Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder that causes muscle weakness and degeneration over time. There are five main types of SMA that account for 95 percent of cases of the disorder. Depending on the type of SMA a person has, symptoms can include respiratory weakness, difficulty swallowing and chewing, impaired motor function, inability to walk, muscle weakness, and fatigue.
Treatments for SMA have greatly advanced in the last decade. This article covers the history of SMA and the progress made since its discovery.
Cases of SMA were first described in the early 1890s by Austrian scientist Guido Werdnig and German scientist Johann Hoffmann. Thanks to their discoveries, what is now known as SMA type 1 was originally referred to as Werdnig-Hoffmann disease (even though the cases they identified were not likely that type).
The first cases of severe SMA in babies were identified around the same time in 1899 and 1903. Milder forms of SMA, which might now be considered type 3 (also known as Kugelberg-Welander disease) or type 4, were first described in the 1950s.
These SMA studies noted what are now considered the hallmark clinical features of the condition — specifically, symmetrical extremity weakness (weakness of the hands or feet mirrored on both sides of the body). They also noticed that much of the motor neuron degeneration characteristic of SMA seemed to take place in a part of the spinal cord associated with muscular function called the anterior horn. This remains a key component of SMA as it’s described today.
Over the next 40 to 50 years, doctors and researchers further defined and characterized SMA according to its severity. They worked to determine whether there were differences between cases of SMA originating in children and adults.
In 1991, an International Consortium on Spinal Muscular Atrophy met and delineated three types of SMA, based on the age of onset of the condition and on a person’s highest level of motor function. Type 4 SMA, for people diagnosed with the condition as adults, and type 0, for prenatal onset, were later classifications.
For years, researchers wondered how one mutation in a single gene could cause a disease that varied so much in both severity and age of onset.
However, in 1995, scientific understanding of SMA improved greatly when researchers, led by French geneticist Dr. Judith Melki, discovered that 95 percent of all SMA cases are caused by a mutated or deleted survival motor neuron 1 (SMN1) gene. The SMN1 gene is responsible for producing a protein essential to neuromuscular function. People diagnosed with SMA do not have a functional copy of the SMN1 gene.
The same research team discovered the SMN2 gene, which is sometimes referred to as the SMA “backup gene.” The severity of a person’s SMA can be influenced by the SMN2 gene. The SMN2 gene produces some survival motor neuron protein, but not enough for normal muscle function.
Some people with SMA have copies of the SMN2 gene that can produce the survival motor neuron protein with some regularity — they do not experience severe forms of spinal muscular atrophy. Others who have fewer copies of the SMN2 gene tend to have more severe forms of SMA.
The SMN2 gene is not the sole determinant of the severity or onset of SMA. Experts are not yet sure what these other factors are, though research is ongoing.
Discovering the role of the SMN genes opened the door for new diagnostic tools and research. Before identifying the SMN1 gene, spinal muscular atrophy was diagnosed based only on signs and symptoms of the disease. Genetic testing can confirm the presence of a genetic mutation and lead to a more certain diagnosis.
The SMN gene breakthrough also allowed scientists to begin animal experiments to expand research on the genetic factors that influence SMA. Experiments on mice, zebra fish, and fruit flies have increased the understanding of SMA, allowing for improved genetic and carrier screening, testing for potential therapies, and in-depth analysis of the way the condition affects the body.
Improved understanding of the genetic pathology of SMA also opened the doors for clinical trials for spinal muscular atrophy, which were rare before the 1990s.
In 2018, SMA was added to the U.S. Department of Health and Human Services Recommended Uniform Screening Panel (RUSP) for newborns. As of November 2020, newborns in 33 states are screened for SMA, with more states likely to add screening in the years to come. Screening is expected to improve early diagnosis and intervention in children with SMA.
Clinical trials for SMA have led to improvements in treatment options, including the first SMA treatment approved by the U.S. Food and Drug Administration (FDA). Spinraza (Nusinersen) was approved in 2016.
Spinraza is a disease-modifying therapy approved for use in children and adults. It is administered via intrathecal injection (injection into the spine). Spinraza must be administered at a treatment center. After initial dosing, it is administered three times a year.
Research into therapies for SMA is ongoing. Among the various therapies under investigation are two oral drugs, Branaplam and Risdiplam. These therapies target the SMN2 gene with the goal of producing full-length SMN proteins. Branaplam is being tested in people with type 1 SMA, while Risdiplam is being tested in people with multiple types of SMA. Preliminary results for both treatments show promise.
Thanks to this research, new treatments that may impact life expectancy and quality of life are on the horizon. If you or a loved one has SMA, you may consider talking to your doctor about the possibility of participating in a clinical trial. This can give you access to newly developed treatment options, as well as help advance scientific knowledge about SMA.
If you or someone you love has been diagnosed with SMA and you would like to find out more about the condition, have your questions answered by others with the same diagnosis, or share your story, post on mySMAteam today.