SciELO - Scientific Electronic Library Online

 
vol.72 issue10Cardiovascular variability in Mexican patients with Parkinson's diseaseCognition in a multiple system atrophy series of cases from Argentina author indexsubject indexarticles search
Home Pagealphabetic serial listing  

Services on Demand

Journal

Article

Indicators

Related links

Share


Arquivos de Neuro-Psiquiatria

Print version ISSN 0004-282X

Arq. Neuro-Psiquiatr. vol.72 no.10 São Paulo Oct. 2014

http://dx.doi.org/10.1590/0004-282X20140126 

Articles

Clinical aspects of patients with sarcoglycanopathies under steroids therapy

Aspectos clínicos de pacientes com sarcoglicanopatias sob efeito de corticoterapia

Marco A. V. Albuquerque

Osório Abath-Neto

Jéssica R. Maximino

Gerson Chadi

Edmar Zanoteli

Umbertina C. Reed

1Departamento de Neurologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo SP, Brazil

ABSTRACT

Patients with sarcoglycanopathies, which comprise four subtypes of autosomal recessive limb-girdle muscular dystrophies, usually present with progressive weakness leading to early loss of ambulation and premature death, and no effective treatment is currently available.

Objective

To present clinical aspects and outcomes of six children with sarcoglycanopathies treated with steroids for at least one year.

Method

Patient files were retrospectively analyzed for steroid use.

Results

Stabilization of muscle strength was noted in one patient, a slight improvement in two, and a slight worsening in three. In addition, variable responses of forced vital capacity and cardiac function were observed.

Conclusions

No overt clinical improvement was observed in patients with sarcoglycanopathies under steroid therapy. Prospective controlled studies including a larger number of patients are necessary to determine the effects of steroids for sarcoglycanopathies.

Key words: steroids; limb-girdle muscular dystrophy; sarcoglycan proteins; myopathy

RESUMO

Pacientes com sarcoglicanopatias, que compreendem quatro subtipos de distrofias musculares de cinturas autossômicas recessivas, geralmente apresentam fraqueza progressiva, levando à perda precoce da deambulação e morte prematura, e não há tratamento eficaz disponível até o momento.

Objetivo

Descrever os aspectos clínicos e a evolução de seis crianças com sarcoglicanopatias tratados com corticosteróides por pelo menos um ano.

Método

Prontuários dos pacientes foram analisados retrospectivamente.

Resultados

Estabilização da força muscular foi observada em um paciente, uma ligeira melhora em dois, e um ligeiro agravamento em três. Além disso, foram observadas respostas variáveis de capacidade vital forçada e da função cardíaca.

Conclusões

Não houve melhora clínica evidente em pacientes com sarcoglicanopatias sob terapia com corticosteróides. Estudos prospectivos controlados incluindo maior número de pacientes são necessários para determinar os efeitos dos corticosteróides para sarcoglicanopatias.

Palavras-Chave: corticosteróides; distrofia muscular de cinturas; proteínas sarcoglicanas; miopatia

Sarcoglycanopathies (SG) comprise four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMD), which are caused by mutations in sarcoglycan protein complex, and involve four distinct trans membrane proteins: α-sarcoglycan (LGMD2D), ß-sarcoglycan (LGMD2E), γ-sarcoglycan (LGMD2C) and δ-sarcoglycan (LGMD2F)1. The sarcoglycan complex is integrated in the muscle membrane as a part of the dystrophin-glycoprotein associated complex2. A wide range of mutations in any of these proteins destabilize the whole sarcoglycan complex, resulting in the different types of LGMDs1. In the Brazilian population, sarcoglycanopathies account for about one third of the classified forms of AR-LGMD3. LGMD2D is the most frequent sarcoglycanopathy, followed by LGMD2E and LGMD2C, while LGMD2F is the most rare4. The clinical phenotype of sarcoglycanopathies is very heterogeneous regarding age of onset and rate of progression, and severity can vary even among members of the same family4. In general, the different forms of the disease are characterized by progressive weakness and degeneration of skeletal muscle, leading to loss of ambulation, difficulties in breathing and often premature death, associated to an elevated serum creatine kinase (CK) level4. Cardiac involvement is frequently reported5,6. Besides a rehabilitation program, there is currently no effective treatment for these patients6,7.

Steroid treatment with prednisone or deflazacort has been shown to slow disease progression in Duchenne muscular dystrophy (DMD)8-11. The treatment is also potentially effective to delay restrictive respiratory insufficiency, scoliosis and in a lesser extent cardiac involvement in patients with this disease8,12-14. The mechanisms of this improvement are not completely clear but steroids may have the potential benefits of inhibiting muscle proteolysis, stabilizing fiber membrane, reducing intracellular calcium concentration, and stimulating myoblast proliferation15-17.

Albeit controversial, steroid therapy has also been sporadically used to treat other forms of muscular dystrophy. There have been reports of positive results in isolated cases of sarcoglycanopathy treated with steroids, especially in those with a rapid progression18-20. Mainly due to these reports, steroid therapy is often empirically tried in sarcoglycanopathy patients in an individual basis. In this work, we retrospectively analyze clinical aspects and outcomes of six such patients, which have been submitted to steroid therapy for at least one year.

METHOD

We retrospectively analyzed medical records of patients of the Neuromuscular Disorders Section of the Hospital das Clínicas of FMUSP with a clinical and histological diagnosis of SG, and selected those that received steroid therapy for at least one year (Table 1).

Table 1 Clinical features of 6 unrelated patients with sarcoglycanopathy. 

Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6
Sex F F F F F F
Consanguinity No No No No No No
Family history No No Yes No No Yes
Age at onset 5y 6y 9y 4y 10y 5y
First symptoms Frequent falls Frequent falls Difficulty climbing stairs Frequent falls Difficulty climbing stairs Difficulty rising from the floor
Calf hypertrophy Yes No Yes No No No
Scoliosis Yes Yes No No No No
Joint contractures + - + + - +
Scapula winging + + + + + +
Molecular study - - c.657delC SGCD c.299T>A SGCB - -

Y: years; mo: months.

RESULTS

In our records we found six children with SG, all female, that had been treated with steroids for at least one year. The age at onset of the disease ranged from 4 to 10 years. Chief complaints in the first clinical consultation were frequent falls (3 patients), difficulty in climbing stairs (2 patients) and inability to rise from the floor (1 patient). All patients had normal cognitive function. The main clinical signs on physical examination were winging of the scapula, scoliosis and calf hypertrophy (Table 1). In all patients the CK level was increased. In three patients (cases 2, 3 and 4) the CK level was markedly increased (40X normal value), and in others (cases 1, 5 e 6) the value ranged from 10 to 20X the normal value.

Muscle biopsies (performed in the biceps brachialis muscle) of four patients showed a dystrophic pattern, classified as severe (cases 2 e 4) or moderate (cases 1 and 5). No inflammatory changes were found. No muscle biopsy was done for cases 3 and 6 because their siblings (patients not included in this report) already had a histological diagnosis of SG, confirmed by the absence of at least one SG protein expression. According to the immunohistochemical staining pattern, the patients were classified as having either a deficiency of α-SG (cases 2, 5 and 6), or a deficiency of γ-SG (case 1).

Analyses of the genes responsible for production of α-, β-, γ- and δ-SG (SGCA, SGCB, SGCG and SGCD, respectively) were done using exon-specific PCR amplification and sequencing for the most frequently mutated exons in our population3. A heterozygous frameshift mutation in exon 8 of the SGCG gene (c.657delC) was detected in case 3, and case 4 harbored a mutation in exon 3 of the SGCB gene, which leads to an exchange of methionine to lysine at position 100 (c.299T>A, p.M100K).

In all cases, treatment with steroids, either prednisolone (case 3) or deflazacort (cases 1, 2, 4, 5 and 6), was initiated when the clinician first noticed a rapid and marked decrease of muscle strength. This was characterized by either an increase in the frequency of falls, greater inability to rise from the floor or worsening of walking capacity. The decision of introducing steroid therapy for patients with SG was made based in an attempt to obtain similar results to those obtained for patients with DMD and other forms of muscular dystrophies, the latter based on a few reports in the literature describing positive effects of this therapy18-20. Prednisolone was used on an intermittent regimen (10 days on and 10 days off) at a dose of 1 mg/kg/day, whereas deflazacort was used daily at a dose of 0.9 mg/kg/day.

Patients received steroids for one year (cases 3, 4 and 5), two years (cases 2 and 6) or four years (case 1). There was stabilization of muscle strength in case 6, a slight improvement in cases 1 and 2, and a slight worsening in cases 3, 4 and 5. No patient lost ambulation during the treatment period (Table 2). In addition, forced vital capacity (FVC) was rendered stable in three children (cases 2, 3 and 6), as shown in repeated pulmonary function tests, had a mild improvement in two (cases 1 and 4), and in only one child there was a mild reduction of FVC from 58% to 52% (case 5). On cardiac tests, two children had a mild improvement of the ventricular ejection fraction (cases 1 and 5) and one child (case 3) had a mild deterioration. In the other patients, the cardiac function remained stable during follow-up (Table 2). No adverse effects were observed in these cases, except a mild increase in body weight in two patients (cases 5 and 6).

Table 2 Treatment response to steroid in 6 unrelated patients with sarcoglycanopathy. 

Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6
Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post
Proximal upper extremity strength 2 3 2 3 4 3 4 4 3 3 4 4
Distal upper extremity strength 4 4 3 4 5 3 4 4 4 4 4 4
Proximal lower extremity strength 2 3 2 2 4 3 4 3 2 2 3 3
Distal lower extremity strength 3 3 3 3 5 3 4 4 4 3 4 4
FVC (% predicted) 68% 97% 73% 68% 70% 77% 40% 67,7% 57% 52% 77% 80%
Echo (FE) 69% 71% 44% 57% 69% 61% 65% 65% 55% 61% 65% 67%
Treatment onset (y) 13 13 14 10 11 11
Treatment duration (mo) 48 24 12 12 12 24
Loss of ambulation No No No No No No

Y: Years; mo: Months; pre: Pretreatment; post: Post treatment; FVC: Forced vital capacity; Extremity strength graded on Medical Research Council (MRC) scale.

DISCUSSION

Patients with SG typically present the first symptoms in the first decade of life with progressive weakness leading to early loss of ambulation and premature death due to cardiomyopathy or respiratory insufficiency. For this reason, as for DMD, the identification of therapies capable of alleviating the progression of the disease is imperative.

In this retrospective study we have analyzed the clinical aspects and outcomes of ambulant children with SG that have been treated with steroids. Despite an absence of inflammatory changes in muscle biopsies in all of them, the indication of steroids for these patients was based in: 1) rapid progression of the disease, especially for walking function; 2) a few reports from the literature describing positive response of SG patients to steroid therapy18-20; and 3) the demonstrated beneficial effects of steroids for DMD, considering that the clinical progression and histopathology of SG are quite similar to those observed in DMD, and in both situations the basic mechanism of the disease is related to the disintegration of a complex of proteins located to the sarcolemma of the muscle fibers1-2. However, we did not observe overt clinical improvement in this group of SG patients treated for different periods of time (one to 4 years); indeed, three patients worsened and three showed a more stable course. This might indicate that the response to steroid therapy can vary individually, e.g., according to the specific mutation. A variable response was also observed for pulmonary and cardiac functions.

In the literature, an effective positive action of steroids in patients with SG has been rarely reported18-20. Angelini et al. described improvement in both muscle strength and functional performance after five months of therapy with deflazacort in a 39 years-old patient with mild muscular dystrophy caused by α-SG deficiency18. Connoly et al. reported maintenance of the proximal muscle strength on quantitative testing after two years of treatment with prednisone and azathioprine in an 8 year-old girl with α-SG deficiency19. Wong-Kisielet et al. described stabilization and improvement of muscle strength in two siblings with β-SG after 30 months of deflazacort therapy20.

In other forms of muscular dystrophies there have also been reports of a positive response to corticosteroids21-22. Godfrey et al. described three children with an LGMD phenotype and pathogenic fukutin mutation that had a remarkable steroid responsiveness21. These patients were ambulant and had marked elevation of serum CK and muscle biopsy with inflammatory changes. Darin et al. described two patients with FKRP deficiency (LGMD2I) and a Duchenne-like phenotype that showed a good clinical response to treatment with prednisolone22. Similarly, both patients had muscle biopsies with dystrophic patterns in association with inflammatory changes, suggesting that patients with inflammatory reaction in the muscle biopsy might present a better response to corticosteroids. In contrast, Walter et al. randomized 25 patients with genetically defined dysferlinopathy (LGMD2B) to receive deflazacort or placebo for six months and demonstrated that deflazacort did not improve muscle strength23. Furthermore, there was a trend of worsening muscle strength in the group under deflazacort treatment, which recovered after discontinuation of the study drug. In addition, patients showed a broad spectrum of steroid side effects23.

Regarding the response to corticosteroids of the cardiac function, our study showed a mild improvement of the ventricular ejection fraction in two patients and in three patients the cardiac function remained stable. In another way, Bauer et al. demonstrated that prednisolone led to a decompensation of cardiac hemodynamics and induced additional cardiac damage in the delta-sarcoglycan-deficient mouse24.

Despite the fact that our study has shown an apparent benefit of the medication to some of our cases, the evaluation period of the effects of steroids was still too short, especially when evaluating the ability to walk. More specific tests, such as 6M walking test, for a longer period of observation, may be used in the future to better assess the effects of steroids on the gait of these cases. Moreover, results of this retrospective analysis are preliminary, thus prospective studies including larger number of patients, with defined subgroups, and inclusion of control groups, will certainly bring more definitive information regarding the real benefits of steroids for SG.

References

. Crosbie RH, Lim LE, Moore SA, Hirano M, Hays AP, Maybaum SW et al. Molecular and genetic characterization of sarcoplasm: insights into sarcoglycan-sacoplasm interactions. Hum Mol Genet. 2000;9(13):2019-27. http://dx.doi.org/10.1093/hmg/9.13.2019 [ Links ]

. Holt KH, Campbell KP. Assembly of the sarcoglycan complex. Insights for muscular dystrophy. J Biol Chem. 1998;273(52):34667-70. http://dx.doi.org/10.1074/jbc.273.52.34667 [ Links ]

. Vainzof M, Passos-Bueno MR, Pavanello RC, Marie SK, Oliveira AS, Zatz M. Sarcoglycanopathis are responsible for 68% of severe autossomal recessive limb-girdle muscular dystrophy in the Brazilian population. J Neurol Sci. 1999;164(1):44-9. http://dx.doi.org/10.1016/s0022-510x(99)00040-4 [ Links ]

. Kirschner J, Lochmüller H. Sarcoglycanopathies. Handb Clin Neurol. 2011;101:41-6. http://dx.doi.org/10.1016/b978-0-08-045031-5.00003-7 [ Links ]

. Melacini P, Fanin M, Duggan DJ, Freda MP, Berardinelli A, Danieli GA et al. Heart involvement in muscular dystrophies due to sarcoglycan gene mutations. Muscle Nerve. 1999;22(4):473-9. http://dx.doi.org/10.1002/(SICI)1097-4598(199904)22:4?ENT(lt)?473::AID-MUS8?ENT(gt)?3.0.CO;2-5 [ Links ]

. Bushby K. Diagnosis and management of the limb girdle muscular dystrophies. Pract Neurol. 2009;9(6):314-23. http://dx.doi.org/10.1136/jnnp.2009.193938 [ Links ]

. Nigro V, Aurino S, Piluso G. Limb girdle muscular dystrophies: update on genetic diagnosis and therapeutic approaches. Curr Opin Neurol. 2011;24(5):429-36. http://dx.doi.org/10.1097/WCO.0b013e32834aa38d [ Links ]

. Henricson EK, Abresch RT, Cnaan A, Hu F, Duong T, Arrieta A et al. The cooperative international neuromuscular research group Duchenne natural history study: glucocorticoid treatment preserves clinically meaningful functional milestones and reduces rate of disease progression as measured by manual muscle testing and other commonly used clinical trial outcome measures. Muscle Nerve. 2013;48(1):55-67. http://dx.doi.org/10.1002/mus.23808 [ Links ]

. Manzur AY, Kuntzer T, Pike M, Swan A. Glucocorticoid corticosteroids for Duchenne muscular dystrophy. Cochrane Database Syst Rev. 2008;1:CD003725. http://dx.doi.org/10.1002/14651858.cd003725.pub2 [ Links ]

. Parreira SL, Resende MB, Zanoteli E, Carvalho MS, Marie SK, Reed UC. Comparison of motor strength and function in patients with Duchenne muscular dystrophy with or without steroid therapy. Arq Neuropsiquiatr. 2010;68(5):683-8. http://dx.doi.org/10.1590/s0004-282x2010000500002 [ Links ]

. Silva EC, Machado DL, Resende MB, Silva RF, Zanoteli E, Reed UC. Motor function measure scale, steroid therapy and patients with Duchenne muscular dystrophy. Arq Neuropsiquiatr. 2012;70(3):191-5. http://dx.doi.org/10.1590/S0004-282X2012000300007 [ Links ]

. Machado DL, Silva EC, Resende MB, Carvalho CR, Zanoteli E, Reed UC. Lung function monitoring in patients with duchenne muscular dystrophy on steroid therapy. BMC Res Notes. 2012;5(1):435. http://dx.doi.org/10.1186/1756-0500-5-435 [ Links ]

. Lebel DE, Corston JA, McAdam LC, Biggar WD, Alman BA. Glucocorticoid treatment for the prevention of scoliosis in children with Duchenne muscular dystrophy: long-term follow-up. J Bone Joint Surg Am. 2013;95(12):1057-61. http://dx.doi.org/10.2106/jbjs.l.01577 [ Links ]

. Schram G, Fournier A, Leduc H, Dahdah N, Therien J, Vanasse M et al. All-cause mortality and cardiovascular outcomes with prophylactic steroid therapy in Duchenne muscular dystrophy. J Am Coll Cardiol. 2013;61(9):948-54. http://dx.doi.org/10.1016/j.jacc.2012.12.008 [ Links ]

. Angelini C. The role of corticosteroids in muscular dystrophy: a critical appraisal. Muscle Nerve. 2007;36:424-35. http://dx.doi.org/10.1002/mus.20812 [ Links ]

. Fisher I, Abraham D, Bouri K, Hoffman EP, Muntoni F, Morgan J. Prednisolone-induced changes in dystrophic skeletal muscle. FASEB J. 2005;19(7):834-6. http://dx.doi.org/10.1096/fj.04-2511fje [ Links ]

. Tamma R, Annese T, Capogrosso RF, Cozzoli A, Benagiano V, Sblendorio V et al. Effects of prednisolone on the dystrophin-associated proteins in the blood-brain barrier and skeletal muscle of dystrophic mdx mice. Lab Invest. 2013;93(5):592-610. http://dx.doi.org/10.1038/labinvest.2013.46 [ Links ]

. Angelini C, Fanin M, Menegazzo E, Freda MP, Duggan DJ, Hoffman EP. Homozygous alpha-sarcoglycan mutation in two siblings: one asymptomatic and one steroid-responsive mild limb-girdle muscular dystrophy patient. Muscle Nerve. 1998;21(6):769-75. http://dx.doi.org/10.1002/(SICI)1097-4598(199806)21:6?ENT(lt)?769::AID-MUS9?ENT(gt)?3.0.CO;2-5 [ Links ]

. Connolly AM, Pestronk A, Mehta S, Al-Lozi M. Primary alpha-sarcoglycan deficiency responsive to immunosuppression over three years. Muscle Nerve. 1998;21(11):1549-53. http://dx.doi.org/10.1002/(SICI)1097-4598(199811)21:11?ENT(lt)?1549::AID-MUS30?ENT(gt)?3.0.CO;2-T [ Links ]

. Wong-Kisiel LC, Kuntz NL. Two siblings with limb-girdle muscular dystrophy type 2E responsive to deflazacort. Neuromuscul Disord. 2010;20(2):122-4. http://dx.doi.org/10.1016/j.nmd.2009.11.005 [ Links ]

. Godfrey C, Escolar D, Brockington M, Clement EM, Mein R, Jimenez-Mallebrera C et al. Fukutin gene mutations in steroid-responsive limb girdle muscular dystrophy. Ann Neurol. 2006;60(5):603-10. http://dx.doi.org/10.1002/ana.21006 [ Links ]

. Darin N, Kroksmark AK, Ahlander AC, Moslemi AR, Oldfors A, Tulinius M. Inflammation and response to steroid treatment in limb-girdle muscular dystrophy 2I. Eur J Paediatr. 2007;11(6):353-7. http://dx.doi.org/10.1016/j.ejpn.2007.02.018 [ Links ]

. Walter MC, Reilich P, Thiele S, Schessl J, Schreiber H, Reiners K et al. Treatment of dysferlinopathy with deflazacort: a double-blind, placebo-controlled clinical trial. Orphanet J Rare Dis. 2013;8:26. http://dx.doi.org/10.1186/1750-1172-8-26 [ Links ]

. Bauer R, MacGowan GA, Blain A, Bushby K, Straub V. Steroid treatment causes deterioration of myocardial function in the {delta}-sarcoglycan-deficient mouse model for dilated cardiomyopathy. Cardiovasc Res. 2008;79(4):652-61. http://dx.doi.org/10.1093/cvr/cvn131 [ Links ]

Received: March 10, 2014; Revised: June 24, 2014; Accepted: July 14, 2014

Correspondence: Umbertina C Reed; Av. Dr. Enéas de Carvalho Aguiar, 255, 5o. andar; 05403-900 Sao Paulo, Brasil; Email: umbertina.reed@hc.fm.usp.br

Conflict of interest: There is no conflict of interests to declare.

Support: Fundação de Amparo à Pesquisa do Estado de São Paulo (#2010/08902-5)

Creative Commons License This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.