Practice Paper 3: Answers
Anthony B. Starr, Hiruni Jayasena, David Capewell, Saran Shantikumar in Get ahead! Medicine, 2016
Muscular dystrophy describes a group of inherited disorders with progressive degeneration of groups of muscles without involvement of the nervous system. It is characterized by symmetrical wasting and weakness, with no fasciculations or sensory loss. The most common muscular dystrophy is the Duchenne type, an X-linked recessive deficiency of the protein dystrophin, which is required to maintain the integrity of muscle cell walls. Duchenne muscular dystrophy begins in childhood and affects the proximal arms and legs. There is pseudohypertrophy of the calves (due to replacement of muscle by fibrosis and fat), a waddling gait and difficultly standing (children may ‘climb’ up their legs to help stand up – Gower’s sign). Affected children are wheelchair-bound by 12–15 years of age. Death by respiratory failure or cardiomyopathy occurs in the early 20s. A diagnosis of muscular dystrophy is confirmed by electromyography and biopsy. Creatine kinase may also be elevated. Management of muscular dystrophy is supportive.
Basic genetics and patterns of inheritance
Hung N. Winn, Frank A. Chervenak, Roberto Romero in Clinical Maternal-Fetal Medicine Online, 2021
Finally, methods for manipulating the expression or splicing of mutant genes are being investigated. Drugs that induce read-through of a stop codon during translation of a mutant gene can result in increased expression of full-length protein. This approach has been tried experimentally with cystic fibrosis and Duchenne muscular dystrophy. In other studies, antisense oligonucleotides have been used to induce skipping during mRNA splicing of exons that contain mutations; this approach will produce a smaller protein, but one that might retain some residual function. This method of therapy has been investigated for Duchenne muscular dystrophy. It is anticipated that more such opportunities will become available in the future for targeted therapy of the disease manifestations of genetic disorders.
Depression and Adjustment in Friedreich's Ataxia
Leon I. Charash, Robert E. Lovelace, Claire F. Leach, Austin H. Kutscher, Rabbi Jacob Goldberg, David Price Roye, Jill C. Crabtree in Muscular Dystrophy and Other Neuromuscular Diseases: Psychosocial Issues, 2014
Is endogenous depression more likely to occur in FA patients than in those with other neuromuscular diseases? Is the association of depression and FA real? Four patients out of 32 does not seem a highly significant number; however, in our experience it is disproportionately high. We see over 750 patients a year in our muscular dystrophy clinic. Although our FA population represents 5 percent of this total, it constitutes 40 percent of our patients who suffer severe depression requiring psychiatric intervention. Most patients with neuromuscular disorders other than FA do express difficulty in coping with their disease but do not exhibit signs and symptoms of endogenous depression. Why does the incidence of significant depression appear to be higher in FA? FA differs from the other neuromuscular diseases. FA patients are not weak; despite adequate strength they may be unable to ambulate or perform a simple task such as reaching for a glass of water. The frustration inherent in this type of neurological disability becomes apparent very early on. Does FA involve an inherent organic affective disorder as part of its spectrum of central nervous system involvement? Could it be that depression, in at least some individuals, manifests in this disease because depression is a biochemical disorder, and a putative dysfunctional gene in endogenous depression may be linked to the gene that is abnormal in FA? These questions remain to be answered.
Clinical features of children and adults with a muscular dystrophy using powered indoor/outdoor wheelchairs: disease features, comorbidities and complications of disability*
Published in Disability and Rehabilitation, 2018
Andrew Oliver Frank, Lorraine H. De Souza
The progressive muscular weakness characteristic of the muscular dystrophies determines the development of a range of clinical manifestations which depend on the disease trajectories of the different types of muscular dystrophy. Many of the common features of muscular dystrophy have been documented [2,14,25]. Individuals may also develop health conditions associated with long-term disability. These features of disability have been reported in other powered wheelchair users [17,26]. In addition, individuals may be diagnosed with other conditions unrelated to the muscular dystrophy, comorbidities, although they may reflect age-related health issues [27]. Collectively, these have been referred to as “Associated Clinical Features” (ACFs) [17,26] as it is acknowledged that some ambiguity exists due to lack of research into the development of conditions across the lifespan of disease.
Duchenne Muscular Dystrophy: recent advances in protein biomarkers and the clinical application
Published in Expert Review of Proteomics, 2020
Cristina Al-Khalili Szigyarto
Muscular dystrophies represent a large group of genetic rare disorders caused by different genetic mutations, with progressive muscle weakness symptom as the common denominator. Several muscular dystrophies share phenotypic characteristics related to deterioration of muscle function, age of onset, severity of muscle wasting symptoms, loss of mobility, short life expectancy in severe cases, and mild to severe cardiac and respiratory impairment [134]. Among them the most common muscular dystrophies besides Duchenne DMD are limb-girdle muscular dystrophy (LGMD), facioscapulohumeral muscular dystrophies (FSHD) and myotonic dystrophy 1 (DM1) with a prevalence of 0.8–6.9, 3.2–4.6 and 1.7–4.2 per 100,000, respectively [135–139]. In addition, Becker muscular dystrophy (BMD) has similarities with DMD as it is caused by in-frame mutations in the dystrophin gene [140,141]. Patients affected by these muscular dystrophies also exhibit elevated serum levels of muscle proteins like CK and CA3. CA3 is a severity marker in DMD and BMD but also a serum biomarker candidate for FSHD, LGMD, congenital, and myotonic dystrophy [70,142]. Serum ratio of lactate dehydrogenase (LDH) isoforms in patients affected by DMD, FSHD, or LGMD has been reported to be disease-specific [143]. These reports support the hypothesis that muscular dystrophies are likely to share muscle wasting biomarkers in blood.
Optimizing assays of zebrafish larvae swimming performance for drug discovery
Published in Expert Opinion on Drug Discovery, 2023
Jeffrey J. Widrick, Matthias R. Lambert, Louis M. Kunkel, Alan H. Beggs
The touch-evoked escape response is normally a qualitative method that relies upon human vision and discretion to judge whether larval swimming velocity and/or displacement is impaired. Some investigators have modified the touch-evoked escape response in order to make the approach more quantitative in nature. For example, by placing a transparent plastic sheet printed with concentric rings under the dish holding the larvae, initiating the escape response with the larvae centered in the inner most ring, and recording the response on video, the time required by the larvae to swim to the outermost ring could be determined [69]. This approach was used to evaluate a novel drug treatment for muscular dystrophy. Another method for quantifying escape response swimming is to record the movement using high-speed videography to then calculate maximum acceleration of larvae after the touch stimulus [48]. This approach was able to differentiate a nemaline myopathy model from wild type larvae.
Related Knowledge Centers
- Becker Muscular Dystrophy
- Mutation
- Neuromuscular Disease
- Skeletal Muscle
- Duchenne Muscular Dystrophy
- Body
- Facioscapulohumeral Muscular Dystrophy
- Myotonic Dystrophy
- Limb–Girdle Muscular Dystrophy
- Congenital Muscular Dystrophy