Ameliorating the age at onset and disease progression in Huntington disease

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.

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

Medizinische Genetik ◽

10.1515/medgen-2021-2101 ◽

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.

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Poster 6: Cerebrospinal Fluid (CSF) Volume Is the Main Marker of Huntington Disease Progression Severity and Age-at-Onset Prediction

Neurotherapeutics ◽

10.1016/j.nurt.2009.09.007 ◽

2010 ◽

Vol 7 (1) ◽

pp. 139-140

Author(s):

F. Squitieri ◽

M. Cannella ◽

M. Simonelli ◽

T. Martino ◽

C. Colonnese ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Disease Progression ◽

Huntington Disease ◽

Age At Onset

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Estimating the causal effects of modifiable, non-genetic factors on Huntington disease progression using propensity score weighting

Parkinsonism & Related Disorders ◽

10.1016/j.parkreldis.2021.01.010 ◽

2021 ◽

Vol 83 ◽

pp. 56-62

Author(s):

Beth Ann Griffin ◽

Marika Suttorp Booth ◽

Monica Busse ◽

Edward J. Wild ◽

Claude Setodji ◽

...

Keyword(s):

Propensity Score ◽

Disease Progression ◽

Huntington Disease ◽

Genetic Factors ◽

Causal Effects ◽

Propensity Score Weighting

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Modulation at Age of Onset in Tunisian Huntington Disease Patients: Implication of New Modifier Genes

Genetics Research International ◽

10.1155/2014/210418 ◽

2014 ◽

Vol 2014 ◽

pp. 1-5 ◽

Cited By ~ 2

Author(s):

Dorra Hmida-Ben Brahim ◽

Marwa Chourabi ◽

Sana Ben Amor ◽

Imed Harrabi ◽

Saoussen Trabelsi ◽

...

Keyword(s):

Huntington Disease ◽

Neurodegenerative Disorder ◽

Age Of Onset ◽

Age At Onset ◽

Specific Effect ◽

Modifier Genes ◽

Cag Repeats ◽

Causative Mutation ◽

Cag Expansion ◽

Tunisian Patients

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder. The causative mutation is an expansion of more than 36 CAG repeats in the first exon of IT15 gene. Many studies have shown that the IT15 interacts with several modifier genes to regulate the age at onset (AO) of HD. Our study aims to investigate the implication of CAG expansion and 9 modifiers in the age at onset variance of 15 HD Tunisian patients and to establish the correlation between these modifiers genes and the AO of this disease. Despite the small number of studied patients, this report consists of the first North African study in Huntington disease patients. Our results approve a specific effect of modifiers genes in each population.

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Association between BDNF Val66Met polymorphism and age at onset in Huntington disease

Neurology ◽

10.1212/01.wnl.0000175977.57661.b1 ◽

2005 ◽

Vol 65 (6) ◽

pp. 964-965 ◽

Cited By ~ 23

Author(s):

J. Alberch ◽

M. Lopez ◽

C. Badenas ◽

J. L. Carrasco ◽

M. Mila ◽

...

Keyword(s):

Huntington Disease ◽

Age At Onset ◽

Val66met Polymorphism ◽

Bdnf Val66met Polymorphism

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The De-Ubiquitinating Enzyme Ataxin-3 does not Modulate Disease Progression in a Knock-in Mouse Model of Huntington Disease

Journal of Huntington s Disease ◽

10.3233/jhd-130058 ◽

2013 ◽

Vol 2 (2) ◽

pp. 201-215 ◽

Cited By ~ 14

Author(s):

Li Zeng ◽

Sara J. Tallaksen-Greene ◽

Bo Wang ◽

Roger L. Albin ◽

Henry L. Paulson

Keyword(s):

Mouse Model ◽

Disease Progression ◽

Huntington Disease

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Genetic risk of Parkinson disease and progression:

Neurology Genetics ◽

10.1212/nxg.0000000000000348 ◽

2019 ◽

Vol 5 (4) ◽

pp. e348 ◽

Cited By ~ 33

Author(s):

Hirotaka Iwaki ◽

Cornelis Blauwendraat ◽

Hampton L. Leonard ◽

Ganqiang Liu ◽

Jodi Maple-Grødem ◽

...

Keyword(s):

Parkinson Disease ◽

Disease Progression ◽

Disease Risk ◽

Age At Onset ◽

Motor Symptom ◽

European Ancestry ◽

Sleep Behavior ◽

Intronic Region ◽

Risk Variants ◽

Faster Development

ObjectiveTo determine if any association between previously identified alleles that confer risk for Parkinson disease and variables measuring disease progression.MethodsWe evaluated the association between 31 risk variants and variables measuring disease progression. A total of 23,423 visits by 4,307 patients of European ancestry from 13 longitudinal cohorts in Europe, North America, and Australia were analyzed.ResultsWe confirmed the importance of GBA on phenotypes. GBA variants were associated with the development of daytime sleepiness (p.N370S: hazard ratio [HR] 3.28 [1.69–6.34]) and possible REM sleep behavior (p.T408M: odds ratio 6.48 [2.04–20.60]). We also replicated previously reported associations of GBA variants with motor/cognitive declines. The other genotype-phenotype associations include an intergenic variant near LRRK2 and the faster development of motor symptom (Hoehn and Yahr scale 3.0 HR 1.33 [1.16–1.52] for the C allele of rs76904798) and an intronic variant in PMVK and the development of wearing-off effects (HR 1.66 [1.19–2.31] for the C allele of rs114138760). Age at onset was associated with TMEM175 variant p.M393T (−0.72 [−1.21 to −0.23] in years), the C allele of rs199347 (intronic region of GPNMB, 0.70 [0.27–1.14]), and G allele of rs1106180 (intronic region of CCDC62, 0.62 [0.21–1.03]).ConclusionsThis study provides evidence that alleles associated with Parkinson disease risk, in particular GBA variants, also contribute to the heterogeneity of multiple motor and nonmotor aspects. Accounting for genetic variability will be a useful factor in understanding disease course and in minimizing heterogeneity in clinical trials.

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Predictability of Age at Onset in Huntington Disease in the Dutch Population

Medicine ◽

10.1097/00005792-200207000-00001 ◽

2002 ◽

Vol 81 (4) ◽

pp. 251-259 ◽

Cited By ~ 21

Author(s):

ANNEKE MAAT-KIEVIT ◽

MONIQUE LOSEKOOT ◽

KOOS ZWINDERMAN ◽

MARIA VEGTER-VAN DER VLIS ◽

RENÉ BELFROID ◽

...

Keyword(s):

Huntington Disease ◽

Age At Onset ◽

Dutch Population

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Practice Parameter: Diagnosis and prognosis of new onset Parkinson disease (an evidence-based review)

Neurology ◽

10.1212/01.wnl.0000215437.80053.d0 ◽

2006 ◽

Vol 66 (7) ◽

pp. 968-975 ◽

Cited By ~ 152

Author(s):

O. Suchowersky ◽

S. Reich ◽

J. Perlmutter ◽

T. Zesiewicz ◽

G. Gronseth ◽

...

Keyword(s):

Parkinson Disease ◽

Disease Progression ◽

Clinical Features ◽

Predictive Factors ◽

Age At Onset ◽

Future Research ◽

Evidence Based ◽

Level Of Evidence ◽

Parkinsonian Syndromes ◽

Olfactory Testing

Objective: To define key issues in the diagnosis of Parkinson disease (PD), to define features influencing progression, and to make evidence-based recommendations. Two clinical questions were identified: 1) Which clinical features and diagnostic modalities distinguish PD from other parkinsonian syndromes? 2) Which clinical features predict rate of disease progression?Methods: Systematic review of the literature was completed. Articles were classified according to a four-tiered level of evidence scheme. Recommendations were based on the evidence.Results and Conclusions: 1. Early falls, poor response to levodopa, symmetry of motor manifestations, lack of tremor, and early autonomic dysfunction are probably useful in distinguishing other parkinsonian syndromes from Parkinson disease (PD). 2. Levodopa or apomorphine challenge and olfactory testing are probably useful in distinguishing PD from other parkinsonian syndromes. 3. Predictive factors for more rapid motor progression, nursing home placement, and shorter survival time include older age at onset of PD, associated comorbidities, presentation with rigidity and bradykinesia, and decreased dopamine responsiveness. Future research into methods for earlier and more accurate diagnosis of the disease and identification and clarification of predictive factors of rapid disease progression is warranted.

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