Fiber density in congenital muscle fiber type disproportion. II. Congenital muscle hypotonia and hip dislocation

Our previous paper presenting electromyographic findings in patients with congenital fiber type disproportion myopathy, confirmed the myogenic character of the disease process. That group of patients was however fairly heterogenous regarding both the clinical features and the morphological changes in muscle fibers (e.g. cases with central cores). In the present study we have examined 13 children with hypotonia and muscle fiber type disproportion operated on in childhood for congenital hip dislocation. In all cases CNEMG and SFEMG with FD estimation was performed in biceps brachii and quadriceps femoris muscles. In all muscles examined either slight EMG changes indicative of myopathy or a normal EMG pattern was found. None of the patients demonstrated an evident increase in FD values. Normal FD and the recruitment pattern proportional to the force of contractures indicate that the normal number of motoneurons is preserved. Accordingly, our present findings confirm the conclusions of our previous paper.     

Disintegration of the motor unit in post-polio syndrome. Part II. Electrophysiological findings in patients with post-polio syndrome

The aim of the study is to investigate the motor unit abnormalities in late postpolio muscular atrophy (PPMA) as compared to those found in patients who had polio 20-30 years prior to examination without any new clinical signs. The quantitative concentric needle EMG and a single fiber EMG techniques were employed. Spontaneous activity, the parameters of individual motor units potentials (MUP), number of complex potentials and their stability, jitter and blocking as well as fiber density (FD) have been evaluated. In PPMA patients (5 subjects) we found in newly weakened muscles: spontaneous activity, high percentage of complex potentials, increased jitter, increased FD. The EMG findings in muscles previously affected but without any signs of progression have been similar. In the patients with stable nonprogressing postpolio muscle atrophy (12) all MUP-s parameters indicated changes similar to PPMA but less marked in initially affected muscle with complete or incomplete recovery as well as sometimes in initially clinically unaffected muscles. These findings suggest that the signs of ongoing reinnervation processes persist many years after polio and that PPMA occurring later in life represents disintegration of the previously reinnervated motor units. It is still unclear whether this disintegration depends on decompensation by different factors of fully reinnervated motor units or whether most of the motor units after polio never regained a stable reinnervation.     

Muscle fiber type disproportion with an autosomal dominant inheritance

Congenital muscle fiber type disproportion (CFTD) has been described as a form of congenital myopathy characterized by the smallness and marked predominance of type 1 fibers in a muscle biopsy. Clinical manifestations include hypotonia, nonprogressive muscle weakness, joint contractures, and skeletal deformities. However, it has also been noted that the same pathologic alterations appeared in clinically diverse conditions. Recently, we experienced a family, a mother and two children, in which a muscle biopsy showed the mother to have muscle fiber type disproportion. This case was unusual in that there was a significant progression of weakness, an absence of neonatal hypotonia, and other commonly associated musculo-skeletal deformities. In this report, we describe the clinicopathologic features of the family with a brief review about muscle fiber type disproportion.     

Mutations of tropomyosin 3 (TPM3) are common and associated with type 1 myofiber hypotrophy in congenital fiber type disproportion

Congenital fiber type disproportion (CFTD) is a rare congenital myopathy characterized by hypotonia and generalized muscle weakness. Pathologic diagnosis of CFTD is based on the presence of type 1 fiber hypotrophy of at least 12% in the absence of other notable pathological findings. Mutations of the ACTA1 and SEPN1 genes have been identified in a small percentage of CFTD cases. The muscle tropomyosin 3 gene, TPM3, is mutated in rare cases of nemaline myopathy that typically exhibit type 1 fiber hypotrophy with nemaline rods, and recently mutations in the TPM3 gene were also found to cause CFTD. We screened the TPM3 gene in patients with a clinical diagnosis of CFTD, nemaline myopathy, and with undefined congenital myopathies. Mutations in TPM3 were identified in 6 out of 13 patients with CFTD, as well as in one case of nemaline myopathy. Review of muscle biopsies from patients with diagnoses of CFTD revealed that patients with a TPM3 mutation all displayed marked disproportion of fiber size, without type 1 fiber predominance. Several mutation‐negative cases exhibited other abnormalities, such as central nuclei and central cores. These results support the utility of the CFTD diagnosis in directing the course of genetic testing. Hum Mutat 30:1–8, 2009. © 2009 Wiley‐Liss, Inc.     

Familial congenital fiber type disproportion (CFTD) with an autosomal recessive inheritance

Two siblings, born to healthy non-consanguineous parents, were found to be affected with congenital progressive severe myopathy. Muscle biopsy revealed fiber type disproportion with no other histological abnormalities, thus confirming the diagnosis of congenital fiber type disproportion and suggesting an autosomal recessive mode of inheritance. This, to our knowledge, is the first reported family in which a strict histological diagnosis of congenital fiber type disproportion has been made and an autosomal recessive mode of inheritance shown.     

Electrical stimulation of a denervated muscle promotes selective reinnervation by native over foreign motoneurons

The effect of electrical stimulation of the denervated posterior cricoarytenoid (PCA) muscle on its subsequent reinnervation was explored in the canine. Eight animals were implanted with a planar array of 36 electrodes for chronic stimulation and recording of spontaneous and evoked electromyographic (EMG) potentials across the entire fan-shaped surface of a muscle pair. Normative EMG data were recorded from each electrode site before unilateral nerve section, and from the innervated partner after nerve section. After randomizing the animals to experimental and control groups, the right recurrent laryngeal nerve innervating the PCA abductor muscle and its adductor antagonists was sectioned and reanastomosed. The PCA muscle in four experimental animals was continuously stimulated during the 11-mo experiment, using a 1-s, 30-pps, biphasic pulse train composed of 1-ms pulses 2-6 mA in amplitude and repeated every 10 s. The remaining four animals served as nonstimulated controls. Appropriate reinnervation by native inspiratory motoneurons was indexed behaviorally by the magnitude of vocal fold opening and electromyographically by the potential across all electrode sites. Inappropriate reinnervation by foreign adductor motoneurons was quantitated by recording EMG potentials evoked reflexly by stimulation of sensory afferents of the laryngeal mucosa. All four experimental animals showed a greater level of correct PCA muscle reinnervation (P < 0.0064) and a lesser level of incorrect reinnervation (P < 0.0084) than the controls. Direct muscle stimulation also appeared to enhance the overall magnitude of reinnervation, but the effect was not as strong (P < 0.113). These findings are consistent with a previous report and suggest that stimulation of a mammalian muscle may profoundly affect its receptivity to reinnervation by a particular motoneuron type.     

Cardiac ankyrin repeat protein is preferentially induced in atrophic myofibers of congenital myopathy and spinal muscular atrophy

Cardiac ankyrin repeat protein (CARP), which is structurally characterized by the presence of four ankyrin repeat motifs in its central region, is believed to be localized in the nucleus and to participate in the regulation of cardiac-specific gene expression in cardiomyocytes. However, we recently found that CARP was induced in skeletal muscle by denervation, leading us to speculate that CARP may be induced under some pathological conditions. In the present study, we immunohistochemically analyzed the expression of CARP in 11 cases of spinal muscular atrophy (SMA) and 14 cases of congenital myopathy. In SMA, CARP was expressed selectively in severely atrophic myofibers, suggesting that CARP expression may reflect the status of muscle atrophy. Furthermore, in the congenital myopathies, the expression patterns of CARP were distinct among the subtypes, which included nemaline myopathy, myotubular myopathy, central core disease, and congenital fiber type disproportion. Although CARP was preferentially expressed in severely damaged myofibers in nemaline myopathy, it was not detected in central core disease. These findings suggest that immunohistochemical evaluation of CARP may be helpful in the diagnosis of SMA and the congenital myopathies.     

Comparison of clinical characteristics between congenital fiber type disproportion myopathy and congenital myopathy with type 1 fiber predominance

Congenital myopathies are clinical and genetic heterogeneous disorders characterized by skeletal muscle weakness and specific structural changes in muscle fiber. Congenital myopathy with fiber type disproportion (CFTD) is an established disorder of congenital myopathy. CFTD is characterized by non-progressive childhood neuromuscular disorders with a relatively good prognosis and type 1 fiber predominance and smallness. Congenital myopathy with type 1 fiber predominance (CMT1P) is also a distinct entity of congenital myopathy characterized by non-progressive childhood neuromuscular disorders and type 1 fiber predominance without smallness. Little is known about CMT1P. Clinical characteristics, including dysmorphic features such as hip dislocation, kyphoscoliosis, contracture, and high arch palate, were analyzed along with laboratory and muscle pathologies in six patients with CMT1P and three patients with CFTD. The clinical manifestations of CFTD and CMT1P were similar. However, the frequency of dysmorphic features is less in CMT1P than in CFTD. Long term observational studies of CMT1P are needed to determine if it will change to another form of congenital myopathy or if CMT1P is a distinct clinical entity.     

Simulation of fibre density in single-fibre electromyography and its relationship to macro-EMG

To elucidate the relationship between various morphological motor unit parameters and electrophysiological findings obtained with single-fibre EMG (fibre density, FD) and macro-EMG, computer simulations were performed. FD and macro-MUP amplitude varied in parallel when fibre loss, fibre loss and corresponding motor unit territory shrinkage or fibre atrophy were simulated. When fibre loss and compensating reinnervation were produced the FD increased whereas the amplitude of the macro-MUP was unchanged. A discrepancy between the relative changes in these two EMG parameters seems to indicate uneven fibre distribution within the motor unit territory.     

Facioscapulohumeral muscular dystrophy. A quantitative electromyographic study

BACKGROUND: Quantitative electromyography (EMG) using different needle techniques has not been performed or reported on a relatively large group of patients with facioscapulohumeral muscular dystrophy (FSHD). Purpose: To establish statistically: (1) correlations between clinical features of patients (age, disease duration and degree of weakness) and quantitative needle EMG/SFEMG,; (2) correlations between different EMG parameters in the patient group, and (3) quantitative EMG differences comparing patients with a healthy control group. METHODS: Nerve conduction studies, and needle EMG (motorunit analysis, MacroEMG, SFEMG) were performed on Mm. triceps brachii and Mm. tibialis anterior according to standard techniques on 20 patients with FSHD. RESULTS: Nerve conduction studies were normal. In Mm. triceps brachii and, to a lesser extent, Mm. tibialis anterior motorunit analysis and MacroEMG showed myopathic changes, that correlated with patient clinical parameters. In Mm. triceps brachii (but not in Mm. tibialis anterior) EMG results were statistically different in patients compared to control group data. The most sensitive indicators of a myopathy were MUP duration (motorunit analysis) and MUP area (MacroEMG). In the Mm. triceps brachii SFEMG revealed correlations between worsening pooled MCD data and patient clinical parameters. Pooled MCD results did not correlate with other MUP parameters. SFEMG showed abnormal jitter only in 2 patients with the longest disease duration. CONCLUSION: Quantitative EMG results are compatible with a mild, slowly progressive myopathy. The most sensitive indicators of early muscle disease were MUP duration (motorunit analysis) and MUP area (MacroEMG) that would not be detected on "routine" EMG SFEMG showed subtle, progressive worsening of neuromuscular junction physiology. However, quantitative EMG and SFEMG showed that muscle fiber degeneration and loss followed a course independent of muscle fiber regeneration and reinnervation.     

The myopathology of floppy and hypotonic infants in Singapore

AIMS: This study attempts to determine the type and relative frequency of muscle diseases contributing to floppy and hypotonic infants in Singapore. METHODS: Eighty consecutive muscle biopsies in the Department of Pathology, National University of Singapore, in the period 1978-2000, in which a clinical diagnosis of floppy or hypotonic infant was made, were reviewed. RESULTS: The commonest cause of severe hypotonia in infancy was spinal muscular atrophy, which accounted for 33% of cases followed by congenital muscular dystrophy (13%). Eight cases (10%) of infantile type II glycogenosis (Pompe's disease) were encountered. There were seven cases of congenital myopathy, of which four were centronuclear myopathy, and one each of central core myopathy, nemaline myopathy and congenital fibre type disproportion. One case of centronuclear myopathy was associated with type I fibre smallness. Type II atrophy, which is generally considered a non-specific change, was encountered in five cases. Of interest is the relatively large number of muscle biopsies (29%) in which no significant pathological features were encountered at the light microscopic, histochemical as well as ultra-structural level. CONCLUSIONS: The study has revealed a great variety of pathology affecting the muscle of children presenting as floppy infants or with hypotonia. The muscle diseases included spinal muscular atrophy, congenital muscular dystrophies, congenital myopathies and metabolic myopathies. However, 23 (29%) cases showed no significant pathology. For this group of floppy and hypotonic infants further studies are needed.     

Arthrogryposis multiplex congenita: spectrum of pathologic changes

The pathologic features of muscle and/or spinal cord were studied in 96 infants and children with contractures of multiple joints (arthrogryposis multiplex congenita), usually in association with other congenital abnormalities. Ninety of these infants had a neurogenic form of arthrogryposis, and six had primary muscle disease. The neurogenic form, unlike the myopathic form, was usually associated with other congenital abnormalities. The most frequently associated congenital changes were low-set ears, micrognathia, wide flat nose, short neck, congenital heart disease, high-arched palate, hypoplastic lungs, and cryptorchidism. Some of the associated abnormalities could be attributed to muscle weakness, occurring during intrauterine development. A variety of skeletal muscle changes were observed, including primary myopathic alterations, fiber type predominance and disproportion, hypoplasia, aplasia, and denervation atrophy. When the primary alterations were in the spinal cord, abnormalities of anterior horn cells of several distinct types were recognized--absence of cells, diminution, dysgenesis, degeneration, and axonal reaction. The changes in anterior roots corresponded to those of the anterior horn cells.     

Congenital myopathy with fiber type disproportion: a family with a chromosomal translocation t(10; 17) may indicate candidate gene regions

A patient with myopathy and congenital fiber type disproportion presented at birth with arthrogryposis multiplex congenita, dislocation of the hips and mild scoliosis. Later in life she developed marked muscle weakness. A balanced chromosomal translocation t(10;17) (p11.2;q25), transmitted by the clinically healthy mother, who nevertheless showed discrete signs of myopathy, was demonstrated. DNA analysis excluded maternal uniparental disomy for loci on both chromosomes 10 and 17. We suggest that the translocation breakpoints are candidate regions for a myopathy gene.     

Embryonic cord transplants in peripheral nerve restore skeletal muscle function

The rapid atrophy of skeletal muscle after denervation severely compromises efforts to restore muscle function. We have transplanted embryonic day 14-15 (E14-E15) ventral spinal cord cells into adult Fischer rat tibial nerve stump to provide neurons for reinnervation. Our aim was to evaluate medial gastrocnemius reinnervation physiologically because this transplant strategy will only be effective if the reinnervated muscle contracts, generates sufficient force to induce joint movement, and is fatigue resistant enough to shorten repeatedly. Twelve weeks posttransplantation, brief duration electrical stimuli applied to the transplants induced medial gastrocnemius contractions that were strong enough to produce ankle movement in 4 of 12 rats (33%). The force of these four "low-threshold" reinnervated muscles and control muscles declined only gradually during five hours of intermittent, supramaximal stimulation and without depression of EMG potential area, which is strong evidence of functional neuromuscular junctions and fatigue resistant muscles. Sectioning of the medial gastrocnemius nerves confirmed that these contractions were innervation dependent. Weakness in low-threshold reinnervated muscles (8% control force) related to incomplete reinnervation, reductions in muscle fiber size, specific tension, and/or the presence of nonfunctional neuromuscular junctions. Muscle reinnervation achieved using this novel transplantation strategy may salvage completely denervated muscle and may provide the potential to evoke limb movement when injury or disease precludes or delays peripheral axon regeneration.     

Intramuscular hematopoiesis in hypotonic infants with type 1 muscle fiber dysmaturation

Three term infants had severe hypotonia, a maturation defect of type 1 muscle fibers, and extramedullary hematopoiesis (EMH) in quadriceps muscle specimens obtained within one month of birth. Although predominantly myelopoietic, signs of inflammatory myopathy were absent. One patient had congenital myopathy with maturation arrest of type 1 fibers, another had transient maturation delay of type 1 fibers, and the third patient was subsequently classified as having spinomuscular atrophy. Extramedullary hematopoiesis was demonstrated in normal muscle obtained from young fetuses, but not in muscle obtained at autopsy from infants representing the third trimester and first postnatal month, or in muscle biopsy specimens from 15 other hypotonic infants with type 1 fiber size disproportion. We conclude that EMH in muscle of hypotonic infants is an abnormal persistence of a fetal state that is associated with delayed muscle maturation with diverse origins. Extramedullary hematopoiesis in muscle may indicate hypoxia, but signs of perinatal asphyxia in these babies were inconclusive. Low blood flow due to inactivity or an unidentified product of immature muscle may promote intramuscular EMH, but there is no evidence to suggest that myelopoiesis is injurious to muscle fibers. Intramuscular EMH should be distinguished from inflammation.     

A distinct form of spondyloepimetaphyseal dysplasia with multiple dislocations.

Three unrelated patients with identical radiological features are presented. Hypotonia was noted at birth and one patient was diagnosed as having congenital fibre type disproportion in the neonatal period. Later muscle biopsies, however, were entirely normal. All patients, now in their teens and twenties, are of normal intelligence, show striking epiphyseal and metaphyseal changes of the long bones, and have joint laxity and multiple dislocations of large joints, which are particularly incapacitating at the knees. These three cases represent a sporadic, previously unreported skeletal dysplasia with spondyloepimetaphyseal distribution and multiple large joint dislocations.     

Effects of acute and chronic denervation on human myotonia

A 32-year-old man with myotonia congenita (Becker type) sustained multiple gunshot wounds. These produced a partial thoracic spinal cord injury and a severe sciatic nerve injury. Six days following the incident, clinical (percussion) and electrophysiologic (EMG) myotonia could be elicited in paretic leg muscles resulting both from the myelopathy and peripheral nerve disruption. Eight months later, the myotonia was no longer present in denervated muscles from the sciatic nerve injury, but was still noted in muscles with upper-motor neuron weakness from the myelopathy. Although myotonia is related principally to abnormalities in the muscle fiber itself, it appears that it is also dependent upon the structural integrity of the peripheral nerve supply to the muscle for myotonia to continue to occur. The findings in this patient suggest that myotonia may well have diminished and disappeared in muscles shortly after the nerves had undergone Wallerian degeneration. Myotonia does not recur if there is no significant reinnervation.     

Jitter analysis utilizing a high speed FM tape recorder

Jitter analysis in single fiber EMG (SFEMG) is usually done on-line during recording. However, this technique frequently prolongs the study and makes re-analysis impossible. We attempted to measure jitter with a high speed FM tape recorder and compare the results with the previously published values. SFEMG data, acquired with voluntary activation on extensor digitorum communis muscle of 25 healthy relatives of children with myasthenia gravis were retrospectively analyzed. Fiber density (FD) was estimated on-line. Five to 18 single fiber action potential (SFAP) pairs were studied in each subject. The wow of the tape recorder was 6 microseconds. Mean (SD) (upper 95th percentile) FD, individual jitter, highest jitter, mean jitter and interspike interval were 1.60 (0.18) (1.90), 25.30 (11.20) (57.00) microseconds, 31.24 (6.87) (47.00) microseconds, 25.08 (5.04) (43.00) microseconds, and 0.67 (0.11) (0.91) ms respectively. Mean jitter in the pooled SFAP pairs and mean MCD were found to be lower than the published values of the Ad Hoc Committee of the AAEM Special Interest Group on Single Fiber EMG. A high speed FM tape recorder can be reliably used for the off-line analysis of jitter.     

Morphology of skeletal muscle in children. An assessment of normal growth and differentiation

Muscle fiber size and relative proportion and size of type 1 and 2 fibers were studied in postmortem samples of diaphragm, rectus abdominis, quadriceps, and deltoid of 28 infants and children. The rate of fiber growth varied with age, muscle, and fiber type. Type 1 fibers were smaller than type 2 fibers in preterm and term neonates and histologic identification of pathologic type 1 fiber size disproportion may thus not be possible in the young infant. Isolated groups of type 1 fibers unaccompanied by other evidence of neuropathy may be seen in normal children and may reflect normal variation in motor unit innervation patterns. Definition of normal muscle growth provides a standard for evaluating diagnostic material and allows insight into normal neuromuscular maturation.     

Thin filament proteins mutations associated with skeletal myopathies: Defective regulation of muscle contraction

In humans, more than 140 different mutations within seven genes (ACTA1, TPM2, TPM3, TNNI2, TNNT1, TNNT3, and NEB) that encode thin filament proteins (skeletal α-actin, β-tropomyosin, γ-tropomyosin, fast skeletal muscle troponin I, slow skeletal muscle troponin T, fast skeletal muscle troponin T, and nebulin, respectively) have been identified. These mutations have been linked to muscle weakness and various congenital skeletal myopathies including nemaline myopathy, distal arthrogryposis, cap disease, actin myopathy, congenital fiber type disproportion, rod-core myopathy, intranuclear rod myopathy, and distal myopathy, with a dramatic negative impact on the quality of life. In this review, we discuss studies that use various approaches such as patient biopsy specimen samples, tissue culture systems or transgenic animal models, and that demonstrate how thin filament proteins mutations alter muscle structure and contractile function. With an enhanced understanding of the cellular and molecular mechanisms underlying muscle weakness in patients carrying such mutations, better therapy strategies can be developed to improve the quality of life.