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The Scientific Basis of Medicine
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
Chris O'Callaghan, Rachel Allen
Background levels of mutation arise from normal cellular and environmental interactions. Mutation rates also reflect the fidelity of DNA replication and its proofreading and/or correction potential. Trinucleotide repeats are known to be particularly unstable and are associated with a range of genetic diseases including Huntington's chorea, myotonic dystrophy and fragile X syndrome. Disease severity is usually proportional to the increase in repeat length.
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
Anticipation is a genetic term which implies that the phenotype (clinical features) of a disease becomes progressively more severe and/or manifests at an earlier age in subsequent generations. It is associated with expansion of a trinucleotide repeat in the genomic DNA sequence of that gene. Diseases showing this feature include fragile X mental retardation, myotonic dystrophy, Huntington disease and several forms of spinocerebellar atrophy. The original observations of anticipation were incorrectly thought to represent spurious selection bias.
Recent and Evolving Therapies in the Management of Endothelial Diseases
Published in Seminars in Ophthalmology, 2023
Shalini Singh, Sunita Chaurasia
In the past couple of decades, there have been rapid advances in understanding trinucleotide repeat expansion disorders, especially in the field of neuromuscular degenerative condition like spinocerebellar ataxia, myotonic dystrophy and Huntington's disease.81 Recently, it has been known that a significant proportion of FECD has trinucleotide repeat disease (TCF4 gene), thus making gene therapies theoretically an option for FECD. Human genome project has led to significant knowledge and techniques for the treatment of both systemic and ophthalmologic diseases. In the recent times, the development of molecular scissors specifically cleaved the diseased targets so that defective genes can be deleted, replaced or repaired in situ. Clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated 9 (Cas9) nucleases are the most interesting innovations in the field of human biomedicine by removing the abnormal DNA segments directly.70 mRNA transcription can be inhibited by designing ssRNA oligonucleotides, which directly attach to the promoter sequences.82
Investigating TBP CAG/CAA trinucleotide repeat expansions in a Taiwanese cohort with ALS
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2021
Kang-Yang Jih, Kon-Ping Lin, Pei-Chien Tsai, Bing-Wen Soong, Yi-Chu Liao, Yi-Chung Lee
SCA17 is a dominantly inherited neurodegenerative disease, characterized by ataxia (95%), dementia (∼90%), and involuntary movements (∼70%) such as chorea and dystonia (5–7). Psychiatric symptoms, pyramidal signs, and rigidity are also common manifestations (8,9). SCA17 is caused by an abnormal expansion of the CAG/CAA trinucleotide repeats within TBP. It is categorized as a polyglutamine disease since both CAG and CAA encode glutamine and the expanded trinucleotide repeats will result in a mutant TBP protein with a prolonged polyglutamine expansion. The normal trinucleotide repeat length in TBP ranges from 25 to 40. Patients carrying the TBP mutant allele with a CAG/CAA repeat size greater than 49 would develop SCA17 with complete penetrance, whereas those with intermediate-length CAG/CAA repeats (41 to 48) are at risk of SCA17 with a reduced penetrance (10). Only few SCA17 patients with 41 − 43 CAG/CAA repeats have been reported (11–13), and the majority of SCA17 cases carry TBP alleles with 44 or more CAG/CAA repeats (6,7).
Emerging therapeutics in Huntington’s disease
Published in Expert Opinion on Emerging Drugs, 2021
Another novel therapeutic approach in HD seeks to use ASO’s or siRNAs to target mRNA that will be translated into DNA damage response (DDR) proteins. DDR proteins may be responsible for inducing the expansion of nucleotide repeats, such as the CAG expanded trinucleotide repeat in HD [33,34]. Triplet Therapeutics has recently completed enrollment in SHIELD HD, a prospective, longitudinal observational study that will follow both early and pre manifest HD patients for 2 years. The study will measure clinical, imaging, and CSF markers over time, and will measure DDR gene expression in patients as well. (NCT04406636) [35] Preclinical studies have found that Triplet Therapeutics’ TTX-3360 reduces the amount of mRNA coding for DDR in cortex and caudate in non-human primates and impedes somatic trinucleotide repeat expansion in transgenic HD animal models [36].