Cover by Claudia Huggins
The Interesting Case of ALS
By William McGlynn
Amyotrophic Lateral Sclerosis, also known as ALS or Lou Gehrig’s disease, is a rare progressive motor neuron disease. A diagnosed patient typically begins to lose various motor functions as the disease progresses. According to nih.gov, symptoms for ALS can be difficult to recognize and can pop up at any point in adult life, although its onset is typically between ages 55 and 75. My father, Patrick McGlynn, is amongst a couple of thousand ALS patients diagnosed in the world, and his life has completely changed as a result. He has visited multiple medical facilities with multiple diagnoses, and to this day, there are still many questions about his condition. ALS is highly complex and needs a serious breakthrough.
Once my father received his diagnosis, his entire life changed. He could no longer run like he used to, and now has trouble with daily tasks. David Crellin, another ALS patient and the father of ultramarathoner Joe Crellin, said, “since it’s a progressive disease, new changes can develop too. I can no longer walk unaided, I need help turning in bed, washing, personal hygiene, dressing, getting up from sitting [and] eating.” No ALS patient lives the same life after their initial diagnosis.
That first diagnosis is also challenging and requires different diagnostic tests. It took Overlook Hospital in Summit, New Jersey, just a week to diagnose my father with ALS while the Hospital for Special Surgery took multiple months to generate other possible diagnoses using several diagnostic tests. “There are multitudes of tests and procedures that can be done to slowly eliminate similar neurodegenerative diseases. These tests may include: Electromyography (EMG), muscle biopsy, Magnetic Resonance Imaging (MRI), genetic tests, Nerve Conduction Velocity (NCV), spinal tap, blood and urine collection, and neurological examinations.” ALS patients can go to multiple visits at the most advanced medical facilities without receiving a formal diagnosis. Most ALS patients are unaware they even have a possibility of having ALS before they start experiencing symptoms. My father had a similar experience because he likely has what is known as sporadic ALS. “This means the disease seems to occur at random with no clearly associated risk factors and no family history of the disease.” About 90% of ALS cases are sporadic ALS cases.
My father and David Crellin have different types of ALS. Crellin’s mother and other relatives had ALS as well, meaning he has familial ALS. Crellin explained, “I did not know that my two sons each have a 50% chance of carrying the [genetic] mutation and if so, around an 80% chance of developing the disease.” Joe Crellin discovered that he also carries the same genetic mutation that his father has, greatly increasing his chances to develop ALS. “About 25 to 40% of all familial cases and a small percentage of sporadic cases are caused by a defect in the C9ORF72 gene, which makes a protein found in motor neurons and nerve cells in the brain,” David Crellin states. Researchers have found that the C9ORF72 gene is subject to repeat expansion of GGGGCC nucleotides (the basic building blocks of DNA and RNA), which can cause ALS. This leads to the translation of proteins in the cytoplasm in affected areas by both diseases, such as the spinal cord and motor cortex. There is a clear association between these proteins’ presence in the cytoplasm of affected individuals and the phenotypic outcome of ALS. This has led researchers to believe that these proteins are toxic to neurons in the brain and spinal cord.
Genetic makeup does not cover the full story. A variety of environmental factors can also affect one’s likelihood to develop the ALS phenotype. These factors include exposure to toxic agents, diets, viruses, and physical trauma. Both Joe and David Crellin heard about Professor Pam Shaw, a Clinical Scientist in neurology and professor of neurology at the University of Sheffield, and her research on the correlation between intense exercise at a young age in those with the C9ORF72 mutation and ALS expression. This led Joe Crellin to take precautionary actions, especially given that he has the same genetic mutation as his father. “I still run a lot, but [I am] always wearing a heart rate monitor and not going fast very often. I’ve also decided to become an ultra-distance runner rather than focusing much on the marathon distance or shorter.” Crellin will not know if these strategies will pay off until much later in life, when the ALS phenotype typically expresses itself.
Environmental factors can also have quite extreme effects on the severity of ALS. One such example is the Madsen twins; identical twin brothers John and Michael Madsen were both diagnosed with familial ALS but have radically different expressions of the disease. John Madsen’s disease is advancing rapidly while Michael has had a much slower progression. John is having trouble walking and is commonly in bed while Michael has only some minor numbness in his wrists. Dr. Jonathan Glass at Emory Health explained the relevance of this phenomenon. “Technically they’re genetically identical. Yet their disease is not identical. I can’t explain it but it’s something that we can use to study [ALS] to understand that there’s something else other than just the genetic basis of the disease that’s driving the disease.” This is a rather extreme case of environmental factors causing differences in ALS, but it is a huge jumping-off point. Extensive research can be conducted to identify differences between two genetically similar individuals. Similarly, David and Joe Crellin are participating in a skin cell trial to see developments amongst themselves over time, since they also share similar DNA.
Brave ALS patients such as David Crellin, my father, and many more are helping to find solutions through research and trials. One of these clinical trials - a study focused on the drug WVE-004 - is being conducted in Sheffield, England. WVE-004 is meant to alter the effect of proteins produced by mRNA in the affected gene of C9ORF72, which are believed to be toxic to neurons. The WVE-004 drug is an antisense oligonucleotide, which can alter RNA and protein expression in the cell. WVE-004 will hopefully target the C9ORF72 and allow for neurons to fire as normally operating neurons would. These neurons use chemical signals to tell the body what it should do, but people with ALS have difficulty with this process. David Crellin was screened for the WVE-004 trial in Sheffield on Oct 6th, 2021 at the Sheffield Institute for Translational Neuroscience and started the trial on Oct 11th.
My father is also undergoing a clinical trial procedure. Since he has a different type of ALS/motor neuron disease from David Crellin, his treatment is different. He is partaking in phase two of a clinical trial for AT-1501, an antibody therapeutic which is meant to “tamp down” the immune system by blocking certain immune cell activations and protecting nerves in the spine. This is vital to ensuring that damage in the neurons does not activate any immune system response unnecessarily. Throughout the trial, my father will receive one 4 milligram dosage of the treatment through biweekly infusions. My father is currently in the midst of this trial, which should last 11 weeks in total. The study has multiple patients receiving various dosages aiming to find the most effective dosage to use for the study.
ALS research is extensive but it has not yielded significant results for patients such as my father and David Crellin. “Over the past few decades, there has been significant progress in our understanding of ALS, but we still do not have any breakthrough treatments for this terrible disease,” said NIH Director Francis S. Collins, M.D., Ph.D.. Luckily, the National Institutes of Health (NIH) committed to donating 25 million dollars over the next five years in hopes of finding research breakthroughs. There have been more funding attempts, such as the ALS ice bucket challenge and Joe Crellin’s fundraising event in which he runs the seven “Munros” (mountains) of Scotland to raise money for ALS research. Joe Crellin has already raised tens of thousands of dollars for ALS through his seven “Munros” run, and the ALS ice bucket challenge famously raised hundreds of millions of dollars for ALS research.
Despite these efforts, ALS is still lagging behind other major diseases in funding and research. In the words of the ALS Therapy Development Institute: “ALS is not an incurable disease. It is an underfunded one.” David Crellin said he felt ALS was underfunded simply because all the patients die too quickly. My hope is that by telling these stories, more people will understand the severity of ALS and will help to find a cure in the future. After all, it is not a disease that affects many people, but it is a devastating disease to deal with.