January 19, 2021Neurology
Several neurological disorders have been linked to repeat expansions, a type of mutation that results in abnormal repetition of certain DNA building blocks. For example, Huntington's disease occurs when a sequence of three DNA building blocks that make up the gene for a protein called huntingtin repeats many more times than normal. These repeats can be used to predict whether someone will develop the illness and even when their symptoms are likely to appear, because the more repeats in the gene, the earlier the onset of disease. On 4 December 2020, the NIH released results of a study that has made a surprising connection between frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which opens a potentially new avenue for diagnosing and treating some individuals with FTD or ALS.
For the study, the authors, taking advantage of technology available at the NIH, screened the entire genomes from large cohorts of FTD/ALS patients and compared them to those of age-matched healthy individuals. While several patients had a well-established genetic marker for FTD/ALS, a small subset surprisingly had the same huntingtin mutation normally associated with Huntington's disease. Remarkably, these individuals did not show the classical symptoms of Huntington's but rather those of ALS or FTD. According to the authors, none of these patients' symptoms would have clued their physicians into thinking that the underlying genetic cause was related to the repeat expansion seen in Huntington's disease. The authors stated that whole genome sequencing is changing how neurological patients can be diagnosed, and that traditionally this has been based on which disease best fit the overall symptoms with treatment aimed at managing those symptoms as best as possible. The authors added that clinicians can now generate genetically defined diagnoses for individual patients, and these do not always align with established symptom-based neurological conditions.
One implication of these findings is that, if successful, these therapies could be applied to the small subset of FTD and ALS patients with that mutation as well. The authors noted that, while the number of FTD/ALS patients seen with the Huntington's-linked mutation is small (roughly 0.12-0.14%), adding genetic screening for the mutation to the standard diagnostic procedure for patients showing symptoms of FTD or ALS should be considered.