Is ALS One Disease, or Many?

By Richard Robinson

As new discoveries are made about the causes of ALS, an important question arises: is ALS one disease or many different ones with similar manifestations?  The answer to the question is important, according to Nigel Leigh, Consultant Neurologist, King’s College London, because it may shed light on differences between patients in disease prognosis and response to therapy, and this may help shape the conduct of clinical trials.

Speaking at the final lecture of the International ALS/Motor Neuron Disease Symposium held in Orlando, Florida and hosted by The ALS Association, Dr. Leigh provided researchers and clinicians with much to think about as they wrapped up their discussions.  Dr. Leigh is a Professor at Institute of Psychiatry at King’s College in London (UK) and has been a leader in both clinical and scientific research in ALS.

Clinicians have long recognized that people whose symptoms begin in the lower limbs tend to live longer than those with onset in the bulbar (swallowing) muscles; however, the reasons for this difference in prognosis are not clear.  According to Dr. Leigh, the fundamental question we have to ask is, “What is the biological significance of these differences?”

As new genes have been discovered in recent years, the ALS picture has grown more complex suggesting that there may be multiple primary causes of the disease.  And mutations in at least one gene, called TDP-43, can cause both ALS and another disease, called frontotemporal dementia.  It may be that the two diseases are two ends of a spectrum, a concept discussed by Virginia Lee, Ph.D., earlier in the meeting (see New Genes, New Clues).

Dr. Leigh believes there is much more to come as new genetic tools will allow the discovery of more genes that influence ALS disease risk.  The recent discovery of the VCP gene is one example.

The ideal classification system would group cases either by the underlying disease mechanism or by similar prognosis.  “Either of these properties would enable a classification to be truly useful in clinical trials,” Dr. Leigh said.

Currently, most trials accept ALS patients of all types, despite differences in prognosis.  This means, however, that a positive effect of treatment on disease progression may be missed, either because it might not be big enough to stand out from the natural variability among all the patients or because the treatment is effective in some ALS subtypes but not others.

“The key question facing researchers is whether we should be ‘lumpers’ or ‘splitters’ in classifying ALS,” Dr. Leigh said. “This needs to be resolved to make further progress in genetics, biomarker and drug discovery.  The persistence in lumping patients in the clinical design of drug trials may be one of the main reasons for the lack of success in finding disease modifying therapies.”

There are practical difficulties with splitting, however. A major challenge in conducting any clinical trial in ALS is enrolling enough patients to achieve “statistical power,” meaning the results, positive or negative, can be considered definitive. If enrollment is to be limited to only certain ALS subtypes, they may be even more difficult to conduct, at least without a large increase in the number of patients entering trials. This challenge is one the ALS clinical trial community is currently grappling with.

Dr. Leigh and colleagues have made a start at defining subtypes relevant for clinical trials by analyzing outcomes among a large group of patients and looking for factors that best predict prognosis.  They found that two factors predicted most of the variability among groups: site of symptom onset (bulbar or limb) and delay from first symptom to diagnosis, with longer delay predicting longer survival.

“This is not the final word on the subject,” Dr. Leigh hastened to add, but it may provide a jumping-off point for further refinement, with the goal of defining natural divisions among cases of ALS that can speed clinical trials.  New insights from genetics may be the most important source of ideas to better understand differences among patients.

“The value of this type of approach is that it may allow us to design clinical trials to give us faster and clearer answers,” according to ALS Association Chief Scientist Lucie Bruijn, Ph.D. “We will continue to search for the best ways to understand ALS in all its forms, and to design therapies to treat each of them. We will also be seeking ways to increase trial enrollment to make sure the results of every trial are definitive.”