Limb girdle muscular dystrophy

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Background   Histopathology & Immunohistochemistry    Differential Diagnosis    Reference

BACKGROUND AND CLINICAL INFORMATION: Head  

Summary    Genetics    SCARMD    Sarcoglycanopathy

Summary: Most of the Limb girdle muscular dystrophies (LGMD) are sarcoglycanopathy. LGMD was originally characterized as adult onset progressive muscle weakness affecting the pelvic and shoulder girdles and proximal limbs, with or without calf hypertrophy. The new molecular classification include both adult and childhood type. Many of the childhood onset types have clinical manifestations that overlap with other neuromuscular disorders including SMA type II (Kugelberg-Welander form), various congenital myopathies, and dystrophinopathies (Duchene and Becker muscular dystrophy) and these entities are formerly known as SCARMD (childhood autosomal recessive muscular dystrophies). Genetically, several specific genes have been identified. The pattern of inheritence is autosomal dominant or recessive. The autosomal dominant types are usually less severe than the autosomal recessive types. Some of the autosomal recessive types are linked to abnormal sarcoglycan (sarcoglycanopathy).  In many other cases, the etiology is still unknown. The histopathologic picture is that of a muscular dystrophy that do not allow separations of different types of LGMD.

Diagnosis: Clinical features and the pattern of genetic transmission must be considered. Histologic and immunochemical studies are helpful in formulation of the empirical diagnosis. Molecular studies are needed for the final typing.

Work up: Initial workup for LGMD should include immunostaining for a-sarcoglycogan and dystrophin to rule out sarcoglycanopathy and dystrophinopathy.

SCARMD stands for severe childhood autosomal recessive muscular dystrophies, particularly, it refers to LGMD 2C in many cases.

·        Childhood onset and rapidly progressive. In LGMD 2C, onset is between 3 to 12 yeas of age and lost of ambulatrion occurs usually by 10-15 years. Some less severe forms may be found.

·        Geographic distribution: They are particularly prevalent in North Africa particulary from Sudan and Tunisia but are also seen in other Arab countries, Brazil, Europe, and North America.

·        Resembles Duchenne or Becker muscular dystrophy: LGMD 2C resembles the severe form of Duchenne muscular dystrophy in all aspects including pseudohypertrophy of the calf muscles, cardiomyopathy and markedly elevated CK in the early stage of disease.

Genetics:

·        In about half of the cases of LGMF, no speicific etiology or protein deficiency can be demonstrated.

·        Severity: The autosomal dominant types are usually less severe than the autosomal recessive types.

·        Classification: A new classification by molecular genetics is proposed by the European Neuromuscular Center [Bushby KM and Beckmann JS, 1995]

Genetic causes of muscular dystrophy with limb girdle distribution:

Sarcoglycanopathy:

·        Etiology: This is a family of muscular dystrophies characterized by abnormalities of the sarcoglycan proteins (LGMD 2C, 2D, 2E, and 2F). Sarcoglycan is part of the dystrophin-glycoprotein complex. There are five sacroglycans- a-, b-, g-, d-, and e-sacroglycan. Deficiency of any of them except e is associated with muscle fiber damage and a clinical phenotype of progressive muscular dystrophy.

·        Clinical presentation: They may present as a severe childhood muscular dystrophy clinically similar to Duchenne muscular dystrophy. These cases, however, are autosomal receissive and not associated with subnormal mentality. Some of them present as a usually severe childhood onset limb girdle dystrophy.

·        Diagnosis: While lost of dystrophin lead to reduction of sarcoglycan in dystrophinopathies, the reverse is not true. Lost of one sarcoglycogan, however, will lead to partial reduction of all other sarcoglycogans (secondary reductiona). Diagnosis and subtyping by quantitative immunochemical analysis is not always possible and should be supplemented by mutational analysis.

HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY: Head  

General: There are no specific histologic or histochemical features that can be used to diagnose LGMD. The histopathologic features can be very similar to that of dystrophinopathies at the level of paraffin sections, semi-thin sections, and electron microscopy. No specific fiber type is affected. The overall picture is that of a dystrophic destruction of muscle fibers with fiber loss and some endomysial fibrosis. Features including marked variation of fiber diameter, fiber degeneration and regeneration, split fibers, ring fibers “moth-eaten” fibers and lobulated fibers. Ring fibers may be present.

DIFFERENTIAL DIAGNOSIS: Head  

Dystrophinopathies vs. limb girdle dystrophy: Duchenne and Becker muscular dystrophy also present with limb girdle like weakness. The genetics, clinical symptoms, and molecular diagnosis are different.

Spinal muscular atrophy vs. limb girdle dystrophy.

LGMD 1B (Bethlem myopathy) vs. Emery-Dreifuss muscular dystrophy: In Emery-Dreifuss muscular dystrophy, there is a clinical triad of heart conduction problem, contractures at elbows, ankles and neck and muscle weakness or wasting; skin biopsy and immunohistochemical demonstration of the absence of emerin in smooth muscle.

Mild form of glycogen storage disease type II (Pompe’s disease)

Trabecular myopathy.

Late onset myotubular myopathy (central nuclear myoapthy).

Late onset acid maltase deficiency and other metabolic myopathies.

Inflammatory myopathies.

REFERENCES: Head

Anderson LV, Davison K, Moss JA, Young C, Cullen MJ, Walsh J, Johnson MA, Bashir R, Britton S, Keers S, Argov Z, Mahjneh I, Fougerousse F, Beckmann JS, Bushby KM. Dysferlin is a plasma membrane protein and is expressed early in human development. Hum Mol Genet 1999 May;8(5):855-61

Bushby KM, Beckmann JS. The limb-girdle muscular dystrophies--proposal for a new nomenclature. Neuromuscul Disord 1995 Jul;5(4):337-43

Beckmann JS, Bushby KM. Advances in the molecular genetics of the limb-girdle type of autosomal recessive progressive muscular dystrophy. Curr Opin Neurol 1996 Oct;9(5):389-93

Galbiati F, Razani B, Lisanti MP. Caveolae and caveolin-3 in muscular dystrophy. Trends Mol Med 2001 Oct;7(10):435-41

Illarioshkin SN, Ivanova-Smolenskaya IA, Greenberg CR, Nylen E, Sukhorukov VS, Poleshchuk VV, Markova ED, Wrogemann K. Identical dysferlin mutation in limb-girdle muscular dystrophy type 2B and distal myopathy. Neurology 2000 Dec 26;55(12):1931-3

Ozawa E, Nishino I, Nonaka I. Sarcolemmopathy: muscular dystrophies with cell membrane defects. Brain Pathol 2001 Apr;11(2):218-30