forms each sib of an affected individual is at 25% risk of getting the disorder. Prenatal diagnosis might be possible in cases/families with a known genetic defect. Whether the severity of the disorder warrants an abortion is an individual decision.

Contact with patient support groups is useful for individual patients.

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