Defeating a Devastating Neuromuscular Disorder

Bryan Traynor’s Search for Genetic Links to ALS

It didn’t take last summer’s Ice Bucket Challenge to get NIH scientist Bryan Traynor fired up about amyotrophic lateral sclerosis (ALS). He has been excited about the possibility of finding a cure for this devastating neuromuscular disease since the 1990s when as a young medical student—at University College Dublin in Ireland—he attended a memorable lecture on the subject.

Bryan Traynor

He also remembers being surprised to learn that several famous people, including his favorite British actor—David Niven—had ALS. In 1981, Traynor and other television viewers were alarmed when they noticed Niven slurring his speech on a live television talk show. They wondered whether he was drunk or had suffered a stroke. It was neither—he was diagnosed with ALS later that year and died in 1983 at the age of 73. Perhaps the most famous person to have had ALS was baseball player Lou Gehrig, who died in 1941. ALS is also called “Lou Gehrig’s disease.”

Today, Traynor—who is a senior investigator in the National Institute of Aging (NIA) and head of its Laboratory of Neurogenetics—is best known for his work on understanding the genetic causes of ALS. He and staff clinician Camilo Toro (National Human Genome Research Institute) presented their work on ALS at the September 3 Clinical Center Grand Rounds. Toro described the etiology, nature, and background of the disease and told how the first cases of ALS were described and diagnosed by the French neurologist Jean-Martin Charcot in the 1860s. (Charcot didn’t coin the term ALS until 1874, however.)

Toro explained how the term “amyotrophic lateral sclerosis” is descriptive of what happens during the progressive degeneration of motor nerve cells: amyotrophy means “muscle wasting”; “lateral” refers to the lateral parts of the spinal cord that are affected; and “sclerosis” refers to the scarring of the nerve cells. Typically, ALS strikes people between the ages of 40 and 70. It occurs worldwide and affects as many as 30,000 people in the United States, with 5,000 new cases diagnosed each year. Most patients die from respiratory failure within three to five years after the onset of symptoms, but 10 percent survive for 10 years or more.

Traynor, who came to NIH in 2005 from Harvard’s Massachusetts General Hospital (Boston), hopes that his research can help more people with ALS survive. At NIH, he was first a clinical associate in neuroscience in the National Institute of Mental Health, later a clinical associate in the National Institute of Neurological Disorders and Stroke (NINDS), and in 2009, he joined NIA, where he is busy finding genes related to ALS and other motor-neuron diseases.

His laboratory published the first genome-wide association study of ALS (2007); was the first to identify (in 2010) an association signal for ALS on the short arm of chromosome 9 in the Finnish founder population (Finland has the highest ALS incidence in the world); and discovered that mutations in the VCP gene are responsible for a significant fraction of familial (inherited) ALS (2010). In 2011, he led the international consortium that identified a pathogenic hexanucleotide repeat expansion in the C9ORF72 gene as the underlying mutation in a large proportion of cases of familial ALS and frontotemporal dementia (FTD) as well as in cases of the more common, sporadic forms of both neurodegenerative diseases.

“From the clinical perspective, knowing the gene is only the starting point,” he explained at the Grand Rounds. One of the starting points was in 1993, when a research group from the Northwestern University Medical School (Chicago) was the first to identify an ALS-associated gene—SOD1. In 2006, researchers from Massachusetts General Hospital and Harvard Medical School found that a small locus (9p21) on the short arm of chromosome 9 accounted for a large percentage of familial ALS and familial frontotemporal dementia cases (FTD). Despite considerable efforts in many leading neurogenetics laboratories around the world, the underlying mutation was proving difficult to find.

“It [9p21] was taking [on] the aura of the Holy Grail,” said Traynor who was prompted to try a different approach to crack the locus: He capitalized on the sequencing resources at the NIH by forming an international consortium.

When Traynor’s group was the first to identify a significant mutation called C9orf72 in 2011, he was surprised and excited to see the result because it was “really, really common as a cause of ALS.” These findings were published back-to-back in September 2011 with the results from the Mayo Clinic group, led by Rosa Rademakers, that independently identified the same mutation. Part of the excitement surrounding this finding was how common it turned out to be. The mutation occurred in 40 percent of familial ALS and eight percent of sporadic ALS as well as in FTD. ALS and FTD have overlapping symptoms; in addition, FTD patients may show distinct symptoms such as personality disorders, inappropriate behavior, and problems with language and speech.

These genes provide several pieces of the puzzle and may help scientists better understand the pathophysiology of ALS, use the genes in cell-based assays and in animal models, identify the target, and bring the knowledge back to the clinic for more effective treatments.

ALS is not one disease but rather a syndrome with a range of variations, Traynor explained. And the boundary between familial and sporadic ALS is less absolute than neurologists previously believed. So the knowledge acquired from understanding the familial form of ALS can help scientists better understand sporadic ALS too. In the United States, 10 percent of people with ALS have the familial type and 90 percent have the sporadic type, in which the occurrence appears to be random.

Several other NIH scientists are doing research that may reveal even more pieces of the ALS puzzle. For example, National Institute of Neurological Disorders and Stroke (NINDS) Clinical Director Avindra Nath’s studies of the pathophysiology of retroviral infections in the nervous system might shed some light on the immunological aspect of ALS. Freya Kamel, in the National Institute of Environmental Health Sciences, is finding genetic and environmental contributors (such as neurotoxicants) to ALS.

In addition, NINDS senior clinician Mary Kay Floeter has established a C9ORF72 clinic that will recruit 60 people with the C9ORF72 mutation for a clinical study, follow their illness for three years, and collect samples and data. Traynor hopes that this study, on which he works with Floeter, will help pave the way for future clinical trials, improve the understanding of the natural history of the disease, and also identify a biomarker for ALS.

Traynor is optimistic that in the next five to seven years, all these efforts will help us understand the entire “genetic etiology of ALS”…and move us closer to finding a cure.

To watch a videocast of the Clinical Center Grand Rounds held on September 3, 2014, go to Traynor will also be giving a Director’s Seminar Series talk, titled “Genomics of Amyotrophic Lateral Sclerosis,” on Friday, April 10, 2015, noon-1:00 p.m., in Wilson Hall (Building One).