Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a progressive neurodegenerative disease that causes muscle weakness, paralysis, and ultimately respiratory failure. There are two types of ALS, sporadic and familial. Sporadic is the most common form of the disease in the United States accounting for 90 – 95% of all cases, and develops with unknown etiology. It may affect anyone, anywhere. Familial ALS (FALS) accounts for 5 – 10% of all cases in the U.S. Familial ALS is an inherited disease. In affected families, there is a 50% chance each offspring will inherit the disease-causing genetic mutation and may develop the disease.
What is ALS?
ALS is the most prevalent, adult-onset, progressive motor neuron disease. Motor neurons extend from the brain to the spinal cord and from the spinal cord to muscles throughout the body, allowing for voluntary muscle contractions. In ALS, progressive degeneration of these motor neurons causes progressive myasthenia (muscle weakness) and muscle atrophy, and eventually leads to partial or total paralysis. The denervation and death of neurons in ALS also causes a robust immune inflammatory response that causes further cell death. While the pathology of ALS has not been fully characterized, genetic mutations that cause familial cases of the disease have been discovered and provide a framework around which to understand pathogenesis.
Who gets ALS?
ALS typically develops between the ages of 40 and 70, with an average age of 55 at the time of diagnosis. However, the disease can affect people as early as in their twenties and thirties. It is estimated that approximately 30,000 Americans have the disease at any given time, with approximately 5,600 people in the U.S. diagnosed with ALS each year. At least 450,000 patients worldwide have ALS. ALS is 20% more common in men than in women. Additionally, it is known that military veterans, particularly those deployed during the Gulf War, are approximately twice as likely to develop ALS.
Most people with ALS live 2-5 years after their first signs of disease. Twenty percent live five years or more, and about 10% of people with ALS survive at least 10 years. This variable rate of disease progression makes prognosis difficult to predict and therapies challenging to develop.
An increasing number of genetic mutations have been shown to be linked to familial ALS. The first causative gene discovered for familial ALS was the superoxide dismutase 1 (SOD1) gene1; since its discovery in 1993 over 160 pathogenic mutations in SOD1 have been described.2 In the past decade, the discovery of mutations in several DNA/RNA binding proteins, such as TAR DNA-binding protein (TARDBP, TDP-43)3 as well as Fused in Sarcoma (FUS)4 have been described. Other fALS causative genes include valosin-containing protein (VCP)5, ubiquilin 2 (UBQLN2)6 and sequestome 1 (SQSTM1).7 In 2011, the largest proportion of fALS cases, approximately 40%, were found to be linked to a hexanucleotide repeat expansion in C9orf728,9, a gene with currently unknown function.
In ALS, motor neurons deteriorate, leading to muscle weakness and paralysis. Why motor neurons are particularly vulnerable in ALS remains unclear, however scientists now understand that this neurodegeneration likely occurs through several pathways. The progressive degeneration of the motor neurons in ALS eventually leads to their death. When the motor neurons die, the ability of the brain to initiate and control muscle movement is lost. Since ALS attacks only motor neurons, the sense of sight, touch, hearing, taste and smell are not affected. For many people, muscles of the eyes and bladder are generally not affected. With voluntary muscle action progressively affected, patients in the later stages of the disease may lose the ability to speak, eat, move, and in some instances, become totally paralyzed.
For a more detailed description of common symptoms of ALS please visit the ALS association website at www.alsa.org/about-als/symptoms.html
ALS is a difficult disease to diagnose. There is no one test or procedure to ultimately establish the diagnosis of ALS. A comprehensive diagnostic workup, consisting of clinical examination and a series of diagnostic tests, are required to rule out neurological conditions whose symptoms closely resemble the disease. Among the tests clinicians may run to diagnose ALS are: Electromyography (EMG) and nerve conduction studies (NCS), muscle biopsy, spinal tap, magnetic resonance imaging (MRI), blood and urine tests, and a thorough neurological examination.
Currently, there is only one medicine approved specifically for treating ALS – Riluzole. The drug, marketed by Sanofi-Aventis under the name Rilutek, extends survival by only 2 to 3 months.10
As ALS progresses and muscles weaken, patients may benefit from participation in a host of rehabilitation services, including physical, respiratory, speech and occupational therapy to help people with ALS breathe easier, keep moving, and stay connected. Palliative care specialists support people with ALS and their caregivers. As ALS weakens muscles used to breathe, the patient may need a ventilator (breathing machine), initially just while sleeping but eventually full time.
For more information regarding ALS visit the ALS Association website at www.alsa.org.
ALS is a horrifying disease with no therapies available. We at Amylyx are determined to bring to patients the first disease-modifying treatment for ALS. We hope you can join us in our fight.
- Rosen, D.R., 1993. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. 362, 59–62.
- Moreira, L.G., et al., 2013. Structural and functional analysis of human SOD1 in amyotrophic lateral sclerosis. PLoS One.
- Sreedharan, J., et al., 2008. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science. 319, 1668–1672.
- Vance, C., et al., 2009. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. 323, 1208–1211.
- Johnson, J.O., et al., 2010. Exome sequencing reveals VCP mutations as a cause of familial ALS. 68, 857–864.
- Deng, H.X., et al., 2011. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. 477, 211–215.
- Fecto, F., Siddique, T., 2012. UBQLN2/P62 cellular recycling pathways in amyotrophic lateral sclerosis and frontotemporal dementia. Muscle Nerve. 45, 157–162.
- DeJesus-Hernandez, M., et al., 2011. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. 72, 245–256.
- Renton, A.E., et al., 2011. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. 72, 257–268.
- Pandya, R.S., et al., 2013. Therapeutic neuroprotective agents for amyotrophic lateral sclerosis. Mol. Life Sci. 70, 4729–4745.