The clinical, electromyographic, and histologic characteristics of a 17-yearold girl with reducing body myopathy are described. She is, to our knowledge, the oldest reported case and the only patient described with severe mitral valve prolapse and scoliosis. Electromyography demonstrated spontaneous positive sharp waves and fibrillation potentials with many lowamplitude, short, polyphasic motor unit potentials. The right deltoid muscle was chaacterized by focal areas with large fibers associated with increased endomysial connective tissue and “split” fibers. Purple-gray sarcoplasmic masses stained with trichrome were PAS-negative, appeared as “empty” spaces with both ATPase and NADH-TR, and stained darkly with menadione NBT. The features described expand the clinical presentation of this myopathy, and may lead to a better understanding of its etiology. Key words: congenital myopathy myopathy reducing mitral valve prolapse * histochemical electromyography MUSCLE & NERVE 15:463-466 1992
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A UNIQUE CASE OF REDUCING BODY MYOPATHY SIMONE NOMIZU, MD, DONALD A. PERSON, MD, COSWIN SAITO, MD, and L. JOHN LOCKET, MD
Reducing body myopathy (RBM) is a rare or under-recognized congenital myopathy, characterized clinically by progressive muscle weakness, and pathologically by the presence of sarcoplasmic bodies which stain positively with menadione nitroblue tetrazolium (NBT). Both a rapidly progressive form and a benign vaiant of this disorder have been since Brooke ad Neville’ first reported their case nearly 20 years ago. CASEREPORT
A 17-year-old Filipino female was born at fullterm gestation with a birth weight of 7 pounds 8 ounces after an unremarkable prenatal course. N o feeding difficulties were noted, and her develop-
From the Department of Pediatrics (Drs Nomiru and Person), the Department of Physical Medicine (Dr. Saito), Tripler Army Medical Center, Honolulu, Hawaii. and the Department of Pathology, Straub Clinic and Hospital, Honolul, Hawaii (Dr Lockett) Presented in part at the 36th Annual AAEE Scientific Meeting, Washington, DC, September 15-16, 1989 The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. Address reprint requests to Dr. Nomizu, Department of Pediatrics, Dewitt Army Community Hospital, Fort Belvoir, VA 22060 Accepted for publication March 21, 1991 CCC 0148-639X1921040463-04 $04.00 0 1992 John Wiley & Sons, Inc
Reducing Body Myopathy
ment was normal throughout infancy and early childhood. Family history for neuromuscular diseases was negative. ‘The patient’s mother noted that, at approximately 13 years of age, her daughter developed diffuse weakness and easily fatigability. During the same year, she was diagnosed with mild scoliosis. She was hospitalized several months later with supraventricular tachycardia for which she was treated with verapamil. At that time, an echocardiogram revealed severe mitral valve prolapse and mitral regurgitation. Over the next 4 years, the patient maintained a weight of only 80 pounds. Flexion contractures developed about the knees, elbows, hips, and ankles. The patient was diagnosed by a geneticist as having Marfan’s syndrome, although repeated eye exams showed no evidence of lens dislocation. Several urine nitroprusside tests to rule out homocystinuria were negative. Beals’ contractural arachnodactyly was also considered as a possible diagnosis. Pulmonary function tests, at age 13 years, initially showed mild ventilatory defects, which progressively worsened over the next 2 years. Forced vital capacity (FVC) decreased to 30% of predicted, while total lung capacity (TLC) reduced to 49% of predicted. Because of deteriorating pulmonary status thought to be secondary to scoliosis, the patient underwent Harrington rod placement at 16 years of age. One year after this surgery, her
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lung volumes fell further to an FVC of 24% of predicted, and a TLC 40% of predicted. Her maximal voluntary ventilation at that time was 43% of predicted. At age 17, the patient was hospitalized and extensively evaluated for poor weight gain, anorexia, and dyspnea. A barium swallow showed an “ineffective second peristaltic wave.” Esophageal manometry demonstrated low normal voltage. An electrocardiogram showed right axis deviation, right ventricular enlargement, possible left atrial enlargement, and a first degree heart block. A thallium myocardial perfusion scan was normal. FVC at this time had declined to 19% of predicted. Urinalysis and complete blood count were normal, as were renal and hepatic profiles, except for a bicarbonate in the range of 26 to 30 mmol/L. A rheumatologic and immunologic work-up was pursued due to her orthopedic deformities and unusual phonation (sometimes seen in dermatomyositis): immunoglobulins were all normal (IgG 106 mg/dL, IgM 211 mg/dL, IgA 182 mg/ dL); tests for antinuclear antibodies and rheumatoid factor were negative; third and fourth components of complement were normal (C3 103 mg/ dI,, C4 20 mg/dI,); erythrocyte sedimentation rate was 4 mm/h; tests for circulating immune complexes included a normal Raji cell assay (13 pg/ mL) and a markedly elevated Clq-binding assay (68.2 pgE/mL) suggestive of high molecular weight circulating immune complexes. 1 Two months later, at age 172, the patient was admitted following an apparent seizure. She was found to have pneumonia with secondary respiratory failure and required mechanical ventilation. Physical examination at that time revealed a markedly wasted adolescent female with flat, symmetric facies; harsh 4/6 holosystolic murmur over the entire precordium radiating to the back; rales and decreased breath sounds at the left lung base; a firm, nontender abdomen; bilateral knee and ankle contractures; intact cranial nerves I1 through XII; slightly decreased deep-tendon reflexes; and bilateral symmetric limb weakness with 3/5 motor strength, her lower extremities being slightly weaker than her upper extremities and her proximal muscles weaker than distal muscles (Fig. 1). Chest x-ray revealed bilateral pleural effusions, a retrocardiac infiltrate, severe thoracolumbar scoliosis, and a markedly narrow anteroposterior diameter. Initial sputum cultures grew nonmucoid Pseudomonas aeruginosa and Staphylococcus au-
464
Reducing Body Myopathy
FIGURE 1. Patient at 17 years of age. Emaciated appearance, knee and ankle contractures, scoliosis.
reus. Creatine phosphokinase was 517 IU on ad-
mission with a postmorbid value of 214 IU. Aldolase was 8.0 pU/m, SGPT 30 U/L, SGOT 46 IU/L, and LDH 281 U/L. Thyroid function tests, as well as parathyroid hormone levels, were normal. Head computerized tomography was normal. Electromyography and nerve conduction tests were consistent with a primary myopathic disorder. Deltoid muscle biopsy was abnormal. The patient was treated for 2 weeks with intravenous antibiotics and intensive ventilatory and nutritional support. She failed several attempts at extubation over the next 2 months, and finally underwent tracheotomy. At this time, she contiues to require nighttime ventilation and enteral feedings, but remains ambulatory. Serum CK values on her 7-year-old sister and her mother were 135 U/L (slightly elevated) and 75 U/L, respectively. SPECIAL STUDIES Electrophysiologic Studies. Distal motor latencies were normal, ranging from 3.3 ms in the left median nerve to 4.4 ms in the left peroneal nerve. Motor nerve conduction velocities were normal, ranging from 40 m/s in the left peroneal nerve to 57 m/s in the left median nerve. Distal sensory latency was normal in the left median nerve at 1.9
MUSCLE & NERVE
April 1992
FIGURE 2. H & E stain. Marked variability in fiber size, split fibers, internal nuclei, and sarcoplasmic masses (bar = 100 prn).
FIGURE 3. Menadione-NBT stain. Dark-staining intracytoplasrnic bodies (bar = 100 pm).
ms. Needle examination study was done in the left rectus femoris, tibialis anterior, medial head of the gastrocnemius, first dorsal interossei, biceps brachii, and deltoid muscles. Spontaneous activity was present as 1+ to 2+ positive sharp waves and 1 + fibrillation potetials. Motor unit potentials ranged from 300 to 300 mV and 4 to 12 ms in duration. There were many small-amplitude, shortduration polyphasic motor unit potentials.
the oldest reported case of RBM, and represents one of the mildest cases reported thus She is the only case in the literature with mitral valve prolapse. Cardiac involvement may be a significant feature in this myopathy, and may be more likely to occur in those patients who survive past childhood. This patient is the only RBM patient thus far with severe scoliosis requiring surgical treatment. Again, this is possibly because she has survived to develop this complication. The abnormal esophageal motility studies, suggestive of a swallowing dysfunction in this girl, may prove to be a feature of reducing body myopathy. Electrodiagnostic studies from previous reports did not describe positive waves and fibrillations which were documented in our patient. ’The significance of this finding is unclear at present, but deserves further study. Our patient is the only one to date who has been immunologically evaluated in detail. The abnormal Clq-binding assay, taken together with positive staining with IgG by immunofluorescence, suggests that a possible immune-mediated process accounts for the degenerative process in RBM. Perhaps, the inclusion bodies represent immune complexes or complement-mediated fibrinogen deposits. This case of reducing body myopathy demonstrated some unique features which serve to expand the clinical picture of this disorder, and perhaps, to steer the direction of future research toward the study of the immunologic aspects of this disease.
Muscle Biopsy. Muscle was obtained at biopsy and prepared for histochemistry as described by Dubowitz and Brooke.“ Hematoxylin-eosin stained sections were markedly abnormal, characterized by marked variability in the size of the fibers with 2 focal areas showing numerous large fibers measuring up to 125 pm. These areas were also characterized by increased endomysial connective tissue, with evidence of phagocytosis, “split” fibers, degenerative sarcoplasm, internal nuclei in more than 3% of the total fiber population, and small foci of dystrophic calcification (Fig. 2). Trichrome staining revealed foci with purple-gray sarcoplasmic masses, which were NADH-TR, PAS, Oil Red 0, and ATPase negative at pH values of 9.4, 4.6, and 4.2. These same foci stained positively with menadione-NBT (Fig. 3). Direct immunofluorescence of these same sections stained in a speckled pattern with IgM, complement, and fibrinogen. DISCUSSION
There are several unique clinical and laboratory findings in the patient we have described. She is
Reducing Body Myopathy
MUSCLE & NERVE
April 1992
465
REFERENCES 1. Brooke MH, Neville HE: Reducing body myopathy. Neurol-
40 1972;22:829- 840. 2. Carpenter S, Karpati G, Holland P: New observations in reducing body myopathy. Neurolo
.
.
A UNIQUE CASE OF REDUCING BODY MYOPATHY SIMONE NOMIZU, MD, DONALD A. PERSON, MD, COSWIN SAITO, MD, and L. JOHN LOCKET, MD
Reducing body myopathy (RBM) is a rare or under-recognized congenital myopathy, characterized clinically by progressive muscle weakness, and pathologically by the presence of sarcoplasmic bodies which stain positively with menadione nitroblue tetrazolium (NBT). Both a rapidly progressive form and a benign vaiant of this disorder have been since Brooke ad Neville’ first reported their case nearly 20 years ago. CASEREPORT
A 17-year-old Filipino female was born at fullterm gestation with a birth weight of 7 pounds 8 ounces after an unremarkable prenatal course. N o feeding difficulties were noted, and her develop-
From the Department of Pediatrics (Drs Nomiru and Person), the Department of Physical Medicine (Dr. Saito), Tripler Army Medical Center, Honolulu, Hawaii. and the Department of Pathology, Straub Clinic and Hospital, Honolul, Hawaii (Dr Lockett) Presented in part at the 36th Annual AAEE Scientific Meeting, Washington, DC, September 15-16, 1989 The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. Address reprint requests to Dr. Nomizu, Department of Pediatrics, Dewitt Army Community Hospital, Fort Belvoir, VA 22060 Accepted for publication March 21, 1991 CCC 0148-639X1921040463-04 $04.00 0 1992 John Wiley & Sons, Inc
Reducing Body Myopathy
ment was normal throughout infancy and early childhood. Family history for neuromuscular diseases was negative. ‘The patient’s mother noted that, at approximately 13 years of age, her daughter developed diffuse weakness and easily fatigability. During the same year, she was diagnosed with mild scoliosis. She was hospitalized several months later with supraventricular tachycardia for which she was treated with verapamil. At that time, an echocardiogram revealed severe mitral valve prolapse and mitral regurgitation. Over the next 4 years, the patient maintained a weight of only 80 pounds. Flexion contractures developed about the knees, elbows, hips, and ankles. The patient was diagnosed by a geneticist as having Marfan’s syndrome, although repeated eye exams showed no evidence of lens dislocation. Several urine nitroprusside tests to rule out homocystinuria were negative. Beals’ contractural arachnodactyly was also considered as a possible diagnosis. Pulmonary function tests, at age 13 years, initially showed mild ventilatory defects, which progressively worsened over the next 2 years. Forced vital capacity (FVC) decreased to 30% of predicted, while total lung capacity (TLC) reduced to 49% of predicted. Because of deteriorating pulmonary status thought to be secondary to scoliosis, the patient underwent Harrington rod placement at 16 years of age. One year after this surgery, her
MUSCLE 8, NERVE
April 1992
463
lung volumes fell further to an FVC of 24% of predicted, and a TLC 40% of predicted. Her maximal voluntary ventilation at that time was 43% of predicted. At age 17, the patient was hospitalized and extensively evaluated for poor weight gain, anorexia, and dyspnea. A barium swallow showed an “ineffective second peristaltic wave.” Esophageal manometry demonstrated low normal voltage. An electrocardiogram showed right axis deviation, right ventricular enlargement, possible left atrial enlargement, and a first degree heart block. A thallium myocardial perfusion scan was normal. FVC at this time had declined to 19% of predicted. Urinalysis and complete blood count were normal, as were renal and hepatic profiles, except for a bicarbonate in the range of 26 to 30 mmol/L. A rheumatologic and immunologic work-up was pursued due to her orthopedic deformities and unusual phonation (sometimes seen in dermatomyositis): immunoglobulins were all normal (IgG 106 mg/dL, IgM 211 mg/dL, IgA 182 mg/ dL); tests for antinuclear antibodies and rheumatoid factor were negative; third and fourth components of complement were normal (C3 103 mg/ dI,, C4 20 mg/dI,); erythrocyte sedimentation rate was 4 mm/h; tests for circulating immune complexes included a normal Raji cell assay (13 pg/ mL) and a markedly elevated Clq-binding assay (68.2 pgE/mL) suggestive of high molecular weight circulating immune complexes. 1 Two months later, at age 172, the patient was admitted following an apparent seizure. She was found to have pneumonia with secondary respiratory failure and required mechanical ventilation. Physical examination at that time revealed a markedly wasted adolescent female with flat, symmetric facies; harsh 4/6 holosystolic murmur over the entire precordium radiating to the back; rales and decreased breath sounds at the left lung base; a firm, nontender abdomen; bilateral knee and ankle contractures; intact cranial nerves I1 through XII; slightly decreased deep-tendon reflexes; and bilateral symmetric limb weakness with 3/5 motor strength, her lower extremities being slightly weaker than her upper extremities and her proximal muscles weaker than distal muscles (Fig. 1). Chest x-ray revealed bilateral pleural effusions, a retrocardiac infiltrate, severe thoracolumbar scoliosis, and a markedly narrow anteroposterior diameter. Initial sputum cultures grew nonmucoid Pseudomonas aeruginosa and Staphylococcus au-
464
Reducing Body Myopathy
FIGURE 1. Patient at 17 years of age. Emaciated appearance, knee and ankle contractures, scoliosis.
reus. Creatine phosphokinase was 517 IU on ad-
mission with a postmorbid value of 214 IU. Aldolase was 8.0 pU/m, SGPT 30 U/L, SGOT 46 IU/L, and LDH 281 U/L. Thyroid function tests, as well as parathyroid hormone levels, were normal. Head computerized tomography was normal. Electromyography and nerve conduction tests were consistent with a primary myopathic disorder. Deltoid muscle biopsy was abnormal. The patient was treated for 2 weeks with intravenous antibiotics and intensive ventilatory and nutritional support. She failed several attempts at extubation over the next 2 months, and finally underwent tracheotomy. At this time, she contiues to require nighttime ventilation and enteral feedings, but remains ambulatory. Serum CK values on her 7-year-old sister and her mother were 135 U/L (slightly elevated) and 75 U/L, respectively. SPECIAL STUDIES Electrophysiologic Studies. Distal motor latencies were normal, ranging from 3.3 ms in the left median nerve to 4.4 ms in the left peroneal nerve. Motor nerve conduction velocities were normal, ranging from 40 m/s in the left peroneal nerve to 57 m/s in the left median nerve. Distal sensory latency was normal in the left median nerve at 1.9
MUSCLE & NERVE
April 1992
FIGURE 2. H & E stain. Marked variability in fiber size, split fibers, internal nuclei, and sarcoplasmic masses (bar = 100 prn).
FIGURE 3. Menadione-NBT stain. Dark-staining intracytoplasrnic bodies (bar = 100 pm).
ms. Needle examination study was done in the left rectus femoris, tibialis anterior, medial head of the gastrocnemius, first dorsal interossei, biceps brachii, and deltoid muscles. Spontaneous activity was present as 1+ to 2+ positive sharp waves and 1 + fibrillation potetials. Motor unit potentials ranged from 300 to 300 mV and 4 to 12 ms in duration. There were many small-amplitude, shortduration polyphasic motor unit potentials.
the oldest reported case of RBM, and represents one of the mildest cases reported thus She is the only case in the literature with mitral valve prolapse. Cardiac involvement may be a significant feature in this myopathy, and may be more likely to occur in those patients who survive past childhood. This patient is the only RBM patient thus far with severe scoliosis requiring surgical treatment. Again, this is possibly because she has survived to develop this complication. The abnormal esophageal motility studies, suggestive of a swallowing dysfunction in this girl, may prove to be a feature of reducing body myopathy. Electrodiagnostic studies from previous reports did not describe positive waves and fibrillations which were documented in our patient. ’The significance of this finding is unclear at present, but deserves further study. Our patient is the only one to date who has been immunologically evaluated in detail. The abnormal Clq-binding assay, taken together with positive staining with IgG by immunofluorescence, suggests that a possible immune-mediated process accounts for the degenerative process in RBM. Perhaps, the inclusion bodies represent immune complexes or complement-mediated fibrinogen deposits. This case of reducing body myopathy demonstrated some unique features which serve to expand the clinical picture of this disorder, and perhaps, to steer the direction of future research toward the study of the immunologic aspects of this disease.
Muscle Biopsy. Muscle was obtained at biopsy and prepared for histochemistry as described by Dubowitz and Brooke.“ Hematoxylin-eosin stained sections were markedly abnormal, characterized by marked variability in the size of the fibers with 2 focal areas showing numerous large fibers measuring up to 125 pm. These areas were also characterized by increased endomysial connective tissue, with evidence of phagocytosis, “split” fibers, degenerative sarcoplasm, internal nuclei in more than 3% of the total fiber population, and small foci of dystrophic calcification (Fig. 2). Trichrome staining revealed foci with purple-gray sarcoplasmic masses, which were NADH-TR, PAS, Oil Red 0, and ATPase negative at pH values of 9.4, 4.6, and 4.2. These same foci stained positively with menadione-NBT (Fig. 3). Direct immunofluorescence of these same sections stained in a speckled pattern with IgM, complement, and fibrinogen. DISCUSSION
There are several unique clinical and laboratory findings in the patient we have described. She is
Reducing Body Myopathy
MUSCLE & NERVE
April 1992
465
REFERENCES 1. Brooke MH, Neville HE: Reducing body myopathy. Neurol-
40 1972;22:829- 840. 2. Carpenter S, Karpati G, Holland P: New observations in reducing body myopathy. Neurolo
