Miopatia w przebiegu niedoboru palmitylotransferazy karnityny II

Congenital deficiency of carnitine palmitoyltransferase (CPT) II is a disease with an autosomal recessive inheritance of phenotypic variability which depends on age at the onset of symptoms. Three entities associated with deficiency of CPT II are known: the perinatal, the infantile and the adult form. The perinatal disease is the most severe form and is invariably fatal. On the other hand, the adult CPT II clinical phenotype is benign and requires additional external triggers such as high-intensity exercise to provoke myopathic symptoms. We report a case of adult CPT II deficiency presenting with the subtle symptoms of myopathy.A 32-year-old man was admitted to the hospital complaining of muscle pain after exercise. Athletic appearance drew attention, because the patient denied practicing sport. Neurological examination revealed marked tiredness during the single-leg hop test without other abnormalities.Electromyography (EMG) and serum biochemistry were not typical for myopathy. Routine histopathological examination did not reveal any abnormalities of structure of muscle fibers. Diagnosis was established after ultrastructural and biochemical analysis which revealed changes typical for CPT II deficiency.     

Muscle pathology in 31 patients with calpain 3 gene mutations

Background and purposeAt present, more than 20 different forms of limb-girdle muscular dystrophies (LGMDs) are known (at least 7 autosomal dominant and 14 autosomal recessive). Although these different forms show some typical phenotypic characteristics, the existing clinical overlap makes their differential diagnosis difficult. Limb-girdle muscular dystrophy type 2 (LGMD2A) is the most prevalent LGMD in many European as well as Brazilian communities and is caused by mutations in the gene CAPN3. Laboratory testing, such as calpain immunohistochemistry and Western-blot analysis, is not totally reliable, since up to 20% of molecularly confirmed LGMD2A show normal content of calpain 3 and a third of LGMD2A biopsies have normal calpain 3 proteolytic activity in the muscle. Thus, genetic testing is considered as the only reliable diagnostic criterion in LGMD2A.Material and methodsIn an attempt to find a correlation between genotype and muscle pathology in limb-girdle muscular dystrophy 2A we performed histopathological investigation of a group of 31 patients subdivided according to the type of pathologic CAPN3 gene mutation.ResultsIn all biopsies typical features of muscular dystrophy such as fiber necrosis and regeneration, variation in fiber size and fibrosis were noted. Lobulated fibers were often encountered in the muscle biopsies of LGMD2A patients. Such fibers were more frequent in patients with 550delA mutation.ConclusionsThese findings may be helpful in establishing diagnostic strategies in LGMD.     

Open muscle biopsy in suspected myopathy: diagnostic yield and clinical utility

Background:  The purpose of the study was to investigate the diagnostic yield and clinical utility of open muscle biopsy and to identify pre-biopsy factors that might predict useful clinical results for suspected myopathy.
Methods:  Two-hundred fifty-eight muscle biopsies, performed for investigation of suspected myopathy, were evaluated.
Results:  A specific clinical diagnosis following muscle biopsy was made in 43% of cases. As a result of the biopsy, clinical diagnosis was changed in 47% and treatment was changed in 33% of cases. Results either led to a specific clinical diagnosis or changed the diagnosis/treatment in 74% of patients. Positive family history of myopathy and findings of myopathic irritability on electromyography had a negative predictive value for diagnosis change.
Conclusions:  Open muscle biopsy is useful in myopathy evaluation in the modern genetic era.     

Needle muscle biopsy in the investigation of neuromuscular disorders

We have evaluated needle muscle biopsies in 220 patients with various neuromuscular disorders, using a method developed previously at Tuft's University. The method uses a 14-gauge needle propelled by an automatic device. An average of 3.5 samplings were taken per patient. Muscle samples were used for histological and molecular genetic analysis, and for the isolation of muscle satellite cells for in vitro cultures. The biopsy is well tolerated by the patients who never declined multiple samplings. Complications were few and minor, with no sequelae. In most cases the small size of the muscle specimen (ca. 15 mg per sampling) was sufficient to perform the various procedures and to yield a diagnosis. Specimens were considered insufficient for histological results in 9 patients (4%), due to technical artifacts or insufficient material. We now routinely use this method, which has several advantages over the surgical technique for most muscle biopsies. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21: 194–200, 1998.     

Distinguishing neuromuscular disorders based on the passive electrical material properties of muscle

Introduction: The passive electrical properties of muscle, including conductivity and permittivity and their directional dependence, may be altered in neuromuscular disease; however, the character of these alterations is unknown. Methods: Fifteen wild‐type mice, 13 amyotrophic lateral sclerosis mice, 9 muscular dystrophy (mdx) mice, and 15 mice with induced disuse atrophy were euthanized, and the gastrocnemius was excised. A 50‐kHz current was applied immediately to the ex vivo muscle, and its material properties were calculated. Results: The disease groups showed distinct material property values [F(12, 119) = 14.6, P < 0.001] according to MANOVA. Post‐hoc tests confirmed that differences existed between all 4 groups. They were most pronounced in the mdx mice, which had markedly increased conductivity. Direction‐dependent properties of current flow also were significantly different among the groups (P < 0.001). Conclusions: These data confirm that the inherent passive electrical properties of muscle differ by disease type. We anticipate that similar data could eventually be obtained via surface measurements, providing an innovative approach to muscle disease diagnosis. Muscle Nerve 51 : 49–55, 2015     

Localization and characterization of dystrophin in muscle biopsy specimens from Duchenne muscular dystrophy and various neuromuscular disorders

Dystrophin, surmised to be the causative protein of Duchenne muscular dystrophy (DMD), was studied for its intracellular localization and characterization by immunostaining and Western blotting using antidystrophin antibodies. In normal controls and in patients with various neuromuscular diseases other than DMD and Becker's muscular dystrophy (BMD), dystrophin was detected homogeneously on the entire surface membrane of the muscle fibers, whereas it was absent in DMD patients and partially observed in BMD cases. The density of dystrophin was low in BMD and female DMD patients. In mouse skeletal and cardiac muscles, too, dystrophin localized in the muscle surface membrane, and its presence in the brain was also suggested. However, dystrophin was not detected in mdx mice. These data suggest that myofiber necrosis in DMD patients and mdx mice is likely to be the result of plasma membrane instability.     

Variations in gene expression among different types of human skeletal muscle

There is a consistent variation in the response of different skeletal muscle groups to mutations in genes known to cause muscular dystrophy, yet these muscles appear histologically similar. To better understand these phenotypic differences, we analyzed gene expression patterns in control muscle specimens obtained from four sites at autopsy: deltoid, quadriceps, gastrocnemius, and tibialis anterior (TA). A total of 35 muscle samples from nine individuals (four pediatric and five geriatric) were studied. Factors potentially influencing gene expression in the different samples included individuality, age, muscle type, gender, cause of death, postmortem interval, and ethnicity. The first three factors, in decreasing order, were found to have a significant impact on the stratification of muscle specimens. A novel analytic method, using a second round of normalization, was used to elicit differences between muscle types. This approach may be extended to a broader survey, potentially elucidating a molecular classification of the skeletal muscles.     

A noninvasive procedure to detect muscle weakness in the mdx mouse

The forward pulling tension exerted by individual mice was measured nearly isometrically in a simple apparatus designed to determine whole body tension (WBT). WBT determinations on control (C57Bl10/SnJ) and experimental (C57Bl10-mdx) mice indicate a muscle weakness which lasts throughout the lifespan of mdx mice. Direct muscle stimulation experiments in vivo also showed significant decreases in peak twitch and tetanic tensions in adult mdx muscle with no obvious alterations in twitch time course or in twitch: tetanus ratios. We suggest that the noninvasive WBT procedure may be used to partially assess various therapies on this murine model of Duchenne muscular dystrophy.     

Invited Review: Polycomb group genes in the regeneration of the healthy and pathological skeletal muscle

The polycomb group (PcG) proteins are epigenetic repressors required during key developmental processes, such as maintenance of cell identity and stem cell differentiation. To exert their repressive function, PcG proteins assemble on chromatin into multiprotein complexes, known as polycomb repressive complex 1 and 2. In this review, we will focus on the role and mode of function of PcG proteins in the development and regeneration of the skeletal muscle, both in normal and pathological conditions and we will discuss the emerging concept of modulation of their expression to enhance the muscle‐specific regenerative process for patient benefit.     

The potential of psychological interventions to improve quality of life and mood in muscle disorders

Quality of life (QoL) and mood are reduced in many patients with muscle disorders. Psychological variables appear to be contributors to both QoL and mood, suggesting that psychological interventions could improve these outcomes, yet research in this area is sparse. We review the roles of psychological variables, plus context and disease severity, in explaining QoL. A cognitive‐behavioral model of disease self‐management, with acceptance as the central component, is discussed. This model is then used to describe how psychological interventions derived from cognitive behavioral therapy (CBT), in particular Acceptance and Commitment Therapy (ACT), might be applied to address the issues of distress, nonadherence to treatments, pain, and fatigue in people with muscle disorders. Muscle Nerve 52 : 131–136, 2015     

Dystrophinopathy muscle biopsies in the genetic testing ERA: One center's data

Introduction: Comprehensive genetic testing for dystrophinopathy can detect ～95% of pathogenic variants in the dystrophin gene (DMD) and is often the preferred diagnostic approach. Methods: We reviewed pathology reports for muscle biopsies evaluated at the University of Iowa with a pathological diagnosis of dystrophinopathy based on dystrophic histopathology and abnormal immunofluorescence staining: reduced to absent dystrophin, expression of utrophin, and loss of neuronal nitric oxide synthase. Results: The percentage of muscle biopsies with dystrophinopathy has been stable since 1997. Among 2,298 biopsies evaluated between 2011 and 2016, 72 (3.1%) had pathologic features of dystrophinopathy. Median age at biopsy was 8 years (range, 0.66–84). Half had undergone DMD genetic testing prior to biopsy. Clinical phenotypes recorded on requisitions were typical of muscular dystrophy for 57 (79%) biopsies. Discussion: Muscle biopsy continues to play an important role in the diagnosis of dystrophinopathy, particularly in patients with later symptom onset, comorbidities, or normal DMD genetic testing results. Muscle Nerve 58 : 148–152, 2018     

The occurrence of paracrystalline mitochondrial inclusions in normal human skeletal muscle

Summary Two different types of paracrystalline mitochondrial inclusions identical with or very similar to those already described in the literature for a variety of muscle diseases were found in human skeletal muscle biopsies obtained under general anesthesia before ischemia and after various periods of anoxia up to 150 min. As these crystalloids could be observed in seven of 14 healthy subjects and occurred in five of these seven cases either before or only 10 min after onset of ischemia, it is suggested that such mitochondrial inclusions develop not only under the influence of variant noxious stimuli, but may also represent a normal constituent of human skeletal muscle mitochondria.     

Pattern of skeletal muscle involvement in primary dysferlinopathies: a whole‐body 3.0‐T magnetic resonance imaging study

Objectives and methods – Mutations in the gene encoding dysferlin cause limb girdle muscular dystrophy type 2B (LGMD2B), distal Miyoshi myopathy (MM), and a rare form of distal anterior compartment myopathy. To study the correlations between clinical manifestations and muscle imaging changes we conducted a 3.0‐T magnetic resonance imaging (MRI) study in six German patients with primary dysferlinopathies defined by absence of dysferlin expression in muscle (MM, n = 3; LGMD2B, n = 2; hyperCKemia without clinical symptoms, n = 1). Results – Patients with manifest myopathy had widespread muscular pathology. In analogy to previous imaging studies, we confirmed an involvement of the anterior and posterior thigh compartments and a predominant involvement of posterior lower legs. However, our whole‐body MRI study further provided evidence of signal alterations in the glutei, erector spinae and shoulder girdle muscles. Correlation of clinical findings with imaging demonstrated the potential of MRI to detect subclinical muscle pathology. Conclusions – Whole‐body 3.0‐T MRI is a non‐invasive method to demonstrate various degrees of skeletal muscle alterations and disease progression in muscular dystrophies. Furthermore, whole‐body high‐field MRI may serve as a helpful diagnostic tool in differentiating primary dysferlinopathies from other forms of LGMD and distal myopathies.     

The effects of hyperthyroidism on muscular dystrophy in the mdx mouse: Greater dystrophy in cardiac and soleus muscle

Muscle damage and repair were studied in mdx mice treated with triiodothyronine (T₃) for 14 days. Hindlimb and cardiac muscles were examined for the severity of dystrophy, the degree of muscle centronucleation, and fiber size. In control and mdx mice, cardiac hypertrophy and skeletal muscle atrophy were present after T₃ treatment. Both cardiac and soleus (but not fast-twitch) muscles had larger, more frequent dystrophic lesions in T₃-treated mdx mice, and mdx soleus had an increased area of new myotubes after T₃. Skeletal myogenesis in mdx mice may have been delayed by excess T₃, possibly related to the general reduction in staining for basic fibroblast growth factor in hyperthyroid mice. These are the first observations of a metabolic perturbation which worsens mdx dystrophy and possibly repair in a musclespecific manner, and are likely related to T₃-induced changes in myosin heavy chain expression, and to increased mechanical strain on dystrophin-deficient muscles. © 1994 John Wiley & Sons, Inc.     

Fatigue in type I fiber predominance: a muscle force and surface EMG study on the relative role of type I and type II muscle fibers

The relative proportions of fiber types within muscle and the characteristics of these fiber types are important determinants of the surface electromyogram (SEMG) during fatigue. In this study, patients suffering from congenital myopathy characterized by a strong type I fiber predominance were studied. Six patients with 95-100% type I fibers, 2 patients with 80% type I fibers, and 12 healthy volunteers participated in an ischemic, isomeric, intermittent exercise test of m. quadriceps femoris at 80% MVC. Considering the results of the morphometric analysis of muscle biopsy specimen and of the anthropometric estimated muscle-bone volume, it was found that type I muscle fibers had a lower force generating capacity than type II fibers. The initial conduction velocity along the muscle fiber membrane (MFCV) was low in patients with 95-100% type I fibers. During the ischemic exercise test, the 95-100% type I fibers showed less fatigability than type II fibers, which was reflected by a nearby absent decrease of the muscle membrane excitability as measured by the MFCV, and only a slight increase of the SEMG amplitude compared with patients having 80% type I fibers and controls. The absence of a definite MFCV decrease was related to the nearby lacking lactate formation in 95-100% type I fibers.     

The effects of altered metabolism (hypothyroidism) on muscle repair in the mdx dystrophic mouse

After dystrophic damage, the limb muscles of the mdx mouse recover very effectively compared to muscles in Duchenne muscular dystrophy (DMD) patients. Since thyroid hormone is required for muscle development and integrity, we examined whether a deficiency of the hormone, induced by 0.05% propylthiouracil (PTU) in drinking water over 8 weeks, would be deleterious to the myogenesis and muscle repair in control and mdx mice. Measured metabolic and growth parameters confirmed hypothyroidism in PTU-treated mice. Histological and morphometric techniques were used to study myogenesis and the repair of the tibialis anterior muscle (TA) after crush injury in mdx mice and their nondystrophic controls (C57B1/10ScSn). After 8 weeks, PTU-treated TA from mdx mice had larger crush sites and lower myotube density than TA in untreated mdx mice. In unoperated mdx TA, there was a larger proportionate area of active dystrophy and smaller fiber diameter in PTU-treated than in untreated mdx TA, which suggested that PTU increased the activity of dystrophy as well. In contrast, in control TA neither the regeneration of myotubes or fiber diameter were affected significantly by PTU. Therefore, these results suggest that mdx muscle regeneration is more affected by hypothyroidism than normal muscle repair. This may be due to the larger pool of muscle precursors in mdx than control muscle, and a possible impairment of precursor cell proliferation or fusion during myotube formation. © 1994 John Wiley & Sons, Inc.