No full-text available
To read the full-text of this research,
you can request a copy directly from the author.
Abstract
A family study was carried out to clarify the problem of two separate muscle disease phenotypes in a large consanguineous pedigree. These were a severe limb-girdle type muscular dystrophy and a mild late onset distal myopathy. Thirty-two first degree and 14 other relatives of 18 previously examined index patients were available for clinical examination. Twenty-three subjects underwent computed tomography of the lower leg muscles. No new cases of limb-girdle type muscular dystrophy were found. Distal myopathy was diagnosed in 14 subjects, 10 first degree relatives and four other relatives. Segregation analysis showed that the corrected proportion of affected with the severe proximal type was 0.246 and the proportion of affected with the distal myopathy was 0.58. Pedigree analysis is compatible with the possibility that the mild, late onset distal myopathy is caused by a dominant gene and that the limb-girdle type may be expressed in homozygotes.
... Tibial muscular dystrophy (TMD, OMIM: #600334, Udd myopathy) is an autosomal dominant distal myopathy with a particularly high prevalence in the Finnish population [1][2][3]. The disease is caused by heterozygous mutations in the last two exons (Mex5-6) of the Titin (TTN) gene [4]. ...
... TMD is clinically characterised by atrophy and weakness in the muscles of the anterior compartment of the lower leg (tibialis anterior, extensor hallucis longus and extensor digitorum longus) [3], with typical onset between 35-55 years [12]. Homozygous FINmaj mutations cause the manifestation of the completely different, and much more severe, early onset LGMD2J (OMIM: #608807) [2,3,13]. ...
... TMD is clinically characterised by atrophy and weakness in the muscles of the anterior compartment of the lower leg (tibialis anterior, extensor hallucis longus and extensor digitorum longus) [3], with typical onset between 35-55 years [12]. Homozygous FINmaj mutations cause the manifestation of the completely different, and much more severe, early onset LGMD2J (OMIM: #608807) [2,3,13]. TMD and LGMD2J patients do not have facial muscle weakness, dysphagia or clinically manifest cardiomyopathy. ...
Tibial muscular dystrophy (TMD) is a late onset, autosomal dominant distal myopathy that results from mutations in the two last domains of titin. The cascade of molecular events leading from the causative Titin mutations to the preterm death of muscle cells in TMD is largely unknown. In this study we examined the mRNA and protein changes associated with the myopathology of TMD. To identify these components we performed gene expression profiling using muscle biopsies from TMD patients and healthy controls. The profiling results were confirmed through quantitative real-time PCR and protein level analysis. One of the pathways identified was activation of endoplasmic reticulum (ER) stress response. ER stress activates the unfolded protein response (UPR) pathway. UPR activation was supported by elevation of the marker genes HSPA5, ERN1 and the UPR specific XBP1 splice form. However, UPR activation appears to be insufficient to correct the protein abnormalities causing its activation because degenerative TMD muscle fibres show an increase in ubiquitinated protein inclusions. Abnormalities of VCP-associated degradation pathways are also suggested by the presence of proteolytic VCP fragments in western blotting, and VCP's accumulation within rimmed vacuoles in TMD muscle fibres together with p62 and LC3B positive autophagosomes. Thus, pathways controlling turnover and degradation, including autophagy, are distorted and lead to degeneration and loss of muscle fibres.
... 7 Several other variants localised in the second to last (Mex5, exon 362) and the last exons of TTN have been described in TMD patients from Belgian, French, Spanish and Italian populations. [8][9][10][11] Homozygosity of the FINmaj variant is rare and causes limb-girdle muscular dystrophy 2J (OMIM 608807), a phenotype with earlier onset and more proximal muscle involvement. 1,6,10 Recently, atypical, more complex or severe phenotypes have been explained by a second TTN variant in several TMD patients from different European countries and in LGMD2J patients being compound heterozygous for the FINmaj variant and an additional TTN variant. ...
... [8][9][10][11] Homozygosity of the FINmaj variant is rare and causes limb-girdle muscular dystrophy 2J (OMIM 608807), a phenotype with earlier onset and more proximal muscle involvement. 1,6,10 Recently, atypical, more complex or severe phenotypes have been explained by a second TTN variant in several TMD patients from different European countries and in LGMD2J patients being compound heterozygous for the FINmaj variant and an additional TTN variant. 12 Hereditary myopathy with early respiratory failure (OMIM 603689), an autosomal dominant disease involving proximal, distal and respiratory muscles, represents yet another entity caused by TTN variants. ...
Variants in the TTN gene have been associated with distal myopathies and other distinctive phenotypes involving skeletal and cardiac muscle. Through whole-exome sequencing we identified a novel stop-gain variant (c.107635C>T, p.(Gln35879Ter)) in the TTN gene, coding a part of the M-line of titin, in 14 patients with autosomal recessive distal myopathy and Serbian ancestry. All patients share a common 1 Mb core haplotype associated with c.107635C>T, suggesting a founder variant. In compound heterozygotes, nine other TTN variants were identified: four stop-gain, three frameshift, one missense and one splice donor variant. Patients homozygous for the common variant did not show significant clinical differences to the compound heterozygous patients. The clinical presentation of all patients was an adult onset distal myopathy with predominant lower limb involvement. In addition, most patients had normal to mildly elevated serum creatine kinase levels, myopathic electromyograms, normal cardiologic and respiratory tests and muscle pathology consistent with a dystrophic process. In this study, we describe a distinct phenotype for patients with distal myopathy associated with novel recessive TTN variants including a Serbian founder variant. Our results expand the phenotypic and genetic spectrum of titinopathies and will facilitate the diagnosis of this condition in patients of Serbian origin.European Journal of Human Genetics advance online publication, 15 March 2017; doi:10.1038/ejhg.2017.16.
... Despite this, internal isolates such as the archipelago of Larsmo (Luoto) in Osthrobotnia are highly consanguineous and provide families suitable for a random search of new disease loci ( Figure 8). A good example of this is a collection of families and mapping of a disease locus for tibial muscular dystrophy, "Larsmo disease"( Haravuori et al. 1998;Udd 1992) . Larsmo was probably not inhabited until the 13th century, and the origin of the founders is unknown. ...
... Larsmo was probably not inhabited until the 13th century, and the origin of the founders is unknown. Because migration between the island and the mainland was very limited until this century, consanguineous marriages have thus been common as far back as family histories can be traced to the 17th century (Udd 1992). ...
The term autosomal recessive congenital ichthyosis (ARCI) refers to a group of rare disorders of keratinization classified as nonsyndromic forms of ichthyosis. This group was traditionally divided into lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma (CIE) but today it also includes harlequin ichthyosis, self-healing collodion baby, acral self-healing collodion baby, and bathing suit ichthyosis. The combined prevalence of LI and CIE has been estimated at 1 case per 138 000 to 300 000 population. In some countries or regions, such as Norway and the coast of Galicia, the prevalence may be higher due to founder effects. ARCI is genetically highly heterogeneous and has been associated with 6 genes to date: TGM1, ALOXE3, ALOX12B, NIPAL4, CYP4F22, and ABCA12. In this article, we review the current knowledge on ARCI, with a focus on clinical, histological, ultrastructural, genetic, molecular, and treatment-related aspects.
... Despite this, internal isolates such as the archipelago of Larsmo (Luoto) in Osthrobotnia are highly consanguineous and provide families suitable for a random search of new disease loci (Figure 8). A good example of this is a collection of families and mapping of a disease locus for tibial muscular dystrophy, " Larsmo disease " (Haravuori et al. 1998; Udd 1992) . Larsmo was probably not inhabited until the 13th century, and the origin of the founders is unknown. ...
... Larsmo was probably not inhabited until the 13th century, and the origin of the founders is unknown. Because migration between the island and the mainland was very limited until this century, consanguineous marriages have thus been common as far back as family histories can be traced to the 17th century (Udd 1992). ...
It seems as though I had not drunk from the cup of wisdom, but had fallen into it Søren Kierkegaard
... The pedigree findings in TMD are consistent with autosomal dominant inheritance as there are affected family members in all generations in about 0.5 proportion and there are male-to-male transmissions excluding X-chromosomal inheritance (Partanen et al.1990, Udd 1992a). There is no significant difference in disease severity between genders. ...
... Three patients had good distal strength and remained ambulatory at an advanced age, whereas the others had also severe distal weakness and were wheelchair bound in early adulthood (Udd et al. 1991a). Limb-girdle type muscular dystrophy was found in a proportion of 0.246 in this pedigree and was suggested to result from a homozygous manifestation of the dominant gene (Udd 1992a). A genome-wide locus search was initiated in this pedigree with multiple inheritance models but it resulted in no significant linkage findings (Nokelainen et al. 1996). ...
Diss. -- Helsingin yliopisto.
... Tibial muscular dystrophy (TMD) is an autosomal dominant late-onset distal myopathy that results from heterogeneous mutations in the last two exons of the Titin gene. TMD is characterized by myofiber atrophy and weakness in the skeletal muscle of the anterior compartment of the lower leg [163]. Gene profiling studies provided evidence that ER stress could be one of the potential reasons for muscle weakness in TMD patients [164]. ...
Skeletal muscle is a highly plastic tissue in the human body that undergoes extensive adaptation in response to environmental cues, such as physical activity, metabolic perturbation, and disease conditions. The endoplasmic reticulum (ER) plays a pivotal role in protein folding and calcium homeostasis in many mammalian cell types, including skeletal muscle. However, overload of misfolded or unfolded proteins in the ER lumen cause stress, which results in the activation of a signaling network called the unfolded protein response (UPR). The UPR is initiated by three ER transmembrane sensors: protein kinase R‐like endoplasmic reticulum kinase, inositol‐requiring protein 1α, and activating transcription factor 6. The UPR restores ER homeostasis through modulating the rate of protein synthesis and augmenting the gene expression of many ER chaperones and regulatory proteins. However, chronic heightened ER stress can also lead to many pathological consequences including cell death. Accumulating evidence suggests that ER stress‐induced UPR pathways play pivotal roles in the regulation of skeletal muscle mass and metabolic function in multiple conditions. They have also been found to be activated in skeletal muscle under catabolic states, degenerative muscle disorders, and various types of myopathies. In this article, we have discussed the recent advancements toward understanding the role and mechanisms through which ER stress and individual arms of the UPR regulate skeletal muscle physiology and pathology.
... Several lines of evidence have shown that the titin M10 domain, responsible for the interaction with obscurin at the M-band, is a hotspot for autosomal and recessive mutations causative for at least three human diseases: the late-onset distal myopathy tibial muscular dystrophy in the heterozygous state [53], the early onset limb girdle muscular dystrophy type 2J in the homozygous state [54] and the Salih congenital muscular dystrophy, an autosomal recessive cardiac and skeletal myopathy [55]. Despite their different onset and development, these muscle pathologies share a common molecular signature characterized by a reduction in the obscurin/titin interaction, confirming the importance of this connection for sarcomere integrity [33]. ...
Introduction:
Obscurin, a giant protein of striated muscles, is emerging as an important player in a wide range of processes including myofibril assembly and maintenance, muscle protein degradation and intracellular signaling. Accordingly, obscurin participates to the mechanisms by which muscles adapt to physiological requirements or to pathological cues associated with cardiac and skeletal muscle diseases. Areas covered: The structure of the different obscurin isoforms identified so far, their tissue distribution and the most recent findings on obscurin in invertebrates and mammals will be reviewed. We will provide a synopsis of known molecular interactions between obscurin and other proteins and the biological relevance of these interactions for striated muscle function. The involvement of obscurin in protein degradation mechanisms and intracellular signaling will be also discussed along with initial evidence of a role of obscurin in the pathophysiology of human diseases. Expert opinion: Although still much remains to be discovered about the role of obscurin either as a structural component of the sarcomere or as a mediator of signaling pathways within muscle cells, it can be envisioned that this protein represents an interesting novel pharmacological target for the prevention and treatment of cardiac and skeletal muscle diseases.
... Analysis of skeletal muscle biopsies from patients with DM1 showed increases in ER stress markers such as GRP78, PERK, eIF2a, and XBP1 (Ikezoe et al., 2007). Tibial muscular dystrophy (TMD) is an autosomal dominant myopathy caused by heterogeneous mutation in the last two exons of the Titin gene and is characterized by atrophy and weakness in the muscles of the anterior compartment of the lower leg (Udd, 1992). Gene profiling studies on muscle biopsies from TMD patients suggested that one of the potential pathophysiological mechanisms was ER stress, evidenced by increased levels of sXBP1 (Screen et al., 2014). ...
Skeletal muscle is the most abundant tissue in the human body and can adapt its mass as a consequence of physical activity, metabolism, growth factors, and disease conditions. Skeletal muscle contains an extensive network of endoplasmic reticulum (ER), called sarcoplasmic reticulum, which plays an important role in the regulation of proteostasis and calcium homeostasis. In many cell types, environmental and genetic factors that disrupt ER function cause an accumulation of misfolded and unfolded proteins in the ER lumen that ultimately leads to ER stress. To alleviate the stress and restore homeostasis, the ER activates a signaling network called the unfolded protein response (UPR). The UPR has three arms, which regulate protein synthesis and expression of many ER chaperone and regulatory proteins. However, the role of individual UPR pathways in skeletal muscle has just begun to be investigated. Recent studies suggest that UPR pathways play pivotal roles in muscle stem cell homeostasis, myogenic differentiation, and regeneration of injured skeletal muscle. Moreover, markers of ER stress and the UPR are activated in skeletal muscle in diverse conditions such as exercise, denervation, starvation, high fat diet, cancer cachexia, and aging. Accumulating evidence also suggests that ER stress may have important roles in the pathogenesis of inflammatory myopathies and genetic muscle disorders. The purpose of this review article is to discuss the role and potential mechanisms by which ER stress and the individual arms of the UPR regulate skeletal muscle formation, plasticity, and function in various physiological and pathophysiological conditions. This article is protected by copyright. All rights reserved.
... In homozygous state, FINmaj causes a completely different phenotype, i.e., limb-girdle muscular dystrophy 2J (LGMD2J, OMIM #608807), which is a severe childhood onset disease affecting all proximal muscles. The disease onset is in the first or second decade, and the disease progresses over the next 20 years to wheelchair confinement [1,4,5]. ...
Tibial muscular dystrophy (TMD) is the first described human titinopathy. It is a mild adult-onset slowly progressive myopathy causing weakness and atrophy in the anterior lower leg muscles. TMD is caused by mutations in the last two exons, Mex5 and Mex6, of the titin gene (TTN). The first reported TMD mutations were dominant, but the Finnish founder mutation FINmaj, an 11-bp insertion/deletion in Mex6, in homozygosity caused a completely different severe early-onset limb-girdle muscular dystrophy 2J (LGMD2J). Later, we reported that not all TMD mutations cause LGMD when homozygous or compound heterozygous with truncating mutation, but some of them rather cause a more severe TMD-like distal disease. We have now performed targeted next-generation sequencing of myopathy-related genes on seven families from Albania, Bosnia, Iran, Tunisia, Belgium, and Spain with juvenile or early adult onset recessive distal myopathy. Novel mutations in TTN Mex5, Mex6 and A-band exon 340 were identified in homozygosity or compound heterozygosity with a frameshift or nonsense mutation in TTN I- or A-band region. Family members having only one of these TTN mutations were healthy. Our results add yet another entity to the list of distal myopathies: juvenile or early adult onset recessive distal titinopathy.
... Patients have mainly involvement of the limb girdle muscles and the anterior tibialis muscles. 130 Patients usually loose ambulation before the age of 30. 130,131 sCK levels can be elevated to 20 times the normal range. ...
Unlabelled:
The limb-girdle muscular dystrophies are a genetically and clinically heterogeneous group of diseases. Most of these proteinopathies show wide inter- and intrafamilial phenotypic heterogeneity, so that limb-girdle involvement may be often considered as one of the possible clinical expressions of a determined protein defect.
Review summary:
This review reports an updated and comprehensive classification of these proteinopathies according to protein defect and transmission modality and focuses on the main associated clinical pictures.
Conclusions:
An accurate diagnosis is often difficult because of the clinical and genetic variability characterizing this group of muscle diseases. Appropriate diagnostic approaches are essential to achieve the correct diagnosis.
... TMD arises when the mutation is present on one allele and presents as an autosomal dominant late-onset distal myopathy with weakness and atrophy of the anterior compartment muscles of the lower leg (8). LGMD2J, a far more severe phenotype, arises when the mutation is present on both alleles and presents as an autosomal recessive early-onset proximal muscular dystrophy (7,9,10). The TMD prevalence was reported to be .1 in 10 000 in Finland, with almost 10% of the patients presenting phenotypes differing from the classical TMD presentation (10). ...
The dominant tibial muscular dystrophy (TMD) and recessive limb-girdle muscular dystrophy 2J are allelic disorders caused by mutations in the C-terminus of titin, a giant sarcomeric protein. Both clinical presentations were initially identified in a large Finnish family and linked to a founder mutation (FINmaj). To further understand the physiopathology of these two diseases, we generated a mouse model carrying the FINmaj mutation. In heterozygous mice, dystrophic myopathology appears late at 9 months of age in few distal muscles. In homozygous (HO) mice, the first signs appear in the Soleus at 1 month of age and extend to most muscles at 6 months of age. Interestingly, the heart is also severely affected in HO mice. The mutation leads to the loss of the very C-terminal end of titin and to a secondary deficiency of calpain 3, a partner of titin. By crossing the FINmaj model with a calpain 3-deficient model, the TMD phenotype was corrected, demonstrating a participation of calpain 3 in the pathogenesis of this disease.
Limb-girdle muscular dystrophy (LGMD) is a hereditary condition primarily affecting skeletal muscle, characterized by progressive, predominantly proximal weakness of the muscles of the pelvic and shoulder girdles, hyperCKemia, degenerative changes over the disease course on muscle imaging and dystrophic changes on muscle biopsy. There is phenotypic and genotypic variability among the disorders caused by different genes. LGMDs are classified by the patterns of inheritance into autosomal dominant LGMD (AD-LGMD) and autosomal recessive LGMD (AR-LGMD). The initial LGMD nomenclature system used “LGMD1” to indicate AD-LGMD and “LGMD2” to indicate AR-LGMD. An English alphabet assigned in order of discovery of the causative genes was placed as a suffix. The new nomenclature system uses the abbreviation LGMD-D for AD-LGMD and LGMD-R for AR-LGMD, followed by a number indicating the causative gene, in order of their discovery. This is because the rapidly growing list of LGMD-causative genes, especially for AR-LGMD, exhausted all the English alphabets. The prevalence of each LGMD-R subtype varies from country to country; however, LGMD-R1 (calpain 3-related LGMD) and LGMD-R2 (dysferlin-related LGMD) are considered the most common subtypes worldwide. Alpha-dystroglycanopathy is the largest group of LGMD-R, encompassing 12 genetically distinct subtypes due to mutations in genes encoding proteins involving in glycosylation of α-dystroglycan. This chapter will focus on the new nomenclature system and phenotypic variability of AR-LGMDs.
This major new edition fulfils the need for a single-volume, up-to-date information resource on the etiology, pathogenesis, diagnosis and treatment of diseases of skeletal muscles, including the muscular dystrophies, mitochondrial myopathies, metabolic myopathies, ion channel disorders, and dysimmune myopathies. As background to the clinical coverage, relevant information on advances in molecular and developmental biology, immunopathology, mitochondrial biology, ion-channel dynamics, cell membrane and signal transduction science, and imaging technology is summarized. Combining essential new knowledge with the fundamentals of history-taking and clinical examination, this extensively illustrated book will continue to be the mainstay for practising physicians and biomedical scientists concerned with muscle disease. Regular updates on the clinical and basic science aspects of muscle disease - written mainly by rising stars of myology - will be published on an accompanying website.
This major new edition fulfils the need for a single-volume, up-to-date information resource on the etiology, pathogenesis, diagnosis and treatment of diseases of skeletal muscles, including the muscular dystrophies, mitochondrial myopathies, metabolic myopathies, ion channel disorders, and dysimmune myopathies. As background to the clinical coverage, relevant information on advances in molecular and developmental biology, immunopathology, mitochondrial biology, ion-channel dynamics, cell membrane and signal transduction science, and imaging technology is summarized. Combining essential new knowledge with the fundamentals of history-taking and clinical examination, this extensively illustrated book will continue to be the mainstay for practising physicians and biomedical scientists concerned with muscle disease. Regular updates on the clinical and basic science aspects of muscle disease - written mainly by rising stars of myology - will be published on an accompanying website.
This major new edition fulfils the need for a single-volume, up-to-date information resource on the etiology, pathogenesis, diagnosis and treatment of diseases of skeletal muscles, including the muscular dystrophies, mitochondrial myopathies, metabolic myopathies, ion channel disorders, and dysimmune myopathies. As background to the clinical coverage, relevant information on advances in molecular and developmental biology, immunopathology, mitochondrial biology, ion-channel dynamics, cell membrane and signal transduction science, and imaging technology is summarized. Combining essential new knowledge with the fundamentals of history-taking and clinical examination, this extensively illustrated book will continue to be the mainstay for practising physicians and biomedical scientists concerned with muscle disease. Regular updates on the clinical and basic science aspects of muscle disease - written mainly by rising stars of myology - will be published on an accompanying website.
This major new edition fulfils the need for a single-volume, up-to-date information resource on the etiology, pathogenesis, diagnosis and treatment of diseases of skeletal muscles, including the muscular dystrophies, mitochondrial myopathies, metabolic myopathies, ion channel disorders, and dysimmune myopathies. As background to the clinical coverage, relevant information on advances in molecular and developmental biology, immunopathology, mitochondrial biology, ion-channel dynamics, cell membrane and signal transduction science, and imaging technology is summarized. Combining essential new knowledge with the fundamentals of history-taking and clinical examination, this extensively illustrated book will continue to be the mainstay for practising physicians and biomedical scientists concerned with muscle disease. Regular updates on the clinical and basic science aspects of muscle disease - written mainly by rising stars of myology - will be published on an accompanying website.
This major new edition fulfils the need for a single-volume, up-to-date information resource on the etiology, pathogenesis, diagnosis and treatment of diseases of skeletal muscles, including the muscular dystrophies, mitochondrial myopathies, metabolic myopathies, ion channel disorders, and dysimmune myopathies. As background to the clinical coverage, relevant information on advances in molecular and developmental biology, immunopathology, mitochondrial biology, ion-channel dynamics, cell membrane and signal transduction science, and imaging technology is summarized. Combining essential new knowledge with the fundamentals of history-taking and clinical examination, this extensively illustrated book will continue to be the mainstay for practising physicians and biomedical scientists concerned with muscle disease. Regular updates on the clinical and basic science aspects of muscle disease - written mainly by rising stars of myology - will be published on an accompanying website.
This major new edition fulfils the need for a single-volume, up-to-date information resource on the etiology, pathogenesis, diagnosis and treatment of diseases of skeletal muscles, including the muscular dystrophies, mitochondrial myopathies, metabolic myopathies, ion channel disorders, and dysimmune myopathies. As background to the clinical coverage, relevant information on advances in molecular and developmental biology, immunopathology, mitochondrial biology, ion-channel dynamics, cell membrane and signal transduction science, and imaging technology is summarized. Combining essential new knowledge with the fundamentals of history-taking and clinical examination, this extensively illustrated book will continue to be the mainstay for practising physicians and biomedical scientists concerned with muscle disease. Regular updates on the clinical and basic science aspects of muscle disease - written mainly by rising stars of myology - will be published on an accompanying website.
This major new edition fulfils the need for a single-volume, up-to-date information resource on the etiology, pathogenesis, diagnosis and treatment of diseases of skeletal muscles, including the muscular dystrophies, mitochondrial myopathies, metabolic myopathies, ion channel disorders, and dysimmune myopathies. As background to the clinical coverage, relevant information on advances in molecular and developmental biology, immunopathology, mitochondrial biology, ion-channel dynamics, cell membrane and signal transduction science, and imaging technology is summarized. Combining essential new knowledge with the fundamentals of history-taking and clinical examination, this extensively illustrated book will continue to be the mainstay for practising physicians and biomedical scientists concerned with muscle disease. Regular updates on the clinical and basic science aspects of muscle disease - written mainly by rising stars of myology - will be published on an accompanying website.
This major new edition fulfils the need for a single-volume, up-to-date information resource on the etiology, pathogenesis, diagnosis and treatment of diseases of skeletal muscles, including the muscular dystrophies, mitochondrial myopathies, metabolic myopathies, ion channel disorders, and dysimmune myopathies. As background to the clinical coverage, relevant information on advances in molecular and developmental biology, immunopathology, mitochondrial biology, ion-channel dynamics, cell membrane and signal transduction science, and imaging technology is summarized. Combining essential new knowledge with the fundamentals of history-taking and clinical examination, this extensively illustrated book will continue to be the mainstay for practising physicians and biomedical scientists concerned with muscle disease. Regular updates on the clinical and basic science aspects of muscle disease - written mainly by rising stars of myology - will be published on an accompanying website.
This major new edition fulfils the need for a single-volume, up-to-date information resource on the etiology, pathogenesis, diagnosis and treatment of diseases of skeletal muscles, including the muscular dystrophies, mitochondrial myopathies, metabolic myopathies, ion channel disorders, and dysimmune myopathies. As background to the clinical coverage, relevant information on advances in molecular and developmental biology, immunopathology, mitochondrial biology, ion-channel dynamics, cell membrane and signal transduction science, and imaging technology is summarized. Combining essential new knowledge with the fundamentals of history-taking and clinical examination, this extensively illustrated book will continue to be the mainstay for practising physicians and biomedical scientists concerned with muscle disease. Regular updates on the clinical and basic science aspects of muscle disease - written mainly by rising stars of myology - will be published on an accompanying website.
This major new edition fulfils the need for a single-volume, up-to-date information resource on the etiology, pathogenesis, diagnosis and treatment of diseases of skeletal muscles, including the muscular dystrophies, mitochondrial myopathies, metabolic myopathies, ion channel disorders, and dysimmune myopathies. As background to the clinical coverage, relevant information on advances in molecular and developmental biology, immunopathology, mitochondrial biology, ion-channel dynamics, cell membrane and signal transduction science, and imaging technology is summarized. Combining essential new knowledge with the fundamentals of history-taking and clinical examination, this extensively illustrated book will continue to be the mainstay for practising physicians and biomedical scientists concerned with muscle disease. Regular updates on the clinical and basic science aspects of muscle disease - written mainly by rising stars of myology - will be published on an accompanying website.
This major new edition fulfils the need for a single-volume, up-to-date information resource on the etiology, pathogenesis, diagnosis and treatment of diseases of skeletal muscles, including the muscular dystrophies, mitochondrial myopathies, metabolic myopathies, ion channel disorders, and dysimmune myopathies. As background to the clinical coverage, relevant information on advances in molecular and developmental biology, immunopathology, mitochondrial biology, ion-channel dynamics, cell membrane and signal transduction science, and imaging technology is summarized. Combining essential new knowledge with the fundamentals of history-taking and clinical examination, this extensively illustrated book will continue to be the mainstay for practising physicians and biomedical scientists concerned with muscle disease. Regular updates on the clinical and basic science aspects of muscle disease - written mainly by rising stars of myology - will be published on an accompanying website.
This major new edition fulfils the need for a single-volume, up-to-date information resource on the etiology, pathogenesis, diagnosis and treatment of diseases of skeletal muscles, including the muscular dystrophies, mitochondrial myopathies, metabolic myopathies, ion channel disorders, and dysimmune myopathies. As background to the clinical coverage, relevant information on advances in molecular and developmental biology, immunopathology, mitochondrial biology, ion-channel dynamics, cell membrane and signal transduction science, and imaging technology is summarized. Combining essential new knowledge with the fundamentals of history-taking and clinical examination, this extensively illustrated book will continue to be the mainstay for practising physicians and biomedical scientists concerned with muscle disease. Regular updates on the clinical and basic science aspects of muscle disease - written mainly by rising stars of myology - will be published on an accompanying website.
This major new edition fulfils the need for a single-volume, up-to-date information resource on the etiology, pathogenesis, diagnosis and treatment of diseases of skeletal muscles, including the muscular dystrophies, mitochondrial myopathies, metabolic myopathies, ion channel disorders, and dysimmune myopathies. As background to the clinical coverage, relevant information on advances in molecular and developmental biology, immunopathology, mitochondrial biology, ion-channel dynamics, cell membrane and signal transduction science, and imaging technology is summarized. Combining essential new knowledge with the fundamentals of history-taking and clinical examination, this extensively illustrated book will continue to be the mainstay for practising physicians and biomedical scientists concerned with muscle disease. Regular updates on the clinical and basic science aspects of muscle disease - written mainly by rising stars of myology - will be published on an accompanying website.
This major new edition fulfils the need for a single-volume, up-to-date information resource on the etiology, pathogenesis, diagnosis and treatment of diseases of skeletal muscles, including the muscular dystrophies, mitochondrial myopathies, metabolic myopathies, ion channel disorders, and dysimmune myopathies. As background to the clinical coverage, relevant information on advances in molecular and developmental biology, immunopathology, mitochondrial biology, ion-channel dynamics, cell membrane and signal transduction science, and imaging technology is summarized. Combining essential new knowledge with the fundamentals of history-taking and clinical examination, this extensively illustrated book will continue to be the mainstay for practising physicians and biomedical scientists concerned with muscle disease. Regular updates on the clinical and basic science aspects of muscle disease - written mainly by rising stars of myology - will be published on an accompanying website.
This major new edition fulfils the need for a single-volume, up-to-date information resource on the etiology, pathogenesis, diagnosis and treatment of diseases of skeletal muscles, including the muscular dystrophies, mitochondrial myopathies, metabolic myopathies, ion channel disorders, and dysimmune myopathies. As background to the clinical coverage, relevant information on advances in molecular and developmental biology, immunopathology, mitochondrial biology, ion-channel dynamics, cell membrane and signal transduction science, and imaging technology is summarized. Combining essential new knowledge with the fundamentals of history-taking and clinical examination, this extensively illustrated book will continue to be the mainstay for practising physicians and biomedical scientists concerned with muscle disease. Regular updates on the clinical and basic science aspects of muscle disease - written mainly by rising stars of myology - will be published on an accompanying website.
This major new edition fulfils the need for a single-volume, up-to-date information resource on the etiology, pathogenesis, diagnosis and treatment of diseases of skeletal muscles, including the muscular dystrophies, mitochondrial myopathies, metabolic myopathies, ion channel disorders, and dysimmune myopathies. As background to the clinical coverage, relevant information on advances in molecular and developmental biology, immunopathology, mitochondrial biology, ion-channel dynamics, cell membrane and signal transduction science, and imaging technology is summarized. Combining essential new knowledge with the fundamentals of history-taking and clinical examination, this extensively illustrated book will continue to be the mainstay for practising physicians and biomedical scientists concerned with muscle disease. Regular updates on the clinical and basic science aspects of muscle disease - written mainly by rising stars of myology - will be published on an accompanying website.
This major new edition fulfils the need for a single-volume, up-to-date information resource on the etiology, pathogenesis, diagnosis and treatment of diseases of skeletal muscles, including the muscular dystrophies, mitochondrial myopathies, metabolic myopathies, ion channel disorders, and dysimmune myopathies. As background to the clinical coverage, relevant information on advances in molecular and developmental biology, immunopathology, mitochondrial biology, ion-channel dynamics, cell membrane and signal transduction science, and imaging technology is summarized. Combining essential new knowledge with the fundamentals of history-taking and clinical examination, this extensively illustrated book will continue to be the mainstay for practising physicians and biomedical scientists concerned with muscle disease. Regular updates on the clinical and basic science aspects of muscle disease - written mainly by rising stars of myology - will be published on an accompanying website.
This major new edition fulfils the need for a single-volume, up-to-date information resource on the etiology, pathogenesis, diagnosis and treatment of diseases of skeletal muscles, including the muscular dystrophies, mitochondrial myopathies, metabolic myopathies, ion channel disorders, and dysimmune myopathies. As background to the clinical coverage, relevant information on advances in molecular and developmental biology, immunopathology, mitochondrial biology, ion-channel dynamics, cell membrane and signal transduction science, and imaging technology is summarized. Combining essential new knowledge with the fundamentals of history-taking and clinical examination, this extensively illustrated book will continue to be the mainstay for practising physicians and biomedical scientists concerned with muscle disease. Regular updates on the clinical and basic science aspects of muscle disease - written mainly by rising stars of myology - will be published on an accompanying website.
This major new edition fulfils the need for a single-volume, up-to-date information resource on the etiology, pathogenesis, diagnosis and treatment of diseases of skeletal muscles, including the muscular dystrophies, mitochondrial myopathies, metabolic myopathies, ion channel disorders, and dysimmune myopathies. As background to the clinical coverage, relevant information on advances in molecular and developmental biology, immunopathology, mitochondrial biology, ion-channel dynamics, cell membrane and signal transduction science, and imaging technology is summarized. Combining essential new knowledge with the fundamentals of history-taking and clinical examination, this extensively illustrated book will continue to be the mainstay for practising physicians and biomedical scientists concerned with muscle disease. Regular updates on the clinical and basic science aspects of muscle disease - written mainly by rising stars of myology - will be published on an accompanying website.
This major new edition fulfils the need for a single-volume, up-to-date information resource on the etiology, pathogenesis, diagnosis and treatment of diseases of skeletal muscles, including the muscular dystrophies, mitochondrial myopathies, metabolic myopathies, ion channel disorders, and dysimmune myopathies. As background to the clinical coverage, relevant information on advances in molecular and developmental biology, immunopathology, mitochondrial biology, ion-channel dynamics, cell membrane and signal transduction science, and imaging technology is summarized. Combining essential new knowledge with the fundamentals of history-taking and clinical examination, this extensively illustrated book will continue to be the mainstay for practising physicians and biomedical scientists concerned with muscle disease. Regular updates on the clinical and basic science aspects of muscle disease - written mainly by rising stars of myology - will be published on an accompanying website.
This major new edition fulfils the need for a single-volume, up-to-date information resource on the etiology, pathogenesis, diagnosis and treatment of diseases of skeletal muscles, including the muscular dystrophies, mitochondrial myopathies, metabolic myopathies, ion channel disorders, and dysimmune myopathies. As background to the clinical coverage, relevant information on advances in molecular and developmental biology, immunopathology, mitochondrial biology, ion-channel dynamics, cell membrane and signal transduction science, and imaging technology is summarized. Combining essential new knowledge with the fundamentals of history-taking and clinical examination, this extensively illustrated book will continue to be the mainstay for practising physicians and biomedical scientists concerned with muscle disease. Regular updates on the clinical and basic science aspects of muscle disease - written mainly by rising stars of myology - will be published on an accompanying website.
This major new edition fulfils the need for a single-volume, up-to-date information resource on the etiology, pathogenesis, diagnosis and treatment of diseases of skeletal muscles, including the muscular dystrophies, mitochondrial myopathies, metabolic myopathies, ion channel disorders, and dysimmune myopathies. As background to the clinical coverage, relevant information on advances in molecular and developmental biology, immunopathology, mitochondrial biology, ion-channel dynamics, cell membrane and signal transduction science, and imaging technology is summarized. Combining essential new knowledge with the fundamentals of history-taking and clinical examination, this extensively illustrated book will continue to be the mainstay for practising physicians and biomedical scientists concerned with muscle disease. Regular updates on the clinical and basic science aspects of muscle disease - written mainly by rising stars of myology - will be published on an accompanying website.
Isolated populations, also called population isolates and genetic isolates, present several characteristic features that make them useful in the study of the genetic basis of both Mendelian and complex disorders. The consensus regarding population isolates is that they have been founded by a small number of individuals, followed by a period of genetic isolation and growth. In modern times characterized by widespread mobility of people around the world, few human populations can be considered genetic isolates. In this chapter we outline the reasons for their usefulness in genetic studies and describe the role they have played and continue to play in gene mapping efforts. Specific examples of gene identification are provided.
Purpose of review The past decade has seen the discovery of the major role that mutations in the protein components of the sarcomere plays as a cause of human muscle disease. An overview of the more precise molecular definitions of these diseases is timely. Recent findings Recent findings include: the beginnings of an understanding of the role of the sarcomere in controlling muscle gene expression; the theoretical analysis of the increasing number of mutations identified in the skeletal muscle actin gene; the identification of mutations in myosin causing hereditary inclusion body myopathy and hyaline body myopathy and the identification of mutations in myotilin in myofibrillar myopathy. Summary An increasing spectrum of human muscle diseases is being shown to be caused by mutations in proteins of all the major components of the sarcomere. Molecular analysis is providing a more accurate delineation of these diseases, but for the giant nebulin and titin genes, molecular diagnosis remains difficult. Treatment options for these disorders will only come through a deeper understanding of the sarcomere and of the pathogenesis of its disorders.
Autosomal recessive limb girdle muscular dystrophies (LGMD2) are a group of genetically heterogeneous diseases that are typically characterised by progressive weakness and wasting of the shoulder and pelvic girdle muscles. Many of the more than 20 different conditions show overlapping clinical features with other forms of muscular dystrophy, congenital, myofibrillar or even distal myopathies and also with acquired muscle diseases. Although individually extremely rare, all types of LGMD2 together form an important differential diagnostic group among neuromuscular diseases. Despite improved diagnostics and pathomechanistic insight, a curative therapy is currently lacking for any of these diseases. Medical care consists of the symptomatic treatment of complications, aiming to improve life expectancy and quality of life. Besides well characterised pre-clinical tools like animal models and cell culture assays, the determinants of successful drug development programmes for rare diseases include a good understanding of the phenotype and natural history of the disease, the existence of clinically relevant outcome measures, guidance on care standards, up to date patient registries, and, ideally, biomarkers that can help assess disease severity or drug response. Strong patient organisations driving research and successful partnerships between academia, advocacy, industry and regulatory authorities can also help accelerate the elaboration of clinical trials. All these determinants constitute aspects of translational research efforts and influence patient access to therapies. Here we review the current status of determinants of successful drug development programmes for LGMD2, and the challenges of translating promising therapeutic strategies into effective and accessible treatments for patients.
The limb-girdle muscular dystrophies are a genetically heterogeneous and phenotypically diverse group of hereditary muscle diseases characterized by progressive proximal lower and upper extremity muscle weakness with relative sparing of extraocular, facial, and distal extremity muscles. Over the past few decades, several of the genes and proteins underlying this group of disorders have been identified, providing a window of opportunity to study pathophysiologic mechanisms of muscle disease and regeneration. While specific therapeutic interventions for these diseases are scarce, better understanding of the mechanisms and modifiers of disease hold the promise for better treatments in the future. Linking pathophysiology with clinical phenotypes when appropriate, the goal of this chapter is to characterize these various disorders in a way that is useful for clinical practice and provide a rational approach to the workup of patients with limb-girdle muscular dystrophy.
Whereas myopathies typically present with proximal weakness, the distal myopathies present with distal weakness in the feet or hands with atrophy in the lower leg, forearm, or intrinsic muscles of the hands and feet. Consequently, the distal myopathies are often misdiagnosed as neurogenic conditions such as polyneuropathies, radiculopathies, or CIDP (chronic inflammatory demyelinating neuropathy). Distal myopathies are genetic disorders with, to date, some 20 genetically distinct disorders; many more are yet to be characterized. In this clinical summary the practical considerations in the diagnosis and management of patients are reviewed.
Le miopatie dei cingoli costituiscono un gruppo eterogeneo di patologie, sia sul piano clinico che genetico. Il numero di loci identificati è esploso nel corso degli ultimi venti anni. La loro identificazione ha permesso di migliorare le conoscenze sulla fisiologia della fibra muscolare. Il termine di distrofia muscolare dei cingoli, più restrittivo, è spesso preferito a quello di miopatia dei cingoli, in quanto dimostra l’alterazione anatomopatologica comune a tutte queste miopatie: la lesione distrofica.
Limb girdle muscular dystrophies (LGMDs) are a genetically heterogeneous group of primary myopathies involving progressive weakness and wasting of the muscles in the hip and shoulder girdles, with distal spread to the bulbar or respiratory musculature in rare cases. Depending on the mode of genetic transmission, six autosomal dominant forms (LGMD1A-F, 10-25%) and ten autosomal recessive forms (LGMD2A-J, 75-90%) are currently known. The prevalence of LGMDs is 0.8/100,000. These conditions are caused by mutations in genes encoding for myotilin (5q31, LGMD1A), lamin A/C (1q11-q21.2, LGMD1B), caveolin-3 (3p25, LGMD1C), unknown proteins (7q, LGMD1D, 6q23, LGMD1E, 7q32.1-32.2., LGMD1F), calpain-3 (15q15.1-21.1, LGMD2A), dysferlin (2p13.3-13.1, LGMD2B), gamma-sarcoglycan (13q12, LGMD2C), alpha-sarcoglycan, also known as adhalin (17q12-q21.3, LGMD2D), beta-sarcoglycan (4q12, LGMD2E), delta-sarcoglycan (5q33-q34, LGMD2F), telethonin (17q11-q12, LGMD2G), E3-ubiquitin ligase (9q31-q34.1, LGMD2H), fukutin-related protein (19q13.3, LGMD2I), and titin (2q31, LGMD2J). Cardiac involvement has been described for LGMD1B-E, LGMD2C-G, and LGMD2I. The time of onset varies between early childhood and middle age. There is no male or female preponderance. Disease progression and life expectancy vary widely, even among different members of the same family. The diagnosis is based primarily on DNA analysis. The history, clinical neurological examinations, blood chemistry investigations, electromyography, and muscle biopsy also provide information that is helpful for the diagnosis. No causal therapy is currently available.
Limb girdle muscular dystrophies (LGMDs) are a genetically heterogeneous group of primary myopathies involving progressive weakness and wasting of the muscles in the hip and shoulder girdles, with distal spread to the bulbar or respiratory musculature in rare cases. Depending on the mode of genetic transmission, six autosomal dominant forms (LGMD1A–F, 10–25%) and ten autosomal recessive forms (LGMD2A–J, 75–90%) are currently known. The prevalence of LGMDs is 0.8/100,000. These conditions are caused by mutations in genes encoding for myotilin (5q31, LGMD1A), lamin A/C (1q11–q21.2, LGMD1B), caveolin-3 (3p25, LGMD1C), unknown proteins (7q, LGMD1D, 6q23, LGMD1E, 7q32.1–32.2., LGMD1F), calpain-3 (15q15.1–21.1, LGMD2A), dysferlin (2p13.3–13.1, LGMD2B), γ–sarcoglycan (13q12, LGMD2C), α-sarcoglycan, also known as adhalin (17q12–q21.3, LGMD2D), β-sarcoglycan (4q12, LGMD2E), δ-sarcoglycan (5q33–q34, LGMD2F), telethonin (17q11–q12, LGMD2G), E3-ubiquitin ligase (9q31–q34.1, LGMD2H), fukutin-related protein (19q13.3, LGMD2I), and titin (2q31, LGMD2J). Cardiac involvement has been described for LGMD1B–E, LGMD2C–G, and LGMD2I. The time of onset varies between early childhood and middle age. There is no male or female preponderance. Disease progression and life expectancy vary widely, even among different members of the same family. The diagnosis is based primarily on DNA analysis. The history, clinical neurological examinations, blood chemistry investigations, electromyography, and muscle biopsy also provide information that is helpful for the diagnosis. No causal therapy is currently available.
A 14-year-old Chinese boy, who first became aware of muscle weakness in the lower limbs at 6 years of age, had progressive distal muscle weakness and atrophy, predominantly in the lower leg muscles. He exhibited reduced ankle dorsiflexion and tended to walk on his toes, showing preferential anterior tibial muscle involvement. Laboratory examination revealed a moderately elevated serum creatine kinase level of 905 IU/I. Computed tomographic scanning of muscle disclosed low density areas in the lower legs. A muscle biopsy specimen from the biceps brachii revealed mild dystrophic changes. We made a diagnosis of distal muscular dystrophy based on these findings, but could not classify it as one of the previously reported forms. The symptoms mimicked those of tibial muscular dystrophy, though the onset of the disease is far earlier than the previously described ones of distal muscular dystrophies. It remains unknown whether this patient has a new type of distal muscular dystrophy, or a variant form of the Miyoshi type or tibial muscular dystrophy.
Limb-girdle muscular dystrophy 2J caused by mutations in C-terminal titin has so far been identified in Finnish patients only. This may in part be due to limited availability of diagnostic tests for titin defects. In this report, a French family with an autosomal-dominant late-onset distal myopathy of the tibial muscular dystrophy phenotype segregating in several members of the family was described. One deceased patient in the family proved to be homozygous for the C-terminal truncating titin mutation because of consanguinity. According to available medical records, the patient had a clearly more severe generalised muscle weakness and atrophy phenotype not recognised as a distal myopathy at the time. Autopsy findings in one of the original Finnish limb-girdle muscular dystrophy 2J patients were reported and the early phenotype in a newly identified young patient with homozygous Finnish C-terminal titin mutation (FINmaj) was detailed.
Late adult onset distal myopathies usually show vacuolar degeneration as a characteristic feature in muscle pathology. In this study vacuolar degeneration was not present in 12 patients with late adult onset distal myopathy. All patients were members of a large kindred, with 26 patients showing this new form of distal leg myopathy. Additionally, a severely disabling proximal muscular dystrophy appeared in eight other members of the large consanguineous kindred. Muscle biopsies were obtained from clinically affected muscles, and from clinically unaffected muscles in patients with distal myopathy. For comparison specimens from various muscles of patients with severe proximal dystrophy were also studied. Histopathological changes correlating to muscular dystrophy were extensive in all muscles studied in patients with proximal dystrophy, and in tibial anterior muscles in patients with distal myopathy. Mild myopathic changes, mainly increased internal nuclei in muscle fibers, were detected in clinically unaffected muscles in the distal myopathy. The spectrum of findings is compatible with the hypothesis of previous clinical and genetic studies, indicating that the severe proximal dystrophy could be a homozygous manifestation of the dominantly inherited gene of the distal tibial muscle dystrophy.
We studied a family with late-onset (fifth or sixth decade) or asymptomatic hereditary myopathy of the anterior tibial muscle. The occurrence of the disease in two successive generations pointed out an autosomal dominant pattern of inheritance. The initial symptom was uni- or bilateral foot drop resembling peroneal paresis. Surprisingly many of the diagnosed patients were asymptomatic and considered themselves healthy whether there was any foot drop or not. The anterior tibial muscles were atrophic in patients with foot drop but the long toe extensors were usually and the short ones were always spared. Apparently the toe extensors could relieve the foot drop symptom. As shown by computed tomography there was often an early uni- or bilateral involvement of the semimembranosus muscle in males. The proband showed also a late involvement of the femoral biceps and the minor gluteal muscles. The muscles of the upper extremity were spared. The anterior tibial muscles had a characteristic myopathic alteration with rimmed vacuoles in histopathological study. This picture was most evident in latent cases without atrophy of the anterior tibial muscle, but with distinctly abnormal EMG of that muscle. Non-affected muscles showed only slight non-specific histopathological changes. We suggest that this disease is a new mild variety of autosomal dominant distal myopathy with rimmed vacuoles.
To clarify the classification of two previously reported groups of patients with anterior tibial distal dystrophy, to find additional patients with the disease, and to describe the clinical features of this disease.
National survey of the records of patients with neuromuscular diseases in Finland. Findings of selected patients were compared with those of previously reported cases.
Thirty-six previously described patients and 30 additional patients from the current survey, with 41 symptomatic patients and 25 subjectively asymptomatic affected relatives.
There were 66 patients with late adult-onset tibial muscular dystrophy. Symptoms appear after the age of 35 years with reduced ankle dorsiflexion, and progress is slow without marked disability. Facial muscles, upper extremities, and proximal muscles are usually spared. Muscle biopsy results reveal nonspecific dystrophic changes in clinically affected muscles, and frequently severe adipose replacement in the anterior tibial muscles occurs. Asymptomatic muscles have mild myopathic changes only. Vacuolar degeneration is detected in a minority of patients. Electromyography shows profound myopathic changes in the anterior tibial muscle, but extensor brevis muscles are well preserved. Computed tomography or magnetic resonance imaging of muscles discloses marked involvement of tibial extensor muscles and focal patches of fatty degeneration in various asymptomatic muscles. Pedigree data suggest autosomal dominant inheritance.
Tibial muscular dystrophy might represent a new form of distal myopathy and it is rather common, at least in Finland.
Tibial muscular dystrophy (TMD) is a recently described muscular disease first discovered in a highly consanguineous family in Finland. The pedigree also included patients whose symptoms resembled another phenotype, classical limb-girdle muscular dystrophy. Extensive linkage analysis was carried out in this complex pedigree using 157 highly polymorphic DNA markers. Because of the presence of two phenotypes, several inheritance models were used in linkage analysis studies to allow for the possibility of intrafamilial heterogeneity. The results summarize information from over 10,000 genotypings and exclude several known loci for muscular dystrophies. The findings suggest that TMD may be caused by a mutation in a previously unknown locus for muscular dystrophy.
Careful comparison of symptomatic individuals with normal controls has revealed the primary biochemical abnormality in many human genetic diseases, particularly recessive disorders. This strategy has proved less successful for most human disorders which are not recessive, and where a single copy of the aberrant gene has clinically significant effects even though the normal gene product is present. An alternative approach that eliminates the impediment of a normal protein in affected individuals is to study homozygotes for the mutant allele. For virtually all dominant human disorders in which homozygotes have been described, symptoms have been significantly more severe in the homozygote than in the heterozygote. Thus, these disorders do not conform to the classical definition of dominance which states that homozygotes and heterozygotes for a defect are phenotypically indistinguishable. Instead, they display incomplete dominance, indicating that the normal allele may play a role in ameliorating the disease process. The D4S10 locus, defined by the probe G8 and linked to the gene for Huntington's disease (HD), has permitted us to identify individuals with a high probability of being homozygous for this autosomal dominant neurodegenerative disorder. These homozygotes do not differ in clinical expression or course from typical HD heterozygotes. HD appears to be the first human disease of genetically documented homozygosity that displays complete phenotypic dominance.
A multicentre, randomised, open trial with a 2 x 2 factorial design was conducted to compare the benefits and risks of two thrombolytic agents, streptokinase (SK, 1·5 MU infused intravenously over 30-60 min) and alteplase (tPA, 100 mg infused intravenously over 3 h) in patients with acute myocardial infarction admitted to coronary care units within 6 h from onset of symptoms. The patients were also randomised to receive heparin (12 500 U subcutaneously twice daily until discharge from hospital, starting 12 h after beginning the tPA or SK infusion) or usual therapy. All patients without specific contraindications were given atenolol (5-10 mg iv) and aspirin (300-325 mg a day). The end-point of the study was the combined estimate of death plus severe left ventricular damage. 12 490 patients were randomised to four treatment groups (SK alone, SK plus heparin, tPA alone, tPA plus heparin). No specific differences between the two thrombolytic agents were detected as regards the combined end-point (tPA 23·1%; SK 22·5%; relative risk 1·04, 95% Cl 0·95-1·13), nor after the addition of heparin to the aspirin treatment (hep 22·7%, no hep 22·9%; RR 0·99, 95% Cl 0·91-1·08). The outcome of patients allocated to the four treatment groups was similar with respect to baseline risk factors such as age, Killip class, hours from onset of symptoms, and site and type of infarct. The rates of major in-hospital cardiac complications (reinfarction, post-infarction angina) were also similar. The incidence of major bleeds was significantly higher in SK and heparin treated patients (respectively, tPA 0·5%, SK 1·0%, RR 0·57, 95% Cl 0·38-0·85; hep 1·0%, no hep 0·6%, RR 1·64, 95% Cl 1·09-2·45), whereas the overall incidence of stroke was similar in all groups. SK and tPA appear equally effective and safe for use in routine conditions of care, in all infarct patients who have no contraindications, with or without post-thrombolytic heparin treatment. The 8·8% hospital mortality of the study population (compared with approximately 13% in the control cohort of the GISSI-1 trial) indicates the beneficial impact of the proven acute treatments for AMI.
A new type of progressive muscular dystrophy, autosomal recessive distal muscular dystrophy, is described, based on observations on 17 cases (8 mals and 9 females) in 8 families, including an autopsied case. The disease developed in young adults. Muscle weakness and atrophy were most marked in the distal parts of the legs, especially in the gastrocnemius and soleus muscles, and then spread to the thighs and gluteal muscles. Early impairment of standing on tip-toe with retention of the ability to stand on the heels was conspicuous. Difficulty in climbing stairs, standing up and walking subsequently appeared, but rarely progressed to confinement to bed. The forearms became mildly atrophic, with decrease in grip strength, but the small hand muscles were spared. The EMG showed myopathic changes and nerve conduction was normal. Serum creatine kinase activity was characteristically increased up to 100-fold in the early stages of the disease. It was also markedly increased in subjects in the preclinical stage and mildly in some heterozygotes.
Muscle biopsies revealed myopathic changes with severe segmental necrosis accompanied by regeneration. The changes were similar to those of Duchenne muscular dystrophy. An autopsied case, aged 68 years, showed generalized muscle abnormalities with a distal predominance. The muscles in the lower legs, especially those of the calves, were severely affected. No lesions were found in the brain, spinal cord or peripheral nerves.
The clinical syndrome of slowly progressive proximal limb and limb girdle muscular weakness and atrophy, or limb girdle syndromes (LGS), has a diverse aetiology. Several of the congenital, mitochondrial and other metabolic myopathies and spinal muscular atrophies are recently recognized causes of LGS. Thus the position of limb girdle muscular dystrophy (LGMD) as a discrete entity in the nosology of muscle disease deserves reappraisal. We have therefore reevaluated our experience of 33 patients in this light. Detailed clinical, electrophysiological, and pathological studies including autopsies in 2 cases, were performed. As a result we are confident that LGMD does exist as a sporadic or autosomal dominant (2 families) or recessive condition (2 families). There are therefore probably at least 2 distinct genotypes. Typical LGMD (18 patients in our series) is characterized by slowly progressive symmetrical proximal upper and lower limb girdle weakness and atrophy, elevation of the serum creatine kinase at some stage, dystrophic or less severe myopathic muscle lesions on biopsy, and myopathic EMG findings. Two minor subgroups of LGMD were identified in our series with similar clinical and laboratory features but distinguishable by the development of either facial (4 patients) or by distal limb muscle involvement (3 patients). A further group of patients with sporadic LGS (5 patients) had slowly progressive proximal symmetrical upper and lower limb-girdle weakness and atrophy with myopathic or neurogenic features on either EMG or muscle biopsy so that the precise characterization was difficult. Two of these patients had distal limb muscle involvement and contractures. One patient had upper limb-girdle muscle atrophy with normal lower limbs. A disorder affecting muscle, nerve or both remains a possibility in these cases.
Two brothers are described with a distal myopathy different from the known hereditary distal myopathies. Early adult onset, beginning in the distal leg muscles with marked elevation of creatine kinase (CK) activity (20 to 30-fold) were the characteristic features. The parents of the patients had no symptoms or signs of myopathy. Their serum CK-activity was in the normal range. There was parental consanguinity, so the distal myopathy in these brothers is probably an autosomal recessive inheritance.
This report describes the clinical, laboratory, and muscle biopsy histochemical and electron microscopic studies of one inherited and two sporadic cases of distal myopathy. Histopathologic and histochemical studies showed numerous myopathic alterations and no significant evidence of denervation. Electron microscopic studies showed a broad spectrum of nonspecific alterations similar to those in other forms of muscular dystrophy. Autophagic vacuoles were prominent in all cases. The inherited case was characterized by an unusual focal granular degeneration that, ultrastructurally, was composed of homogeneous fine granules devoid of other organelles or myofilamens.
With the exception of the large series of adult-onset hereditary distal myopathy from Sweden, few cases of primary muscle disease with a definite distal predilection have been published. We report 3 sporadic cases of distal myopathy with the following features: (1) early adult onset (26 to 33 years); (2) slowly progressive weakness affecting first the distal leg muscles and later the arms; (3) marked elevation of creatine phosphokinase (more than 10 times the normal value); and (4) electromyographic and histological evidence of myopathy in distal muscles. The differential diagnosis is discussed and other reported cases are reviewed. The differences between hereditary cases reported by others and the sporadic cases reported here form the basis for a tentative subclassification of this syndrome.
This report describes a large consanguineous family with muscular dystrophy in 23 patients showing intrafamilial variation of clinical expression. One main variant appeared in the first decade with proximal muscle weakness progressing over the next 20 years to wheelchair confinement, and appeared compatible with classical limb-girdle muscular dystrophy. The other main variant showed onset of distal muscle weakness in lower limbs in the third or fourth decade, progressing very slowly without greater disability throughout the lifetime. Tibial muscle weakness and wasting were clinical landmarks in this variant, but computed tomography of skeletal muscle revealed focal areas of fatty degeneration also in truncal, pelvifemoral, and distal leg muscles in a way not previously reported in distal myopathy. The overall difference in clinical findings between these main variants would suggest 2 separate genetic entities, genealogical data makes a common genetic background possible.
The autosomal dominant disorder facioscapulohumeral muscular dystrophy (FSHD) is the last of the major progressive muscular dystrophies in which the gene had not been located. In linkage analysis on ten Dutch families with this disorder a lod score of 6.34 at a recombination fraction of 0.13 was obtained with the microsatellite marker Mfd 22 (D4S171). This maps the FSHD gene to chromosome 4. Only one family was uninformative for this marker. We found no evidence of genetic heterogeneity.
The clinical syndrome of slowly progressive proximal limb and limb girdle muscular weakness and atrophy, or limb girdle syndromes (LGS), has a diverse aetiology. Several of the congenital, mitochondrial and other metabolic myopathies and spinal muscular atrophies are recently recognized causes of LGS. Thus the position of limb girdle muscular dystrophy (LGMD) as a discrete entity in the nosology of muscle disease deserves reappraisal. We have therefore reevaluated our experience of 33 patients in this light. Detailed clinical, electrophysiological, and pathological studies including autopsies in 2 cases, were performed. As a result we are confident that LGMD does exist as a sporadic or autosomal dominant (2 families) or recessive condition (2 families). There are therefore probably at least 2 distinct genotypes. Typical LGMD (18 patients in our series) is characterized by slowly progressive symmetrical proximal upper and lower limb girdle weakness and atrophy, elevation of the serum creatine kinase at some stage, dystrophic or less severe myopathic muscle lesions on biopsy, and myopathic EMG findings. Two minor subgroups of LGMD were identified in our series with similar clinical and laboratory features but distinguishable by the development of either facial (4 patients) or by distal limb muscle involvement (3 patients). A further group of patients with sporadic LGS (5 patients) had slowly progressive proximal symmetrical upper and lower limb-girdle weakness and atrophy with myopathic or neurogenic features on either EMG or muscle biopsy so that the precise characterization was difficult. Two of these patients had distal limb muscle involvement and contractures. One patient had upper limb-girdle muscle atrophy with normal lower limbs. A disorder affecting muscle, nerve or both remains a possibility in these cases.
Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant inherited disorder. Recent biochemical studies have revealed that amyloid protein in FAP of Japanese, Swedish and Portuguese origin mainly consists of a variant transthyretin (TTR) (formerly called prealbumin) with one amino acid substitution of methionine for valine at position 30. In a 56-year-old man with typical polyneuropathy, gastrointestinal problems and vitreous amyloid, we diagnosed homozygosity for the TTR-met30-gene using RFLP analysis. In a family study, a sister presented the same homozygous RFLP pattern; however, in a careful clinical investigation we were not able to demonstrate any of the typical symptoms of FAP, nor could we demonstrate amyloid deposits in a biopsy skin specimen. This is the first report of homozygosity for the TTR-met30-gene, and it shows that the mutation of the protein involved in amyloid formation may be necessary but is clearly not sufficient for the clinical symptoms.
Molecular genetics has transformed clinical concepts of Duchenne muscular dystrophy (DMD) in several different ways. (1) The disease can now be defined as a myopathy due to mutation at Xp21, a specific locus on the short arm of the X chromosome. (2) As a consequence of that discovery, any myopathy due to mutation at Xp21 should be a variant of DMD and should affect the same gene product. Moreover, any myopathy due to mutation at a location other than Xp21 should affect some other gene product. (3) For these reasons, DNA analysis is now needed for clinical diagnosis of muscle disease. (4) Xp21 myopathies may be mild or severe, may occur in females even though X-linked, and may be manifest only by high serum levels of creatine kinase. (5) Mental retardation is not consistently related to diseases that are encoded at Xp21. The association of mental retardation with DMD may be due to mutation in a separate gene near that for DMD. Concepts may soon be altered again as we learn about the affected gene product (dystrophin) and its role in these diseases.
A new type of progressive muscular dystrophy, autosomal recessive distal muscular dystrophy, is described, based on observations on 17 cases (8 males and 9 females) in 8 families, including an autopsied case. The disease developed in young adults. Muscle weakness and atrophy were most marked in the distal parts of the legs, especially in the gastrocnemius and soleus muscles, and then spread to the thighs and gluteal muscles. Early impairment of standing on tip-toe with retention of the ability to stand on the heels was conspicuous. Difficulty in climbing stairs, standing up and walking subsequently appeared, but rarely progressed to confinement to bed. The forearms became mildly atrophic, with decrease in grip strength, but the small hand muscles were spared. The EMG showed myopathic changes and nerve conduction was normal. Serum creatine kinase activity was characteristically increased up to 100-fold in the early stages of the disease. It was also markedly increased in subjects in the preclinical stage and mildly in some heterozygotes. Muscle biopsies revealed myopathic changes with severe segmental necrosis accompanied by regeneration. The changes were similar to those of Duchenne muscular dystrophy. An autopsied case, aged 68 years, showed generalized muscle abnormalities with a distal predominance. The muscles in the lower legs, especially those of the calves, were severely affected. No lesions were found in the brain, spinal cord or peripheral nerves.
A family with a hitherto unrecognized type of distal myopathy is described. The disorder appears to be of late onset and to be inherited through a dominant autosome. It has a more malignant course than the distal myopathies described earlier, from which it can be differentiated clinically by an early involvement of thenar muscles and hand flexors. The key to the correct diagnosis is provided by the morphological and immunohistological investigation of muscle biopsies, which show typical sarcoplasmic bodies and an abundance of intermediate-sized (skeletin) filaments.
As defined classically, in completely dominant traits a single copy of the allele in question results in the same degree of involvement as the homozygous state of the gene. This idea appears in many textbooks of medical genetics: '... A dominant gene is considered to be one that produces an effect in every individual who inherits it, irrespective of the state of the other allele' [Nora and Fraser, 1981]; '... embodied in the definition of dominance is the concept that we cannot distinguish the homozygote from the heterozygote ' [Porter, 1968] and 'If an individual has two different alleles for a given locus, dominance causes him to have the same phenotype as an individual homozygous for one of them' [Levitan and Montagu, 1971]. Yet virtually no instance of such true phenotypic dominance has been demonstrated in man except for a possible case of cataract of Komai. All so-called dominant disorders of man in fact appear to result in much more severe phenotypic expression when present in double dose. An older edition of Lenz's textbook [Lenz, 1963] addressed this issue particularly thoroughly. He suggested that for clinical purposes (and, indeed, dominance is simply a descriptive phenotypic concept) four operational definitions of dominance be used: Dominance would simply refer to clinically, significant expression in the heterozygote; complete dominance would indicate no distinguishing features between homozygote and heterozygote, while intermediate dominance would be used when the homozygote is more severely affected; if homozygosity is unknown for a given disorder, the term conditional dominance would be used. In this sense, even at the descriptive phenotypic level, virtually all human dominant disorders which homozygosity has been suspected or presumed seem intermediate dominants. In a table on summarized conditions previously reported in which the putative homozygous state is clearly more severe than the heterozygous state. This table shows the bases for the apparent homozygosity-which could result from consanguinity, from assortative mating among individuals with externally evident traits, or by chance. While consanguinous unions assure identity of the gene in question, they also increase the likelihood of identity of unrelated (recessive) alleles that could confound characterization of the homozygous state.
In three familial cases and one sporadic case of late-onset distal myopathy, muscle wasting started in the distal portions of the lower extremities. The most striking change seen by light microscopy was the appearance of rimmed vacuoles. These were presumed to be autophagic, because they were found by electron microscopy to contain membranous lamellar structures and other heterogenous materials enclosed by a limiting membrane. On the other hand, lysosomal activity was markedly increased in skeletal muscle. In 6% to 22% of affected muscle fibers there were acid phosphatase-positive granules deep in the sarcoplasm, whereas control muscles had no such granules. The degenerative process in distal myopathy may be different from that in other muscular dystrophies.
Is the homozygous form of telan-giectasia lethal?
- Snyder Lf
- Doan
Snyder LF, Doan CA. Is the homozygous form of telan-giectasia lethal? J Lab Clin Med 1944;29:121 1-6.
Coronary heart disease Principles and practice of medical gen-etics
- G Uterman
Uterman G. Coronary heart disease. In: Emery AEH, Rimoin DL, eds. Principles and practice of medical gen-etics. Edinburgh: Churchill-Livingstone, 1983:966-8.
Distal myopathy -a variety characterized by prominent vacuolar degeneration of muscle
- H Mizusawa
- I Nakano
- K Inone
- F Takagi
- T Mannen
- Toyokura
Mizusawa H, Nakano I, Inone K, Takagi F, Mannen T, Toyokura Y. Distal myopathy -a variety characterized by prominent vacuolar degeneration of muscle. Neurol Med Chir (Tokyo) 1980;12:40.
Distal muscular dystrophy in an English family Distal myopathy: electron microscopic and histochemical studies
- D Sumner
- Mda Crawfurd
- Dgf Harriman
- Wr Markesbery
- Rc Griggs
- Rp Leach
- Lw Laphom
Sumner D, Crawfurd MDA, Harriman DGF. Distal muscular dystrophy in an English family. Brain 1971;94:51.
9 Markesbery WR, Griggs RC, Leach RP, Laphom LW.
Distal myopathy: electron microscopic and histochemical
studies. Neurology 1977;27:727-35.
Human genetics. Principles and methods
- C C Li
- Li, C.C.
Li CC. Human genetics. Principles and methods. New York:
McGraw-Hill, 1961:58-78.
In: Huntington's chorea
- M R Hayden
- Hayden, M.R.
Hayden MR. In: Huntington's chorea. Berlin: Springer-
Verlag, 1981:108-9.
Limb-girdle syndromes
- Rw Jr
RW Jr. Limb-girdle syndromes. In: Engel AG,
Banker BQ, eds. Myology basic and clinical. New York:
McGraw-Hill, 1986:1349-65.
Sporadic distal myopathy with early adult onset A new type of hereditary distal myopathy with characteristic sarcoplasmic bodies and intermediate (skeletin) filaments
- Rg Miller
- Nk Blank
- Rb Layzer
- Le Thornell
- A Eriksson
10 Miller RG, Blank NK, Layzer RB. Sporadic distal
myopathy with early adult onset. Ann Neurol 1979;5:220.
11 Edstrom L, Thornell LE, Eriksson A. A new type of
hereditary distal myopathy with characteristic sarcoplasmic bodies and intermediate (skeletin) filaments. Jf Neurol
Sci 1980;47:171.
Limb-girdle syndromes
- R W Shields
- RW, Jr, Shields
The limb girdle syndromes
- W G Bradley
- Bradley, W.G.