scholarly journals Molecular pathology of dentatorubral--pallidoluysian atrophy

1999 ◽  
Vol 354 (1386) ◽  
pp. 1069-1074 ◽  
Author(s):  
Ichiro Kanazawa
Keyword(s):  
Age Of Onset ◽  
Neuronal Cell Death ◽  
Somatic Mosaicism ◽  
Neuronal Cell ◽  
Repeat Length ◽  
Cag Repeat ◽  
Autosomal Dominant Disorder ◽  
Myoclonus Epilepsy ◽  
Chromosome 12P ◽  
Sporadic Cases

Dentatorubral–pallidoluysian atrophy (DRPLA) is an autosomal dominant disorder characterized clinically by myoclonus, epilepsy, cerebellar ataxia, choreoathetosis and dementia. Cardinal pathological features of DRPLA are a combined degeneration of both the dentatorubral and the pallidoluysian systems. Although the early sporadic cases were reported by Western neuropathologists, a strong heritability and an age of onset–dependent variability of the clinical features were carefully deduced by Japanese clinicians. The disease is fairly common in Japan, but extremely rare in Caucasians. Since the gene was identified in 1994, DRPLA is known as one of the CAG repeat expansion diseases, in which the responsible gene is located on chromosome 12p and its product is called atrophin 1. DRPLA shows prominent ‘anticipation’, which is genetically clearly explained by a marked instability of the expanded CAG repeat length during spermatogenesis. Moreover, the instability of the CAG repeat length also seems to occur in the somatic cells, resulting in ‘somatic mosaicism’. Possible mechanism(s) underlying the neuronal cell death in DRPLA are discussed in terms of molecular pathological points of view.

scholarly journals The Association between CAG Repeat Length and Age of Onset of Juvenile-Onset Huntington’s Disease

2020 ◽  
Vol 10 (9) ◽  
pp. 575 ◽  
Author(s):  
Jordan L. Schultz ◽  
Amelia D. Moser ◽  
Peg C. Nopoulos
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Age Of Onset ◽  
Repeat Length ◽  
Cag Repeat ◽  
Linear Regression Models ◽  
Juvenile Onset ◽  
Additional Information ◽  
Using Data ◽  
The Relationship

There is a known negative association between cytosine–adenine–guanine (CAG) repeat length and the age of motor onset (AMO) in adult-onset Huntington’s Disease (AOHD). This relationship is less clear in patients with juvenile-onset Huntington’s disease (JOHD), however, given the rarity of this patient population. The aim of this study was to investigate this relationship amongst a relatively large group of patients with JOHD using data from the Kids-JOHD study. Additionally, we analyzed data from the Enroll-HD platform and the Predict-HD study to compare the relationship between CAG repeat length and AMO amongst patients with AOHD to that amongst patients with JOHD using linear regression models. In line with previous reports, the variance in AMO that was predicted by CAG repeat length was 59% (p < 0.0001) in the Predict-HD study and 57% from the Enroll-HD platform (p < 0.0001). However, CAG repeat length predicted 84% of the variance in AMO amongst participants from the Kids-JOHD study (p < 0.0001). These results indicate that there may be a stronger relationship between CAG repeat length and AMO in patients with JOHD as compared to patients with AOHD. These results provide additional information that may help to model disease progression of JOHD, which is beneficial for the planning and implementation of future clinical trials.

scholarly journals A-095 Processing Speed Indicators in Juvenile Huntington’s Disease: Assessing CAG Repeat, Age of Onset, and Mood

2020 ◽  
Vol 35 (6) ◽  
pp. 888-888
Author(s):  
Goecke N ◽  
Dawson D ◽  
Choate A ◽  
Boress K ◽  
Espe-Pfeifer P ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Symptom Onset ◽  
Processing Speed ◽  
Age Of Onset ◽  
Depressive Mood ◽  
Repeat Length ◽  
Cag Repeat ◽  
Age At Diagnosis ◽  
Juvenile Huntington’S Disease

Abstract Objective In adult onset Huntington’s Disease (HD), processing speed deficits and depression can be detected in the prodromal stages. These factors, along with CAG repeat length, may be predictive of age of symptom onset. However, less is known about the relationship between the aforementioned factors for patients diagnosed with Juvenile Huntington’s Disease (JHD). The current study aimed to investigate the relationships between age of symptom onset, CAG repeat, processing speed, and mood to improve prediction of symptom manifestation for JHD patients. Method Data was analyzed from the Kids HD study and included 30 participants (age at diagnosis M = 13.6, SD = 5.4, CAG repeat mean = 69, SD = 16). Bivariate partial correlations, independent t-tests, and regression analyses examined differences in processing speed across CAG repeat, age of onset, and depressive symptomology. Results CAG repeat length significantly predicted the natural log of age at diagnosis, β = −.59, t(25) = −3.59, p &lt; .01, and significantly explained variance in the natural log of age at diagnosis, R2 = .35, F(1, 25) = 12.86, p &lt; .01. Finally, results indicated that CAG repeat length also predicted processing speed abilities when controlling for depressed mood symptomology, R2 = .39, F(3,24) = 5.18, p &lt; .01. Conclusion CAG repeat length holds predictive power for the age of diagnosis and for processing speed, even when accounting for covariate depressive mood indicators. Overall, results indicate evidence of impacted processing speed abilities given expansive CAG repeat numbers. This is consistent with a subcortical neurodegenerative process, such as HD.

scholarly journals Approaches to Sequence the HTT CAG Repeat Expansion and Quantify Repeat Length Variation

2021 ◽  
Vol 10 (1) ◽  
pp. 53-74
Author(s):  
Marc Ciosi ◽  
Sarah A. Cumming ◽  
Afroditi Chatzi ◽  
Eloise Larson ◽  
William Tottey ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Disease Onset ◽  
Somatic Mosaicism ◽  
Genotyping By Sequencing ◽  
Repeat Length ◽  
Cag Repeat ◽  
Length Variation ◽  
Allele Size ◽  
Pcr Products ◽  
Alternative Approaches

Background: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of the HTT CAG repeat. Affected individuals inherit ≥36 repeats and longer alleles cause earlier onset, greater disease severity and faster disease progression. The HTT CAG repeat is genetically unstable in the soma in a process that preferentially generates somatic expansions, the proportion of which is associated with disease onset, severity and progression. Somatic mosaicism of the HTT CAG repeat has traditionally been assessed by semi-quantitative PCR-electrophoresis approaches that have limitations (e.g., no information about sequence variants). Genotyping-by-sequencing could allow for some of these limitations to be overcome. Objective: To investigate the utility of PCR sequencing to genotype large (>50 CAGs) HD alleles and to quantify the associated somatic mosaicism. Methods: We have applied MiSeq and PacBio sequencing to PCR products of the HTT CAG repeat in transgenic R6/2 mice carrying ∼55, ∼110, ∼255 and ∼470 CAGs. For each of these alleles, we compared the repeat length distributions generated for different tissues at two ages. Results: We were able to sequence the CAG repeat full length in all samples. However, the repeat length distributions for samples with ∼470 CAGs were biased towards shorter repeat lengths. Conclusion: PCR sequencing can be used to sequence all the HD alleles considered, but this approach cannot be used to estimate modal allele size or quantify somatic expansions for alleles ⪢250 CAGs. We review the limitations of PCR sequencing and alternative approaches that may allow the quantification of somatic contractions and very large somatic expansions.

The Relationship Between CAG Repeat Length and Age of Onset Differs for Huntington's Disease Patients with Juvenile Onset or Adult Onset

2006 ◽  
Vol 71 (3) ◽  
pp. 295-301 ◽  
Author(s):  
J. Michael Andresen ◽  
Javier Gayán ◽  
Luc Djoussé ◽  
Simone Roberts ◽  
Denise Brocklebank ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Age Of Onset ◽  
Repeat Length ◽  
Cag Repeat ◽  
Adult Onset ◽  
Juvenile Onset ◽  
The Relationship

scholarly journals A Huntington’s disease (HD) phenocopy leads to the identification of the HD toxin as polyalanine. The relationship between repeat length and age of onset can be reframed as a rate equation and the toxic polyalanine length is found to be about 30.6.

2019 ◽  
Author(s):  
Eugen Tarnow
Keyword(s):  
Rate Equation ◽  
Age Of Onset ◽  
Repeat Sequence ◽  
Repeat Length ◽  
Cag Repeat ◽  
Reading Frame ◽  
The Third ◽  
Repeat Expansions ◽  
First Time ◽  
The Relationship

Huntington&rsquo;s disease (HD) is one of the most well defined &ldquo;repeat diseases&rdquo;, associated with a short repeated genetic sequence, CAG.First, taking into account that a phenocopy of HD has a different repeat that is associated with a different gene, I suggest that the gene is not important for HD, only the repeat sequence is important, in agreement with Lee et al (2019) who reached the same conclusion using a GWAS technique.Second, taking into account that a phenocopy of HD has a CTG repeat rather than a CAG repeat, and that the toxin should be the same for both disease types and that the third base in a codon is the least important, I suggest that the reading frame is shifted for the repeat expansions and that the A/T substitution takes place on the third base. The most likely sense and antisense reading frames are then (GCA)n and (GCT)n and (GCT)n and (GCA)n and the corresponding amino acid is polyalanine.Third, the more repeats, the earlier the HD onset (Brinkman et al, 1997; Wexler, 2004). I suggest that this relationship can be thought of as a rate equation. If the concentration is proportional to the probability of creating a polyalanine of length m in a repeat expansion of length n, the corresponding equation is borne out by the data on age of onset and repeat length and m is found to be about 30.6. This explains for the first time, at least approximately, why HD is not active unless there are at least 36 CAG repeats.If true, HD may be the first disease where frameshifting is the cause of the disease.

scholarly journals Discovery of a Novel Small-Molecule Targeting Selective Clearance of Mutant Huntingtin Fragments

2007 ◽  
Vol 12 (3) ◽  
pp. 351-360 ◽  
Author(s):  
Myra Coufal ◽  
Michele M. Maxwell ◽  
Deborah E. Russel ◽  
Allison M. Amore ◽  
Stephen M. Altmann ◽  
...  
Keyword(s):  
Fluorescent Protein ◽  
Age Of Onset ◽  
Repeat Length ◽  
Cag Repeat ◽  
Toxicity Tests ◽  
Functional Assay ◽  
Chemical Screen ◽  
Green Fluorescent ◽  
Fluorescent Protein Reporter ◽  
Precise Molecular Mechanism

CAG-triplet repeat extension, translated into polyglutamines within the coding frame of otherwise unrelated gene products, causes 9 incurable neurodegenerative disorders, including Huntington's disease. Although an expansion in the CAG repeat length is the autosomal dominant mutation that causes the fully penetrant neurological phenotypes, the repeat length is inversely correlated with the age of onset. The precise molecular mechanism(s) of neurodegeneration remains elusive, but compelling evidence implicates the protein or its proteolytic fragments as the cause for the gain of novel pathological function(s). The authors sought to identify small molecules that target the selective clearance of polypeptides containing pathological polyglutamine extension. In a high-throughput chemical screen, they identified compounds that facilitate the clearance of a small huntingtin fragment with extended polyglutamines fused to green fluorescent protein reporter. Identified hits were validated in dose-response and toxicity tests. Compounds have been further tested in an assay for clearance of a larger huntingtin fragment, containing either pathological or normal polyglutamine repeats. In this assay, the authors identified compounds selectively targeting the clearance of mutant but not normal huntingtin fragments. These compounds were subjected to a functional assay, which yielded a lead compound that rescues cells from induced mutant polyglutamine toxicity. ( Journal of Biomolecular Screening 2007:351-360)

scholarly journals A Huntington’s Disease (HD) Phenocopy Leads to the Identification of the HD Toxin as Polyalanine. The Relationship Between Repeat Length and Age of Onset Can Be Reframed as a Rate Equation and the Toxic Polyalanine Length Is Found to Be about 30.6.

2019 ◽  
Author(s):  
Eugen Tarnow
Keyword(s):  
Rate Equation ◽  
Age Of Onset ◽  
Repeat Sequence ◽  
Repeat Length ◽  
Cag Repeat ◽  
Reading Frame ◽  
The Third ◽  
Repeat Expansions ◽  
First Time ◽  
The Relationship

Huntington&rsquo;s disease (HD) is one of the most well defined &ldquo;repeat diseases&rdquo;, associated with a short repeated genetic sequence, CAG.First, taking into account that a phenocopy of HD has a different repeat that is associated with a different gene, I suggest that the gene is not important for HD, only the repeat sequence is important, in agreement with Lee et al (2019) who reached the same conclusion using a GWAS technique.Second, taking into account that a phenocopy of HD has a CTG repeat rather than a CAG repeat, and that the toxin should be the same for both disease types and that the third base in a codon is the least important, I suggest that the reading frame is shifted for the repeat expansions and that the A/T substitution takes place on the third base. The most likely sense and antisense reading frames are then (GCA)n and (GCT)n and (GCT)n and (GCA)n and the corresponding amino acid is polyalanine.Third, the more repeats, the earlier the HD onset (Brinkman et al, 1997; Wexler, 2004). I suggest that this relationship can be thought of as a rate equation. If the concentration is proportional to the probability of creating a polyalanine of length m in a repeat expansion of length n, the corresponding equation is borne out by the data on age of onset and repeat length and m is found to be about 30.6. This explains for the first time, at least approximately, why HD is not active unless there are at least 36 CAG repeats.If true, HD may be the first disease where frameshifting is the cause of the disease.

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