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Degenerative Diseases of the Nervous System
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
James A. Mastrianni, Elizabeth A. Harris
Five of the eight neurologic disorders caused by an increase in the number of CAG repeats result in spinocerebellar ataxia (Table 16.14). The other three are spinal and bulbar muscular atrophy (SBMA or Kennedy's disease), HD, and DRPLA. These disorders are characterized by autosomal dominant or X-linked inheritance, onset in midlife, a progressive course, anticipation, preponderance of unstable repeats from the paternal chromosome, and correlation of increased CAG repeats with earlier age at symptom onset. The abnormal proteins in each disorder are expressed in a wide range of tissues and are not limited to the affected brain regions.
Aicardi Syndrome and Klinefelter Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Gene polymorphisms often occur in the androgen receptor gene mapped to Xq11.2–12, which contains a highly polymorphic CAG trinucleotide repeat (range 9–37). The CAG repeat length is inversely related to receptor activity. Long CAG repeat length (low receptor activity) often correlates with tall stature, arm span, gynecomastia, small testes, HDL cholesterol, hematocrit, and later reactivation of pituitary−testicular axis; whereas short CAG repeat length (high receptor activity) correlates with longer penile length, higher bone density, and higher likelihood of having a stable partnership or professional employment [7].
The nervous system and the eye
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
James A.R. Nicoll, William Stewart, Fiona Roberts
In this autosomal dominant disorder progressive dementia is accompanied by involuntary choreiform movements. Huntington's disease (HD) usually begins in the 40 or 50 s and has an incidence of about 47 per 100,000 population. The cause of Huntington's disease is an increased number of trinucleotide repeats (CAG), which encode the amino acid glutamine, in the huntingtin gene on chromosome 4. The normal gene contains 9–37 CAG repeats, whereas in patients with HD there may be in the region of 37–100. This knowledge allows prediction of susceptibility in as yet unaffected family members and antenatal testing. The mutation is unstable and the phenomenon of anticipation may occur: in succeeding generations the disease occurs with an earlier age of onset and increasing severity as the number of CAG repeats increases. On examination of the brain the most striking feature is selective atrophy of the caudate nucleus (Figure 12.35). There may also be cortical atrophy. Histological examination reveals loss of small neurons and gliosis in the caudate nuclei with variable involvement of other nuclei in the basal ganglia and the cerebral cortex. The huntingtin protein produced in HD is abnormal, containing a long chain of glutamine amino acid residues as a consequence of the CAG repeats in the huntingtin gene, and accumulates as dot-like intranuclear inclusions.
The number of androgen receptor CAG repeats and mortality in men
Published in The Aging Male, 2022
Adrian Heald, Michael Cook, Leen Antonio, Dirk Vanderschueren, Ahmed Javed, Helene Fachim, Geoff Hackett, Fred Wu, Terence O’Neill
Genetic analysis was done in 2008. DNA extracted from whole blood was subjected to polymerase chain reaction (PCR) to amplify the region of the AR gene containing AR exon 1 CAG triplet repeat. PCR preparation, primers, and conditions were as described in a previous study [7]. Genotyping of the CAG repeat was carried out in the laboratory of the Centre for Integrated Genomic Medical Research (The University of Manchester), using fluorescently-labeled PCR. Ten nanograms of DNA were amplified in 10-l reactions containing 2.5 pmol each of fluorescently labeled forward and reverse primer, 10 PCR buffer, 1.5 mM MgCl2, 0.2 mM dNTPs, and 0.2 U Taq DNA polymerase. The primer sequences were: forward, 5-TCC AGA ATC TGT TCC AGA GCG TGC-3; and reverse, 5-GCT GTG AAG GTT GCT GTT CCT CAT-3. Reactions were cycled at 95 °C for 5 min; 10 cycles of 94 °C for 10 s, 55 °C for 30 s, and 72 °C for 30 s; 20 cycles of 89 °C for 20 s, 55 °C for 30 s, and 72 °C for 30 s; and finally, 72 °C for 10 min. Samples were then run on an ABIPRISM 3100 Genetic Analyser (Applied Biosystems, Foster City, CA) and genotyped using Genescan (Applied Biosystems). Allele frequencies were checked for consistency with HapMap data or literature where possible.
Molecular spectrum, family screening and genetic counselling of Spinocerebellar Ataxia (SCA) cases in an Indian scenario
Published in Journal of Neurogenetics, 2021
Priyanka Vishwakarma, Sarita Agarwal, Deepika Delsa Dean, Srinivasan Muthuswamy, Kausik Mandal
After this, we also established the genotype and phenotype correlation in affected individuals that have been shown in Table 2. In genotype-phenotype correlation identification, we found that the gait problem and slow saccadic eye movement and dysarthria were the most prominent features in all SCA positive cases. It was identified that the classical features of a particular SCA subtype were present in only 20% (4) of the total number of positive SCA cases (18) identified. This was in concordance with a study by Moro et al. (2019) who reported it to be approximately 30% of affected individuals (Moro et al., 2019). Also, the clinical features were considerably overlapping in all patients as reported in earlier studies (Bhattacharyya et al., 2016; Wang et al., 2016). making clinical diagnosis challenging. Although the number of pathological CAG repeats is the major determinant of phenotypic variation, still in our study we did not find any relationship between the presence of lower repeat size and the absence of classical disease symptoms. These findings point out the presence of other undefined genetic modifiers that affects the clinical picture of SCA. In fact, recently it is affirmed that DNA repair genes can modify the expanded CAG repeats and are significantly associated with the age of onset of SCAs. (Sullivan, Yau, O’Connor, & Houlden, 2019). Future studies in this direction would provide further insights into the genetic factors influencing the clinical characteristics of SCA.
Simultaneous ALS and SCA2 associated with an intermediate-length ATXN2 CAG-repeat expansion
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2021
Helia Ghahremani Nezhad, John P. Franklin, James J. P. Alix, Tobias Moll, Michael Pattrick, Johnathan Cooper-Knock, Priya Shanmugarajah, Nick J. Beauchamp, Marios Hadjivissiliou, David Paling, Christopher Mcdermott, Pamela J. Shaw, Thomas M. Jenkins
It has been suggested that ATXN2-ALS is exclusively associated with interrupted CAG-repeat expansions within ATXN2 versus pure CAG-repeats in SCA2 (10). In contrast, our case carried an uninterrupted CAG-repeat expansion but presented with ALS. Interrupted CAG-repeat expansions may be more stable than pure repeats through cell division leading to reduced somatic mosaicism (11). In our framing of the relationship between expansion length and phenotype this could explain an overrepresentation of interrupted CAG-repeats in blood samples from patients presenting initially with ALS: patients carrying uninterrupted unstable alleles would be more likely to develop longer expansion lengths in the CNS, which would in turn be associated with early presentation of SCA2 prior to any motor neuron degeneration.