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Neuromuscular disorders
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Variation in severity within families may be marked, and both autosomal dominant and recessive inheritance have been recorded for the main types. The X-linked form of lethal centronuclear (myotubular) myopathy is more common than previously thought as a cause of neonatal death and is easily confused with congenital myotonic dystrophy; molecular analysis can distinguish the two. The term ‘congenital muscular dystrophy’ should be reserved for those specific forms that are progressive, as well as having congenital onset; they may also show central nervous system (CNS) (and sometimes oculomotor) involvement.
Ethical Framework for Next-Generation Genome and Epigenome Editing
Published in The American Journal of Bioethics, 2020
Kyoko Akatsuka, Mitsuru Sasaki-Honda, Tsutomu Sawai
Merosin-deficient congenital muscular dystrophy is a type of congenital muscular dystrophy characterized by severe muscle weakness from birth and caused by a mutation in the LAMA2 gene. Therapeutic effects were obtained in animal models by activating LAMA1, which is a disease-modifier gene and is usually intact in patients, via epigenome editing (Kemaladewi et al. 2019). Thus, this treatment does not modify LAMA2 mutations. To obtain a therapeutic effect, it may be necessary to “transfer” the system continuously using a vector, suggesting that this approach is “revising,” since it involves controlling nonpathogenic genes, and not “correcting” abnormal epigenetic conditions or gene expressions. Thus, the outcome for evaluation includes both off-target effects and other possible effects on an individual’s physiology.
Proteomic serum biomarkers for neuromuscular diseases
Published in Expert Review of Proteomics, 2018
Sandra Murphy, Margit Zweyer, Rustam R. Mundegar, Dieter Swandulla, Kay Ohlendieck
Muscle weakness and atrophy, and to a lesser extent, muscle pain, are the manifesting symptoms of primary neuromuscular disorders and of secondary nerve and/or muscle involvement in other diseases. Skeletal muscle wasting and weakness may be transient or highly progressive, and can range from mild to severe impairments. For patients afflicted with progressive forms of neuromuscular disorders, chronic muscle weakness can have a devastating impact on their quality of life [1–3]. Distinct molecular, cellular, and functional changes in the skeletal musculature may be triggered by (i) physiological adaptations to extended periods of physical inactivity versus high activity levels and strenuous exercise; (ii) pathophysiological consequences of disuse atrophy related to spinal cord injuries, traumatic motor denervation or the prolonged immobilization of extremities; (iii) metabolic alterations associated with malnutrition, fasting, diabetes, or obesity; (iv) inherited metabolic diseases such as glycogen storage disorder or mitochondrial myopathy; (v) the age-related decline in muscle mass and function in sarcopenia; (vi) acquired myopathies based on toxic, inflammatory, or endocrine mechanisms; (vii) primary and progressive myopathies such as the inherited disorders including limb-girdle muscular dystrophy, congenital muscular dystrophy, and Duchenne muscular dystrophy; (viii) disorders at the neuromuscular junction including acquired autoimmune myasthenia gravis and hereditary congenital myasthenia; (ix) channelopathies such as myotonic syndromes, malignant hyperthermia and periodic paralyses; or (x) secondary muscle abnormalities in cancer cachexia, kidney disease, chronic obstructive pulmonary disorder, heart disease, and sepsis [4].
An update on diagnostic options and considerations in limb-girdle dystrophies
Published in Expert Review of Neurotherapeutics, 2018
Corrado Angelini, Laura Giaretta, Roberta Marozzo
NGS strategies include targeted re-sequencing of specific genes; WES targeting for the entire set of human exons. NGS has been found to be a cost-effective procedure that can be used to study patients with unknown myopathies [39]. Mutation detection rates increased from 3% to 33% of LGMD cases using NGS and from 35% to 45% using WES. WES is useful for identifying novel genes in LGMD patients and has the advantage to combine screening of all LGMD-related genes and genes are associated with both congenital muscular dystrophy and LGMD [40].