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American Society for Experimental Neurotherapeutics Abstracts
August 2001

PHAROS: Phenoconversion to Manifest Huntington Disease

Arch Neurol. 2001;58(8):1317. doi:

The Prospective Huntington At Risk Observational Study (PHAROS) was initiated by the Huntington Study Group in 1999 to characterize and measure the motor onset of Huntington disease (HD) in a diverse cohort of individuals who are at immediate risk of having inherited the HD gene. PHAROS participants include healthy adults, aged 30 to 55 years, who have not undergone testing for the HD gene and who wish to remain unaware of their HD gene status, yet are interested in contributing to knowledge about HD through research. Under a stringent arrangement that conceals the individual's genetic information and protects anonymity, a blood sample is obtained from each participant to measure CAG trinucleotide repeat lengths (CAGn) of the HD gene. Systematic clinical assessment, including standardized diagnostic criteria for the onset of motor abnormalities, is carried out at approximately 9-month intervals during a 4- to 6-year period of observation by investigators who are kept unaware of HD gene–carrier status. The onset of gene-specific signs predictive of manifest HD defines "phenoconversion," a therapeutically relevant end point for preventive trials aimed at postponing the clinical onset of HD.

Forty-two Huntington Study Group sites in the United States and Canada are currently engaged in this research effort. More than 475 participants have already been enrolled, and the full complement of 1000 participants is expected to be enrolled in 2001. The completion of PHAROS will provide objective and prospective data on the rate, specificity, and reliability of phenoconversion, as well as confident estimates of power, sample size, effect size, and duration requirements for designing therapeutic prevention trials involving individuals at high risk for carrying the HD gene. The PHAROS will also lead to an understanding of the feasibility, confidentiality, legal, and ethical requirements relevant to the study of this potentially vulnerable population. Collectively, these data will form the basis for subsequent investigations to evaluate the efficacy of experimental interventions to prevent clinical expression of the HD gene or slow the early clinical course of this neurodegenerative disease.

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