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Advanced microscopic and histochemical techniques : diagnostic tools in the molecular era of myology
No full textOver the past two centuries, myology (i.e. the basic and clinical science of muscle and muscle disease) has passed through 3 stages of development: the classical period, the modern stage and the molecular era. The classical period spans the last part of nineteenth century and the earlier part of the twentieth century. During this time, several major muscle diseases were clinically and pathologically characterized, including Duchenne muscular dystrophy (DMD), myotonic dystrophy (DM) and facioscapulohumeral dystrophy (FSHD). The modern stage in the second half of the twentieth century is characterized by the adaptation of histo and cytochemical techniques to the study of muscle biopsies. These tools improved the diagnostic accuracy and made possible the identification of new changes and structures (Engel and Cunningham, 1963; Scarlato, 1975)
Clinical aspects, molecular pathomechanisms and management of myotonic dystrophies
Full text linkMyotonic dystrophy (DM) is the most common adult muscular dystrophy, characterized by autosomal dominant progressive myopathy, myotonia and multiorgan involvement. To date two distinct forms caused by similar mutations have been identified. Myotonic dystrophy type 1 (DM1, Steinert's disease) was described more than 100 years ago and is caused by a (CTG)n expansion in DMPK, while myotonic dystrophy type 2 (DM2) was identified only 18 years ago and is caused by a (CCTG)n expansion in ZNF9/CNBP. When transcribed into CUG/CCUG-containing RNA, mutant transcripts aggregate as nuclear foci that sequester RNA-binding proteins, resulting in spliceopathy of downstream effector genes. Despite clinical and genetic similarities, DM1 and DM2 are distinct disorders requiring different diagnostic and management strategies. DM1 may present in four different forms: congenital, early childhood, adult onset and late-onset oligosymptomatic DM1. Congenital DM1 is the most severe form of DM characterized by extreme muscle weakness and mental retardation. In DM2 the clinical phenotype is extremely variable and there are no distinct clinical subgroups. Congenital and childhood-onset forms are not present in DM2 and, in contrast to DM1, myotonia may be absent even on EMG. Due to the lack of awareness of the disease among clinicians, DM2 remains largely underdiagnosed. The delay in receiving the correct diagnosis after onset of first symptoms is very long in DM: on average more than 5 years for DM1 and more than 14 years for DM2 patients. The long delay in the diagnosis of DM causes unnecessary problems for the patients to manage their lives and anguish with uncertainty of prognosis and treatment
Unusual diagnostic and management problems in neuromuscular diseases: Mitochondrial disorders
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IDMC-6 - The sixth International Myotonic Dystrophy Consortium Meeting
No full textIn 1992 three groups of investigators found that myotonic dystrophy of Steinert, classical myotonic dystrophy, now known as myotonic dystrophy type 1 (DM1), results from an unstable CTG repeat expansion in the non-coding 3� region of serinethreonine kinase gene DMPK at 19q13.3. Almost a decade later in 2001 collaborators in Minnesota and Germany discovered a second gene defect responsible for myotonic dystrophy type 2 (DM2), another autosomal dominant, multisystem disease, that is similar to but distinct from DM1. DM2 results from an unstable CCTG repeat expansion in intron 1 of the zinc finger protein 9 gene ZNF9 at 3q21. The exact cause for the instability of the DNA at these two different loci, and the explanation for the tissue mosaicism that exists in different tissues in DM1 and DM2 remains a mystery although part of the answer probably lies in faulty repair of DNA. Why the CTG repeat expansion in DM1 is larger in skeletal and cardiac muscle and in certain parts of the brain than in circulating leucocytes and some other tissues is not clear. Whether this tissue mosaicism accounts for or plays a major role in determining the spectrum of disease manifestations requires further investigation.Whether it is possible to use the tissue instability of DNA in refining the diagnosis and prognosis of patients with DM1 and DM2 is a question that has yet to be explored
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