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Genetics
Published in Ibrahim Natalwala, Ammar Natalwala, E Glucksman, MCQs in Neurology and Neurosurgery for Medical Students, 2022
Ibrahim Natalwala, Ammar Natalwala, E Glucksman
Myotonic dystrophy is a disease that affects skeletal and smooth muscle as well as multiple other organ systems. There is myotonic dystrophy type 1 (DM1) and type 2. DM1 can be categorised into three overlapping phenotypes: mild, classic and congenital. The patient in this question is likely to have classic DM1 since he has cataracts, myotonia and muscle weakness. Patients can also have cardiac abnormalities and endocrine changes. Congenital DM1 is usually characterised by severe muscle weakness and hypotonia at birth which can often lead to respiratory complications and mortality. It displays an autosomal dominant inheritance pattern and genetic anticipation.2 Genetic anticipation is the concept that a worsening severity of disease or an earlier onset of disease is evident in succeeding generations. This is because succeeding generations display a longer trinucleotide repeat sequence than their predecessors. Other trinucleotide repeat disorders include HD and fragile X syndrome.3
Genetics and metabolic disorders
Published in Jagdish M. Gupta, John Beveridge, MCQs in Paediatrics, 2020
Jagdish M. Gupta, John Beveridge
The absent/deficient protein in both Duchenne and Becker dystrophies is known as dystrophin. Becker dystrophy significantly shortens life but affected individuals live longer than those with Duchenne dystrophy. Myotonic dystrophy is characterized by an extreme paucity of new mutations. Congenitally affected infants are almost always born to affected mothers, many of whom are not aware they have the disease at the time the affected infant is born. Facio-scapulo-humeral (FSH) dystrophy is an autosomal dominant disorder characterized by extreme variability of expression. Charcot-Marie-Tooth (CMT) disease can be inherited in autosomal recessive, autosomal dominant and an X-linked manner. X-linked CMT is now recognized as the second most common type after autosomal dominant types.
Neuromuscular disorders
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Myotonic dystrophy is an autosomal dominant disorder, for long a special interest of the original author. It ranks second only to Duchenne muscular dystrophy as a major genetic counselling problem in inherited muscle disease and is the most common muscular dystrophy of adult life. Its extreme clinical variability adds special difficulty.
Status update in the use of cell-penetrating peptides for the delivery of macromolecular therapeutics
Published in Expert Opinion on Biological Therapy, 2021
Kaido Kurrikoff, Birgit Vunk, Ülo Langel
Recently, Pip6a was assessed as a treatment strategy for myotonic dystrophy DM1. Pip6a–ASO conjugate efficiently reversed DM1 molecular defects and demonstrated physiological benefit in a mouse model [32]. The efficacy was demonstrated after systemic administration, where the clinical effects were observed at lower cumulative doses than with alternative ASO treatments. It is encouraging that substantial levels of ASO were also detected in the heart and diaphragm tissues, as the mouse model does not allow assessment of the functional effects in these tissues, but these are critically affected in DM1 disease. Furthermore, the authors also tested the efficacy in human myogenic DM1 cells and similarly to the mouse model, the molecular indications of DM1 correction were achieved [32]. The question that should be asked now is – how efficient is Pip6a–ASO tissue penetration in humans?
Meet and eat, an interdisciplinary group intervention for patients with myotonic dystrophy about healthy nutrition, meal preparation, and consumption: a feasibility study
Published in Disability and Rehabilitation, 2020
Suzanne G. M. van Hees, Simone Knuijt, Heleen Dicke, Jan T. Groothuis, Joost Raaphorst, Ton Satink, Edith H. C. Cup
Nine patients with DM1 participated, four women and five men, age ranging from 31 to 68 years and mean age of 45. All had a genetically confirmed DM1, of whom two had a juvenile type of MD1. Most participants had complaints varying from mild to severe swallowing problems including frequent choking incidents. Other clinical complaints included bowel complaints and sometimes problems of incontinence, fatigue and daytime sleepiness, diminished hand function, and myotonic flexors of the underarm. Also, some mild frontal cognitive impairments were described including lack of initiative. So, although the genetic diagnosis was myotonic dystrophy type 1 for all nine participants, the clinical complaints varied. Six participants lived with at least one family member. Seven family members participated, two mothers, two wives, and three husbands.
Mir-206 partially rescues myogenesis deficiency by inhibiting CUGBP1 accumulation in the cell models of myotonic dystrophy
Published in Neurological Research, 2019
Wei Dong, Xuanying Chen, Menghong Wang, Zeqi Zheng, Xing Zhang, Qunlin Xiao, Xiaoping Peng
Myotonic dystrophy (DM) is an autosomal-dominant disorder characterized by muscle weakness, myotonia, and multisystemic involvement [1]. There are two types of DM, of which DM1 is the more frequent and severe [2]. The genetic mutation underlying DM1 is an expansion of CUG triplet repeats located in the 3′-untranslated region (UTR) of the DM protein kinase gene DMPK [3]. The CUG repeat number in unaffected individuals varies from 5 to 37. In contrast, it increases to more than 50, and sometimes up to thousands, in DM1 patients [4]. Both MBNL1 and Celf1 contribute to the pathogenesis of DM1. MBNL1 is sequestered by the expanded CUG repeats, resulting in loss of function and aberrant alternative splicing of its targets [5]. Celf1 regulates the cell cycle and is partially responsible for defective myoblast differentiation in DM RNA toxicity [6]. In skeletal muscle, Celf1 overexpression reproduces DM1-like features and is associated with Celf1-responsive alternative splicing or aberrant stability of the Celf1 targets p21 and MEF2A [7]. However, other data suggest that CUG expansion causes these effects [8] by inhibiting the expression of the crucial myogenic factor MyoD, which may explain the lack of muscle regeneration in severe DM1 cases [9].