An Integrated Stating System (ISS) for Huntington disease (HD) was internally validated in a position paper published in The Lancet Neurology.

HD is a neurodegenerative disease caused by short repeat expansions in the Huntington (HTT) gene. Clinical motor diagnosis of HD is based on the Unified HD Rating Scale which was formulated in 1999 prior to the discovery of HTT. In 2019, the Movement Disorder Society stated a standardization to refine clinical diagnosis criteria is needed. In this study, an evidence-based research framework for HD was used to define an ISS which would streamline HD diagnosis and allow for clinical trials to recruit targeted populations.

The HD-ISS was formulated by the Regulatory Science Forum working group which is part of the HD Regulatory Science Consortium. The framework was developed by evaluating trends in data from biological, clinical, and functional assessments. Findings were validated among participants with 40 or more HTT CAG (cytosine, adenine, and guanine) repeats.


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The biological definition of HD is the expansion of CAG repeats (27 or more repeats) in HTT. However, not all individuals with expanded tracts develop disease-specific symptoms within the expected lifespan of 82 years. Stratifying by number of repeats, the researchers found that 98% of individuals with 40 or more repeats developed symptoms and is therefore causal.

Stratified by clinical presentation and number of repeats, the researchers proposed a staging system categorizing individuals with 40 or more repeats with no clinical characteristics as Stage 0; biomarker evidence of pathogenesis as Stage 1; biomarker evidence of pathogenesis and signs or symptoms as Stage 2; biomarker evidence of pathogenesis, signs or symptoms, and functional impairments as Stage 3.

The landmarks of pathogenesis were defined by changes to the putamen and caudate volumes indicating transition to neurodegeneration (Stage 1). Deviations in the Total Motor Score and Symbol Digit Modalities Test indicating detriments to motor and cognitive function (Stage 2). Stage 3 is further subdivided into mild, moderate, and severe subgroups, stratified by Total Functional Capacity and Independence Scale instruments. Patients with mild Stage 3 disease do not require assistance with routine daily activities, moderate disease is defined by requiring assistance to perform daily activities, and in severe disease patients cannot do any routine activities independently.

In the validation cohort, longitudinal data indicated that 87% of patterns were consistent with monotone progression through the proposed HD-ISS stages. In general, the researchers observed that as CAG length increased, patients progressed through the HD-ISS stages at younger ages and at quicker speeds.

This study may have been limited by combining data from multiple studies which had differing examination schedules and durations.

The study authors concluded, “We have developed a biological definition of Huntington’s disease and an evidence-based staging system of the entire disease course. We hope that the Huntington’s disease research community will adopt this biological Huntington’s disease definition and the HD-ISS in clinical research studies to increase comparability between studies and data sharing. […] Additional research will be needed to evaluate the correspondence between the HD-ISS and existing measures, scales, and staging systems.”

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.

Reference

Tabrizi SJ, Schobel S, Gantman EC, et al. A biological classification of Huntington’s disease: the integrated staging system. Lancet Neurol. Published online July 1, 2022. doi:10.1016/S1474-4422(22)00120-X