Abstract
The frequency, patterns of inheritance and clinical phenotypes of inherited myopathies with histologic features of rimmed vacuoles, tubulofilamentous inclusions and absence of inflammation (familial and hereditary inclusion body myopathy [f-IBM]) are poorly defined. Quadriceps sparing is a characteristic of f-IBM seen in the Iranian Jewish population. Among 101 patients with the feature of a red-rimmed vacuolar myopathy, characterized as inclusion body myopathy, seen during the last 4 years, we identified 13 families with f-IBM (12.8% frequency when one member per family was considered). Five families had an autosomal dominant and eight had an autosomal recessive form of inheritance. Among the latter group, five patients with early-onset disease (two Caucasian Americans, an Asian Indian, and two unrelated Iranian Jews) had the distinct feature of quadriceps sparing, which was confirmed by MRI of the thighs. Their disease began with weakness and atrophy of the foot extensors, forearm flexors, and first dorsal interossei muscles and progressed to the forearm flexors, girdle, and axial muscles, but spared the quadriceps. Serum CK was normal. Muscle biopsies showed rimmed vacuoles, small fibers in groups, amyloid deposition (in one patient), tubulofilaments, and no inflammation. Immunocytochemistry did not reveal abnormalities of various membrane or cytoskeletal proteins. Major histocompatibility complex (MHC) class I antigen was expressed only in a few degenerating fibers invaded by macrophages. T-cell infiltrates were not present. We conclude that in a large referral population, dominant and recessive hereditary and familial forms of IBM are not rare. Quadriceps-sparing myopathy appears to be a clinically distinct, autosomal recessive, nonimmune, distal vacuolar myopathy that is not limited to Iranian-Jewish ethnic groups.
NEUROLOGY 1996;47: 977-984
The sporadic form of inclusion body myositis (s-IBM) is characterized by slowly progressive muscle weakness that begins after the age of 40 years with early involvement of quadriceps and forearm flexor muscles. [1-3] The presence of red-rimmed vacuolated muscle fibers in muscle biopsy preparations stained with Gomori's trichrome, along with cytotoxic T cells invading non-necrotic muscle fibers and amyloid deposition within the vacuolated fibers, are the histologic hallmarks of the disease. [1-4]
In addition to s-IBM, there are patients who have histologically similar myopathies, except for the absence of endomysial inflammation, affecting more than one family member. [5-10] These patients comprise a heterogeneous group, currently categorized under the ill-defined rubric of familial or hereditary inclusion body myopathy (f-IBM). Among patients with f-IBM, there is a prototypic disease of autosomal recessive inheritance considered to be exclusive to Iranian and related Jewish populations, and which has a clinical landmark--the sparing of the quadriceps muscle. [5-7] A similar myopathy also occurs in the Tunisian population. [11] Whether such a well-defined subset of inherited myopathy with quadriceps sparing occurs in other ethnic groups and in the U.S. population is unknown, but this information is potentially important in categorizing these myopathies for molecular genetics studies.
In our effort to identify genetic patterns and unique clinical phenotypes among patients with the histologic diagnosis of inclusion body myopathy, we retrospectively examined and studied all patients referred to our neuromuscular clinic at the National Institutes of Health over the last 6 years. We present the genetic, clinical, radiologic, and histologic features of the identified patients and discuss the significance of quadriceps sparing as a distinguishing characteristic of the nosologic entity of familial or hereditary inclusion body myopathy.
Methods.
Initial record review.
We reviewed the records of 101 patients previously studied and examined at the Neuromuscular Diseases Section of the National Institutes for Neurological Disorders and Stroke from 1989 to 1995 by at least one of the authors. These patients, who were diagnosed as having inclusion body myopathy, had in their muscle biopsy red-rimmed vacuoles with Gomori's trichrome stain, variation of fiber size, and small fibers in groups. The presence of inflammatory cells was not inclusion criterion because inflammation can be absent even in s-IBM. [2-4] Patients with exposure to myotoxic drugs, with a clinical picture consistent with the previously described syndromes of distal myopathy or oculopharyngeal muscular dystrophy, and those with metabolic myopathies were excluded. Our goal was to identify patients with a family history of a similar muscle disease, examine their clinical profiles, and determine the pattern of inheritance.
Examination of identified patients.
Patients and, when possible, their family members fulfilling the clinicopathologic pattern mentioned above were readmitted and reexamined. Clinical signs of involvement of the quadriceps muscle were sought in every patient. Muscle biopsies were repeated for several of the patients and their family members to reconfirm the histologic patterns and to perform additional studies, as described below. A serum chemistry profile, various autoantibodies, and muscle enzymes were obtained.
Special studies.
1. MRI of the thighs were performed in selected patients to confirm the clinical impression of quadriceps sparing. The MRI scans were compared with the scans of the thighs of patients with typical s-IBM.
2. Open muscle biopsy, processed for muscle enzyme histochemistry, Congo-red staining, and electron microscopy.
3. Immunocytochemistry to evaluate the accumulation or absence of relevant cytoskeletal or membrane proteins and to characterize the type of the endomysial inflammatory cells. The immunocytochemical studies were performed on the muscle biopsy preparations, as previously described, [12] utilizing the following mouse immunoglobulin G (IgG) monoclonal antibodies directed against (1) desmin (1:100) from Dako; (2) vimentin (1:200) and A beta amyloid (1:10), both from Zymed; (3) dystrophin--N-terminal (1:20), dystrophin--rod portion (1:20), adhalin (1:50), dystroglycan (1:200), spectrin (1:50), utrophin--N-terminal (1:20), and ubiquitin (1:10), all from Novacastra; and (4) T cells, macrophages, neural-cell adhesion molecule (N-CAM), and MHC class 1 molecules, as previously described. [11] Immunoreactivity was visualized with secondary peroxidase-conjugated antimouse IgG antibodies (for T cells, macrophages, N-CAM, and MHC class 1 molecules), fluorescein isothiocymate-conjugated antimouse IgG (for dystroglycan), and rhodamine-conjugated goat antimouse IgG (for all other antibodies). Control specimens included normal muscle and muscle biopsies from patients with s-IBM and Duchenne muscular dystrophy.
Results.
Among the 101 patients who had a histologic diagnosis of a red-rimmed vacuolar myopathy on Gomori's trichrome stain, we identified 13 families each with two or more members affected (12.8% prevalence when one member per family was considered) Table 1. Five of them had an autosomal dominant and eight had a likely autosomal recessive pattern of inheritance. Twelve patients in the sporadic group did not have the characteristic clinical phenotype of early involvement of quadriceps and forearm flexor muscles seen in patients with s-IBM. All other patients were given a diagnosis of s-IBM based on the clinical and histologic picture.
Table 1. Patients with red-rimmed vacuolar inclusion body myopathies (N = 101)
Families with an autosomal dominant pattern of inheritance.
No unique clinical phenotype, such as early and selective involvement of the forearm muscles, was identified among the five families in this group Figure 1. The age at onset of myopathy varied, beginning before the age of 40 years in three families and after the age of 40 years in the other two families. A combination of proximal and distal muscle weakness dominated the clinical picture. Patients in two families had prominent wasting and weakness of the neck, scapular, and intercostal muscles. Redrimmed vacuoles, eosinophilic inclusions, and significant fiber size variation with small, rounded fibers scattered or in small groups were the characteristic findings in the muscle biopsy preparations of all the patients. No primary endomysial inflammation was noted. Focal, small, homogeneous, basophilic, smudge-like collections were seen with hematoxylin and eosin and trichrome stains in subsarcolemmal and central locations in some fibers of the muscles of four different families. These collections immunoreacted with desmin (not shown) but not with the other antibodies used. The creatine kinase was normal or slightly elevated in some families.
Figure 1. Pedigree of families with an inclusion body myopathy of autosomal dominant inheritance (open square male; open circle female; ???? deceased; ???? proband; fill square affected; ???? number of siblings of either gender; ????, ???? incomplete clinical syndrome; ????, ???? untested).
Families with likely autosomal recessive pattern of inheritance.
No quadriceps sparing.
Four families in this group Figure 2 did not show evidence of quadriceps sparing, and their clinical phenotype did not follow a characteristic or known clinical pattern such as involvement of the extensor compartment of the leg. In two of the families the symptoms began after the age of 40 years, the biopsies did not show endomysial inflammation, and the clinical phenotype was a combination of proximal and distal weakness. The CK levels in these patients were normal.
Figure 2. Pedigree of families with an inclusion body myopathy (with clinical involvement of quadriceps) of likely autosomal recessive inheritance (open circle open square number of siblings of the same gender; refer to Figure 1 for the meanings of the other symbols).
One family of two brothers Figure 2C had the clinical phenotype of s-IBM with early involvement of the quadriceps and forearm muscles and endomysial inflammation histologically indistinguishable from that of s-IBM. [1,2]
Quadriceps sparing.
Four families (one Caucasian American, one Asian Indian, and two unrelated Iranian Jewish families) had early-onset disease and a characteristic sparing of the quadriceps muscle despite advanced involvement of other muscle groups. The clinical and histologic features of these patients are described below, and their clinical similarities with the two Iranian Jewish patients are illustrated.
Description of the phenotype in patients.
Patient 1.
A 29-year-old white woman who had normal motor development and a healthy, active childhood developed muscle weakness at the age of 22 years. No consanguinity was present in the family. She had an older brother who had a similar myopathy (patient 2). The initial manifestation was bilateral foot drop due to weakness of the foot extensors. This was followed by weakness of the long flexors of the index and middle fingers and, subsequently, of all the fingers. Within 2 years from onset, she developed proximal upper and lower extremity weakness that spared the quadriceps in size and strength. When examined at 29 years of age, her disease had progressed with severe weakness and atrophy affecting all muscle groups, proximal and distal, except for the quadriceps muscle and the abductors of the hips. The quadriceps had a strikingly normal bulk and strength Figure 3A. Atrophy was particularly noticeable in the extensor muscles of the feet and in the extensor digitorum brevis Figure 3B and the first dorsal interossei muscles. Facial and bulbar muscles were spared. Tendon reflexes were intact in the upper extremities. In the lower extremities, only the knee reflex was present. Mentation, cranial nerves, sensation, and coordination were normal. The combination of proximal and distal muscle weakness that spared the quadriceps muscle resulted in a waddling gait with slapping of the feet and locking of the knees. Serum CK was normal (90 U/liter). Electromyography was consistent with a myopathy.
Figure 3. (A) Patient 1. The quadriceps has normal bulk and contour. (B) Patient 1. Groove adjacent to the tibia shows the wasting of the extensor muscles of the leg. The extensor digitorum brevis is also wasted. (C) Patient 3. The quadriceps is well preserved, but the distal muscles are wasted and weak. Foot drop is noted.
Patient 2.
This 34-year-old man was the sibling of Patient 1. He had a progressive myopathy that began at the age of 21 years with bilateral foot drop followed over the next 2 years by proximal upper extremity weakness and later by weakness of the long finger flexors and proximal muscles of the lower extremities. Initial neurologic examination documented the preservation of the quadriceps muscle's bulk and strength. By the time of our examination 13 years after onset, his muscle weakness had progressed to paralysis of all limbs except for minimal movement at finger and elbow flexion, shoulder adduction, hip abduction, and knee extension. Neck flexion was moderately weak with no facial or bulbar muscle weakness. Tendon reflexes were absent. Mentation, sensation, and coordination were intact. He was unable to walk. CK was 78 U/liter.
Patient 3.
This 52-year-old Asian Indian woman had progressive limb weakness from the age of 24 years. Her symptoms began with a foot drop and hip weakness. By the age of 30 she had developed a waddling gait. At 38 years of age she had documented bilateral foot drop and moderate weakness of the hips but normal strength of the hamstrings, quadriceps, and gastrocnemius. Gradually her finger flexors and hand grip became weak and she developed wasting of the first dorsal interosseous muscle and weakness of the proximal muscles of the upper extremities.
She was born to nonconsanguineous parents from Gujarat, India. Her younger brother, who is 48 years old Figure 4, had developed similar symptoms at the age of 18 years, but he was not available for examination. His initial problem was the foot drop. The disease progressed rapidly and he became wheelchair dependent by the age of 28 years.
Figure 4. Pedigree of two non-Iranian families with quadriceps-sparing myopathy showing a likely autosomal recessive pattern of inheritance (???? multiple mating; refer to Figure 1 for the meanings of the other symbols).
When we examined her at the age of 52 years she had wasting of all the lower extremity muscles except the quadriceps, which was hypertrophic Figure 3C. There was wasting of the first dorsal interossei muscles and the shoulder girdle muscles. Neck flexion weakness was mild with no weakness of the facial or the bulbar muscles. She had severe weakness in all the muscles of the lower extremities, except for the quadriceps muscle, which had normal strength, and the hip abductors, which were preserved. There was a moderate degree of weakness of all the muscles in the upper extremities, more prominent in the flexors of the arms and forearms. Tendon reflexes were present and mental and sensory examinations were normal. Gait was a combination of a waddle with slapping of the feet. CK was 225 U/liter (normal being 52-386 U/liter).
Clinical comparison with two Iranian Jewish patients with autosomal recessive quadriceps-sparing myopathy.
Patients 1, 2, and 3 had the identical clinical picture with two Iranian Jewish patients we examined in reference to pattern of inheritance, age of onset, initial clinical manifestations, pattern of weakness, and sparing of the quadriceps muscle Table 2. One patient was a 34-year-old Iranian Jewish woman born to nonconsanguineous parents from Isfahan and Tehran. She had developed a progressive myopathy from the age of 25 years. A maternal aunt and a second cousin were reported to have a myopathy with similar features. The other patient was a 35-year-old Iranian Jewish woman born to nonconsanguineous parents from southern Iran. Her symptoms began at the age of 32 years and have been slowly progressive. One of the patient's seven siblings, who was not available for examination, was affected with a similar myopathy that began at the age of 36 years.
Table 2. Homogeneity of quadriceps-sparing myopathy in different ethnic groups
Magnetic resonance imaging.
T1-weighted studies of the quadriceps muscle were performed in patients 1, 2, and 3 and in the Iranian Jewish (Teh) patient. Characteristic sparing of the quadriceps muscle, compared with fatty or fibrous replacement of the hamstring muscles, was noted in these patients, who belong to three different ethnic groups Figure 5.
Figure 5. T1-weighted MR images of the thighs in patients with quadriceps-sparing myopathy from three different ethnic groups: Caucasian (patient 1), Asian Indian (patient 3), and Iranian Jew (IJP2). There is prominent sparing of the quadriceps muscle in the extensor compartment, in contrast to the hyperintensity of the hamstrings in the flexor compartment due to fatty or connective tissue replacement of atrophic muscles.
Muscle biopsy findings.
Muscle biopsies from patients 1 and 3, performed on the clinically normal quadriceps muscle, showed fiber size variation with hypertrophic and atrophic fibers, internalized nuclei, fiber splitting, eosinophilic inclusions, and several rimmed and nonrimmed vacuoles Figure 6A. Small fibers, usually rounded, were found scattered and in groups (see Figure 6A). A few mononuclear inflammatory cells were found only around scattered degenerating fibers. Inflammatory cells around non-necrotic fibers were not found. Enlarged and vesicular nuclei, at times with increased chromatin, were noted. No signs of denervation or reinnervation were seen. Congo-red staining visualized with rhodamine filters detected amyloid in patient 1 (not shown).
Figure 6. (A) Patient 1. Cross section of muscle stained with trichrome shows red-rimmed vacuolated fibers, fiber size variation, and absence of inflammation (times280, before 12.7% reduction). (B) Patient 3. Electron microscopy of the muscle shows typical cytoplasmic tubulofilaments (arrow) that are 15 to 20 nm in diameter (times38,400, before 26.7% reduction).
Immunohistochemistry.
No abnormalities were detected in the cytoskeletal and membrane protein staining patterns. Ubiquitin and beta-amyloid staining were not detected by immunohistochemistry. Diffusely increased staining of desmin and vimentin was found in a few scattered fibers undergoing regeneration and in a few vacuolated fibers. MHC class 1 and N-CAM expression was found only in some degenerating (often vacuolated) fibers Figure 7. Immunostaining for inflammatory cells revealed only macrophages, most of which were around degenerating or necrotic fibers. No lymphocytes were detected. These findings did not reveal an apparent autoimmune basis for the myopathy.
Figure 7. Patient 3. (A) Cross section of muscle stained with trichrome shows two fibers with small vacuoles. Serial sections immunostained with antibodies to major histocompatibility complex class 1 molecule (MHC-1) (B) and N-CAM (C) demonstrate expression of MHC-1 and N-CAM in the two vacuolated fibers. There is no upregulation of MHC-1 expression in healthy muscle fibers (times250).
Electron microscopy.
Vacuoles containing membrane degradation products were found in the muscle biopsies of three patients, one from each ethnic group. In a few fibers, proliferation of mitochondria with irregular size and shape was also seen. Cytoplasmic tubulofilaments were found in patient 3 Figure 6B. No abnormalities of the nuclei were detected.
Discussion.
We identified a myopathy in two Caucasian Americans and one Asian Indian patient characterized by: (1) family history suggestive of autosomal recessive inheritance; (2) onset of predominantly distal limb weakness in early adulthood, beginning at the extensor compartment of the legs and the extensor digitorum brevi; (3) development of generalized proximal muscle weakness with characteristic sparing of the quadriceps; (4) a normal CK level; and (5) a clinicohistologic and inheritance pattern identical to the "rimmed vacuolar myopathy sparing the quadriceps" seen in the Iranian Jews. [5-8] Our findings suggest that quadriceps-sparing myopathy is not unique to the Iranian Jewish ethnic group, an observation which is useful to establish the underlying genetic defect in a larger population. The recent short report describing quadriceps-sparing myopathy in a Tunisian family [12] supports our conclusion. Furthermore, there are descriptions of Japanese families with distal myopathies where the quadriceps muscle has been less affected. [13,14]
The evolving difficulties related to the nosology and classification of hereditary and familial inclusion body myopathy has attracted considerable attention. In our series, these difficulties became evident during the enrollment of patients in treatment trials with immunosuppressive medications and during the selection of homogeneous patient groups for genetic studies. Although red-rimmed vacuoles, tubulofilamentous inclusions, and accumulation of congophilic amyloid deposits are shared by most distal, usually inherited, myopathies, as noted by others, [15-18] their clinical phenotype and pattern of inheritance are quite variable. A classification of both autosomal recessive and autosomal dominant distal myopathies was based on the age of onset, geographic incidence, predominance of upper or lower extremity involvement, flexor or extensor compartment involvement, and degree of CK elevation. [19] Although some clinical resemblance is noted with Nonaka's type of autosomal recessive distal myopathy, [13,14] quadriceps-sparing myopathy is a distinctly distal, red-rimmed vacuolar myopathy that occurs in more than one ethnic group and has the unique clinical pattern of sparing the quadriceps muscle. Compared with s-IBM, patients with quadriceps-sparing myopathy differ not only by the reversal of quadriceps involvement and autosomal recessive inheritance, but also by (1) disease onset before the age of 40 years, (2) early involvement of distal musculature with subsequent involvement of the proximal muscles, (3) lack of lymphocytic cell infiltrates around non-necrotic fibers, and (4) expression of MHC class 1 antigen limited to a few N-CAM-positive or vacuolated fibers, but not to healthy fibers.
In addition to quadriceps-sparing myopathy, we encountered nine other families with predominantly distal, red-rimmed vacuolar inclusion body myopathy, four of apparent autosomal recessive and five of autosomal dominant inheritance, that did not have quadriceps sparing, highlighting the clinical and genetic heterogeneity of these disorders. These patients did not resemble the previously described subtypes of distal myopathies. [13,14,19] In the autosomal recessive form without quadriceps sparing, the age of onset and normal CK levels resembled the pattern of Nonaka's distal myopathy, [13,14] but the typical onset of weakness and wasting in the extensor compartment of the legs was absent. In addition, in previous descriptions of other families with inclusion body myopathy the quadriceps muscle was not spared. [8-10] It is unclear whether the histologic features common to all such myopathies reflect similar pathogenetic mechanisms. The presence of desmin seen in four of our families with the autosomal dominant pattern of inheritance is of uncertain significance, as there are similar changes in various other myopathies. [20] Furthermore, our patients did not have the cardiac involvement seen in the so-called desmin-storage myopathies. [21] At present, and until future molecular genetic work provides us with a better classification, clinical and inheritance patterns may be used to study such patients as distinct subtypes, rather than allelic diseases.
Because the vacuolar formation in familial myopathy seems to require the presence of innervation and hence contraction of muscle fibers in culture, [22] abnormalities of membrane, structural, or contractile proteins and their genes may be causally related to the muscle fiber destruction. Although our immunohistochemical analysis did not detect an abnormal staining pattern of known protein products, future studies may identify abnormalities in other undefined proteins and their genes.
- Copyright 1996 by Advanstar Communications Inc.
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