Blood Test Tracks Huntington's Disease Progression

Expresion of mutant huntingtin (mHTT) protein is correlated with the onset and progression of Huntington's Disease (HD) and new therapies are being developed to reduce the expression of mHTT.

Huntington’s disease is caused by an autosomal dominant pathogenic mutation, resulting in an expanded stretch of 36 or more glutamine residues in the N terminus of the huntingtin (HTT) protein and in order to evaluate these new therapies, doctors need to be able to quantify the amount of mHTT in a particular patient.

At the University College London (UK) scientists investigated the blood of eight HD gene carriers without manifestations of the disease, 10 early-stage and eight moderate-stage patients with HD, and 12 control subjects. Monocytes, T cells, and B cells were isolated using magnetic-activated cell sorting. Cheek swabs to harvest buccal epithelial cells were collected from 84 subjects from the same experimental groups. Multiple swabs and/or blood samples were taken from some subjects.

Time-resolved Förster resonance energy transfer (TR-FRET) immunoassays were used to quantify mutant and total HTT protein levels in leukocytes from patients with HD. TR-FRET analysis of an allelic series of purified HTT with increasing polyglutamine repeat lengths showed 10-fold to 20-fold higher sensitivity for mHTT than that of the wild-type protein. Total HTT levels did not differ significantly between patients with HD and controls.

Mean mHTT levels increased with successive disease stage in each leukocyte cell type, with differences between premanifest HD patients and patients with manifest HD and between premanifest and early-stage HD patients, but not between patients with early-stage and moderate-stage HD. Such an increase was not observed in buccal cells. There was a strong positive association between disease burden and mHTT in monocytes and T cells. A significant association was observed for B cells, but no evidence of an association was found in buccal epithelial cells.

Huntington's disease is a fatal, inherited neurodegenerative disorder caused by a mutation in the gene encoding huntingtin. The authors concluded that mHTT can be detected in immune cells isolated during a normal blood draw. The levels of mHTT were significantly correlated with disease symptom severity, indicating that this test could serve as a noninvasive biomarker for Huntington's disease. The study was published on September 17, 2012, in the Journal of Clinical Investigation.

Related Links:
University College London