Sudden cardiac death, or cardiac arrest, is a major health problem, causing about 166,200 deaths each year among adults in the United States. It may be caused by almost all known heart diseases. Most cardiac arrests occur when the diseased heart begins to exhibit rapid and/or chaotic activity, such as ventricular tachycardia or fibrillation. Some are due to extreme slowing of the heart. All these events are called life-threatening arrhythmias. Arrhythmogenic cardiomyopathy is a frequent feature in several muscular dystrophies with a potential risk of cardiac sudden death. Among the measures able to predict the propensity to develop life-threatening arrhythmias, heart rate variability is an accepted non invasive measurement of cardiac autonomic modulation. The use of heart rate variability to measure the extent of changes in autonomic nervous system is an established risk stratification procedure in different diseases. In fact numerous studies have demonstrated the positive prognostic power of altered heart rate variability values to predict all-cause mortality, cardiac events, sudden cardiac death and heart transplantation. Usefulness of heart rate variability as a predictor of sudden cardiac death in muscular dystrophies has been reviewed.
Heart rate variability; sudden cardiac death; muscular dystrophies
Myotonic dystrophy type 1 (DM1) is the most frequently inherited neuromuscular disease in adults. It is a multisystemic disorder with major cardiac involvement most commonly represented by first-degree atrioventricular heart block (AVB), followed by different degrees of bundle-branch and intraventricular blocks. In search for candidate genes, modifiers of the AVB phenotype in DM1, the expression of the small-conductance calcium activated potassium channel (SK3) gene was analysed in muscle biopsies from DM1 patients. The association between SK3 polymorphisms and the AVB phenotype was then studied analyzing 40 DM1 patients with AVB and 40 age-matched DM1 affected individuals with no ECG abnormalities. [CTG]n repeat length and cardiac clinical picture were also assessed for correlation. QRT-PCR experiments showed an over-expression of the SK3 transcript in DM1 muscle biopsies compared to healthy controls. However, no statistical association between the AVB phenotype and either the [CTG]n expansion length or the presence of specific SNPs in the SK3 gene were detected. These findings suggest that modifier genes, other than SK3, should be identified in order to explain the cardiac phenotypic variability among DM1 patients.
Myotonic dystrophy; cardiac phenotype; SK3; SNPs; association study
This article is dedicated to our teacher, Prof. Erich Kuhn, Heidelberg, on the occasion of his 88th birthday on 23th November 2008. In contrast to muscular dystrophies, the muscle channelopathies, a group of diseases characterised by impaired muscle excitation or excitation-contraction coupling, can fairly well be treated with a whole series of pharmacological drugs. However, for a proper treatment proper diagnostics are essential. This article lists state-of-the-art diagnostics and therapies for the two types of myotonic dystrophies, for recessive and dominant myotonia congenita, for the sodium channel myotonias, for the primary dyskalemic periodic paralyses, for central core disease and for malignant hyperthermia susceptibility in detail. In addition, for each disorder a short summary of aetiology, symptomatology, and pathogenesis is provided.
Chloride and sodium channel myotonias; periodic paralyses; malignant hyperthermia and central core disease
The term limb-girdle muscular dystrophies (LGMD) identify about two dozens of distinct genetic disorders. Additional genes must play a role, since there are LGMD families excluded from any known locus. The aim of our work is to test a number of candidate genes in unclassified LGMD patient and control DNA samples.
We selected the following 11 candidate genes: myozenin 1, 2 and 3), gamma-filamin, kinectin-1, enolase-3 beta, ZASP, TRIM 11 and TRIM 17, OZZ and zeta –sarcoglycan. These candidates were chosen for a combination of different reasons: chromosomal position, sequence homology, interaction properties or muscular dystrophy phenotypes in animal models.
The exon and flanking intron sequences were subjected to molecular testing by comparative mutation scanning by HT-DHPLC of LGMD patients versus control.
We identified a large number of variations in any of the genes in both patients and controls. Correlations with disease or possible modifying effects on the LGMD phenotype remain to be investigated.
limb-girdle muscular dystrophies
Hereditary motor and sensory neuropathy Lom type (HMSNL), also called CMT 4D, a hereditary autosomal recessive neuropathy, caused by mutation in N-Myc downstream regulated gene 1 (NDRG1 gene), was first described in a Bulgarian Gypsy population near Lom and later has been found in Gypsy communities in Italy, Spain, Slovenia and Hungary. We present two siblings with HMSNL, female and male, aged 30 and 26, respectively in a Serbian non-consanguineous family of Gypsy ethnic origin. They had normal developmental milestones. Both had symptoms of lower limb muscle weakness and walking difficulties with frequent falls, which began at the age of seven. At the age of 12, they developed hearing problems and at the age of 15 hand muscle weakness. Neurological examination revealed sensorineural hearing loss, dysarthria, severe distal and mild proximal muscle wasting and weakness, areflexia and impairment of all sensory modalities of distal distribution. Electrophysiological study revealed denervation with severe and early axonal loss. Sensorineural hearing loss was confirmed on electrocochleography and brainstem evoked potentials. Molecular genetic testing confirmed homozygote C564t (R148X) mutation in NDRG1 gene.
Hereditary motor and sensory neuropathy; Lom type; NDRG1;
Calpainopathy is an autosomal-recessive limb girdle muscular dystrophy (LGMD2A) characterized by selective atrophy and weakness of proximal limb girdle muscles. The clinical phenotype of the disease is highly variable inter-familial, but little is known about intra-familial variability. This study reports the phenotypic variability in eight sibling pairs with genetically proven LGMD2A. Although siblings with identical mutations were often similarly affected, in some families the age of onset and the clinical course varied considerably.
Calpainopathy; limb-girdle muscular dystrophy; genotype phenotype correlation; LGMD2A; sibling
Distinct mechanisms such as humeral immunity in dermatomyositis (DM) and T-cell-mediated cytotoxicity in polymyositis (PM) contribute to the pathology of inflammatory myopathies. In addition, different subsets of macrophages are present in both diseases. Herein, the characteristics of 25F9-positive macrophages in skeletal muscle inflammation are outlined. Muscle biopsies of subjects with DM and PM were studied by immunohistochemical multi-labelling using the late-activation marker 25F9, together with markers characterizing macrophage function including IFN-γ, iNOS, and TGF-β. In PM, a robust expression of IFN-γ, iNOS, and TGF-β was observed in inflammatory cells. Double- and serial-labelling revealed that a subset of 25F9-positive macrophages in the vicinity of injured muscle fibres expressed iNOS and TGF-β, but not IFN-γ. In DM, IFN-γ, iNOS and TGF-β were also expressed in inflammatory cells in the endomysium. Double- and serial-labelling studies in DM indicated that 25F9-positive macrophages expressed TGF-β and to a lesser degree iNOS, but not IFN-γ. In conclusion, our data suggest that late-activated macrophages contribute to the pathology of inflammatory myopathies.
Dermatomyositis; polymyositis; 25F9-positive macrophages
Gene-targeted therapies, such as adeno-associated viral vector (AAV)-mediated gene therapy and cell-mediated therapy using myogenic stem cells, are hopeful molecular strategies for muscular dystrophy. In addition, drug therapies based on the pathophysiology of muscular dystrophy patients are desirable. Multidisciplinary approaches to drug design would offer promising therapeutic strategies. Myostatin, a member of the transforming growth factor-β superfamily, is predominantly produced by skeletal muscle and negatively regulates the growth and differentiation of cells of the skeletal muscle lineage. Myostatin inhibition would increase the skeletal muscle mass and prevent muscle degeneration, regardless of the type of muscular dystrophy. Myostatin inhibitors include myostatin antibodies, myostatin propeptide, follistatin and follistatin-related protein. Although follistatin possesses potent myostatin-inhibiting activity, it works as an efficient inhibitor of activins. Unlike myostatin, activins regulate the growth and differentiation of nearly all cell types, including cells of the gonads, pituitary gland and skeletal muscle. We have developed a myostatin-specific inhibitor derived from follistatin, designated FS I-I. Transgenic mice expressing this myostatin-inhibiting peptide under the control of a skeletal muscle-specific promoter showed increased skeletal muscle mass and strength. mdx mice were crossed with FS I-I transgenic mice and any improvement of the pathological signs was investigated. The resulting mdx/FS I-I mice exhibited increased skeletal muscle mass and reduced cell infiltration in muscles. Muscle strength was also recovered in mdx/FS I-I mice. Our data indicate that myostatin inhibition by this follistatin-derived peptide has therapeutic potential for muscular dystrophy.
Myostatin; follistatin; muscular dystrophy
Duchenne muscular dystrophy (DMD) is a lethal X-linked disorder of striated muscle caused by the absence of dystrophin. Recently, impairment of vascular dilation under shear stress has been found in DMD, but the underlying molecular mechanism is not fully understood. Moreover, dilation of intramuscular arterioles, which may be a key to the molecular pathogenesis, has not been addressed yet. We examined dilation of arterioles in the mouse cremaster muscle under shear stress due to ligation. The vasodilation was significantly impaired in dystrophin-deficient mdx mice as well as in neuronal nitric oxide synthase (nNOS)-deficient mice; however, neither endothelial NOS-deficient mice nor α1-syntrophin-deficient mice showed any difference in vasodilation from control mice. These results indicate that nNOS is the main supplier of nitric oxide in shear stress-induced vasodilation in skeletal muscle, but that the sarcolemmal localization of nNOS is not indispensable for the function. In contrast, the response to acetylcholine or sodium nitroprusside was not impaired in mdx or nNOS-deficient mice, suggesting that pharmacological treatment using a vasoactive agent may ameliorate skeletal and cardiac muscle symptoms of DMD.
Duchenne muscular dystrophy; blood flow; dystrophin, nitric oxide synthase; vasodilation
Caveolins, components of the uncoated invaginations of plasma membrane, regulate signal transduction and vesicular trafficking. Loss of caveolin-3, resulting from dominant negative mutations of caveolin-3 causes autosomal dominant limb-girdle muscular dystrophy (LGMD) 1C and autosomal dominant rippling muscle disease (AD-RMD). Myostatin, a member of the muscle-specific transforming growth factor (TGF)-β superfamily, negatively regulates skeletal muscle volume. Herein we review caveolin-3 suppressing of activation of type I myostatin receptor, thereby inhibiting subsequent intracellular signaling. In addition, a mouse model of LGMD1C has shown atrophic myopathy with enhanced myostatin signaling. Myostatin inhibition ameliorates muscular phenotype in the model mouse, accompanied by normalized myostatin signaling. Enhanced myostatin signaling by caveolin-3 mutation in human may contribute to the pathogenesis of LGMD1C. Therefore, myostatin inhibition therapy may be a promising treatment for patients with LGMD1C. More recent studies concerning regulation of TGF-β superfamily signaling by caveolins have provided new insights into the pathogenesis of several human diseases.
caveolin-3; limb-girdle muscular dystrophy 1C (LGMD1C); autosomal dominant rippling muscle disease (AD-RMD); myostatin; transforming growth factor-β (TGF-β)
Fukuyama type congenital muscular dystrophy accompanies central nervous system and ocular lesions. Morphological findings suggest that major central nervous system lesions, such as cortical dysplasia, are caused by the abnormal glia limitans due to an impairment of astrocytes. Increase of corpora amylacea and neurofibrillary tangles suggests acceleration of the aging process in the Fukuyama type congenital muscular dystrophy brain. Glycosylation of α-dystroglycan is decreased in the central nervous system of Fukuyama type congenital muscular dystrophy in a similar manner to the skeletal muscle, but dystroglycan mRNA levels appear to be increased. Glycosylated α-dystroglycan is reduced in the glia limitans formed by astrocytic endfeet. Slight accumulation of Nε-(carboxymethyl)lysine, an oxidative modification product, is observed in astrocytes of Fukuyama type congenital muscular dystrophy and in an astrocytoma cell line with suppressed fukutin expression. Cerebral cortical neurons of Fukuyama type congenital muscular dystrophy and controls react with an antibody for core α-dystroglycan but not with an antibody for glycosylated α-dystroglycan. Carboxymethyl lysine is accumulated in cortical neurons of a severe case of Fukuyama type congenital muscular dystrophy. Both astrocytes and neurons appear to be sensitive to oxidative stress when fukutin is suppressed. However, it is still unclear how the loss of fukutin causes astrocytic and neuronal dysfunction. Since the central nervous system is composed of several components that are closely related to each other, more investigations are needed for thorough understanding of the Fukuyama type congenital muscular dystrophy brain. Moreover, since astrocytes and epithelial cells may show different cellular responses to fukutin suppression, it seems important to evaluate the functions of fukutin in each type of cell or tissue, not only to prove the pathogenesis of Fukuyama type congenital muscular dystrophy, but also for applying appropriate therapies, especially those at molecular level.
Fukuyama type congenital muscular dystrophy (FCMD); neuron; glia
The pathogenesis of dilated cardiomyopathy in Emery- Dreifuss muscular dystrophy (EDMD) is still unknown. Autoimmune mechanisms have recently been taken into account. The aim of this investigation was to determine whether the level of circulating antibodies to heart proteins which were previously detected, correlates with disease progression. Troponin I was chosen as the target. Ten patients with EDMD and 10 age-matched normal controls were tested. An enzyme linked immunoassay (ELISA) technique was used to determine the possible relation between the level of anti-troponin I antibodies at diagnosis and at follow-up. Autoantibodies against troponin I were detected in all EDMD patients. At diagnosis the level was higher in the X-linked EDMD form (X-EDMD), as compared to the autosomal dominant form (AD-EDMD). At follow-up the elevated level of the autoantibodies persisted in all the EDMD cases. However, in the AD-EDMD form, the level was found to be significantly rising with disease progression, in the X-EDMD form, on the other hand, it was declining. No clear-cut relationship between the level of the circulating antibodies and cardiac symptomatology was present. Detection of anti-troponin I antibodies may provide a non-invasive marker of early stages of dilated cardiomyopathy in EDMD.
Cardiac autoantibodies; dilated cardiomyopathy; Emery-Dreifuss muscular dystrophy
Skeletal muscle contraction is controlled by motor neurons, which contact the muscle at the neuromuscular junction (NMJ). The formation and maintenance of the NMJ, which includes the aggregation of densely packed clusters of acetylcholine receptor (AChR) opposite the motor nerve terminal, is orchestrated by muscle-specific receptor tyrosine kinase, MuSK. Recently, a MuSK-interacting cytoplasmic adaptor-like protein Dok-7 was identified and its localization at the postsynaptic region of the NMJ was revealed. Mice lacking Dok-7 have a phenotype indistinguishable from MuSK-deficient mice, and fail to form both AChR clusters and NMJs. In cultured myotubes, Dok-7 is required for MuSK activation and AChR clustering. Thus, Dok-7 is essential for neuromuscular synaptogenesis and it appears that the regulatory interaction of Dok-7 with MuSK is integrally involved in this process. In humans there are both autoimmune and genetic causes of defective neuromuscular transmission that gives rise to the fatigable muscle weakness known as myasthenia. DOK7 has been found to be a major locus for mutations that underlie a genetic form of myasthenia with a characteristic ‘limb girdle’ pattern of muscle weakness (DOK7 CMS). Patients with DOK7 CMS have small, simplified NMJs but normal AChR function. The most common mutation causes a COOH-terminal truncation, which greatly impairs Dok-7’s ability to activate MuSK. Recently, a series of differing DOK7 mutations have been identified, which affect not only the COOH-terminal region but also the NH2-terminal moiety. The study of these mutations may help understand the underlying pathogenic mechanism of DOK7 CMS.
DOK7 congenital myasthenic syndrome; neuromuscular junction; protein tyrosine kinase; Dok-7; MuSK