Huntington's Disease and Related Disorders

Anderson, Karen E.

doi:10.1016/j.psc.2004.10.001

Cited by 21 publications

(10 citation statements)

References 95 publications

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“…The underlying genetic defect is an unstable CAG trinucleotide repeat expansion in exon 1 of the HD gene, formerly called IT-15, on the short arm of chromosome 4. A repeat CAG length of 36 and longer is pathogenic and results in the synthesis of an abnormal polyglutamic tract in Huntington’s, a widely expressed protein of uncertain function [4,5] causing accumulation of intracellular protein aggregates, neurotrophic factor deprivation, impairment of energetic metabolism, transcriptional deregulation and, finally, hyperactivation of programmed cell-death mechanisms. Progressive dysfunction and neuronal loss, mainly in the caudate nucleus and in the putamen, start several years before the onset of motor symptoms.…”

Section: Introductionmentioning

confidence: 99%

Neuropsychiatric Burden in Huntington’s Disease

et al. 2017

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Huntington’s disease is a disorder that results in motor, cognitive, and psychiatric problems. The symptoms often take different forms and the presence of disturbances of the psychic sphere reduces patients’ autonomy and quality of life, also impacting patients’ social life. It is estimated that a prevalence between 33% and 76% of the main psychiatric syndromes may arise in different phases of the disease, often in atypical form, even 20 years before the onset of chorea and dementia. We present a narrative review of the literature describing the main psychopathological patterns that may be found in Huntington’s disease, searching for a related article in the main database sources (Medline, ISI Web of Knowledge, Scopus, and Medscape). Psychiatric conditions were classified into two main categories: affective and nonaffective disorders/symptoms; and anxiety and neuropsychiatric features such as apathy and irritability. Though the literature is extensive, it is not always convergent, probably due to the high heterogeneity of methods used. We summarize main papers for pathology and sample size, in order to present a synoptic vision of the argument. Since the association between Huntington’s disease and psychiatric symptoms was demonstrated, we argue that the prevalent and more invalidating psychiatric components should be recognized as early as possible during the disease course in order to best address psychopharmacological therapy, improve quality of life, and also reduce burden on caregivers.

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Section: Introductionmentioning

confidence: 99%

Neuropsychiatric Burden in Huntington’s Disease

et al. 2017

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“…HD is neuropathologically characterized by early selective loss of medium spiny neurons in striatum (caudate and putamen) with later neuronal loss in cortex, globus pallidus, and other structures. Although it is now known that an expansion of the triple repeat CAG in the IT15 gene on chromosome 4 leads to production of an abnormal polyglutamine string on the huntingtin protein, it is still unclear how this leads to selective neuronal cell death (1). In postmortem specimens from the striatum of patients with HD, reduced activity of the mitochondrial electron transport system (ETS) (29-76% decreases in complexes II and III and 30-62% decreases in complex IV) has been measured in vitro, although these findings have not been universal (2)(3)(4)(5)(6).…”

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confidence: 99%

Selective defect of in vivo glycolysis in early Huntington's disease striatum

Powers

Videen

Markham

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

152

153

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Activity of complexes II, III, and IV of the mitochondrial electron transport system (ETS) is reduced in postmortem Huntington's disease (HD) striatum, suggesting that reduced cerebral oxidative phosphorylation may be important in the pathogenesis of neuronal death. We investigated mitochondrial oxidative metabolism in vivo in the striatum of 20 participants with early, genetically proven HD and 15 age-matched normal controls by direct measurements of the molar ratio of cerebral oxygen metabolism to cerebral glucose metabolism (CMRO2/CMRglc) with positron emission tomography. There was a significant increase in striatal CMRO2/CMRglc in HD rather than the decrease characteristic of defects in mitochondrial oxidative metabolism (6.0 ؎ 1.6 vs. 5.1 ؎ 0.9, P ‫؍‬ 0.04). CMRO2 was not different from controls (126 ؎ 37 vs. 134 ؎ 31 mol 100 g ؊1 min ؊1 , P ‫؍‬ 0.49), whereas CMRglc was decreased (21.6 ؎ 6.1 vs. 26.4 ؎ 4.6 mol 100 g ؊1 min ؊1 , P ‫؍‬ 0.01). Striatal volume was decreased as well (13.9 ؎ 3.5 vs. 17.6 ؎ 2.0 ml, P ‫؍‬ 0.001). Increased striatal CMRO2/CMRglc with unchanged CMRO2 is inconsistent with a defect in mitochondrial oxidative phosphorylation due to reduced activity of the mitochondrial ETS. Because HD pathology was already manifest by striatal atrophy, deficient energy production due to a reduced activity of the mitochondrial ETS is not important in the mechanism of neuronal death in early HD. Because glycolytic metabolism is predominantly astrocytic, the selective reduction in striatal CMRglc raises the possibility that astrocyte dysfunction may be involved in the pathogenesis of HD.cerebral metabolism ͉ mitochondria ͉ oxidative phosphorylation ͉ basal ganglia H untington's disease (HD) is a degenerative neurological disease that is manifested by abnormal involuntary movements, psychiatric disorders, and dementia. It has a variable age at onset and progresses slowly to death 15-25 years after symptoms develop. HD is neuropathologically characterized by early selective loss of medium spiny neurons in striatum (caudate and putamen) with later neuronal loss in cortex, globus pallidus, and other structures. Although it is now known that an expansion of the triple repeat CAG in the IT15 gene on chromosome 4 leads to production of an abnormal polyglutamine string on the huntingtin protein, it is still unclear how this leads to selective neuronal cell death (1). In postmortem specimens from the striatum of patients with HD, reduced activity of the mitochondrial electron transport system (ETS) (29-76% decreases in complexes II and III and 30-62% decreases in complex IV) has been measured in vitro, although these findings have not been universal (2-6). These findings and the correlative effects of mitochondrial toxins in producing striatal neuronal loss in animal models suggest that excitotoxicity triggered by reduced ATP production as a consequence of impaired mitochondrial oxidative phosphorylation may be an important mechanism for neuronal death in HD (7). Alternatively, these mitochondrial changes may be ...

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“…[1][2][3] The genetic defect underlying Huntington's disease is an unstable and expanded CAG repeat in exon 1 of gene IT15 on the short arm of chromosome 4, which is expressed as a mutant polyglutamic tract in the protein huntingtin (Htt). [4][5][6][7] The mechanisms by which the mutant Htt protein induces a cascade of cellular changes, leading to cell dysfunction and degeneration, have not yet been fully elucidated. Modulation of genetic functioning through the IT15 gene, neuronal death in relation to intranuclear inclusions of aggregated mutant Htt, and progressive cerebral degeneration starting in the caudate nucleus and the putamen may all be part of the pathophysiology of Huntington's disease.…”

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confidence: 99%

Psychopathology in Verified Huntington’s Disease Gene Carriers

Duijn

Kingma²,

Mast³

2007

JNP

238

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Huntington's disease is characterized by motor, cognitive, and neuropsychiatric symptoms. This study reviews original research on psychopathology in Huntington's disease that uses standardized instruments in verified gene carriers. Frequently reported neuropsychiatric symptoms are depressed mood, anxiety, irritability, and apathy, with prevalences of 33% to 76%. Obsessive-compulsive symptoms and psychosis occur less often with prevalences of 10% to 52% and 3% to 11%, respectively. Available research provides little insight into the true prevalences of psychopathology in Huntington's disease due to small sample sizes, use of different methodologies, and lack of comparison groups. Future research requires larger cohorts stratified to disease stage, consistent methodologies, and adequate comparison groups.

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Huntington's Disease and Related Disorders

Cited by 21 publications

References 95 publications

Neuropsychiatric Burden in Huntington’s Disease

Neuropsychiatric Burden in Huntington’s Disease

Selective defect of in vivo glycolysis in early Huntington's disease striatum

Psychopathology in Verified Huntington’s Disease Gene Carriers

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