Disease Onset in Huntington's Disease: When Is the Conversion?

Area of Science:

• Neurology
• Neurodegenerative Diseases
• Huntington's Disease Research

Background:

• Clinical diagnosis of Huntington's disease (HD) onset relies on clinician experience and motor signs.
• The diagnostic confidence level (DCL) assesses certainty of motor abnormalities indicating HD, with level 4 signifying ≥99% confidence.
• Current DCL criteria lack specificity regarding which motor signs or how many are required for diagnosis.

Purpose of the Study:

• To evaluate the accuracy of the diagnostic confidence level (DCL) in predicting Huntington's disease (HD) onset using the Enroll-HD dataset.
• To compare DCL and motor scores in premanifest individuals who later converted to manifest HD versus those who did not.
• To establish reliable diagnostic criteria for phenoconversion in HD research.

Main Methods:

• Utilized the Enroll-HD dataset, comparing premanifest participants who converted to manifest HD (converters) with non-converters at baseline.
• Assessed clinical symptoms and diagnostic confidence levels (DCL) at baseline and longitudinally in converters.
• Defined clinical disease onset using a Total Motor Score >5 on the Unified Huntington's Disease Rating Scale (UHDRS).

Main Results:

• Out of 3731 participants, 455 were converters and 3276 non-converters.
• Baseline DCL was significantly higher in converters (P < 0.001).
• 51% of converters had a baseline motor score >5 (mean 6.7), with converters showing more baseline symptoms and higher disease burden (P < 0.001). DCL ranged from 1 to 3 before onset.

Conclusions:

• The diagnostic confidence level (DCL) is not a reliable tool for determining phenoconversion in Huntington's disease (HD).
• Current DCL assessments do not accurately reflect the transition to manifest HD.
• Development of more precise diagnostic criteria is crucial for ongoing clinical trials targeting disease-modifying therapies for HD.