The core clinical features of Huntington’s Disease (HD) were outlined by George Huntington in 1872 (Huntington 1872). Like nowadays , in George Huntington’s time no cure for HD was yet available. However, genetic testing for HD that is now available can reliably predict the individuals at risk that will develop the disease. In such premanifest individuals slowing down the disease process may potentially delay the onset of disease symptoms. Therefore, there is an increasing need of finding the markers for the disease progression in premanifest HD individuals. A biomarker is defined as an attribute of the disease that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological response to a therapeutic intervention (Biomarkers definitions working group 2001). In adult HD mouse it has been demonstrated that stopping the expression of mutant Huntingtin may reverse the clinical and pathological phenotype (Yamamoto et al 2000). However, treatment trials expected to modify disease progression remain confined to population of manifest HD patients until reliable markers of disease process progression can be found for the premanifest HD gene carriers. Clinical measures may be used as primary endpoints and we will first focus on them. In our opinion, a comprehensive neurological and physical examination of premanifest HD gene carriers represents a reliable way towards identification of potential clinical biomarkers.
2. Clinical biomarkers for HD
A broad consensus exists among clinicians that a clinical diagnosis of HD can be made with certainty only in the presence of specific motor disorders. Thus, fixing the onset of the motor disorder in this way is a more or less reproducible method to conduct age at onset surveys or genotype-phenotype correlation studies (Kremer 2002). The most complete technique of assessing the early signs and symptoms of HD is to follow up a cohort of at risk individuals for an extended period of time. The most instructive follow-up study continues to be the one of the Venezuelan HD kindred (Penney et al 1990). It was performed prior to identification of the gene; nevertheless its conclusions are still valid. It demonstrated that patients pass through a transitional state from the normal presymptomatic phase to the time at which the diagnosis can clearly be made on neurological examination. The study revealed that there..