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.

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.

10.20944/preprints201905.0383.v1 ◽

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’s disease (HD) is one of the most well defined “repeat diseases”, 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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The Association between CAG Repeat Length and Age of Onset of Juvenile-Onset Huntington’s Disease

Brain Sciences ◽

10.3390/brainsci10090575 ◽

2020 ◽

Vol 10 (9) ◽

pp. 575 ◽

Cited By ~ 1

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.

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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

SunText Review of Neuroscience & Psychology ◽

10.51737/2766-4503.2021.030 ◽

2021 ◽

Vol 02 (02) ◽

Author(s):

Tarnow E

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Rate Equation ◽

Age Of Onset ◽

Repeat Length ◽

The Relationship

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

Annals of Human Genetics ◽

10.1111/j.1469-1809.2006.00335.x ◽

2006 ◽

Vol 71 (3) ◽

pp. 295-301 ◽

Cited By ~ 80

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

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CAG-repeat length and the age of onset in Huntington disease (HD): A review and validation study of statistical approaches

American Journal of Medical Genetics Part B Neuropsychiatric Genetics ◽

10.1002/ajmg.b.30992 ◽

2009 ◽

Vol 153B (2) ◽

pp. 397-408 ◽

Cited By ~ 171

Author(s):

Douglas R. Langbehn ◽

Michael R. Hayden ◽

Jane S. Paulsen ◽

Keyword(s):

Validation Study ◽

Huntington Disease ◽

Age Of Onset ◽

Repeat Length ◽

Cag Repeat ◽

Statistical Approaches

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Render unto Caesar Just a Little Bit Longer: The Relationship between Constitutional Reforms and Executive Survival

Government and Opposition ◽

10.1017/gov.2021.53 ◽

2021 ◽

pp. 1-22

Author(s):

Tofigh Maboudi ◽

Ghazal P. Nadi ◽

Todd A. Eisenstadt

Keyword(s):

Term Limits ◽

Institutional Constraints ◽

Third Wave ◽

Political Leaders ◽

Constitutional Order ◽

The Third ◽

Constitutional Reforms ◽

The Impact ◽

First Time ◽

The Relationship

Abstract Since the third wave of democracy, term limits have become a popular fixture of most constitutions intended to constrain the executive. Yet, recent constitutional reforms around the world show that presidents seeking re-election sometimes overturn the entire constitutional order to extend their power. What is the impact of these constitutional manipulations on the longevity of the executive in office? Using survival analysis of all political leaders and national constitutions from 1875 to 2015, this article demonstrates, for the first time, that when ‘authoritarian-aspiring’ presidents remove constitutional term limits, they increase their stay in office by more than 40%. Our findings contrast with a widely held position in the comparative authoritarian literature suggesting that dictators survive longer under institutional constraints. On the contrary, we argue that by removing constitutional barriers, rulers consolidate more power at the expense of their most ambitious allies and can stay in power longer.

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Schizophrenia Following Pre-natal Exposure to Influenza Epidemics Between 1939 and 1960

The British Journal of Psychiatry ◽

10.1192/bjp.160.4.461 ◽

1992 ◽

Vol 160 (4) ◽

pp. 461-466 ◽

Cited By ~ 173

Author(s):

Pak C. Sham ◽

Eadbhard O'Callaghan ◽

Noriyoshi Takei ◽

Graham K. Murray ◽

Edward H. Hare ◽

...

Keyword(s):

Viral Infection ◽

Adult Life ◽

England And Wales ◽

The Third ◽

Schizophrenic Patients ◽

First Time ◽

The Relationship

We examined the relationship between the dates of births of schizophrenic patients admitted to hospitals for the first time in England and Wales between 1970 and 1979, and the occurrence of influenza epidemics between 1939 and 1960. Our results indicate that exposure to influenza epidemics between the third and seventh month of gestation is associated with schizophrenia in adult life. The hypothesis that maternal viral infection is an important cause of schizophrenia can explain many aspects of the enigmatic epidemiology of the condition.

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The relationship between anogenital distance and the androgen receptor CAG repeat length

Asian Journal of Andrology ◽

10.1038/aja.2012.126 ◽

2013 ◽

Vol 15 (2) ◽

pp. 286-289 ◽

Cited By ~ 5

Author(s):

Michael L Eisenberg ◽

Tung-Chin Hsieh ◽

Alexander W Pastuszak ◽

Matthew G McIntyre ◽

Rustin C Walters ◽

...

Keyword(s):

Androgen Receptor ◽

Repeat Length ◽

Cag Repeat ◽

Anogenital Distance ◽

The Relationship

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The Interaction of UGT1A, HO1 and α-Thalassemia Variants with Bilirubin Levels and Gallstones in Sickle Cell Disease.

Blood ◽

10.1182/blood.v108.11.1202.1202 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1202-1202

Author(s):

Nisha Vasavda ◽

Stephan Menzel ◽

Sheila Kondaveeti ◽

Emma Maytham ◽

Moji Awogbade ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Genetic Variants ◽

Serum Bilirubin ◽

Repeat Length ◽

Major Influence ◽

Cell Disease ◽

First Time ◽

The Relationship ◽

Rate Limiting

Abstract Chronic hyperbilirubinemia is common in patients with sickle cell disease (SCD), frequently resulting in the formation of gallstones. This hyperbilirubinemia (predominantly unconjugated) is attributed to hemolysis that exceeds the conjugating capacity of the hepatic UDP-glucuronosyltransferase (UGT1A) enzyme. Previous studies have shown that genetic variants ([TA]n repeats) in the promoter region of the UGT1A gene have a major influence on the levels of bilirubin and gallstones. Alpha-thalassemia, which is associated with reduced hemolysis, has also been shown to affect bilirubin levels. Another potential modulating factor is heme-oxygenase, a rate-limiting enzyme in the heme catabolic pathway that results in the production of bilirubin. While the severity of jaundice and cholelithiasis in patients with SCD is predisposed by the inheritance of certain variants of the UGT1A gene, inconsistencies have been observed. We propose that some of these inconsistencies may be explained by the modulating effects of genetic variants of HO1 and α-thalassemia. A total of 263 patients with SCD attending specialist clinics in two hospitals were studied: King’s 116 SS, 5 Sβ0 and 59 SC; St Thomas’ 83 SS. 81 ethnically matched subjects were recruited as controls (HbAA). Groups were age and sex matched. Cholelithiasis data, ascertained by liver ultrasound, was available for a subset of SCD patients (76 SS, 4 SC). Samples were genotyped for variants of UGT1A, HO1 and α-thalassemia. The different genetic allele distributions were statistically similar between groups. Data was analysed according to the sum of [TA] repeats on both alleles of UGT1A. A range of 10–15 [TA] repeats was observed. For HO1, the median sum of repeats on both alleles was 63, so samples were grouped as <63 or ≥ 63. α-thalassemia genotypes were as follows: SS, 127 αα/αα, 55 αα/α-, 11 α-/α-; SC, 37 αα/αα, 20 αα/α-; controls 51 αα/αα, 22 αα/α-, 4 α-/α-. Median bilirubin levels varied as expected between groups according to β-globin genotype and were as follows: King’s SS 42 (15–269.5); St Thomas’ SS 52.5 (15.5–696.5); King’s SC 22 (10–81.8); AA Controls 10 (5–24), median (range) mmol/L. Regression analysis showed that serum bilirubin levels were strongly associated with UGT1A repeat length in all subjects (p<0.0001). Furthermore, the increase in serum bilirubin (21.3% mean for SS/Sβ0, 20.5% for SC) and cholelithiasis risk odds (86.5% mean for SS/Sβ0, 67.6% for SC) could be quantified per [TA] repeat. HO1 genotype did not affect serum bilirubin in SCD patients or the control cohort. The presence of α- thalassemia correlated (negatively) with serum bilirubin in SCD patients (p<0.0001) but not controls. This is the first time the relationship between UGT1A [TA] repeat length, serum bilirubin and cholelithiasis has been shown quantitatively. Additionally, co-existing α-thalassemia appears to moderate bilirubin levels but HO1 variants do not.

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