scholarly journals Overlap between age-at-onset and disease-progression determinants in Huntington disease

Neurology ◽  
2018 ◽  
Vol 90 (24) ◽  
pp. e2099-e2106 ◽  
Author(s):  
N. Ahmad Aziz ◽  
Jorien M.M. van der Burg ◽  
Sarah J. Tabrizi ◽  
G. Bernhard Landwehrmeyer
Keyword(s):  
Weight Loss ◽  
Disease Progression ◽  
Huntington Disease ◽  
Age At Onset ◽  
Cag Repeat ◽  
Optimal Timing ◽  
Mixed Effect ◽  
Mixed Effect Models ◽  
Intuitive Method ◽  
Average Body

ObjectiveA fundamental but still unresolved issue regarding Huntington disease (HD) pathogenesis is whether the factors that determine age at onset are the same as those that govern disease progression. Because elucidation of this issue is crucial for the development as well as optimal timing of administration of novel disease-modifying therapies, we aimed to assess the extent of overlap between age-at-onset and disease-progression determinants in HD.MethodsUsing observational data from Enroll-HD, the largest cohort of patients with HD worldwide, in this study we present, validate, and apply an intuitive method based on linear mixed-effect models to quantify the variability in the rate of disease progression in HD.ResultsA total of 3,411 patients with HD met inclusion criteria. We found that (1) about two-thirds of the rate of functional, motor, and cognitive progression in HD is determined by the same factors that also determine age at onset, with CAG repeat–dependent mechanisms having by far the largest effect; (2) although expanded HTT CAG repeat size had a large influence on average body weight, the rate of weight loss was largely independent of factors that determine age at onset in HD; and (3) about one-third of the factors that determine the rate of functional, motor, and cognitive progression are different from those that govern age at onset and need further elucidation.ConclusionOur findings imply that targeting of CAG repeat–dependent mechanisms, for example through gene-silencing approaches, is likely to affect the rate of functional, motor, and cognitive impairment, but not weight loss, in manifest HD mutation carriers.

scholarly journals Huntington disease update: new insights into the role of repeat instability in disease pathogenesis

2021 ◽  
Vol 33 (4) ◽  
pp. 293-300
Author(s):  
Larissa Arning ◽  
Huu Phuc Nguyen
Keyword(s):  
Disease Progression ◽  
Dna Sequences ◽  
Huntington Disease ◽  
Trinucleotide Repeat ◽  
Age At Onset ◽  
Repeat Sequence ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Causative Mutation ◽  
Cognitive Disability

Abstract The causative mutation for Huntington disease (HD), an expanded trinucleotide repeat sequence in the first exon of the huntingtin gene (HTT) is naturally polymorphic and inevitably associated with disease symptoms above 39 CAG repeats. Although symptomatic medical therapies for HD can improve the motor and non-motor symptoms for affected patients, these drugs do not stop the ongoing neurodegeneration and progression of the disease, which results in severe motor and cognitive disability and death. To date, there is still an urgent need for the development of effective disease‐modifying therapies to slow or even stop the progression of HD. The increasing ability to intervene directly at the roots of the disease, namely HTT transcription and translation of its mRNA, makes it necessary to understand the pathogenesis of HD as precisely as possible. In addition to the long-postulated toxicity of the polyglutamine-expanded mutant HTT protein, there is increasing evidence that the CAG repeat-containing RNA might also be directly involved in toxicity. Recent studies have identified cis- (DNA repair genes) and trans- (loss/duplication of CAA interruption) acting variants as major modifiers of age at onset (AO) and disease progression. More and more extensive data indicate that somatic instability functions as a driver for AO as well as disease progression and severity, not only in HD but also in other polyglutamine diseases. Thus, somatic expansions of repetitive DNA sequences may be essential to promote respective repeat lengths to reach a threshold leading to the overt neurodegenerative symptoms of trinucleotide diseases. These findings support somatic expansion as a potential therapeutic target in HD and related repeat expansion disorders.

scholarly journals Weight loss and incident dementia in elderly Yoruba Nigerians: a 10-year follow-up study

2010 ◽  
Vol 23 (3) ◽  
pp. 387-394 ◽  
Author(s):  
Adesola Ogunniyi ◽  
Su Gao ◽  
Frederick W. Unverzagt ◽  
Olusegun Baiyewu ◽  
Oyewusi Gureje ◽  
...  
Keyword(s):  
Weight Loss ◽  
Normal Subjects ◽  
Smoking History ◽  
Close Monitoring ◽  
Cognitive Assessments ◽  
Mixed Effect ◽  
Mixed Effect Models ◽  
Dementia Risk ◽  
Incident Dementia

ABSTRACTBackground: The relationship between weight and dementia risk has not been investigated in populations with relatively low body mass index (BMI) such as the Yoruba. This study set out to achieve this objective using a prospective observational design.Methods: The setting was Idikan Ward in Ibadan City, Nigeria. The participants were all aged 65 years or older and were enrolled in the Indianapolis-Ibadan Dementia Project. Repeated cognitive assessments and clinical evaluations were conducted to identify participants with dementia or MCI during 10 years of follow-up (mean duration: 5.97 years). BMI measures, information on alcohol, smoking history, cancer, hypertension, diabetes, heart attack, stroke and depression were collected at each follow-up evaluation. Mixed effect models adjusted for covariates were used to examine the differences in BMI among participants who developed dementia or MCI and those who remained cognitively normal during the follow-up.Results: This analysis included 1559 participants who had no dementia at their first BMI measurements. There were 136 subjects with incident dementia, 255 with MCI and 1168 with normal cognition by the end of the study. The mean BMI at baseline was higher for female participants (22.31; SD = 4.39) than for male (21.09; SD = 3.61, p < 0.001). A significantly greater decline in BMI was found in those with either incident dementia (p < 0.001) or incident MCI (p < 0.001) compared to normal subjects.Conclusion: Decline in BMI is associated with incident MCI and dementia in elderly Yoruba. This observation calls for close monitoring of weight loss in elderly individuals which may indicate future cognitive impairment for timely detection and tailored interventions.

Weight loss in Huntington disease increases with higher CAG repeat number

Neurology ◽  
2008 ◽  
Vol 71 (19) ◽  
pp. 1506-1513 ◽  
Author(s):  
N. A. Aziz ◽  
J.M.M. van der Burg ◽  
G. B. Landwehrmeyer ◽  
P. Brundin ◽  
T. Stijnen ◽  
...  
Keyword(s):  
Weight Loss ◽  
Huntington Disease ◽  
Cag Repeat ◽  
Repeat Number

scholarly journals Bioenergetics in fibroblasts of patients with Huntington disease are associated with age at onset

2018 ◽  
Vol 4 (5) ◽  
pp. e275 ◽  
Author(s):  
Sarah L. Gardiner ◽  
Chiara Milanese ◽  
Merel W. Boogaard ◽  
Ronald A.M. Buijsen ◽  
Marye Hogenboom ◽  
...  
Keyword(s):  
Huntington Disease ◽  
Mitochondrial Respiration ◽  
Disease Duration ◽  
Age At Onset ◽  
Fibroblast Cell ◽  
Cag Repeat ◽  
Spare Capacity ◽  
Atp Concentration ◽  
Repeat Size ◽  
Residual Variation

ObjectiveWe aimed to assess whether differences in energy metabolism in fibroblast cell lines derived from patients with Huntington disease were associated with age at onset independent of the cytosine-adenine-guanine (CAG) repeat number in the mutant allele.MethodsFor this study, we selected 9 pairs of patients with Huntington disease matched for mutant CAG repeat size and sex, but with a difference of at least 10 years in age at onset, using the Leiden Huntington disease database. From skin biopsies, we isolated fibroblasts in which we (1) quantified the ATP concentration before and after a hydrogen-peroxide challenge and (2) measured mitochondrial respiration and glycolysis in real time, using the Seahorse XF Extracellular Flux Analyzer XF24.ResultsThe ATP concentration in fibroblasts was significantly lower in patients with Huntington disease with an earlier age at onset, independent of calendar age and disease duration. Maximal respiration, spare capacity, and respiration dependent on complex II activity, and indices of mitochondrial respiration were significantly lower in patients with Huntington disease with an earlier age at onset, again independent of calendar age and disease duration.ConclusionsA less efficient bioenergetics profile was found in fibroblast cells from patients with Huntington disease with an earlier age at onset independent of mutant CAG repeat size. Thus, differences in bioenergetics could explain part of the residual variation in age at onset in Huntington disease.

scholarly journals CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion

Neurology ◽  
2012 ◽  
Vol 79 (9) ◽  
pp. 952-953 ◽  
Author(s):  
N. A. Aziz ◽  
R. A. C. Roos ◽  
J. F. Gusella ◽  
J.-M. Lee ◽  
M. E. MacDonald
Keyword(s):  
Huntington Disease ◽  
Age At Onset ◽  
Repeat Expansion ◽  
Cag Repeat ◽  
Cag Repeat Expansion

Interaction of normal and expanded CAG repeat sizes influences age at onset of Huntington disease

2003 ◽  
Vol 119A (3) ◽  
pp. 279-282 ◽  
Author(s):  
L. Djoussé ◽  
B. Knowlton ◽  
M. Hayden ◽  
E.W. Almqvist ◽  
R. Brinkman ◽  
...  
Keyword(s):  
Huntington Disease ◽  
Age At Onset ◽  
Cag Repeat

Ameliorating the age at onset and disease progression in Huntington disease

Neurology ◽  
2018 ◽  
Vol 90 (24) ◽  
pp. 1087-1088 ◽  
Author(s):  
Patrick J. Morrison ◽  
Martin B. Delatycki
Keyword(s):  
Disease Progression ◽  
Huntington Disease ◽  
Age At Onset

WEIGHT LOSS IN HUNTINGTON DISEASE INCREASES WITH HIGHER CAG REPEAT NUMBER

Neurology ◽  
2009 ◽  
Vol 73 (7) ◽  
pp. 572-572 ◽  
Author(s):  
G. J. Gilbert ◽  
N.A. Aziz ◽  
J.M.M. van der Burg ◽  
G.B. Landwehrmeyer ◽  
P. Brundin ◽  
...  
Keyword(s):  
Weight Loss ◽  
Huntington Disease ◽  
Cag Repeat ◽  
Repeat Number

scholarly journals Clinical presentation of juvenile Huntington disease

2006 ◽  
Vol 64 (1) ◽  
pp. 5-9 ◽  
Author(s):  
Heloísa H. Ruocco ◽  
Iscia Lopes-Cendes ◽  
Tiago L. Laurito ◽  
Li M. Li ◽  
Fernando Cendes
Keyword(s):  
Huntington Disease ◽  
Disease Gene ◽  
Clinical Presentation ◽  
Brain Mri ◽  
Age At Onset ◽  
Cag Repeat ◽  
Cortical Atrophy ◽  
Volume Loss ◽  
Juvenile Onset ◽  
Juvenile Huntington Disease

OBJECTIVE: To describe the clinical presentation a group of patients with juvenile onset of Huntington disease. METHOD: All patients were interviewed following a structured clinical questioner. Patients were genotyped for the trinucleotide cytosine-adenine-guanine (CAG) repeat in the Huntington Disease gene. High resolution brain MRI was performed in all patients. RESULTS: We identified 4 patients with juvenile onset of disease among 50 patients with Huntington disease followed prospectively in our Neurogenetics clinic. Age at onset varied from 3 to 13 years, there were 2 boys, and 3 patients had a paternal inheritance of the disease. Expanded Huntington disease allele sizes varied from 41 to 69 trinucleotide repeats. The early onset patients presented with rigidity, bradykinesia, dystonia, dysarthria, seizures and ataxia. MRI showed severe volume loss of caudate and putamen nuclei (p=0.001) and reduced cerebral and cerebellum volumes (p=0.01). CONCLUSION: 8% of Huntington disease patients seen in our clinic had juvenile onset of the disease. They did not present with typical chorea as seen in adult onset Huntington disease. There was a predominance of rigidity and bradykinesia. Two other important clinical features were seizures and ataxia, which related with the imaging findings of early cortical atrophy and cerebellum volume loss.

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