Rimmed vacuoles in facioscapulohumeral muscular dystrophy: a unique ultrastructural feature

Rimmed vacuoles (RV) are a characteristic pathological feature in inclusion body myositis, but may also occur in other neuromuscular disorders, such as distal myopathies, oculopharyngeal myopathy, polymyositis, rigid spine syndrome, congenital myopathies, and some limb girdle muscular dystrophies, as well as in various neurogenic diseases. We describe a patient with RV in familial facioscapulohumeral muscular dystrophy (FSHD) associated with an FSHD-typical deletion on chromosome 4q35. Thus, FSHD should be included in the differential diagnosis of neuromuscular disorders with RV.     

Syncoilin upregulation in muscle of patients with neuromuscular disease

Syncoilin may have a role in linking the desmin-associated intermediate filament network of the muscle fiber with the dystrophin-associated protein complex (DAPC). We have evaluated syncoilin in a range of neuromuscular disorders including Duchenne and Becker muscular dystrophy, central core disease, congenital muscular dystrophies, and neurogenic disorders. Our results show that syncoilin immunolabeling is not only altered in muscle fibers with alterations in the DAPC but also in response to a variety of genetic defects, including those associated with proteins of the extracellular matrix and the intracellular Ca2+-release channel (ryanodine receptor). The pattern of syncoilin immunolabeling in these diseases appeared to reflect a rearrangement of the intermediate filament-associated cytoskeleton that characterizes both muscle fiber development and conditions in which the cytoskeletal organization of the muscle fiber is significantly affected. These observations raise the possibility that mutations in the gene encoding for syncoilin may underlie some forms of muscle disease.     

What we do not know about pregnancy in hereditary neuromuscular disorders

Only sparse information is available concerning the relationship between pregnancy and hereditary neuromuscular disorders. This review deals with several issues like the effects of such conditions on female fertility (myotonic dystrophy type 1 and mitochondrial disorders), on the risk to the fetus (myotonic dystrophy type 1 and Charcot-Marie-Tooth disease), on the ability to carry pregnancy and its complications (markedly increased preterm labor in myotonic dystrophies and spinal muscular atrophy), on the labor and its possible need for interventions (myotonic dystrophy type 1, facioscapulohumeral dystrophy and Charcot-Marie-Tooth disease). It also discusses the question of pregnancy effects on the course of the inherited neuromuscular disorders (myotonic dystrophies, spinal muscular atrophy, facioscapulohumeral dystrophy, Charcot-Marie-Tooth disease, congenital myopathy and limb-girdle muscular dystrophy). The aim of this critical review is to point at pregnancy-related problems that need further research.     

Limb-girdle muscular dystrophies--from genetics to molecular pathology

The limb-girdle muscular dystrophies are a diverse group of muscle-wasting disorders characteristically affecting the large muscles of the pelvic and shoulder girdles. Molecular genetic analyses have demonstrated causative mutations in the genes encoding a disparate collection of proteins involved in all aspects of muscle cell biology. Muscular dystrophy includes a spectrum of disorders caused by loss of the linkage between the extracellular matrix and the actin cytoskeleton. Within this are the forms of limb-girdle muscular dystrophy caused by deficiencies of the sarcoglycan complex and by aberrant glycosylation of alpha-dystroglycan caused by mutations in the fukutin-related protein gene. However, other forms of this disease have distinct pathophysiological mechanisms. For example, deficiency of dysferlin disrupts sarcolemmal membrane repair, whilst loss of calpain-3 may exert its pathological influence either by perturbation of the IkappaBalpha/NF-kappaB pathway, or through calpain-dependent cytoskeletal remodelling. Caveolin-3 is implicated in numerous cell-signalling pathways and involved in the biogenesis of the T-tubule system. Alterations in the nuclear lamina caused by mutations in laminA/C, sarcomeric changes in titin, telethonin or myotilin at the Z-disc, and subtle changes in the extracellular matrix proteins laminin-alpha2 or collagen VI can all lead to a limb-girdle muscular dystrophy phenotype, although the specific pathological mechanisms remain obscure. Differential diagnosis of these disorders requires the careful application of a broad range of disciplines: clinical assessment, immunohistochemistry and immunoblotting using a panel of antibodies and extensive molecular genetic analyses.     

Congenital muscular dystrophy phenotype with neuromuscular spindles excess in a 5-year-old girl caused by HRAS mutation

We report on a 5-year-old girl who presented with an association of symptoms reminiscent of an Ullrich-like congenital muscular dystrophy including congenital hypotonia, proximal joint contractures, hyperlaxity of distal joints, normal cognitive development, and kyphoscoliosis. There was an excess of neuromuscular spindles on the skeletal muscle biopsy. This very peculiar feature on muscle biopsy has been reported only in patients with mutations in the HRAS gene. Sequence analysis of the subject’s HRAS gene from blood leukocytes and skeletal muscle revealed a previously described heterozygous missense mutation (c.187G>A, p. Glu63Lys). The present report thus extends the differential diagnosis of congenital muscular dystrophy with major “retractile” phenotypes and adds congenital muscular dystrophy to the clinical spectrum of HRAS-related disorders.     

The expression of the distal dystrophin isoforms Dp140 and Dp71 in the human epileptic hippocampus in relation to cognitive functioning

Dystrophin is an important protein within the central nervous system. The absence of dystrophin, characterizing Duchenne muscular dystrophy (DMD), is associated with brain related comorbidities such as neurodevelopmental (e.g., cognitive and behavioural) deficits and epilepsy. Especially mutations in the downstream part of the DMD gene affecting the dystrophin isoforms Dp140 and Dp71 are found to be associated with cognitive deficits. However, the function of Dp140 is currently not well understood and its expression pattern has previously been implicated to be developmentally regulated. Therefore, we evaluated Dp140 and Dp71 expression in human hippocampi in relation to cognitive functioning in patients with drug‐resistant temporal lobe epilepsy (TLE) and post‐mortem controls. Hippocampal samples obtained as part of epilepsy surgery were quantitatively analyzed by Western blot and correlations with neuropsychological test results (i.e., memory and intelligence) were examined. First, we demonstrated that the expression of Dp140 does not appear to differ across different ages throughout adulthood. Second, we identified an inverse correlation between memory loss (i.e., verbal and visual memory), but not intelligence (i.e., neither verbal nor performance), and hippocampal Dp140 expression. Finally, patients with TLE appeared to have similar Dp140 expression levels compared to post‐mortem controls without neurological disease. Dp140 may thus have a function in normal cognitive (i.e., episodic memory) processes.     

A novel form of recessive limb girdle muscular dystrophy with mental retardation and abnormal expression of alpha-dystroglycan

The limb girdle muscular dystrophies are a heterogeneous group of conditions characterized by proximal muscle weakness and disease onset ranging from infancy to adulthood. We report here eight patients from seven unrelated families affected by a novel and relatively mild form of autosomal recessive limb girdle muscular dystrophy (LGMD2) with onset in the first decade of life and characterized by severe mental retardation but normal brain imaging. Immunocytochemical studies revealed a significant selective reduction of alpha-dystroglycan expression in the muscle biopsies. Linkage analysis excluded known loci for both limb girdle muscular dystrophy and congenital muscular dystrophies in the consanguineous families. We consider that this represents a novel form of muscular dystrophy with associated brain involvement. The biochemical studies suggest that it may belong to the growing number of muscular dystrophies with abnormal expression of alpha-dystroglycan.     

Congenital muscular dystrophies and the extracellular matrix

During the past decade, considerable progress in the field of congenital muscular dystrophies (CMDs) had led to the identification of a growing number of causative genes. This genetic progress has uncovered crucial pathophysiological concepts and has been instrumental in redefining clinical phenotypes. Important new pathogenic mechanisms include the disorders of O-mannosyl-linked glycosylation of alpha-dystroglycan as well as the involvement of a collagen type VI in the pathogenesis of congenital disorders of muscle. Thus, an emerging theme among gene products involved in the pathogenesis of congenital muscular dystrophy is their intimate connection to the extracellular matrix. In this review, we focus on the clinical phenotypes that we are correlating with the novel genetic and biochemical findings encountered within CMD. This correlation will frequently lead to a considerably expanded clinical spectrum associated with a given CMD gene.     

Congenital myopathies/dystrophies

The congenital myopathies and congenital muscular dystrophies are a group of relatively infrequent neuromuscular disorders. Ultimate understanding of these disorders, however, will undoubtedly shed considerable light on skeletal muscle development and function. Three classical congenital myopathies are central core disease, nemaline myopathy, and centronuclear myopathy. The congenital muscular dystrophies are often distinguished by whether or not they are associated with clinically evident cerebral involvement.     

Merosin-deficient congenital muscular dystrophy with mental retardation and cerebellar cysts unlinked to the LAMA2, FCMD and MEB loci

We report a case of congenital muscular dystrophy with secondary merosin deficiency, structural involvement of the central nervous system and mental retardation in an 8-year-old girl from a consanguineous family. She had early-onset hypotonia, generalized muscle wasting, with weakness especially of the neck muscles, joint contractures, mental retardation and high creatine kinase. Muscle biopsy showed dystrophic changes with partial deficiency of the laminin ₂ chain. Cranial magnetic resonance imaging revealed multiple small cysts in the cerebellum, without cerebral cortical dysplasia or white matter changes. The laminin ₂ chain (6q2), Fukuyama type congenital muscular dystrophy (9q31–q33) and muscle–eye–brain disease (1p32–p34) loci were all excluded by linkage analysis. We suggest that this case represents a new entity in the nosology of congenital muscular dystrophy.     

The abnormal expression of utrophin in Duchenne and Becker muscular dystrophy is age related

J. Taylor, F. Muntoni, V. Dubowitz and C. A. Sewry (1997) Neuropathology and Applied Neurobiology 23, 399–405 The abnormal expression of utrophin in Duchenne and Becker muscular dystrophy is age related Utrophin is a 395 kDa protein with considerable homology to dystrophin. It is highly expressed in the sarcolemma of normal fetal muscle fibres but is confined to neuromuscular and myotendinous junctions, and blood vessels in adult muscle. Sarcolemmal expression occurs on regenerating fibres, irrespective of the disease, and is also seen on mature fibres in Duchenne and Becker muscular dystrophies (DMD, BMD), and inflammatory myopathies. The reasons for the abnormal expression in DMD and BMD are unclear. We have studied this expression of utrophin immunocytochemically on mature fibres in 42 cases of DMD and BMD, aged 3 months–24 years of age. All cases had some mature fibres, with no detectable fetal myosin, that showed sarcolemmal expression of utrophin. The number of these fibres and the intensity of fluorescence was low in young cases before the age of 2 years and increased with age. The fluorescence was graded on a scale of 0 to ++++ and there were significantly more cases under 2 years of age (10/12) with a grading of utrophin of only +, compared with those over 2 years (4/30, P < 0.001). Some revertant fibres, but not all, expressed utrophin and dystrophin. Our data show that the abnormal expression of utrophin on mature muscle fibres in DMD and BMD is not a continuation of the expression that occurs in fetal or regenerating muscle, but is a secondary event caused by unknown factors. The immunocytochemical intensity of utrophin is variable between cases and there is no correlation with clinical severity. As all cases studied had some expression of utrophin on mature fibres, this may be a useful additional tool for distinguishing BMD from other dystrophies, especially in cases with minimal abnormalities in dystrophin expression and/or no detectable mutation in the gene.     

Cardiac involvement in the muscular dystrophies

Cardiac disease is a common clinical manifestation present in a variety of neuromuscular disorders, most notably the muscular dystrophies. Heart disease may produce the presenting or predominant symptoms in these disorders but more often not does not result in clinical features at the time of initial presentation. Cardiac involvement in the muscular dystrophies results from pathologic changes in the myocardium and the cardiac conduction system, leading to cardiomyopathy and/or rhythm disturbances including supraventricular arrhythmias, life‐threatening ventricular arrhythmias, and sudden cardiac death. This Review covers the spectrum of cardiac dysfunction in these inherited muscle disorders and proposes practical recommendations for monitoring and management. Muscle Nerve 57 : 707–715, 2018     

The role of skeletal muscle biopsy in the diagnosis of neuromuscular disorders

Muscle biopsy is required to provide a definitive diagnosis in many neuromuscular disorders. Biopsy findings may indicate whether the pathological process is of neurogenic or myopathic origin. The muscle biopsy may give important information on the course of the disease (acute or chronic) and on the disease stage and progression. The interpretation of muscle biopsy, including histochemical and ultrastructural analysis, is a key factor in the diagnosis of muscular dystrophies, glycogenoses, inflammatory myopathies and congenital myopathies. An assessment of muscle biopsy on electron microscopy enables a definite diagnosis of oculopharyngeal muscular dystrophy, mitochondrial myopathy or inclusion body myositis. This paper presents an overview of general indications for muscle biopsy, biopsy procedures, as well as transportation and preparation of muscle tissue for final microscopic analysis. The interpretation of specific microscopic findings and a brief discussion on the clinical usefulness of muscle biopsy in the era of molecular diagnosis are also presented.     

Heterogeneity of classic congenital muscular dystrophy with involvement of the central nervous system: report of five atypical cases

A heterogeneous group of patients with congenital muscular dystrophy associated with clinical or radiologic central nervous system involvement other than the severe classic form with merosin deficiency, muscle-eye-brain disease, and Walker-Warburg syndrome is described. A probable hereditary or familial occurrence could be suggested in all patients. One merosin-positive patient presented severe motor incapacity and cerebral atrophy without any clinical manifestation of central nervous system involvement. A second patient, also merosin-positive, had moderate motor and mental handicap, and epilepsy with no changes in neuroimaging. A third patient, found to have partial merosin deficiency by muscle biopsy, manifested severe psychomotor retardation and cerebral atrophy with foci of abnormal white-matter signal on magnetic resonance imaging. Finally, two merosin-positive siblings with microcephaly, mental retardation, and an incapacitating progressive neuromuscular course, exhibited cataracts without defects of neuronal migration or brain malformation. This report emphasizes the broad clinical spectrum and heterogeneity of merosin-positive congenital muscular dystrophy with associated central nervous system involvement, and illustrates the importance of further studies on clinical, immunohistochemical, and genetic grounds for identifying new subsets of congenital muscular dystrophy.     

Congenital muscular dystrophy and cerebral CT scan anomalies. Results of a collaborative study of the Société de Neurologie Infantile

We present the results of a collaborative study on the association of congenital muscular dystrophy with central nervous system anomalies revealed by CT scan investigation of 10 patients. In seven children, an abnormal hypodensity of the cerebral white matter is found; in four of these patients, this radiological anomaly is either isolated, or associated with a moderate intellectual impairment; in one case, severe mental retardation and ocular changes had occurred; in the other two cases, the muscular disease was progressing slowly, in association with microcephaly, epilepsy, and moderate mental retardation. Three children were afflicted with a severe early encephalopathy and congenital muscular dystrophy, and presented signs of cortical and subcortical atrophy on CT scan. Two of these patients corresponded to different types of cerebro-ocular dysplasia-muscular dystrophy syndromes, and the third patient of Fukuyama's congenital muscular dystrophy. These observations are discussed and compared with those reported in the literature. The authors emphasize the need to investigate possible cerebral CT scan anomalies in congenital muscular dystrophies, and to look for muscular changes in some prenatal encephalopathies.     

Variabilité phénotypique et corrélations génotype-phénotype des dystrophinopathies : contribution des banques de données

The objective of this work was to study the natural history of dystrophinopathies and the genotype-phenotype correlations made possible by the development of the clinical part of the French DMD database. The collection of 70,000 clinical data for 600 patients with an average longitudinal follow-up of 12 years enabled clarification of the natural history of Duchenne and Becker muscular dystrophies and clinical presentations in symptomatic females. We were able to specify the phenotypic heterogeneity of motor, orthopedic and respiratory involvements (severe, standard and intermediary form), of the cardiac disorder (severe, standard or absent cardiomyopathy, absence of correlation between motor and cardiac involvements), and of brain function (mental deficiency in the patients with Becker muscular dystrophy, psychopathological disorders in dystrophinopathies). Phenotypic variability did not correlate with a specific mutational spectrum. We propose a model of phenotypic analysis based on the presence or not of muscular and cardiac involvements (described by age at onset and rate of progression) and brain involvement (described by the type and the severity of the cognitive impairment and of the psychological disorders). The methodology developed for the DMD gene can be generalized and used for other databases dedicated to genetic diseases. Application of this model of phenotypic analysis for each patient and further development of the database should contribute substantially to clinical research providing useful tools for future clinical trials.     

Efficacy and tolerance of gastrostomy feeding in Japanese muscular dystrophy patients

Although muscular dystrophy patients often have feeding difficulty and need long-term enteral nutrition, only a few reports have described gastrostomy feeding in these patients. This study was designed to evaluate the efficacy and tolerance of gastrostomy feeding in patients with muscular dystrophy. We performed a retrospective, multicenter study on 144 patients with muscular dystrophy who received gastrostomy feeding between 2007 and 2009 in 25 neuromuscular centers in Japan. There were 77 Duchenne muscular dystrophy (median age at gastrostomy placement 26 years, range 13-47 years), 40 myotonic dystrophy (median age 54.5 years, range 13-70 years), 11 Fukuyama congenital muscular dystrophy (median age 22 years, range 13-29 years), 5 limb girdle muscular dystrophy (median age 62 years, range 43-78 years), and 5 facioscapulohumeral muscular dystrophy (median age 52 years, range 28-67 years) patients. Many benefits including amelioration of malnutrition, swallowing difficulty and respiratory status were observed after the introduction of gastrostomy feeding. Especially in patients with Duchenne muscular dystrophy, mean body weight significantly increased after gastrostomy placement. Although most complications, which are commonly observed in other populations, were tolerable, respiratory failure and peritonitis were important concerns. These findings suggest that gastrostomy placement at an appropriate time is advisable in patients with muscular dystrophy.     

Nutritional inadequacy in adults with muscular dystrophy

Patients with muscular dystrophy may be prone to nutrient deficiency due to mobility limitations or oropharyngeal weakness. Patients with myotonic muscular dystrophy (DM1) may be particularly prone to nutritional deficiencies from associated dysmotility of the entire gastrointestinal tract. We prospectively evaluated nutritional intake, body composition, and muscle strength in adult patients with DM1 (n = 29) and other muscular dystrophies (n = 22) on two occasions separated by approximately 6 months. Handgrip was significantly lower and knee extension higher for DM1 compared to other dystrophies, with no between-group differences in nutritional intakes. Many patients in both groups demonstrated inadequate nutrient intake of protein, energy, vitamins (water and fat soluble), and minerals (calcium and magnesium). Significant correlations were found between measures of strength and certain individual nutrients (e.g., copper and water-soluble vitamins). These data indicate that a substantial number of adults with muscular dystrophy do not meet current dietary intake recommendations. The potential clinical implications of these findings are discussed.     

Genetic modifiers of Duchenne and facioscapulohumeral muscular dystrophies

Muscular dystrophy is defined as the progressive wasting of skeletal muscles that is caused by inherited or spontaneous genetic mutations. Next‐generation sequencing has greatly improved the accuracy and speed of diagnosis for different types of muscular dystrophy. Advancements in depth of coverage, convenience, and overall reduced cost have led to the identification of genetic modifiers that are responsible for phenotypic variability in affected patients. These genetic modifiers have been postulated to explain key differences in disease phenotypes, including age of loss of ambulation, steroid responsiveness, and the presence or absence of cardiac defects in patients with the same form of muscular dystrophy. This review highlights recent findings on genetic modifiers of Duchenne and facioscapulohumeral muscular dystrophies based on animal and clinical studies. These genetic modifiers hold great promise to be developed into novel therapeutic targets for the treatment of muscular dystrophies. Muscle Nerve 57 : 6–15, 2018     

Isotonic fatigue in laminin alpha2-deficient dy/dy dystrophic mouse diaphragm

Laminin alpha2 deficiency causes approximately 50% of human congenital muscular dystrophies. Muscle in the corresponding dy/dy mouse model has reduced force but increased fatigue resistance during isometric contractions. To determine whether a similar pattern of alterations is present during isotonic contractions, dy/dy diaphragm was studied in vitro. During 20% load, dystrophic diaphragm had significantly reduced shortening, shortening velocity, work and power deficits, which persisted during the fatigue-inducing stimulation. In contrast, during 40% load, isotonic contractile performance of diseased muscle was impaired only mildly and only for some contractile parameters. At both loads, rate of isotonic fatigue when expressed relative to initial contractile values was similar for dystrophic and normal muscle, or in some instances slightly higher for dystrophic muscle. Therefore, fatigue resistance is considerably impaired during isotonic contractions relative to that reported previously for isometric contractions. This has important implications for increased susceptibility to respiratory failure in laminin alpha2-deficient muscular dystrophy.