Trinucleotide repeat length and progression of illness in Huntington's disease.

Kieburtz, Karl; MacDonald, Marcy E.; Shih, Charles C.-Y.; Feigin, Andrew; Steinberg, Kim; Bordwell, Kathy; Zimmerman, Carol; Srinidhi, Jayalakshmi; Sotack, Jenny; Gusella, James F.

doi:10.1136/jmg.31.11.872

Cited by 136 publications

(62 citation statements)

References 12 publications

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“…A 54-year-old male with HD was evaluated for 12 months preoperatively and 18 months postoperatively according to a modified CAPIT-HD protocol (23,24). The diagnosis was confirmed genetically for CAG repeat length (25).…”

Section: Methods Patient Evaluationmentioning

confidence: 99%

Transplanted fetal striatum in Huntington's disease: Phenotypic development and lack of pathology

Freeman

Cicchetti

Hauser

et al. 2000

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

244

157

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Neural and stem cell transplantation is emerging as a potential treatment for neurodegenerative diseases. Transplantation of specific committed neuroblasts (fetal neurons) to the adult brain provides such scientific exploration of these new potential therapies. Huntington's disease (HD) is a fatal, incurable autosomal dominant (CAG repeat expansion of huntingtin protein) neurodegenerative disorder with primary neuronal pathology within the caudate-putamen (striatum). In a clinical trial of human fetal striatal tissue transplantation, one patient died 18 months after transplantation from cardiovascular disease, and postmortem histological analysis demonstrated surviving transplanted cells with typical morphology of the developing striatum. Selective markers of both striatal projection and interneurons such as dopamine and c-AMP-related phosphoprotein, calretinin, acetylcholinesterase, choline acetyltransferase, tyrosine hydroxylase, calbindin, enkephalin, and substance P showed positive transplant regions clearly innervated by host tyrosine hydroxylase fibers. There was no histological evidence of immune rejection including microglia and macrophages. Notably, neuronal protein aggregates of mutated huntingtin, which is typical HD neuropathology, were not found within the transplanted fetal tissue. Thus, although there is a genetically predetermined process causing neuronal death within the HD striatum, implanted fetal neural cells lacking the mutant HD gene may be able to replace damaged host neurons and reconstitute damaged neuronal connections. This study demonstrates that grafts derived from human fetal striatal tissue can survive, develop, and are unaffected by the disease process, at least for 18 months, after transplantation into a patient with HD. R ecent findings in genetics, stem cell biology, and neural transplantation suggest that brain repair will be possible for the treatment of neurodegenerative diseases (1, 2). Before initiating large clinical trials that test the efficacy of novel donor cells, it is important to determine the clinical feasibility of such cell-based therapies. Transplantation of specific committed neuroblasts (fetal neurons) to the adult human brain provides such a scientific exploration of feasibility of cell-based therapies.The underlying genetic mutation of Huntington's disease (HD) is a polyglutamine repeat in the N-terminal region of the huntingtin gene (3). This mutation results in brain pathology dominated by massive neuronal loss of the medium spiny projection neurons of the caudate and putamen (4). Recent studies of HD postmortem brain tissue show that the N-terminal region of the mutant huntingtin protein aggregates in nuclear inclusions in both cortical and striatal neurons (5-7). These aggregates may represent evidence of ongoing cellular pathology (5-7). Implanted fetal neural cells lacking the mutant HD gene may be able to replace dead or dysfunctional host neurons and reconstitute disrupted neuronal connections (8, 9).Physiological and anatomical evidence in animal st...

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Section: Methods Patient Evaluationmentioning

confidence: 99%

Transplanted fetal striatum in Huntington's disease: Phenotypic development and lack of pathology

Freeman

Cicchetti

Hauser

et al. 2000

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

244

157

View full text Add to dashboard Cite

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“…In contrast, the molecular analysis reveals that the affected gene (HTT) contains multiple repeats of the CAG sequence, coding for glutamine. The normal gene codes for less than 27 glutamine amino-acid repeats, while the mutated version codes for 36 or more (Kieburtz et al 1994). The number of additional glutamines in the final gene product is related to the rate of neuronal decay, and thus to the severity of the symptoms (Chong et al 1997).…”

Section: Mendelian Errors and Molecular Genotypingmentioning

confidence: 99%

Mechanism schemas and the relationship between biological theories

Baetu¹

2011

Causality in the Sciences

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Current accounts of the relationship between classical genetics and molecular biology favor the 'explanatory extension' thesis, according to which molecular biology elucidates aspects of inheritance unexplained by classical genetics. I identify however an unresolved tension between the 'explanatory extension' account and examples of 'explanatory interference' (cases when the accommodation of data from molecular biology results in a more precise genotyping and more adequate classical explanations). This paper provides a new way of analyzing the relationship between classical genetics and molecular biology capable of resolving this tension.The proposed solution makes use of the properties of mechanism schemas and sketches, which can be completed by elucidating some or all of their remaining 'black boxes' and instantiated via the filling-in of phenomenon-specific details. This result has implications for the reductionismantireductionism debate since it shows that molecular elucidations have a positive impact on classical explanations without entailing the reduction of classical genetics to molecular biology.

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“…While the relationship between CAG repeat and age at onset is relevant, the effect of trinucleotide length on the rate of HD progression is less clear. Although some investigators have suggested that larger CAG expansions result in more rapid progression (7), two prospective studies have failed to demonstrate a clear relationship between CAG repeat and illness progression (8)(9)(10). A plausible hypothesis to explain this discrepancy point is the instability in the length of the CAG repeat (10).…”

Section: Introductionmentioning

confidence: 99%

Striatal and extrastriatal atrophy in Huntington's disease and its relationship with length of the CAG repeat

Ruocco

Lopes‐Cendes

et al. 2006

Braz J Med Biol Res

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Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that affects the striatum most severely. However, except for juvenile forms, relative preservation of the cerebellum has been reported. The objective of the present study was to perform MRI measurements of caudate, putamen, cerebral, and cerebellar volumes and correlate these findings with the length of the CAG repeat and clinical parameters. We evaluated 50 consecutive patients with HD using MRI volumetric measurements and compared them to normal controls. Age at onset of the disease ranged from 4 to 73 years (mean: 43.1 years). The length of the CAG repeat ranged from 40 to 69 (mean: 47.2 CAG). HD patients presented marked atrophy of the caudate and putamen, as well as reduced cerebellar and cerebral volumes. There was a significant correlation between age at onset of HD and length of the CAG repeat, as well as clinical disability and age at onset. The degree of basal ganglia atrophy correlated with the length of the CAG repeat. There was no correlation between cerebellar or cerebral volume and length of the CAG repeat. However, there was a tendency to a positive correlation between duration of disease and cerebellar atrophy. While there was a negative correlation of length of the CAG repeat with age at disease onset and with striatal degeneration, its influence on extrastriatal atrophy, including the cerebellum, was not clear. Extrastriatal atrophy occurs later in HD and may be related to disease duration.

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Trinucleotide repeat length and progression of illness in Huntington's disease.

Cited by 136 publications

References 12 publications

Transplanted fetal striatum in Huntington's disease: Phenotypic development and lack of pathology

Transplanted fetal striatum in Huntington's disease: Phenotypic development and lack of pathology

Mechanism schemas and the relationship between biological theories

Striatal and extrastriatal atrophy in Huntington's disease and its relationship with length of the CAG repeat

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