Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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Reducing body myopathy, a rare condition with early infant to adult onset, is characterized by abnormal inclusions in muscle fibers that are highlighted by special stains. A protein, FHL1, has been identified in these inclusions by proteomic techniques, and mutations in the corresponding gene identified in both sporadic and familial cases. Although the pathophysiology remains poorly understood, inclusions may be involved in processing and assembling ribosomes. Thus, their activity seems to be related intimately to muscle mass and function and leads to progressive muscle weakness, with wasting, and, in some, death due to respiratory failure.
• Reducing body myopathy is rare and manifests as infant/early childhood and adult-onset forms.
• The disorder may be chronic and benign, or progressive and fatal.
• Presentation can involve muscles of the upper or lower body, which may be affected in symmetric or asymmetric fashion.
• Cytoplasmic inclusions identified microscopically may represent processing defects of ribosomes.
• Cases may be sporadic; familial cases appear to be X-linked recessive (developing from mutations in FHL1) or autosomal dominant with variable penetrance.
• Death is most often from respiratory failure, although cardiomyopathies may contribute.
Reducing body myopathy is a rare disease of skeletal muscle, often classified as a congenital myopathy, although onset is more likely in early infancy (12) and adult onset is recognized. This condition was first described in 2 unrelated children in whom muscle biopsy showed unusual structures that were termed "reducing bodies" (05). Over 30 cases have been reported in the medical literature, and the clinical presentation is variable.
Muscle biopsies show variation in muscle fiber size; fibers may be regenerative, necrotic, or swirled, with the latter showing desmin and dysferlin accumulation (21). Reducing bodies are defined by distinctive histochemical and ultrastructural abnormalities. Histologically, reducing bodies contain a substance that can reduce dihydroxydinaphthyl disulfide, confirming that sulfhydryl groups are present. They also stain black with menadione-linked alpha-glycerophosphate dehydrogenase and are able to reduce nitroblue tetrazolium even in the absence of the substrate alpha-glycerophosphate, giving the same intensive stain. By electron microscopy, reducing bodies appear as dense osmiophilic material that, at higher magnification, consists of closely packed variably and irregularly shaped particles mixed with fibrillar material, measuring 12 nm to 18 nm in width. Proliferation of cytoplasmic bodies and rimmed vacuoles is recognized. In reducing body myopathy, cytoplasmic bodies (CBs) may localize to peripheral, subsarcolemmal regions, giving an appearance termed “necklace cytoplasmic bodies” (Uruha et al 2015).
According to age at onset, reducing body myopathy may be classified into 3 forms: (1) a severe infantile form in which the disease starts during the first 4 years of life with rapid progression and fatal outcome due to respiratory failure (05; 12; 06; 26); (2) congenital, with delayed developmental milestones and relatively benign course mimicking nemaline rod myopathy and central core disease (51; 36); and (3) late-onset form with a progressive course (22; 35; 04; 34). Eight patients with the severe infantile type (12; 06; 26) or with the late-onset form (22; 04; 14) showed asymmetric limb weakness and wasting at onset, with a progressive course advancing to severe generalized muscle wasting, weakness, and respiratory failure. Slight to moderate elevation of creatine kinase has been reported in a subset of patients. Peripheral neuropathy has not been reported. Both dilated and hypertrophic forms of cardiomyopathy are recognized, and inclusions are identified in some samples of cardiac muscle (46). Female carriers of the X-linked form may have mild muscle weakness proximally or be asymptomatic, which may represent varying degrees of X-inactivation (43; 08). Presentation and muscle involvement are variable and may be asymmetric, involving upper or lower muscle groups (15). Preservation or hypertrophy of gluteus maximus in the context of lower leg muscle wasting has been advanced as a diagnostic clue (25). Axial muscle involvement can be pronounced, with fatty infiltration of postero-medial thigh muscles identified by MRI (21).
The cases reported as congenital variants of reducing body myopathy have a benign course and static muscle weakness. Severe infantile variants and late-onset variants, frequently starting with asymmetric limb weakness, show progressive muscle weakness with loss of motor functions, swallowing difficulty, and respiratory failure. Scoliosis, spinal rigidity, and contractures (especially involving the Achilles tendon) may also develop (45; 44). At the mild end of the FHL1 spectrum, myopathic changes can be weak, with only isolated ankle contractures (38). In 1 case of adult onset, progression was slow (ie, several years), although it resulted in diffuse weakness (14). The presence of a cardiomyopathy, most often of the dilated type (although the hypertrophic form may also occur), complicates the clinical course.
A patient, the fifth of 7 siblings, was admitted at the age of 15 years for progressive generalized weakness. The parents were not related and the mother had 2 spontaneous abortions. Pregnancy and delivery were uneventful. The patient had normal intellectual and motor development. Muscle weakness appeared at 9 years when she started to fall frequently, had difficulty standing up from sitting, and had a waddling gait with left leg lag. At that time neurologic examination disclosed generalized weakness in a proximal distribution. Creatine kinase was slightly elevated (110 UI; normal value < 70). At 10 years, she had severe lordosis, winging of the scapulae, and bilateral pes equinus. By 13 years of age, she was restricted to a wheelchair. Neurologic examination showed an alert girl with normal intellectual function. There was a generalized severe muscle weakness with limitation of elbow and knee joints. Neck movements also were limited but bulbar functions and facial movements were spared. Respiratory function test showed a restrictive respiratory syndrome. Cardiological examinations were normal. Laboratory rheumatological tests, creatine kinase, and lactate dehydrogenase were normal. EMG of the right quadriceps muscle showed a myopathic pattern with few fibrillation potentials and no spontaneous discharges. Motor and sensory nerve conduction studies were normal.
A muscle biopsy was performed on the right triceps brachii. Morphology of the muscle biopsy showed marked endomysial fibrosis and increased diameter variability. Most fibers contained round or polymorphic masses that stained dark purple with modified Gomori trichrome and were closely related to smaller multiple round or oval, bright red cytoplasmic bodies.
Many of these fibers also contained rimmed vacuoles. These polymorphic masses stained dark brown with menadione-nitroblue tetrazolium reaction and did not stain for oxidative enzymes, myofibrillar ATPase, or myophosphorylase.
Reducing bodies showed negative immunofluorescence with antibodies for keratins and vimentin and positive immunofluorescence with antibodies for desmin, and were closely related with some round bright red rod-shaped structures when using phalloidin-rhodamine.
Ultrastructurally, these bodies showed 2 types of myofibrillar abnormalities: (1) some areas composed of finely granular and filamentous material resembling cytoplasmic bodies; and (2) strongly osmiophilic large masses composed at high magnification of tubular-filamentous profiles of 16 to 17 nm in diameter resembling reducing bodies. Biochemical studies confirmed increased amount of proteins at 53 kd (desmin) and 70 kd (not characterized further). These bodies are composed of FHL1 protein (33).
Until 2008, the cause of reducing body myopathy was unknown. Various etiologies had been considered, including a viral infection, an RNA disorder, and a myofibrillar degeneration disorder. New proteomic technology is proving helpful in understanding the composition of these inclusions (32). When the cellular inclusions characteristic of the myopathy were dissected using laser technology followed by chromatography-tandem mass spectrometry and proteomic analysis, the protein FHL1 (four-and-half-LIM protein 1) was identified (46). At least 10 mutations have been identified in 15 patients from 10 families (45; 47). Additional mutations in FHL1 continue to be identified (48), with whole exome sequencing diagnostic in the mildest forms (38). Experimental and clinical evidence suggests that the myopathy results from a loss of FHL1 function (11; 53). The sporadic appearances in females, absence of male-to-male transmission, and familial appearances in severely affected sons and less affected mothers strongly support an X-linked pattern of inheritance.
Other myopathies associated with FHL1 mutations include X-linked myopathy with postural muscle atrophy and scapuloperoneal myopathy (53). Although clinical features vary among these disorders, each manifests similar protein aggregates in muscle. Cardiomyopathies of the dilated or hypertrophic form also occur in patients with FHL1 mutations (10).
Brooke and Neville first suggested a viral or ribosomal origin, but these causes were excluded later by others because these bodies did not exhibit orange-red fluorescence after staining with acridine orange (05). The condition is not transmissible in rat muscle or in primate kidney cultures (06; 26). However, transfection of cultured kidney and skeletal muscle cells with mutant FHL1 causes the formation of inclusions (46). FHL1 localizes to the sarcomere and is involved in muscle growth and differentiation. As a consequence, deletions are associated with muscle hypertrophy (28; 54) and strength enhancement (09). Mutations in the FHL1 gene or other genes in the FHL family have been identified in other myopathies (55). In addition to its effect on skeletal muscle, the FHL1 gene plays a role in certain cardiomyopathies, probably through several pathways (55; 08). The type and/or location of gene mutations (at least 11 are recognized) are thought to be important in genotype-phenotype relationships (43; 08) and continue to be elucidated. For example, reducing body myopathy has been associated with filamin C mutations in a child born to first cousins (24).
In patients with reducing body myopathy, many muscle fibers show bizarre and abnormal nuclei (06) or degenerating nuclei (26), myofiber necrosis, and phagocytosis. Reducing bodies are particularly abundant in fibers undergoing degeneration of myofibrils and nuclei. Many of these fibers also show increased rimmed vacuole formation, suggesting active autophagic phenomena. These bodies are strongly positive for ubiquitin, whose synthesis increases in various neuromuscular disorders with proliferation of rimmed vacuoles and abnormally increased filamentous proteins such as inclusion-body myositis (01), oculopharyngeal dystrophy (29), and distal myopathy with rimmed vacuole formation (42). Continuing research supports the involvement of an aggresome-autophagy pathway in FHL1-associated pathophysiology (41). In 1 study, strong immunoreactivity to dystrophin, alpha-sarcoglycan, and vimentin was reported (14). By electron microscopy, reducing bodies are composed of characteristic tubulo-filamentous structures of 12 to 18 nm in diameter closely related with intermediate filaments and thin filaments (04; 14). Using TUNEL staining, Ikezoe and colleagues have demonstrated significant increases in the density of DNA fragments in myonuclei and intensity of chromatin condensation, suggesting that apoptosis plays a role in muscle fiber degeneration (23). Because reducing bodies contain material that appears to be preribosomes and associated proteins and stain positively for nucleolar organizer regions, they resemble nucleoli and may result from defects in the processing and assembly of ribosomes (49) or impaired extralysosomal degradation of proteins (19). Misfolded proteins appear to accumulate in the endoplasmic reticulum and are, in this way, important to the formation of reducing bodies (30).
The few biochemical studies have shown an increase of a 53-kd protein (06) by 1-dimensional SDS-polyacrylamide gel electrophoresis corresponding to desmin by Western blot studies (04). Other proteins of 62 kd and 70 kd, characterized only by gel electrophoresis, are also abnormally elevated (06; 04). Increased desmin was proved also by immunofluorescence in 3 cases (04; 34; 14) but has not been confirmed by others (26). Two-dimensional electrophoresis demonstrates that desmin hyperphosphorylated isoforms are increased. This is analogous to what is found in other neuromuscular disorders characterized by a biochemical increase in desmin but with different clinical and ultrastructural features (40). For these reasons, the remarkable increase of desmin may be involved in the pathogenesis of the disease but appears to be a secondary phenomenon. Precursors to reducing bodies and other inclusions (fingerprint bodies, cylindrical spirals, zebra bodies, hyaline bodies, and tubular aggregates) have not been identified (17; 18).
The disorder is extremely rare in the childhood group of myopathies. Over 30 cases have been reported in the medical literature. Reducing body myopathy also seems to be a rare morphological abnormality because only 3 biopsies showed such abnormalities in a review of 3500 muscle biopsies (26).
To date, 9 affected families have been recognized, but some are without molecular confirmation (44). None of the parents were consanguineous. In a family with a large kinship of 7 sibs, there were 2 spontaneous abortions (04). Because of the extreme rarity of the condition, the gene frequency is presently unknown and genetic screening at the population level highly impractical. Reichmann and colleagues reported a father and daughter with progressive proximal myopathy and rigid spine phenotype (39). In the father, anatomic changes consisted of cytoplasmic bodies, increased desmin, sarcoplasmic and intranuclear tubulo-filamentous inclusions, and features of reducing body myopathy. The possibility of autosomal dominant inheritance was suggested by these cases. A second family, reported by Goebel and colleagues, also had changes suggestive of a mixed congenital myopathy in the maternal grandmother, mother, and teenaged male proband (20). The young man began having symptoms at 5 years of age (progressive rigid spine, torsion scoliosis, and flexion contractures of the elbows, hips, knees, and ankles); biopsies at 7, 11, and 14 years of age showed reducing bodies and cytoplasmic bodies ultrastructurally. Grandmother developed weakness in the hands and legs after 50 years; histologic examination showed similar inclusions, though they were not further characterized by histochemistry or electron microscopy. Mother’s muscle biopsy showed increased fiber diameters in quadriceps. The authors concluded that if the condition(s) was/were familial, genetic transmission would most likely have been X-linked recessive, though autosomal dominant transmission with variable penetrance was also possible. In another family, the mother developed foot-drop at 29 years and was confined to a wheelchair by 34; her son began having difficulty dressing at 10 years of age and could not stand alone a year later (37). Both autosomal dominant and X-linked recessive inheritance have been postulated (39; 17; 37).
For the congenital-onset form, reducing body myopathy has to be distinguished from all the disorders that cause floppiness in infancy. Severe infantile and late-onset forms may give the impression of an inflammatory myopathy if muscle weakness progresses quickly or may be confused with a facioscapulohumeral dystrophy when there is asymmetrical wasting and weakness. This disorder must be differentiated from other myopathies that show proliferation of cytoplasmic bodies, particularly cytoplasmic body myopathy (03) or other disorders with increased immunochemistry for desmin (40). Morphology of the muscle biopsy in reducing body myopathy is distinctive if combined with histochemical and ultrastructural findings. Reducing body-like inclusions have been observed in late-onset glycogen storage disease type II (16), scapuloperoneal myopathy, and rigid spine syndrome (08). FHL1 mutations cause a number of heterogeneous myopathies in addition to reducing body myopathy; these include X-linked scapulo-axio-peroneal myopathy (scapuloperoneal myopathy), rigid spine syndrome, and X-linked myopathy with postural muscle atrophy. Patients with hypertrophic cardiomyopathy or Emery-Dreifuss muscular dystrophy may show less expression of the gene (53; 13). Myopathies related to FHL1 mutations may or may not have reducing bodies (07). Reducing body myopathy was diagnosed in a 6-year-old patient with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase myopathy, suggesting the co-occurrence of an immune-mediated mechanism and highlighting the need for systematic workups (50).
With the discovery of FHL1 involvement in patients with reducing body myopathy and other previously uncharacterized myopathies, mutation screening takes on obvious importance in diagnosis (55). The diversity of clinical and pathologic findings emphasizes this importance and the need for genotype-phenotype correlation (31). Patients and families should be worked up fully by obtaining complete histories, including family details and neurologic examination; a serum creatine kinase should be performed because it may be slightly elevated. Electromyography shows a myopathic pattern, and nerve conduction studies exclude peripheral neuropathy. In 1 study, MRI showed a distinctive pattern of involvement of posterior and medial muscles of the thigh and soleus in the lower leg, with sparing of (hypertrophic) gluteal muscles (02). In a CT-based study, imaging showed early changes in the flexors of thigh and brachium and, later, more severe degeneration of paraspinal musculature (27). Muscle changes should be characterized by muscle biopsy and studied with histochemistry, including menadione-nitroblue tetrazolium stain, avoiding the substrate for alpha-glycerophosphate dehydrogenase. These methods will demonstrate round and polymorphic masses in many fibers that stain dark purple with the modified Gomori trichrome associated with typical cytoplasmic bodies. Frequently, type 1 fiber predominance with myofibrillar ATPase stain and proliferation of rimmed vacuoles are noted. These bodies are highly acidophilic in hematoxylin and eosin, are negative for oxidative enzyme activity, and show reducing activity. Electron microscopy shows typical osmiophilic masses composed of granular or tubulo-filamentous profiles mixed with autophagic vacuoles, cytoplasmic bodies, and accumulation of glycogen and intermediate filaments. Immunofluorescence for desmin and ubiquitin will show an increased signal in correspondence to reducing bodies in most cases. Biochemical studies by 1- and 2-dimensional electrophoresis should be performed to confirm the increase of other proteins in addition to desmin (06; 04).
The patient should be advised to lead as normal a lifestyle as possible. Physical therapy becomes important when the progression of the disease causes remarkable motor weakness and disability in addition to scapular winging, joint contractures, and rigid spine with kyphoscoliosis.
Patients should be monitored periodically for nocturnal respiratory oxygen desaturation and with respiratory function tests when respiratory failure is present.
Affected women have given birth, but in most instances this appears to have occurred before onset of symptoms.
Limitations are applicable as for all myopathies with respiratory failure. Malignant hyperthermia has not been reported in reducing body myopathy. Anesthetics should be given with caution, as is generally advised with any myopathy.
Joseph R Siebert PhD
Dr. Siebert of the University of Washington has no relevant financial relationships to disclose.See Profile
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