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Case Reports

Indian Pediatrics 2003; 40:1077-1081 

Gamma-Sarcoglycanopathy


Sheffali Gulati
Surbhi Leekha
M.C. Sharma*
Veena Kalra

From the Departments of Pediatrics and *Pathology, All India Institute of Medical Sciences, New Delhi 110 029, India.

Correspondence to: Professor Veena Kalra, Head, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi 110 029, India.
E-mail: [email protected]

Manuscript received: May 28, 2002;Initial review completed: June 26, 2002;Revision accepted: March 31, 2003.

Abstract:

The best known muscular dystrophies are "X-linked dystrophinopathies". A clinically and genetically heterogeneous group presenting with weakness of the pelvic and shoulder girdles is that of the limb-girdle muscular dystrophies (LGMDs). Sarcoglycanopathies (SGPs) are autosomal recessive LGMDs. We report a rare case of primary gamma-sarcoglycanopathy (SGP) which emphasizes the evolving concept of "dystrophinopathy to sarco-glycanopathy".

Key words: Sarcoglycanopathy, Muscular dystrophies

 

The term muscular dystrophy encompasses a group of inherited disorders characterized by progressive muscle weakness. The best known are "X-linked dystrophinopathies", Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD)–a milder form which together account for more than two-thirds of muscular dystrophy patients. A clinically and genetically heterogeneous group presenting with weakness of the pelvic and shoulder girdles is that of the limb-girdle muscular dystrophies (LGMDs). Their mode of inheritance can be autosomal dominant (LGMD 1A, 1B, 1C) or autosomal recessive (LGMD 2A-H)(1).

Advances in immunohistochemistry and genetics have allowed a better understanding and precise molecular classification of these disorders. Sarcoglycanopathies (SGPs) are autosomal recessive LGMDs and are caused by mutations in any of the four sarcoglycan genes: alpha (LGMD 2D), beta (LGMD 2E), gamma (LGMD 2C) and delta (LGMD 2F)(1). We report a rare case of primary gamma-sarcoglycanopathy (SGP) which has not been reported from India. This emphasizes the evolving new concept in the field of muscular dystrophies" from dystrophinopathy to sarcoglycanopathy".

Case Report

A nine-year-old boy born out of a non-consanguineous marriage presented with history of walking on toes and broad based gait noticed for the last two years. He belongs to Khatri community and is from Budayun in Uttar Pradesh. There was associated difficulty in running, climbing stairs, and getting up from the floor for the past 18 months. Over the last six months he started having frequent falls and the parents noticed enlargement of muscles of the calf. All these symptoms were progressively increasing. There was no associated muscle pain, weakness of muscles of the arms, neck, back or face or difficulty in chewing or swallowing. Birth history was non-contributory and developmental miles-tones were normal. There was no family history of a similar disease. He has a twin sister who is normal clinically and has normal creatine phosphokinase levels.

On examination, the child had slightly elongated facies. There was pseudohyper-trophy of both the calves, no contractures and the child was able to walk unassisted but the gait was waddling and toe based. Gower’s sign was positive. Muscle power was graded 3-4 for the shoulder girdle and 2-3 for the hip girdle. Chest X-ray and electrocardiogram were normal. The serum creatine phospho-kinase was 7330 IU/L (normal range: 15-195). Electromyography was consistent with a myopathic pattern.

A biopsy of the left deltoid muscle was done. The tissue was immediately transported and frozen in liquid nitrogen at –160º C. 5 mm cryostat sections were prepared and stained for histological examination. Hematoxylin and eosin (H&E) stained sections showed variation in fiber size with central migration of nuclei. Myophagocytosis was seen, with mild endomysial and perimysial fibrosis and occasional regenerating fibers.

Some fibers were hypertrophied. Immunohistochemistry (Fig. 1) for dystrophin I, II and III, alpha-sarcoglycan and beta-sarcoglycan showed normal staining patterns but staining was completely absent with antibodies to gamma-sarcoglycan.

Fig. 1. Photograph showing positivity for dystrophin (A, × 100), alpha-sarcoglycan (B, × 100), beta-sarcoglycan (C, × 100) and negative staining for gamma-sarcoglycan (D, × 100).

Gene deletion screening for 25 exons of the DMD gene using multiplex PCR method identified no deletion. Thus a diagnosis of primary gamma-sarcoglycanopathy was made. Mutations of sarcoglycan genes could not be studied due to non availability.

Discussion

Soon after the discovery of dystrophin, the dystrophin-associated proteins (DAPs), expressed on the sarcolemma, were described (Fig. 2). Among them was the sarcoglycan (SG) complex, a distinct group of five transmembrane proteins (alpha, beta, gamma, delta and epsilon-sarcoglycans). This trans-membrane complex links the cytoskeleton to the extracellular matrix and is essential for the preservation of the integrity of the muscle cell membrane. Pathogenic mutations in any of the SG genes (except epsilon-SG) disrupt the entire SG complex and leads to secondary deficiency of the other SG proteins(2).

Fig. 2. Molecular architecture of dystrophin and dystrophin associated proteins on the cell membrane.

Mutations in the gamma-SG gene were first described from North Africa. Tunisian patients with muscular dystrophy were thought to have a defect in alpha-SG based on decreased immunostaining with alpha-SG. However mapping to chromosome 13 ruled out a defect in that gene and pointed to the gamma-SG gene at 13q12.

Primary SGP (including gamma-SGP) have been described with a broad range of clinical presentations. Many cases have been previously described under the name "SCARMD" (severe childhood autosomal recessive muscular dystrophy) or DMD-like muscular dystrophy. However, the term SCARMD used to describe the severity of the disease is not always accurate as a description of the myopathy associated with primary SGP because the phenotype may be milder, with juvenile or adult onset(3). In fact, it has been reported that SGP caused by an identical mutation in the gamma SG gene was characterized by either severe or mild symptoms(4).

The diagnosis of SGP begins with documentation of symptoms and signs, and elicitation of an accurate family history. They have autosomal recessive inheritance, preferential and early involvement of pelvic girdle muscles and subsequent involvement of shoulder girdle muscles(5). Establishing autosomal recessive mode of inheritance may not be easy but may be the only way of clinically distinguishing SGP from dystro-phinopathy especially BMD(6). In SGP, there is absence of mental retardation, facial and ocular muscles involvement and cardiac involvement(5). Calvo, et al.(7) have however, reported right ventricular hypertrophy and diastolic dysfunction among gamma SGP, particularly in advanced stages of the disease. The clinical course of gamma SGP is intermediate between DMD and BMD. They have onset of weakness in childhood and become wheel chair bound by 25 years(5).

Immunohistochemical analysis is the most reliable method of diagnosis. A mutation in anyone of the SG genes may lead to secondary deficiency of other SG proteins, presumably due to destabilization of the SG complex(10). The most frequently reported pattern is that of multiple SG deficiencies in various combinations. In a study on 25 patients, with SGP, Khadilkar, et al.(8) reported 84% with multiple SG deficiencies. Sarcoglycan gene mutation analysis is essential to know the specific diagnosis in such cases with multiple deficiencies. Though there may be equal loss of all the SG, generally the one that stains most weakly is the one whose gene is mutated(2,9). Gamma SGP patients may have normal or near normal alpha SG levels, hence the screening with alpha SG can lead to underestimation of gamma SGP cases.

Secondary dystrophin deficiency is well known in patients with SG deficiency and is seen more often with gamma SGP(3). It should also be remembered that the SG complex is remarkably reduced in amount or even absent in DMD patients in addition to the absence of dystrophin and gene defects are not detected in 30 percent of DMD cases(10). When dystrophin appears at normal levels or is only slightly decreased in amount, and no defect in the dystrophin gene is found, a diagnosis of SGP is likely(6).

In conclusion, SGP is an example of muscular dystrophy in which the same phenotype results from mutations in different genes. The four muscular dystrophies belonging to this group are indistinguishable not only clinically but also by immuno-histochemistry (in case of multiple deficiencies), and molecular studies are required to characterize the mutated gene. Accurate diagnosis is important for prognosis, genetic counseling and possible implications for gene therapy.

Contributors: VK and SG were incharge of the case, SG and SL drafted the manuscript, VK critically reviewed the manuscript and will act as guarantor for the paper, MCS reported the muscle biopsy. All the authors were involved in finalization and approval.

Funding: None.

Competing interests: None stated.

 

 References


 

1. Duggan DJ, Gorospe JR, Fanin M, Hoffman EP, Angelini C. Mutations in the sarcoglycan genes in patients with myopathy. N Engl J Med 1997; 336: 618-624.

2. Vainzof M, Passos-Bueno MR, Canovas M, Moreira ES, Pavanello RCM, Marie SK, et al. The sarcoglycan complex in the six autosomal recessive limb-girdle muscular dystrophies. Hum Mol Genet 1996; 5: 1963-1969.

3. Fanin M, Duggan DJ, Mostacciuolo ML, Martinello F, Freda MP, Soraru, et al. Genetic epidemiology of muscular dystrophies resulting from sarcoglycan gene mutations. J Med Genet 1997; 34: 973-977.

4. McNally EM, Passos-Bueno MR, Bonnemann CG, Vainzof M, de Sa Moreira E, Lidov HGW, et al. Mild and severe muscular dystrophy caused by a single sarcoglycan gene mutation. Am J Hum Genet 1996; 59: 1040-1047.

5. Angelini C, Fanin M, Freda MP, Duggan DJ, Siciliano G, Hoffman EP. The clinical spectrum of sarcoglycanopathies. Neurology 1999; 52: 176-179.

6. Ozawa E, Noguchi S, Mizuno Y, Hagiwara Y, Yoshida M. From dystrophinopathy to sarcoglycanopathy: Evolution of a concept of muscular dystrophy. Muscle Nerve 1998; 21: 421-438.

7. Calvo F, Teijeira S, Fernandez JM, Teijeiro A, Fernandez-Hojas R, Fernandez-Lopez XA, et al. Evaluation of heart involvement in gamma sarcoglycanopathy (LGMD2C): A study of ten patients. Neuromusc disord 2000; 10: 560-566.

8. Khadilkar SV, Singh RK, Katrak SM. Sarcoglycanopathies: A Report of 25 cases. Neurol India 2002; 50: 27-32.

9. Jones KJ, Kim SS, North KN. Abnormalities of dystrophin, the sarcoglycans, and laminin alpha-2 in the muscular dystrophies. J Med Genet 1999; 35: 379-386.

10. Mizuno Y, Yoshida M, Nonaka I, Hirari S, Ozawa E. Statement of utrophin (dystrophin-related protein) and dystrophin-associated glycoproteins in muscle from patients with Duchenne muscular dystrophy. Muscle Nerve 1994; 17: 206-216.

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