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Immune-mediated rippling muscle disease in a patient with treated hypothyroidism
Journal of the Neurological Sciences 383 (2017) 53–55
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Immune-mediated rippling muscle disease in a patient with treated hypothyroidism
MARK
A R T I C L E I N F O Keywords: Rippling muscle disease Rippling phenomenon Autoimmune disorders Immune-mediated rippling disease Hypothyroidism Muscle biopsy Treatment
Dear Editor, Rippling muscle disease (RMD) is a myopathy with symptoms and signs of muscular hyperirritability [1]. Hereditary RMD is caused by caveolin-3 deficiency due to mutations in the CAV-3 gene and in PTRF gene coding for cavin-1 [1–3]. The rare cases of acquired RMD are usually associated with myasthenia gravis (MG). In these situations, RMD has been named as “immune-mediated RMD (iRMD)” [4–7]. There are also descriptions of RMD preceding malignant lymphoma [8] and breast cancer [9]. We describe a 17-year-old girl who has been treated for hypothyroidism for 10 years, and at moment she is asymptomatic. In the last two years, she started with brief muscle contractions followed by intense muscle pain in the limbs, abdomen and back. Symptoms appeared at rest, during exercise and during sleep. Clinical features included muscle hypertrophy in the lower limbs and local mounding and rippling phenomenon after skeletal muscle percussion and sudden stretching of the quadriceps femoris muscle. Needle electromyography showed electrical silence during the rippling phenomenon. Repetitive nerve stimulations were normal. Laboratory tests showed that free T4, TSH and thyroid peroxidase autoantibodies were normal, the CK level was 647 U/L (normal < 145 U/L) and anti-AChR antibodies were not detectable. Whole-body FDG-PET/CT was normal. The muscle biopsy was compatible with nonspecific myopathic features with rare infiltration of inflammatory cells in endomysial tissue along with type 1 and 2 fiber atrophy (Fig. 1). Immunohistochemical analysis of sarcolemmal proteins showed moderate reduction in the mosaic pattern in caveolin-3 and partial reduction in dysferlin (Fig. 1). Molecular investigation using a next generation exome sequencing customized panel for 88 genes involved in genetic neuromuscular disorders (http://laboratorio.genoma. ib.usp.br), including the CAV-3 and DYSF genes, did not find any significant pathogenic variant in the coding region of these genes that could explain the phenotype. There was significant improvement in her symptoms during corticosteroids and azathioprine therapies, but she returned to having symptoms after withdrawal, in two different occasions, suggesting an autoimmune etiological role in this case. iRMD is usually described to be associated with MG, with or without thymoma, particularly after the third decade of life [4–7]. Hypothyroidism was only recently described in one patient with iRMD associated with MG [4] and few cases of iRMD without MG are described to date [10]. Muscle biopsy features in iRMD were described with inflammatory changes or as nonspecific myopathy. The most frequent features consisted of rare interstitial and perivascular lymphocytic infiltrates in addition to scattered atrophic type I and II muscle fibers, as seen in our patient [7]. A different feature seen in RMD patients with CAV-3 mutations is that caveolin-3 in the muscle biopsies of iRMD patients were moderately reduced as a mosaic pattern [4–8,10]. Ultrastructural studies showed a loss of caveolae and alterations of the T tubules in iRMD [7]. It is possible that the mosaic pattern of the caveolin-3 in the muscle biopsy is a hallmark of iRMD, but the precise mechanism leading to that mosaic finding in iRMD is unknown. Similar to our case, mild deficiency of dysferlin was also reported in iRMD [6,7,10]. Therapy of iRMD was immunosuppressant drugs, such as steroids, azathioprine and cyclosporine, in several cases [4,6,10]. Phasmapheresis [10] and intravenous immunoglobulin [9] were also reported. Our report also highlights that it is extremely important to distinguish between hereditary RMD and iRMD because iRMD can respond to immunosuppressive therapy. Conflicts of interest None.
Abbreviations: CAV-3, caveolin-3; DYSF, dysferlin; RMD, Rippling muscle disease; iRMD, immune-mediated Rippling muscle disease; MG, myasthenia gravis http://dx.doi.org/10.1016/j.jns.2017.10.016 Received 7 July 2017; Received in revised form 7 October 2017; Accepted 9 October 2017 Available online 13 October 2017 0022-510X/ © 2017 Elsevier B.V. All rights reserved.
Journal of the Neurological Sciences 383 (2017) 53–55
Letter to the Editor
Fig. 1. Histopathological features from biceps brachialis (B, D–F) and vastus lateralis (A, C) muscle biopsies showing minimal myopathic pattern with rare lymphohistiocytic infiltration (A, hematoxylin-eosin stain; B, nonspecific esterase stain; C, acid phosphatase stain). Endomysial lymphohistiocytic infiltration of muscle fibers is strongly reactive in the non-specific esterase (B) and acid phosphatase reaction (C). Immunohistochemical analysis of sarcolemmal caveolin-3 shows moderate reduction in a mosaic pattern (D, E) compared to the control in the vastus lateralis muscle (G, H). Sarcolemmal dysferlin immunofluorescence staining was reduced (F) compared to the control in the vastus lateralis muscle (I). Bar = 50 μm.
Formatting of funding sources This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector. Acknowledgements We would like to thank the laboratorial support of the NGS Diagnostic Laboratory of the Human Genome Research Center, Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP-CEPID), Conselho Nacional de Pesquisa (CNPq-INCT), Fundação Araucária, Financiadora de Projetos (FINEP) and CETAC Diagnóstico por Imagem. References [1] P.J. Lorenzoni, R.H. Scola, N. Vieira, M. Vainzof, A.L. Carsten, L.C. Werneck, A novel missense mutation in the caveolin-3 gene in rippling muscle disease, Muscle Nerve 36 (2007) 258–260. [2] H. Couchoux, H. Bichraoui, C. Chouabe, X. Altafaj, R. Bonvallet, B. Allard, et al., Caveolin-3 is a direct molecular partner of the Cav1.1 subunit of the skeletal muscle L-type calcium channel, Int. J. Biochem. Cell Biol. 43 (2011) 713–720. [3] A. Ardissone, C. Bragato, L. Caffi, F. Blasevich, S. Maestrini, M.L. Bianchi, L. Morandi, I. Moroni, M. Mora, Novel PTRF mutation in a child with mild myopathy and very mild congenital lipodystrophy, BMC Med. Genet. 14 (2013) 89. [4] M. Bettini, H. Gonorazky, M. Chaves, E. Fulgenzi, A. Figueredo, S. Christiansen, et al., Immune-mediated rippling muscle disease and myasthenia gravis, J. Neuroimmunol. 299 (2016) 59–61. [5] J.S. George, S. Harikrishnan, I. Ali, R. Baresi, C.O. Hanemann, Acquired rippling muscle disease in association with myasthenia gravis, J. Neurol. Neurosurg. Psychiatry 81 (2010) 125–126. [6] B. Schoser, S. Jacob, D. Hilton-Jones, W. Müller-Felber, C. Kubisch, D. Claus, et al., Immune-mediated rippling muscle disease with myasthenia gravis: a report of seven patients with long-term follow-up in two, Neuromuscul. Disord. 19 (2009) 223–228. [7] W.J. Schulte-Mattler, R.A. Kley, E. Rothenfusser-Korber, S. Böhm, R. Brüning, J. Hackemann, et al., Immune-mediated rippling muscle disease, Neurology 64 (2005) 364–367. [8] A. Takagi, S. Kojima, T. Watanabe, M. Ida, S. Kawagoe, Rippling muscle syndrome preceding malignant lymphoma, Intern. Med. 41 (2002) 147–150. [9] T. Liewluck, B.P. Goodman, M. Milone, Electrically active immune-mediated rippling muscle disease preceding breast cancer, Neurologist 18 (2012) 155–158. [10] H.P. Lo, E. Bertini, M. Mirabella, A. Domazetovska, R.C. Dale, S. Petrini, et al., Mosaic caveolin-3 expression in acquired rippling muscle disease without evidence of myasthenia gravis or acetylcholine receptor autoantibodies, Neuromuscul. Disord. 21 (2011) 194–203.
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Journal of the Neurological Sciences 383 (2017) 53–55
Letter to the Editor
Renata Dal-Prá Ducci, Rosana Herminia Scola⁎, Paulo José Lorenzoni, Claudia Suemi Kamoi Kay, Marcelo Rezende Young Blood Neurology Division, Internal Medicine Department, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil E-mail address: [email protected] Leonardo G. Leão, Mariz Vainzof Human Genome Research Center, University of São Paulo, São Paulo, Brazil Lineu Cesar Werneck Neurology Division, Internal Medicine Department, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil
⁎
Corresponding author at: Serviço de Doenças Neuromusculares, Hospital de Clínicas da UFPR, Rua General Carneiro 181/30 andar, 80060-900 Curitiba, PR, Brasil.
55
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Immune-mediated rippling muscle disease in a patient with treated hypothyroidism
MARK
A R T I C L E I N F O Keywords: Rippling muscle disease Rippling phenomenon Autoimmune disorders Immune-mediated rippling disease Hypothyroidism Muscle biopsy Treatment
Dear Editor, Rippling muscle disease (RMD) is a myopathy with symptoms and signs of muscular hyperirritability [1]. Hereditary RMD is caused by caveolin-3 deficiency due to mutations in the CAV-3 gene and in PTRF gene coding for cavin-1 [1–3]. The rare cases of acquired RMD are usually associated with myasthenia gravis (MG). In these situations, RMD has been named as “immune-mediated RMD (iRMD)” [4–7]. There are also descriptions of RMD preceding malignant lymphoma [8] and breast cancer [9]. We describe a 17-year-old girl who has been treated for hypothyroidism for 10 years, and at moment she is asymptomatic. In the last two years, she started with brief muscle contractions followed by intense muscle pain in the limbs, abdomen and back. Symptoms appeared at rest, during exercise and during sleep. Clinical features included muscle hypertrophy in the lower limbs and local mounding and rippling phenomenon after skeletal muscle percussion and sudden stretching of the quadriceps femoris muscle. Needle electromyography showed electrical silence during the rippling phenomenon. Repetitive nerve stimulations were normal. Laboratory tests showed that free T4, TSH and thyroid peroxidase autoantibodies were normal, the CK level was 647 U/L (normal < 145 U/L) and anti-AChR antibodies were not detectable. Whole-body FDG-PET/CT was normal. The muscle biopsy was compatible with nonspecific myopathic features with rare infiltration of inflammatory cells in endomysial tissue along with type 1 and 2 fiber atrophy (Fig. 1). Immunohistochemical analysis of sarcolemmal proteins showed moderate reduction in the mosaic pattern in caveolin-3 and partial reduction in dysferlin (Fig. 1). Molecular investigation using a next generation exome sequencing customized panel for 88 genes involved in genetic neuromuscular disorders (http://laboratorio.genoma. ib.usp.br), including the CAV-3 and DYSF genes, did not find any significant pathogenic variant in the coding region of these genes that could explain the phenotype. There was significant improvement in her symptoms during corticosteroids and azathioprine therapies, but she returned to having symptoms after withdrawal, in two different occasions, suggesting an autoimmune etiological role in this case. iRMD is usually described to be associated with MG, with or without thymoma, particularly after the third decade of life [4–7]. Hypothyroidism was only recently described in one patient with iRMD associated with MG [4] and few cases of iRMD without MG are described to date [10]. Muscle biopsy features in iRMD were described with inflammatory changes or as nonspecific myopathy. The most frequent features consisted of rare interstitial and perivascular lymphocytic infiltrates in addition to scattered atrophic type I and II muscle fibers, as seen in our patient [7]. A different feature seen in RMD patients with CAV-3 mutations is that caveolin-3 in the muscle biopsies of iRMD patients were moderately reduced as a mosaic pattern [4–8,10]. Ultrastructural studies showed a loss of caveolae and alterations of the T tubules in iRMD [7]. It is possible that the mosaic pattern of the caveolin-3 in the muscle biopsy is a hallmark of iRMD, but the precise mechanism leading to that mosaic finding in iRMD is unknown. Similar to our case, mild deficiency of dysferlin was also reported in iRMD [6,7,10]. Therapy of iRMD was immunosuppressant drugs, such as steroids, azathioprine and cyclosporine, in several cases [4,6,10]. Phasmapheresis [10] and intravenous immunoglobulin [9] were also reported. Our report also highlights that it is extremely important to distinguish between hereditary RMD and iRMD because iRMD can respond to immunosuppressive therapy. Conflicts of interest None.
Abbreviations: CAV-3, caveolin-3; DYSF, dysferlin; RMD, Rippling muscle disease; iRMD, immune-mediated Rippling muscle disease; MG, myasthenia gravis http://dx.doi.org/10.1016/j.jns.2017.10.016 Received 7 July 2017; Received in revised form 7 October 2017; Accepted 9 October 2017 Available online 13 October 2017 0022-510X/ © 2017 Elsevier B.V. All rights reserved.
Journal of the Neurological Sciences 383 (2017) 53–55
Letter to the Editor
Fig. 1. Histopathological features from biceps brachialis (B, D–F) and vastus lateralis (A, C) muscle biopsies showing minimal myopathic pattern with rare lymphohistiocytic infiltration (A, hematoxylin-eosin stain; B, nonspecific esterase stain; C, acid phosphatase stain). Endomysial lymphohistiocytic infiltration of muscle fibers is strongly reactive in the non-specific esterase (B) and acid phosphatase reaction (C). Immunohistochemical analysis of sarcolemmal caveolin-3 shows moderate reduction in a mosaic pattern (D, E) compared to the control in the vastus lateralis muscle (G, H). Sarcolemmal dysferlin immunofluorescence staining was reduced (F) compared to the control in the vastus lateralis muscle (I). Bar = 50 μm.
Formatting of funding sources This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector. Acknowledgements We would like to thank the laboratorial support of the NGS Diagnostic Laboratory of the Human Genome Research Center, Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP-CEPID), Conselho Nacional de Pesquisa (CNPq-INCT), Fundação Araucária, Financiadora de Projetos (FINEP) and CETAC Diagnóstico por Imagem. References [1] P.J. Lorenzoni, R.H. Scola, N. Vieira, M. Vainzof, A.L. Carsten, L.C. Werneck, A novel missense mutation in the caveolin-3 gene in rippling muscle disease, Muscle Nerve 36 (2007) 258–260. [2] H. Couchoux, H. Bichraoui, C. Chouabe, X. Altafaj, R. Bonvallet, B. Allard, et al., Caveolin-3 is a direct molecular partner of the Cav1.1 subunit of the skeletal muscle L-type calcium channel, Int. J. Biochem. Cell Biol. 43 (2011) 713–720. [3] A. Ardissone, C. Bragato, L. Caffi, F. Blasevich, S. Maestrini, M.L. Bianchi, L. Morandi, I. Moroni, M. Mora, Novel PTRF mutation in a child with mild myopathy and very mild congenital lipodystrophy, BMC Med. Genet. 14 (2013) 89. [4] M. Bettini, H. Gonorazky, M. Chaves, E. Fulgenzi, A. Figueredo, S. Christiansen, et al., Immune-mediated rippling muscle disease and myasthenia gravis, J. Neuroimmunol. 299 (2016) 59–61. [5] J.S. George, S. Harikrishnan, I. Ali, R. Baresi, C.O. Hanemann, Acquired rippling muscle disease in association with myasthenia gravis, J. Neurol. Neurosurg. Psychiatry 81 (2010) 125–126. [6] B. Schoser, S. Jacob, D. Hilton-Jones, W. Müller-Felber, C. Kubisch, D. Claus, et al., Immune-mediated rippling muscle disease with myasthenia gravis: a report of seven patients with long-term follow-up in two, Neuromuscul. Disord. 19 (2009) 223–228. [7] W.J. Schulte-Mattler, R.A. Kley, E. Rothenfusser-Korber, S. Böhm, R. Brüning, J. Hackemann, et al., Immune-mediated rippling muscle disease, Neurology 64 (2005) 364–367. [8] A. Takagi, S. Kojima, T. Watanabe, M. Ida, S. Kawagoe, Rippling muscle syndrome preceding malignant lymphoma, Intern. Med. 41 (2002) 147–150. [9] T. Liewluck, B.P. Goodman, M. Milone, Electrically active immune-mediated rippling muscle disease preceding breast cancer, Neurologist 18 (2012) 155–158. [10] H.P. Lo, E. Bertini, M. Mirabella, A. Domazetovska, R.C. Dale, S. Petrini, et al., Mosaic caveolin-3 expression in acquired rippling muscle disease without evidence of myasthenia gravis or acetylcholine receptor autoantibodies, Neuromuscul. Disord. 21 (2011) 194–203.
54
Journal of the Neurological Sciences 383 (2017) 53–55
Letter to the Editor
Renata Dal-Prá Ducci, Rosana Herminia Scola⁎, Paulo José Lorenzoni, Claudia Suemi Kamoi Kay, Marcelo Rezende Young Blood Neurology Division, Internal Medicine Department, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil E-mail address: [email protected] Leonardo G. Leão, Mariz Vainzof Human Genome Research Center, University of São Paulo, São Paulo, Brazil Lineu Cesar Werneck Neurology Division, Internal Medicine Department, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil
⁎
Corresponding author at: Serviço de Doenças Neuromusculares, Hospital de Clínicas da UFPR, Rua General Carneiro 181/30 andar, 80060-900 Curitiba, PR, Brasil.
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