Normal and mutant
            <i>HTT</i>
            interact to affect clinical severity and progression in Huntington disease

Aziz, N. Ahmad; Jurgens, Caroline K.; Landwehrmeyer, G. Bernhard; Roon‐Mom, Willeke M. C. van; Ommen, G.J.B. van; Stijnen, T.; Roos, Raymund A.C.

doi:10.1212/wnl.0b013e3181bd1121

Cited by 85 publications

(63 citation statements)

References 29 publications

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“…16,24 In Huntington disease, increasing sizes of the normal alleles were found to correlate with a more severe phenotype, whereas in patients with large expansions, the size of the normal allele had the opposite effect. 26 It is hypothesized that these associations are due to an interaction of the poyglutamine domains of the normal and expanded disease protein. The present observations in male patients with SCA6 together with previously published data on a relation between larger normal alleles and earlier disease onset in SCA6 suggest that longer normal alleles in SCA6 are associated with a more severe phenotype characterized by earlier disease onset and faster progression.…”

Section: Resultsmentioning

confidence: 99%

The natural history of spinocerebellar ataxia type 1, 2, 3, and 6

et al. 2011

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Objective: To obtain quantitative data on the progression of the most common spinocerebellar ataxias (SCAs) and identify factors that influence their progression, we initiated the EUROSCA natural history study, a multicentric longitudinal cohort study of 526 patients with SCA1, SCA2, SCA3, or SCA6. We report the results of the 1-and 2-year follow-up visits. Methods:As the primary outcome measure we used the Scale for the Assessment and Rating of Ataxia (SARA, 0-40), and as a secondary measure the Inventory of Non-Ataxia Symptoms (INAS, 0-16) count. Results:The annual increase of the SARA score was greatest in SCA1 (2.18 Ϯ 0.17, mean Ϯ SE) followed by SCA3 (1.61 Ϯ 0.12) and SCA2 (1.40 Ϯ 0.11). SARA progression in SCA6 was slowest and nonlinear (first year: 0.35 Ϯ 0.34, second year: 1.44 Ϯ 0.34). Analysis of the INAS count yielded similar results. Larger expanded repeats and earlier age at onset were associated with faster SARA progression in SCA1 and SCA2. In SCA1, repeat length of the expanded allele had a similar effect on INAS progression. In SCA3, SARA progression was influenced by the disease duration at inclusion, and INAS progression was faster in females.

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Section: Resultsmentioning

confidence: 99%

The natural history of spinocerebellar ataxia type 1, 2, 3, and 6

et al. 2011

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“…6 -9 Recently, an interaction of the expanded and normal allele was reported in a large study to modify age at onset based upon motor signs, cognitive change, and behavioral manifestations. 10 Counterintuitively, longer normal alleles (e.g., 30 CAGs) seemingly delayed age at onset of subjects with longer expanded CAG alleles (e.g., Ͼ50 CAGs). 10 This finding would have important implications for the precise molecular mechanism that initiates HD pathogenesis, as it would suggest that individual huntingtin molecules might physically interact, with a resultant alteration of the pathogenic potential of the expanded repeat.…”

Section: Discussionmentioning

confidence: 99%

“…10 Counterintuitively, longer normal alleles (e.g., 30 CAGs) seemingly delayed age at onset of subjects with longer expanded CAG alleles (e.g., Ͼ50 CAGs). 10 This finding would have important implications for the precise molecular mechanism that initiates HD pathogenesis, as it would suggest that individual huntingtin molecules might physically interact, with a resultant alteration of the pathogenic potential of the expanded repeat. Similarly, if the normal allele can modify HD pathogenesis, it would provide a potential route to therapeutic intervention to delay or prevent onset via a genetic modifier validated to act via a mechanism that operates in humans with HD.…”

Section: Discussionmentioning

confidence: 99%

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

Ramos²,

et al. 2012

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Objective: Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs. Methods:We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression. Results:An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a wellbehaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele. Conclusions:Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors. Neurology ® 2012;78:690-695

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“…The size of the expansion correlates with age of disease onset and rate of disease progression, although there can be considerable variation between individuals [2]. The age of onset is clearly determined by a variety of other genetic and environmental factors [3], possibly including the size of the non-mutant allele [4]. Neuropsychiatric symptoms including personality changes, irritability, social withdrawal, obsessivecompulsive disorder, psychosis, and depression may precede the development of the movement disorder.…”

Section: Huntington's Diseasementioning

confidence: 99%

Differential Diagnosis of Chorea

Walker

2011

Curr Neurol Neurosci Rep

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Chorea is a common movement disorder that can be caused by a large variety of structural, neurochemical (including pharmacologic), or metabolic disturbances to basal ganglia function, indicating the vulnerability of this brain region. The diagnosis is rarely indicated by the simple phenotypic appearance of chorea, and can be challenging, with many patients remaining undiagnosed. Clues to diagnosis may be found in the patient's family or medical history, on neurologic examination, or upon laboratory testing and neuroimaging. Increasingly, advances in genetic medicine are identifying new disorders and expanding the phenotype of recognized conditions. Although most therapies at present are supportive, correct diagnosis is essential for appropriate genetic counseling, and ultimately, for future molecular therapies.

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Normal and mutant HTT interact to affect clinical severity and progression in Huntington disease

Cited by 85 publications

References 29 publications

The natural history of spinocerebellar ataxia type 1, 2, 3, and 6

The natural history of spinocerebellar ataxia type 1, 2, 3, and 6

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

Differential Diagnosis of Chorea

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