Abstracts
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.
steroids; limb-girdle muscular dystrophy; sarcoglycan proteins; myopathy
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.
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)11 . 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
https://doi.org/10.1093/hmg/9.13.2019...
. The
sarcoglycan complex is integrated in the muscle membrane as a part of the
dystrophin-glycoprotein associated complex22 . 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
https://doi.org/10.1074/jbc.273.52.34667...
. A wide range of mutations in any of these proteins destabilize
the whole sarcoglycan complex, resulting in the different types of LGMDs11 . 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
https://doi.org/10.1093/hmg/9.13.2019...
. In the Brazilian population,
sarcoglycanopathies account for about one third of the classified forms of AR-LGMD33 . 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
https://doi.org/10.1016/s0022-510x(99)00...
. LGMD2D is the most frequent
sarcoglycanopathy, followed by LGMD2E and LGMD2C, while LGMD2F is the most rare44 . 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
https://doi.org/10.1016/b978-0-08-045031...
. 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 family44 . 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
https://doi.org/10.1016/b978-0-08-045031...
. 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) level44 . 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
https://doi.org/10.1016/b978-0-08-045031...
. Cardiac involvement is frequently reported55 . 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
https://doi.org/10.1002/(SICI)1097-4598(...
,66 . 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
https://doi.org/10.1136/jnnp.2009.193938...
. Besides a rehabilitation program, there is currently
no effective treatment for these patients66 . 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
https://doi.org/10.1136/jnnp.2009.193938...
,77 . 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
https://doi.org/10.1097/WCO.0b013e32834a...
.
Steroid treatment with prednisone or deflazacort has been shown to slow disease
progression in Duchenne muscular dystrophy (DMD)88 . 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
https://doi.org/10.1002/mus.23808...
9 . 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
https://doi.org/10.1002/14651858.cd00372...
10 . 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
https://doi.org/10.1590/s0004-282x201000...
-1111 . 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
https://doi.org/10.1590/S0004-282X201200...
. The treatment is also potentially effective to delay
restrictive respiratory insufficiency, scoliosis and in a lesser extent cardiac
involvement in patients with this disease88 . 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
https://doi.org/10.1002/mus.23808...
,1212 . 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
https://doi.org/10.1186/1756-0500-5-435...
13 . 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
https://doi.org/10.2106/jbjs.l.01577 ...
-1414 . 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
https://doi.org/10.1016/j.jacc.2012.12.0...
. 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 proliferation1515 . 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
https://doi.org/10.1002/mus.20812...
16 . 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
https://doi.org/10.1096/fj.04-2511fje...
-1717 . 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
https://doi.org/10.1038/labinvest.2013.4...
.
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
progression1818 . 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
https://doi.org/10.1002/(SICI)1097-4598(...
19 . 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
https://doi.org/10.1002/(SICI)1097-4598(...
-2020 . 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
https://doi.org/10.1016/j.nmd.2009.11.00...
. 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).
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
population33 . 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
https://doi.org/10.1016/s0022-510x(99)00...
. 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 therapy1818 . 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
https://doi.org/10.1002/(SICI)1097-4598(...
19 . 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
https://doi.org/10.1002/(SICI)1097-4598(...
-2020 . 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
https://doi.org/10.1016/j.nmd.2009.11.00...
. 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).
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 therapy1818 . 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
https://doi.org/10.1002/(SICI)1097-4598(...
19 . 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
https://doi.org/10.1002/(SICI)1097-4598(...
-2020 . 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
https://doi.org/10.1016/j.nmd.2009.11.00...
; 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 fibers11 . 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
https://doi.org/10.1093/hmg/9.13.2019...
-22 . 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
https://doi.org/10.1074/jbc.273.52.34667...
. 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 reported1818 . 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
https://doi.org/10.1002/(SICI)1097-4598(...
19 . 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
https://doi.org/10.1002/(SICI)1097-4598(...
-2020 . 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
https://doi.org/10.1016/j.nmd.2009.11.00...
. 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
deficiency1818 . 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
https://doi.org/10.1002/(SICI)1097-4598(...
. 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 deficiency1919 . 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
https://doi.org/10.1002/(SICI)1097-4598(...
.
Wong-Kisielet et al. described stabilization and improvement of muscle strength in
two siblings with β-SG after 30 months of deflazacort therapy2020 . 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
https://doi.org/10.1016/j.nmd.2009.11.00...
.
In other forms of muscular dystrophies there have also been reports of a positive
response to corticosteroids2121 . 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
https://doi.org/10.1002/ana.21006...
-2222 . 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
https://doi.org/10.1016/j.ejpn.2007.02.0...
. Godfrey et al. described three children with an LGMD
phenotype and pathogenic fukutin mutation that had a remarkable
steroid responsiveness2121 . 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
https://doi.org/10.1002/ana.21006...
. 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 prednisolone2222 . 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
https://doi.org/10.1016/j.ejpn.2007.02.0...
.
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 strength2323 . 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
https://doi.org/10.1186/1750-1172-8-26...
. 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 effects2323 . 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
https://doi.org/10.1186/1750-1172-8-26...
.
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 mouse2424 . 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
https://doi.org/10.1093/cvr/cvn131 ...
.
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
-
1Crosbie 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
» https://doi.org/10.1093/hmg/9.13.2019 -
2Holt 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
» https://doi.org/10.1074/jbc.273.52.34667 -
3Vainzof 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
» https://doi.org/10.1016/s0022-510x(99)00040-4 -
4Kirschner J, Lochmüller H. Sarcoglycanopathies. Handb Clin Neurol. 2011;101:41-6. http://dx.doi.org/10.1016/b978-0-08-045031-5.00003-7
» https://doi.org/10.1016/b978-0-08-045031-5.00003-7 -
5Melacini 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
» https://doi.org/10.1002/(SICI)1097-4598(199904)22:4?ENT(lt)?473::AID-MUS8?ENT(gt)?3.0.CO;2-5 -
6Bushby 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
» https://doi.org/10.1136/jnnp.2009.193938 -
7Nigro 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
» https://doi.org/10.1097/WCO.0b013e32834aa38d -
8Henricson 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
» https://doi.org/10.1002/mus.23808 -
9Manzur 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
» https://doi.org/10.1002/14651858.cd003725.pub2 -
10Parreira 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
» https://doi.org/10.1590/s0004-282x2010000500002 -
11Silva 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
» https://doi.org/10.1590/S0004-282X2012000300007 -
12Machado 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
» https://doi.org/10.1186/1756-0500-5-435 -
13Lebel 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
» https://doi.org/10.2106/jbjs.l.01577 -
14Schram 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
» https://doi.org/10.1016/j.jacc.2012.12.008 -
15Angelini 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
» https://doi.org/10.1002/mus.20812 -
16Fisher 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
» https://doi.org/10.1096/fj.04-2511fje -
17Tamma 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
» https://doi.org/10.1038/labinvest.2013.46 -
18Angelini 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
» https://doi.org/10.1002/(SICI)1097-4598(199806)21:6?ENT(lt)?769::AID-MUS9?ENT(gt)?3.0.CO;2-5 -
19Connolly 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
» https://doi.org/10.1002/(SICI)1097-4598(199811)21:11?ENT(lt)?1549::AID-MUS30?ENT(gt)?3.0.CO;2-T -
20Wong-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
» https://doi.org/10.1016/j.nmd.2009.11.005 -
21Godfrey 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
» https://doi.org/10.1002/ana.21006 -
22Darin 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
» https://doi.org/10.1016/j.ejpn.2007.02.018 -
23Walter 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
» https://doi.org/10.1186/1750-1172-8-26 -
24Bauer 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
» https://doi.org/10.1093/cvr/cvn131
Publication Dates
-
Publication in this collection
Oct 2014
History
-
Received
10 Mar 2014 -
Reviewed
24 June 2014 -
Accepted
14 July 2014