SPORADIC LATE-ONSET NEMALINE MYOPATHY AS A RARE CAUSE OF SLOWLY PROGRESSIVE MUSCLE WEAKNESS WITH YOUNG ADULT ONSET MEIKO HASHIMOTO MAEDA, MD, PhD,1,2,3 HIKARI OHTA, MD,4 KOJI IZUTSU, MD, PhD,4 JUN SHIMIZU, MD, PhD,2 and YOSHIKAZU UESAKA, MD, PhD1,3 Department of Neurology, Federation of National Public Service Personnel Mutual Aid Associations Toranomon Hospital, Tokyo, Japan 2 Department of Neurology, University of Tokyo, Graduate School of Medicine, Tokyo, Japan 3 Okinaka Memorial Institute for Medical Research, 2-2-2 Toranomon, Minato-ku, Tokyo 105-8470, Japan 4 Department of Haematology, Federation of National Public Service Personnel Mutual Aid Associations, Toranomon Hospital, Tokyo, Japan 1
Accepted 3 November 2014 ABSTRACT: Introduction: Sporadic late-onset nemaline myopathy (SLONM) is a rare intractable acquired myopathy characterized by progressive muscle weakness and atrophy, usually with middle to late adult onset. Autologous peripheral blood stem cell transplantation (auto-PBSCT) has been reported to be a promising treatment for SLONM. Methods: In this study we performed clinical characterization, muscle histopathological analysis, and muscle power monitoring after auto-PBSCT in a 27-year-old HIVnegative man with monoclonal gammopathy. Results: He showed improved muscle strength after treatment with high-dose melphalan and auto-PBSCT. Conclusions: Considering the recent reports of successful treatment of SLONM, early and correct diagnosis of this condition in association with monoclonal gammopathy is important. SLONM should be added to the list of diseases to consider in the differential diagnosis of progressive muscle weakness with young adult onset. Muscle Nerve 51: 772–774, 2015
Progressive
skeletal muscle weakness with young adult onset is relatively rare. In many such cases, hereditary neuromuscular diseases are the cause, and careful history-taking may reveal their earlier onset. Some cases caused by familial motor neuron disease have been known to start in young adulthood. As acquired neuromuscular diseases, cases of inflammatory neuropathy or myopathy show clinical features of slowly progressive muscle weakness in young adulthood, but such cases are rare. Sporadic late-onset nemaline myopathy (SLONM) is a rare, intractable, acquired myopa-
thy characterized by progressive muscle weakness and atrophy. Autoimmune dysregulation has been suspected to be the pathogenesis of the condition. Although many SLONM patients are human immunodeficiency virus (HIV)-positive, with young adult onset (average age 34.8 6 9.1 years, range 23–49 years), HIV-negative SLONM patients have been reported to have middle to later adult onset (average age 53.7 6 10.5 years, range 31–78 years). As an autoimmune dysregulation, monoclonal gammopathy is associated with SLONM without HIV infection. Among the 51 HIV-negative SLONM patients reported thus far, 21 had monoclonal gammopathy. As 7 of these 21 patients (33.3%) died within 5 years, the presence of monoclonal gammopathy suggests an unfavorable outcome.1 However, there have been several recent case reports of successful treatment of SLONM with monoclonal gammopathy with highdose melphalan followed by autologous peripheral blood stem cell transplantation (autoPBSCT).2–5 We report the case of a man with SLONM with monoclonal gammopathy who had disease onset at 27 years of age.
CASE REPORT Abbreviations: auto-PBSCT, autologous peripheral blood stem cell transplantation; HIV, human immunodeficiency virus; MRC, Medical Research Council; SLONM, sporadic late-onset nemaline myopathy Key words: auto-PBSCT; HIV-negative patients; monoclonal gammopathy; sporadic late-onset nemaline myopathy; young adult onset Correspondence to: M.H. Maeda; e-mail: [email protected] This work was supported in part by a Health and Labour Sciences Research Grant for Intractable Diseases (Neuroimmunological Diseases), Ministry of Health, Labour and Welfare of Japan; the Ministry of Education, Science, Sports and Culture; a Grant-in-Aid for Scientific Research (C), 2012–2014 (24591289 to J.S.); and an Intramural Research Grant (26-8) for Neurological and Psychiatric Disorders from the National Center of Neurology and Psychiatry. C 2014 Wiley Periodicals, Inc. V
Published online 8 November 2014 in Wiley Online Library (wileyonlinelibrary. com). DOI 10.1002/mus.24509
772
Late-Onset Nemaline Myopathy
A 27-year-old man with an unremarkable medical history noticed head drop and swallowing difficulty 9 months before admission. In the next 5–7 months, he gradually realized that his upper body leaned backward when walking due to difficulty carrying his bag related to shoulder muscle weakness. During this time, his body weight had decreased by 10 kg. On admission, muscle atrophy was obvious in the shoulders, paraspinal region, and hips. Using the Medical Research Council (MRC) scale, muscle strength scores were as follows: neck extension 5 2; neck flexion 5 5; deltoid 5 2; serratus anterior 5 3; MUSCLE & NERVE
May 2015
FIGURE 1. Left deltoid muscle biopsy. (A) Many small atrophic fibers contain nemaline rods (Gomori trichrome stain). Scale bar 5 100 lm. (B) Electron microscopy shows affected fibers with a number of cytoplasmic rods with the same electron density as the Z-band. Scale bar 5 5 lm. (C) Muscle symptoms before and after auto-PBSCT. The patient was unable to extend his neck against gravity before auto-PBSCT (left); he regained the ability to keep his head up against gravity 3 months after auto-PBSCT (right). (D) Average muscle score.6 Three months before auto-PBSCT, the patient’s average muscle score decreased rapidly from 8.059 to 7.382. After PBSCT, his score increased gradually to 7.824.
iliopsoas 5 3; gluteus maximus 5 3; gluteus medius 5 4; and other distal muscles 5 5. Laboratory examinations showed that the patient’s serum creatine kinase level was normal. He was negative for the anti-HIV antibody. A monoclonal IgG-k–type protein was detected by immunoelectrophoresis. An M-protein spike of 0.66 g/L was observed by serum protein electrophoresis. The serum free light-chain ratio was abnormal (j/k ratio 0.18). A bone marrow test showed a slight increase in the number of plasma cells (2.2%). Whole-body computed tomography (CT) demonstrated splenomegaly. Needle electromyography (EMG) showed myopathic changes with abnormal spontaneous activity in the deltoid and iliopsoas muscles. Muscle CT images showed atrophy and fatty changes in the paravertebral and gluteus medius muscles. Muscle biopsy was obtained from the left deltoid muscle. The biopsy showed abundant small atrophic fibers with nemaline rods (Fig. 1A), which stained positive for myotilin and a-actinin. Neither necrotic or regenerating fibers or inflammatory cell infiltration was observed. The expression of major histocompatibility complex class I Late-Onset Nemaline Myopathy
on the sarcolemma of non-necrotic fibers was not upregulated. Electron microscopy showed a number of cytoplasmic rods with a square lattice structure (Fig. 1B). We made a diagnosis of SLONM on the basis of these histopathological findings. During the period of diagnostic confirmation, the patient’s muscle weakness progressed. Two months after admission, he had difficulty holding his head erect and had to support his chin with his hand to sustain normal head posture; moreover, he was unable to climb stairs. He also developed dyspnea with a vital capacity of 3.71 L (74% of predicted). After diagnosis, intravenous immunoglobulin 0.4 g/kg day for 5 days and 2 courses of methylprednisolone pulse therapy at 1000 mg/day for 3 days were administered as the initial treatments. Despite these treatments, proximal limb weakness continued to worsen, and he became unable to walk more than 10 m. Because of his poor response to the treatment and the rapid worsening of muscle weakness, we decided to perform auto-PBSCT. Five months after admission, after gaining approval of the ethics committee, we treated the patient with high-dose melphalan MUSCLE & NERVE
May 2015
773
(200 mg/m2), followed by auto-PBSCT (with an uneventful posttransplantation course). One month after auto-PBSCT, strength in his shoulder muscles gradually increased, which he realized while changing his clothes. Three months after auto-PBSCT, strength in his lower limbs had increased enough for him to be able to walk >1000 meters. Twelve months after auto-PBSCT, his neck extension muscle score improved from 2 to 3 on the MRC scale (Fig. 1C), and average muscle score6 increased from 7.382 to 7.824 (Fig. 1D). Although he noted improvement in dysphagia and dyspnea, follow-up examination of vital capacity showed no improvement. Twelve months after auto-PBSCT, the monoclonal protein was not detectable by protein electrophoresis, but it could still be detected by immunoelectrophoresis. Improved muscle power continued until around 1.5 years after auto-PBSCT, when he began to feel fatigability and again had gradually decreased muscle power. Two years after auto-PBSCT, although muscle power and scores of activities of daily living remained higher than before autoPBSCT, there was a gradual decrease in muscle strength.
gammopathy showing a clearly favorable response to auto-PBSCT. It is not clear whether delayed initiation of auto-PBSCT may have affected his response to treatment (treatment initiated 14 months after disease onset). Because auto-PBSCT has many serious side effects,11 we should use caution in its application for SLONM. However, considering that this patient and those reported previously showed favorable responses,2–5 auto-PBSCT should become a treatment option for SLONM. In selecting the appropriate treatment option for this condition—an intractable acquired myopathy with progressive muscle weakness—an early and accurate diagnosis is essential. Because of its rarity, it is sometimes difficult to diagnose patients who show diffuse muscle atrophy and dysphagia as having SLONM, and they are sometimes misdiagnosed as having amyotrophic lateral sclerosis, thereby losing an opportunity for early treatment.1,3 For an early and correct diagnosis and better treatment approach, we suggest SLONM should be added to the list of diseases to consider in the differential diagnosis of progressive muscle weakness with young adult onset.
DISCUSSION
REFERENCES
Thus far, 5 patients with SLONM that started in their 20s have been reported.7–10 All these patients were positive for HIV. With regard to their clinical course, 2 patients treated with corticosteroids showed almost full recovery 6 months after initiation of treatment, and 1 patient treated with plasma exchange showed partial recovery with persistence of substantial muscle weakness.7–10 The clinical course of the remaining patients was not described. Here we report the case of a man with SLONM and monoclonal gammopathy with age of onset of 27 years. To our knowledge, our patient is the youngest observed with HIV-negative SLONM. Considering the clinical course of our patient before and after auto-PBSCT, we believe that autoPBSCT was effective, not only in attenuating disease activity but also in improving the patient’s muscle strength. Although further follow-up of the clinical features of our patient requires more detail (as he showed some signs of decreased muscle strength 2 years after auto-PBSCT), we believe that this is another case of SLONM with monoclonal
1. Chahin N, Selcen D, Engel AG. Sporadic late onset nemaline myopathy. Neurology 2005;65:1158–1164. 2. Benveniste O, Laforet P, Dubourg O, Solly S, Musset L, Choquet S, et al. Stem cell transplantation in a patient with late-onset nemaline myopathy and gammopathy. Neurology 2008;71:531–532. 3. Voermans NC, Minnema M, Lammens M, Schelhaas HJ, Kooi AV, Lokhorst HM, et al. Sporadic late-onset nemaline myopathy effectively treated by melphalan and stem cell transplant. Neurology 2008; 71:532–534. 4. Novy J, Rosselet A, Spertini O, Lobrinus JA, Pabst T, Kuntzer T. Chemotherapy is successful in sporadic late onset nemaline myopathy (SLONM) with monoclonal gammopathy. Muscle Nerve 2010;41: 286–287. 5. Doppler K, Knop S, Einsele H, Sommer C, Wessig C. Sporadic late onset nemaline myopathy and immunoglobulin deposition disease. Muscle Nerve 2013;48:983–988. 6. Brooke MH, Griggs RC, Mendell JR, Fenichel GM, Shumate JB, Pellegrino RJ. Clinical trial in Duchenne dystrophy. I. The design of the protocol. Muscle Nerve 1981;4:186–197. 7. Dalakas MC, Pezeshkpour GH, Flaherty M. Progressive nemaline (rod) myopathy associated with HIV infection. N Engl J Med 1987; 317:1602–1603. 8. Gonzales MF, Olney RK, So YT, Greco CM, McQuinn BA, Miller RG, et al. Subacute structural myopathy associated with human immunodeficiency virus infection. Arch Neurol 1988;45:585–587. 9. Cabello A, Martinez-Martin P, Gutierrez-Rivas E, Madero S. Myopathy with nemaline structures associated with HIV infection. J Neurol 1990;237:64–65. 10. Dwyer BA, Mayer RF, Lee SC. Progressive nemaline (rod) myopathy as a presentation of human immunodeficiency virus infection. Arch Neurol 1992;49:440. 11. Dispenzieri A. POEMS syndrome: 2014 Update on diagnosis, riskstratification, and management. Am J Hematol 2014;89:213–223.
774
Late-Onset Nemaline Myopathy
MUSCLE & NERVE
May 2015
Accepted 3 November 2014 ABSTRACT: Introduction: Sporadic late-onset nemaline myopathy (SLONM) is a rare intractable acquired myopathy characterized by progressive muscle weakness and atrophy, usually with middle to late adult onset. Autologous peripheral blood stem cell transplantation (auto-PBSCT) has been reported to be a promising treatment for SLONM. Methods: In this study we performed clinical characterization, muscle histopathological analysis, and muscle power monitoring after auto-PBSCT in a 27-year-old HIVnegative man with monoclonal gammopathy. Results: He showed improved muscle strength after treatment with high-dose melphalan and auto-PBSCT. Conclusions: Considering the recent reports of successful treatment of SLONM, early and correct diagnosis of this condition in association with monoclonal gammopathy is important. SLONM should be added to the list of diseases to consider in the differential diagnosis of progressive muscle weakness with young adult onset. Muscle Nerve 51: 772–774, 2015
Progressive
skeletal muscle weakness with young adult onset is relatively rare. In many such cases, hereditary neuromuscular diseases are the cause, and careful history-taking may reveal their earlier onset. Some cases caused by familial motor neuron disease have been known to start in young adulthood. As acquired neuromuscular diseases, cases of inflammatory neuropathy or myopathy show clinical features of slowly progressive muscle weakness in young adulthood, but such cases are rare. Sporadic late-onset nemaline myopathy (SLONM) is a rare, intractable, acquired myopa-
thy characterized by progressive muscle weakness and atrophy. Autoimmune dysregulation has been suspected to be the pathogenesis of the condition. Although many SLONM patients are human immunodeficiency virus (HIV)-positive, with young adult onset (average age 34.8 6 9.1 years, range 23–49 years), HIV-negative SLONM patients have been reported to have middle to later adult onset (average age 53.7 6 10.5 years, range 31–78 years). As an autoimmune dysregulation, monoclonal gammopathy is associated with SLONM without HIV infection. Among the 51 HIV-negative SLONM patients reported thus far, 21 had monoclonal gammopathy. As 7 of these 21 patients (33.3%) died within 5 years, the presence of monoclonal gammopathy suggests an unfavorable outcome.1 However, there have been several recent case reports of successful treatment of SLONM with monoclonal gammopathy with highdose melphalan followed by autologous peripheral blood stem cell transplantation (autoPBSCT).2–5 We report the case of a man with SLONM with monoclonal gammopathy who had disease onset at 27 years of age.
CASE REPORT Abbreviations: auto-PBSCT, autologous peripheral blood stem cell transplantation; HIV, human immunodeficiency virus; MRC, Medical Research Council; SLONM, sporadic late-onset nemaline myopathy Key words: auto-PBSCT; HIV-negative patients; monoclonal gammopathy; sporadic late-onset nemaline myopathy; young adult onset Correspondence to: M.H. Maeda; e-mail: [email protected] This work was supported in part by a Health and Labour Sciences Research Grant for Intractable Diseases (Neuroimmunological Diseases), Ministry of Health, Labour and Welfare of Japan; the Ministry of Education, Science, Sports and Culture; a Grant-in-Aid for Scientific Research (C), 2012–2014 (24591289 to J.S.); and an Intramural Research Grant (26-8) for Neurological and Psychiatric Disorders from the National Center of Neurology and Psychiatry. C 2014 Wiley Periodicals, Inc. V
Published online 8 November 2014 in Wiley Online Library (wileyonlinelibrary. com). DOI 10.1002/mus.24509
772
Late-Onset Nemaline Myopathy
A 27-year-old man with an unremarkable medical history noticed head drop and swallowing difficulty 9 months before admission. In the next 5–7 months, he gradually realized that his upper body leaned backward when walking due to difficulty carrying his bag related to shoulder muscle weakness. During this time, his body weight had decreased by 10 kg. On admission, muscle atrophy was obvious in the shoulders, paraspinal region, and hips. Using the Medical Research Council (MRC) scale, muscle strength scores were as follows: neck extension 5 2; neck flexion 5 5; deltoid 5 2; serratus anterior 5 3; MUSCLE & NERVE
May 2015
FIGURE 1. Left deltoid muscle biopsy. (A) Many small atrophic fibers contain nemaline rods (Gomori trichrome stain). Scale bar 5 100 lm. (B) Electron microscopy shows affected fibers with a number of cytoplasmic rods with the same electron density as the Z-band. Scale bar 5 5 lm. (C) Muscle symptoms before and after auto-PBSCT. The patient was unable to extend his neck against gravity before auto-PBSCT (left); he regained the ability to keep his head up against gravity 3 months after auto-PBSCT (right). (D) Average muscle score.6 Three months before auto-PBSCT, the patient’s average muscle score decreased rapidly from 8.059 to 7.382. After PBSCT, his score increased gradually to 7.824.
iliopsoas 5 3; gluteus maximus 5 3; gluteus medius 5 4; and other distal muscles 5 5. Laboratory examinations showed that the patient’s serum creatine kinase level was normal. He was negative for the anti-HIV antibody. A monoclonal IgG-k–type protein was detected by immunoelectrophoresis. An M-protein spike of 0.66 g/L was observed by serum protein electrophoresis. The serum free light-chain ratio was abnormal (j/k ratio 0.18). A bone marrow test showed a slight increase in the number of plasma cells (2.2%). Whole-body computed tomography (CT) demonstrated splenomegaly. Needle electromyography (EMG) showed myopathic changes with abnormal spontaneous activity in the deltoid and iliopsoas muscles. Muscle CT images showed atrophy and fatty changes in the paravertebral and gluteus medius muscles. Muscle biopsy was obtained from the left deltoid muscle. The biopsy showed abundant small atrophic fibers with nemaline rods (Fig. 1A), which stained positive for myotilin and a-actinin. Neither necrotic or regenerating fibers or inflammatory cell infiltration was observed. The expression of major histocompatibility complex class I Late-Onset Nemaline Myopathy
on the sarcolemma of non-necrotic fibers was not upregulated. Electron microscopy showed a number of cytoplasmic rods with a square lattice structure (Fig. 1B). We made a diagnosis of SLONM on the basis of these histopathological findings. During the period of diagnostic confirmation, the patient’s muscle weakness progressed. Two months after admission, he had difficulty holding his head erect and had to support his chin with his hand to sustain normal head posture; moreover, he was unable to climb stairs. He also developed dyspnea with a vital capacity of 3.71 L (74% of predicted). After diagnosis, intravenous immunoglobulin 0.4 g/kg day for 5 days and 2 courses of methylprednisolone pulse therapy at 1000 mg/day for 3 days were administered as the initial treatments. Despite these treatments, proximal limb weakness continued to worsen, and he became unable to walk more than 10 m. Because of his poor response to the treatment and the rapid worsening of muscle weakness, we decided to perform auto-PBSCT. Five months after admission, after gaining approval of the ethics committee, we treated the patient with high-dose melphalan MUSCLE & NERVE
May 2015
773
(200 mg/m2), followed by auto-PBSCT (with an uneventful posttransplantation course). One month after auto-PBSCT, strength in his shoulder muscles gradually increased, which he realized while changing his clothes. Three months after auto-PBSCT, strength in his lower limbs had increased enough for him to be able to walk >1000 meters. Twelve months after auto-PBSCT, his neck extension muscle score improved from 2 to 3 on the MRC scale (Fig. 1C), and average muscle score6 increased from 7.382 to 7.824 (Fig. 1D). Although he noted improvement in dysphagia and dyspnea, follow-up examination of vital capacity showed no improvement. Twelve months after auto-PBSCT, the monoclonal protein was not detectable by protein electrophoresis, but it could still be detected by immunoelectrophoresis. Improved muscle power continued until around 1.5 years after auto-PBSCT, when he began to feel fatigability and again had gradually decreased muscle power. Two years after auto-PBSCT, although muscle power and scores of activities of daily living remained higher than before autoPBSCT, there was a gradual decrease in muscle strength.
gammopathy showing a clearly favorable response to auto-PBSCT. It is not clear whether delayed initiation of auto-PBSCT may have affected his response to treatment (treatment initiated 14 months after disease onset). Because auto-PBSCT has many serious side effects,11 we should use caution in its application for SLONM. However, considering that this patient and those reported previously showed favorable responses,2–5 auto-PBSCT should become a treatment option for SLONM. In selecting the appropriate treatment option for this condition—an intractable acquired myopathy with progressive muscle weakness—an early and accurate diagnosis is essential. Because of its rarity, it is sometimes difficult to diagnose patients who show diffuse muscle atrophy and dysphagia as having SLONM, and they are sometimes misdiagnosed as having amyotrophic lateral sclerosis, thereby losing an opportunity for early treatment.1,3 For an early and correct diagnosis and better treatment approach, we suggest SLONM should be added to the list of diseases to consider in the differential diagnosis of progressive muscle weakness with young adult onset.
DISCUSSION
REFERENCES
Thus far, 5 patients with SLONM that started in their 20s have been reported.7–10 All these patients were positive for HIV. With regard to their clinical course, 2 patients treated with corticosteroids showed almost full recovery 6 months after initiation of treatment, and 1 patient treated with plasma exchange showed partial recovery with persistence of substantial muscle weakness.7–10 The clinical course of the remaining patients was not described. Here we report the case of a man with SLONM and monoclonal gammopathy with age of onset of 27 years. To our knowledge, our patient is the youngest observed with HIV-negative SLONM. Considering the clinical course of our patient before and after auto-PBSCT, we believe that autoPBSCT was effective, not only in attenuating disease activity but also in improving the patient’s muscle strength. Although further follow-up of the clinical features of our patient requires more detail (as he showed some signs of decreased muscle strength 2 years after auto-PBSCT), we believe that this is another case of SLONM with monoclonal
1. Chahin N, Selcen D, Engel AG. Sporadic late onset nemaline myopathy. Neurology 2005;65:1158–1164. 2. Benveniste O, Laforet P, Dubourg O, Solly S, Musset L, Choquet S, et al. Stem cell transplantation in a patient with late-onset nemaline myopathy and gammopathy. Neurology 2008;71:531–532. 3. Voermans NC, Minnema M, Lammens M, Schelhaas HJ, Kooi AV, Lokhorst HM, et al. Sporadic late-onset nemaline myopathy effectively treated by melphalan and stem cell transplant. Neurology 2008; 71:532–534. 4. Novy J, Rosselet A, Spertini O, Lobrinus JA, Pabst T, Kuntzer T. Chemotherapy is successful in sporadic late onset nemaline myopathy (SLONM) with monoclonal gammopathy. Muscle Nerve 2010;41: 286–287. 5. Doppler K, Knop S, Einsele H, Sommer C, Wessig C. Sporadic late onset nemaline myopathy and immunoglobulin deposition disease. Muscle Nerve 2013;48:983–988. 6. Brooke MH, Griggs RC, Mendell JR, Fenichel GM, Shumate JB, Pellegrino RJ. Clinical trial in Duchenne dystrophy. I. The design of the protocol. Muscle Nerve 1981;4:186–197. 7. Dalakas MC, Pezeshkpour GH, Flaherty M. Progressive nemaline (rod) myopathy associated with HIV infection. N Engl J Med 1987; 317:1602–1603. 8. Gonzales MF, Olney RK, So YT, Greco CM, McQuinn BA, Miller RG, et al. Subacute structural myopathy associated with human immunodeficiency virus infection. Arch Neurol 1988;45:585–587. 9. Cabello A, Martinez-Martin P, Gutierrez-Rivas E, Madero S. Myopathy with nemaline structures associated with HIV infection. J Neurol 1990;237:64–65. 10. Dwyer BA, Mayer RF, Lee SC. Progressive nemaline (rod) myopathy as a presentation of human immunodeficiency virus infection. Arch Neurol 1992;49:440. 11. Dispenzieri A. POEMS syndrome: 2014 Update on diagnosis, riskstratification, and management. Am J Hematol 2014;89:213–223.
774
Late-Onset Nemaline Myopathy
MUSCLE & NERVE
May 2015
