Landmark studies identify new gene as the most common cause of ALS and Frontotemporal Dementia (FTD)

Two studies published in the September 21 online issue of Neuron report the identification of the long-sought genetic abnormality which authors say is the most common cause of two different but related forms of neurodegenerative disease: FTD and ALS.

The first study, entitled “Expanded  GGGGCC hexanucleotide repeat in non-coding region of  C9ORF72 causes chromosome 9p-linked frontotemporal dementia and amyotrophic lateral sclerosis” was led by neurogeneticist Rosa Rademakers, PhD, at the Mayo Clinic inFlorida.  The researchers identified a short DNA sequence repeated hundreds to thousands of times in almost 12 per cent of familial FTD and more than 22 per cent of familial ALS of samples studied.  Ian Mackenzie, MD, neuropathologist atVancouverGeneralHospitaland professor in the department of pathology and laboratory medicine at the University of British Columbia (UBC) also served as a lead investigator in this study.

“This is the most common genetic defect, in both familial and sporadic cases, identified to date in these two different, but equally devastating neurodegenerative conditions, and confirms an overlap between FTD and ALS at the molecular level,” says Dr. Mackenzie.

Using invaluable samples from a number of well-characterized BC families with FTD and ALS, Dr. Mackenzie identified a pattern of pathology in the post-mortem brain tissue of patients that accurately predicted the presence of the mutation.  This work proved critical in demonstrating the impact of the mutation on brain cells by demonstrating abnormal patterns of protein expression and the presence of the potentially toxic accumulations of mutant RNA.

Dr. Mackenzie has been a featured speaker at the ALS Canada Research Forum and you can read more about his work in the Summer Edition of Research News.

The second study, entitled “A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD” was led by scientist Bryan Traynor, MD, Laboratory of Neurogenetics, National Institute on Aging, Maryland. This study took advantage of the genetically homogeneous Finnish population to identify the GGGGCC expansion in the first intron of the same gene in familial ALS and sporadic ALS patients, as well as in FTD patients, and further confirmed the finding in familial ALS cases of outbred European descent.  Toronto-based investigatorsLorne Zinman,MD, MSc, medical director of the ALS/Neuromuscular Clinic at the Sunnybrook Health Sciences Centre and chair of the Canadian ALS Research Network and Ekaterina Rogaeva, PhD, associate professor, Centre for Research in Neurodegenerative Diseases,University ofToronto, were co-authors on this study.

“The discovery of a gene underlying the largest proportion of familial ALS and FTD cases to date is a seminal finding.  It is a critical step that will assist us in determining how the disease develops and progresses, why its presentation and course is so variable, and provides us with a new target for therapeutic intervention, says Dr. Zinman.”

Findings reported today represent the culmination of years of genetics studies of familial ALS and ALS-FTD including seminal work by groups led by Guy Rouleau, MD, PhD, professor, department of medicine at the University of Montreal, Robert H. Brown Jr., MD, DPhil, professor of neurology at Harvard Medical School and associate neurologist at the Massachusetts General Hospital, and Christopher E. Shaw, MD, department of neurology, King’s College London School of Medicine.

Last year, two separate studies employing the genome-wide association approach confirmed linkage of ALS to the region of chromosome 9 in which the newly reported gene C9ORF72  resides.

What does this breakthrough discovery mean for the ALS community?

One immediate consequence will be the benefit of precise genetic screening to aid in the genetic counselling process for the affected families (FTD and ALS).   Further, the reported observations of the variability of presenting symptoms in both ALS and FTD patients bearing the mutation can provide both impetus and opportunity to learn more about patient care and management in individuals presenting with what appear to be separate clinical entities.

Finally, the substantial import of these new study results is the opportunity to learn more about mechanisms of degeneration related to both ALS and FTD. The gene mutations account for a significant proportion of patients with both clinical (as well as the combined) syndromes, and thus further study of the mechanisms can be expected to contribute to meaningful therapeutic development.  Both studies support the likelihood of more than one potential downstream mechanism resulting from the hexanucleotide expansions.  And, both studies agree that disruption of RNA processing, particularly in the nucleus, is highly likely to be one of those downstream disease mechanisms. Altered regulation of RNA function is already a proposed mechanism in motor neuron degeneration), which continues to receive support from experimental models of ALS.  These new findings will add momentum to this important line of research.

Taking a step back from the excitement generated by these two new studies, Denise Figlewicz, PhD, vice president research for the ALS Society ofCanadasays:  “2011 has been an exceptionally productive year for research related to ALS.  Looking at the field from the outside, someone might wonder … New genes!  New mechanisms!  Significant new findings related to established mechanisms!  What is really important with respect to ALS and moving towards treatments?  The answer is …  all of these studies are important. Over the past decades it has frequently been said that there is no known cause of ALS. This is not correct. In the cases where ALS is inherited as a familial trait, we do know the causes for many of these.  Mutations in a number of genes, beginning with SOD1 and ending with the C9ORF72 gene, account for a large fraction of those familial cases.  In addition, studies in recent years have demonstrated the involvement of many of those genes in cases of sporadic ALS.  This means that experimental models based on those mutant genes must be providing very important information about mechanisms of motor neuron degeneration which occurs as a result of the primary causes.  And, the phenomenon of disease progression from one region of the body to another, corresponding to one region of the nervous system to another, is being intensely investigated at the level of the motor neurons and their neighbouring cells (glia) as well as inside the motor neurons at the molecular level.  Halting the progression of ALS is the expected outcome of therapies which effectively target any of these pathways and mechanisms currently being studied.  Targeting more than one of these at the same time may prove to be the most effective strategy.

In conclusion, there has never been more reason to be hopeful and optimistic that research will bear fruit and provide the badly needed therapies for those living with ALS.”