CSF MicroRNA Levels Investigated for Prodromal HD

Huntington disease (HD) is a progressive brain disorder that causes uncontrolled movements, emotional problems, and loss of thinking ability (cognition). Adult-onset HD is the most common form of this disorder and the mean age of onset of HD is 35 to 44 years and the median survival time is 15 to 18 years after onset.

A genetically confirmed diagnosis of HD requires molecular genetic testing to determine the number of CAG repeats in exon 1 of the huntingtin (HTT) gene. The feasibility of microRNA (miRNA) levels in cerebrospinal fluid (CSF) as biomarkers for prodromal Huntington disease (HD) has been investigated.

Scientists at the Carver College of Medicine, (University of Iowa, Iowa City, IA, USA) and their colleagues profiled miRNA levels in CSF from 30 not-yet-diagnosed individuals carrying the type of huntingtin gene expansions linked to the neurodegenerative condition. By looking at levels of more than 2,000 miRNAs patterns and comparing them with those in CSF samples from 15 individuals previously diagnosed with HD and 15 unaffected controls, they searched for telltale miRNAs with ties to eventual HD development.

The team processed 15 µL of CSF was for miRNA levels using the miRNA whole transcriptome protocol HTG EdgeSeq system. This process includes specific probes for 2,083 miRNAs, producing both raw small-RNA sequencing files and pre-quantified data. A maximum of 24 samples can be processed in a single run and samples were randomly assigned to each of three batches.

The team noted that six miRNAs appeared to be present at higher-than-usual levels in CSF samples from those with preclinical HD, known as the prodromal stage of disease. Those miRNA: miR-520f-3p, miR-135b-3p, miR-4317, miR-3928-5p, miR-8082, and miR-140-5p, appeared to ramp up with increasing HD risk, the group noted, suggesting they may warrant follow up as potential biomarkers for HD prior to symptom development.

Richard H. Myers, PhD, director of Boston University's Genome Science Institute and a senior author of the study, said, “Importantly, miRNAs were detected in the prodromal HD groups furthest from diagnosis where treatments are likely to be most consequential and meaningful. The levels of the microRNAs begin to increase many years before the individual shows symptoms and continue to increase as disease onset approaches. Clinical trials for new HD treatments that may reduce the levels of the microRNAs suggest that these treatments may postpone the onset of the disease.” The study was published on December 27, 2017, in the journal Neurology.

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Carver College of Medicine