The term “pathophysiology” refers to the abnormalities in the body that underlie or cause a disease or condition. For example, in spinal muscular atrophy (SMA), a genetic neuromuscular disorder, the pathophysiology is influenced primarily by genetic or hereditary factors. These genetic abnormalities cause the degeneration of motor nerves in the spinal cord and lower brain stem.

The pathophysiology of SMA may also describe its characteristic symptoms, including the progressive muscle weakness and atrophy that underlie many other symptoms of SMA.

Understanding the pathophysiology of SMA can help you understand why there are different types of SMA and how they might best be treated.

Genetic Causes and Pathophysiology

SMA is caused by inherited genetic factors (genes passed from generation to generation), which is why SMA tends to run in families.

The biggest risk factor for developing SMA is mutations of the SMN1 gene. This gene codes for a protein called the survival motor neuron (SMN) protein. SMN proteins play a critical role in the health and function of the nerves that control muscles responsible for movement, especially in the torso, arms, and legs. When the SMN1 gene is mutated, the body does not make enough of the SMN protein. When the nerves and muscles can’t communicate with each other, the muscles begin to weaken and waste away. This leads to problems with breathing, swallowing, walking, or sitting up.

SMA is inherited in an autosomal recessive manner, which means that someone who inherits the disease has two copies of the mutated SMN1 gene — one from each parent. Sometimes, however, the gene isn’t mutated, but completely missing. This is called a deletion.

But SMN1 isn’t working alone to cause SMA. The amount of full-length (or functional) SMN protein someone makes also depends on the interaction between SMN1 and another gene — SMN2. The SMN2 gene is near SMN1 on the chromosome (a molecule of genetic material), and they work together to make functional SMN protein. People can have between zero and eight copies of the SMN2 gene. The number of SMN2 copies — and the amount of functional SMN protein produced — correlates with how severe the disease is. The more copies of the SMN2 gene a child has, the better their prognosis (disease outlook or chance of survival) will be. Fewer copies of the SMN2 gene leads to a more serious disease course. In fact, the number of copies of SMN2 someone has plays a role in the type of SMA they develop.

Types of SMA and Pathophysiology

There are four different types of SMA. These types are determined by the age of onset, SMA’s underlying pathophysiology, and the highest milestone achieved by the person with SMA. Depending on the type of SMA, a person may show different disease signs.

SMA Type 1

Also known as Werdnig-Hoffmann disease or infantile-onset SMA, this type of SMA is evident usually before 6 months of age. Sometimes, it can be detected while the baby is in utero (before birth). The breathing difficulties that result from this type of SMA can lead to death. In fact, if no treatments are performed, the majority of affected children tend to die of respiratory failure before they reach the age of 2 years.

SMA Type 2

This form of SMA usually becomes evident between 6 and 18 months of age. Progression and prognosis of SMA type 2 is variable depending on when (or if) treatment begins. With proper care, children born with SMA type 2 can live into adolescence or young adulthood. SMA type 2 causes the inability to sit or walk without support.

SMA Type 3

Also known as Kugelberg-Welander disease, SMA type 3 develops after 18 months of age. SMA type 3 is milder than SMA types 1 and 2 and generally has a better prognosis and life expectancy. SMA type 3 has symptoms such as delayed difficulties with walking or climbing stairs.

SMA Type 4

Also known as adult-onset SMA, SMA type 4 occurs when SMA begins later in life (usually after the age of 21). SMA type 4 is considered to be the mildest form of SMA, with near-normal life expectancy. SMA type 4 symptoms may include tiredness, muscle numbness, or tingling.

Genetic Treatments for SMA

Having a better understanding of SMA’s pathophysiology has led to new treatment options that can slow the course of the disease. For example, researchers are studying the use of gene therapy to treat SMA. Studies in mice that have SMN1 mutations demonstrate that artificial viruses can act as transport mechanisms to help increase SMN protein levels, as well as life span. Similar clinical trials of gene therapy methods that increase SMN protein levels in children with SMA have also shown that gene therapy may improve measures such as walking, standing, sitting, feeding, and talking. This new genetic treatment is called Zolgensma (onasemnogene abeparvovec-xioi, previously known as AVXS-101).

Another genetic treatment for SMA is Spinraza (nusinersen). Spinraza is an antisense oligonucleotide, which means that instead of targeting DNA, Spinraza targets RNA. Specifically, Spinraza targets SMN2 RNA to help the gene make more full-length SMN protein. Studies show that this treatment decreases mortality and increases motor function in children with SMA.

Researchers are also interested in targeting the SMN2 gene. In theory, if genetic therapies could increase the number of copies of SMN2, the severity of SMA could be reduced. However, more research is needed before this treatment may become a viable option.

Genetic Testing for SMA

Genetic testing is used to diagnose spinal muscular atrophy in people who show symptoms of the disease. Genetic tests are also available during pregnancy to determine if a fetus has inherited mutated SMN1 genes from their parents. However, testing during pregnancy is usually only done if the parents are known carriers of the mutant SMN1 gene. Genetic counseling can also be done prior to pregnancy if parents are concerned that they are carriers. Currently, 38 states in the U.S. screen newborns for SMA as well.

Talk To Others Who Understand

On mySMAteam, the social network for people with spinal muscular atrophy and their loved ones, members come together to ask questions, give advice, and share their stories with others who understand life with spinal muscular atrophy.

Are you living with spinal muscular atrophy? Share your experience in the comments below, or start a conversation by posting on mySMAteam.