scholarly journals Age of onset in Huntington’s disease is influenced by CAG repeat variations in other polyglutamine disease-associated genes

Brain ◽  
2017 ◽  
Vol 140 (7) ◽  
pp. e42-e42 ◽  
Author(s):  
Geerte Stuitje ◽  
Martine J. van Belzen ◽  
Sarah L. Gardiner ◽  
Willeke M. C. van Roon-Mom ◽  
Merel W. Boogaard ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Age Of Onset ◽  
Cag Repeat ◽  
Polyglutamine Disease ◽  
Disease Associated Genes

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 Conformational studies of pathogenic expanded polyglutamine protein deposits from Huntington’s disease

2019 ◽  
Vol 244 (17) ◽  
pp. 1584-1595 ◽  
Author(s):  
Irina Matlahov ◽  
Patrick CA van der Wel
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Structural Biology ◽  
Age Of Onset ◽  
Repeat Expansion ◽  
Cag Repeat ◽  
Mutant Huntingtin ◽  
Cag Repeat Expansion ◽  
Recent Developments ◽  
Mutant Huntingtin Protein

Huntington’s disease, like other neurodegenerative diseases, continues to lack an effective cure. Current treatments that address early symptoms ultimately fail Huntington’s disease patients and their families, with the disease typically being fatal within 10–15 years from onset. Huntington’s disease is an inherited disorder with motor and mental impairment, and is associated with the genetic expansion of a CAG codon repeat encoding a polyglutamine-segment-containing protein called huntingtin. These Huntington’s disease mutations cause misfolding and aggregation of fragments of the mutant huntingtin protein, thereby likely contributing to disease toxicity through a combination of gain-of-toxic-function for the misfolded aggregates and a loss of function from sequestration of huntingtin and other proteins. As with other amyloid diseases, the mutant protein forms non-native fibrillar structures, which in Huntington’s disease are found within patients’ neurons. The intracellular deposits are associated with dysregulation of vital processes, and inter-neuronal transport of aggregates may contribute to disease progression. However, a molecular understanding of these aggregates and their detrimental effects has been frustrated by insufficient structural data on the misfolded protein state. In this review, we examine recent developments in the structural biology of polyglutamine-expanded huntingtin fragments, and especially the contributions enabled by advances in solid-state nuclear magnetic resonance spectroscopy. We summarize and discuss our current structural understanding of the huntingtin deposits and how this information furthers our understanding of the misfolding mechanism and disease toxicity mechanisms. Impact statement Many incurable neurodegenerative disorders are associated with, and potentially caused by, the amyloidogenic misfolding and aggregation of proteins. Usually, complex genetic and behavioral factors dictate disease risk and age of onset. Due to its principally mono-genic origin, which strongly predicts the age-of-onset by the extent of CAG repeat expansion, Huntington’s disease (HD) presents a unique opportunity to dissect the underlying disease-causing processes in molecular detail. Yet, until recently, the mutant huntingtin protein with its expanded polyglutamine domain has resisted structural study at the atomic level. We present here a review of recent developments in HD structural biology, facilitated by breakthrough data from solid-state NMR spectroscopy, electron microscopy, and complementary methods. The misfolded structures of the fibrillar proteins inform our mechanistic understanding of the disease-causing molecular processes in HD, other CAG repeat expansion disorders, and, more generally, protein deposition disease.

scholarly journals Huntington’s Disease in a Patient Misdiagnosed as Conversion Disorder

2018 ◽  
Vol 2018 ◽  
pp. 1-4
Author(s):  
João Machado Nogueira ◽  
Ana Margarida Franco ◽  
Susana Mendes ◽  
Anabela Valadas ◽  
Cristina Semedo ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Psychiatric Symptoms ◽  
Age Of Onset ◽  
Late Onset ◽  
Psychiatric Patients ◽  
Conversion Disorder ◽  
Cag Repeat ◽  
Clinical Assessments ◽  
Clinical Presentations

Huntington’s disease (HD) is an inherited, progressive, and neurodegenerative neuropsychiatric disorder caused by the expansion of cytosine-adenine-guanine (CAG) trinucleotide in Interested Transcript (IT) 15 gene on chromosome 4. This pathology typically presents in individuals aged between 30 and 50 years and the age of onset is inversely correlated with the length of the CAG repeat expansion. It is characterized by chorea, cognitive deficits, and psychiatric symptoms. Usually the psychiatric disorders precede motor and cognitive impairment, Major Depressive Disorder and anxiety disorders being the most common presentations. We present a clinical case of a 65-year-old woman admitted to our Psychiatric Acute Unit. During the 6 years preceding the admission, the patient had clinical assessments made several times by different specialties that focused only on isolated symptoms, disregarding the syndrome as a whole. In the course of her last admission, the patient was referred to our Neuropsychiatric Team, which made the provisional diagnosis of late-onset Huntington’s disease, later confirmed by genetic testing. This clinical vignette highlights the importance of a multidisciplinary approach to atypical clinical presentations and raises awareness for the relevance of investigating carefully motor symptoms in psychiatric patients.

Huntington’s Disease

2008 ◽  
Author(s):  
Adam Rosenblatt
Keyword(s):  
Huntington's Disease ◽  
Movement Disorder ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Age Of Onset ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Triplet Repeat Expansion ◽  
Common Time ◽  
The Individual

Huntington’s disease (HD) is a hereditary neurodegenerative disorder characterized by the triad of a movement disorder, dementia, and various psychiatric disturbances. HD is caused by the abnormal expansion of a trinucleotide (CAG) repeat in the huntingtin gene of chromosome 4—a mutation that is inherited as an autosomal dominant. When the number of CAG repeats exceeds 39, the individual harboring it goes on to develop HD. The most common time of onset is in the fourth or fifth decade, but the age of onset is inversely correlated with the size of the triplet repeat expansion. In rare instances, persons with very large expansions may have onset in childhood, and those with expansions only just into the abnormal range may have onset late in life. Children of affected fathers, if they receive the abnormal allele, tend to inherit an allele that is even further expanded, and thus usually experience the onset of symptoms at a younger age than their fathers; this phenomenon is known as paternal anticipation. The progression of HD is inexorable and usually leads to death within 15 to 20 years of symptom onset; patients in the final stages have severe dementia and are unable to speak, eat, or purposefully move. Death typically results from the consequences of immobility such as pneumonia or malnutrition. The movement disorder of HD has two major manifestations: involuntary movements (eg, chorea, dystonia) and impairments of voluntary movement (eg, clumsiness, dysarthria, swallowing difficulties, falls, bradykinesia, rigidity). Chorea generally predominates early in the course and is gradually eclipsed by motor impairment as the disease becomes more advanced. In the end stages, patients are rigid and immobile. A variety of medications are used to suppress chorea in HD, including neuroleptics, benzodiazepines, and dopamine-depleting agents such as tetrabenazine, but it remains controversial whether these agents convey functional, as opposed to cosmetic, benefits. HD, like many other neurodegenerative disorders, is associated with a variety of psychiatric problems. Some of these problems such as insomnia or demoralization may be thought of as nonspecific. They have a variety of causes and are associated with many different medical conditions.

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.

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 Free carnitine and branched chain amino acids are not good biomarkers in Huntington’s disease

2020 ◽  
Vol 78 (2) ◽  
pp. 81-87
Author(s):  
Raphael Machado CASTILHOS ◽  
Marina Coutinho AUGUSTIN ◽  
José Augusto dos SANTOS ◽  
José Luiz PEDROSO ◽  
Orlando BARSOTTINI ◽  
...  
Keyword(s):  
Amino Acids ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Age Of Onset ◽  
Branched Chain Amino Acids ◽  
Free Carnitine ◽  
Cag Repeat ◽  
Isoleucine Leucine ◽  
Branched Chain

ABSTRACT Background: Huntington’s disease (HD), caused by an expanded CAG repeat at HTT, has no treatment, and biomarkers are needed for future clinical trials. Objective: The objective of this study was to verify if free carnitine and branched chain amino acids levels behave as potential biomarkers in HD. Methods: Symptomatic and asymptomatic HD carriers and controls were recruited. Age, sex, body mass index (BMI), age of onset, disease duration, UHDRS scores, and expanded CAG tract were obtained; valine, leucine, isoleucine, and free carnitine were measured. Baseline and longitudinal analysis were performed. Results: Seventy-four symptomatic carriers, 20 asymptomatic carriers, and 22 non-carriers were included. At baseline, valine levels were reduced in symptomatic and asymptomatic HD carriers when compared to non-carriers. No difference in free carnitine or isoleucine+leucine levels were observed between groups. BMI of symptomatic individuals was lower than those of non-carriers. Valine levels correlated with BMI. Follow-up evaluation was performed in 43 symptomatic individuals. UHDRS total motor score increased 4.8 points/year on average. No significant reductions in BMI or valine were observed, whereas free carnitine and isoleucine+leucine levels increased. Conclusions: Although valine levels were lower in HD carriers and were related to BMI losses observed in pre-symptomatic individuals, none of these metabolites seem to be biomarkers for HD.

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