A Closer Look at Spinal Muscular Atrophy: From Early Symptoms to Treatment Strategies

This blog is designed to provide information about Spinal Muscular Atrophy (SMA) for those living with this condition, their caregivers, loved ones, and anyone interested in learning about this disease. Here, you’ll find information about what Spinal Muscular Atrophy is, how it is diagnosed, the symptoms, the available therapies, and  ongoing research into investigational treatments.

What is Spinal Muscular Atrophy?

Spinal Muscular Atrophy (SMA) refers to a group of genetic neuromuscular disorders that affect the nerve cells in the lower part of the brain and spinal cord, which control voluntary movements, breathing and swallowing.^{1, 2, 3} Without these nerves cells, called motor neurons, muscles don’t receive the nerve signals that make them function, causing muscles to become weak and waste away (atrophy). ^{2, 3, 4}

Spinal Muscular Atrophy is considered a group of disorders due to its variability, including how early symptoms appear, how severe they are, and how quickly the condition progresses. There are five subtypes of Spinal Muscular Atrophy, ranging from the most severe and early appearing form (type 0), to the mildest form that appears later in life (type 4). ^{2, 4} While Spinal Muscular Atrophy shares similarities with Amyotrophic Lateral Sclerosis (ALS) —both affect motor neurons and result in progressive muscle weakness — differences in genetics, symptoms, and affected populations distinguish the two conditions. ^{5, 6}

Spinal Muscular Atrophy is a rare condition, occurring in about 1 in 10,000 live births globally. In the U.S, it is estimated to affect 1 in 14,694 newborns.^1, 7, 8

What causes Spinal Muscular Atrophy?

The most common form of Spinal Muscular Atrophy is caused by mutations (changes in the DNA) in the survival motor neuron 1 (SMN1) gene, which is located on chromosome 5. ^{3, 9} This gene is responsible for producing a protein called SMN, which is essential for the health and function of motor neurons. Without sufficient SMN protein, motor neurons degenerate, leading to muscle weakness and wasting. ^{9, 10}

Another gene, called SMN2, also makes SMN protein. However, most of the protein made by the SMN2 gene is incomplete and nonfunctional, with only about 10–15% being fully functional. ^{9, 10, 11} People can have several copies, or duplicates, of the SMN2 gene, ranging from zero to as many as eight, depending on the individual. Those with more copies of the SMN2 gene can produce more functional SMN protein, which helps compensate for the loss of SMN1. As a result, having more SMN2 copies is linked to a milder form of the disease (Types 2-4). ^{3, 9, 11}

Most cases of Spinal Muscular Atrophy occur when the affected gene is passed down from the person’s parents. Spinal Muscular Atrophy is an autosomal recessive disorder, meaning a child must inherit two mutated copies of the SMN1 gene — one from each parent — to develop the condition. A person who has only one mutated gene, known as ‘carrier’, typically does not have symptoms of the disease but can still pass the mutation on to their children. This condition can also occur sporadically in an affected individual, without inheriting two mutated genes, however this is extremely rare. ³

What are the symptoms of Spinal Muscular Atrophy?

Spinal Muscular Atrophy symptoms result from the progressive loss of motor neurons and muscle function. While symptoms vary across the five subtypes, they commonly include muscle weakness and shrinkage (atrophy), low muscle tone (hypotonia), reduced or absent reflexes, and muscle twitching (fasciculations). ^{1, 4} Specific symptoms depending on the subtype may include:

• Type 0 (prenatal Spinal Muscular Atrophy): This is the most severe form, which develops before birth. Symptoms are already apparent at birth and can include severe muscle weakness, joint deformity and tightening (contractures) and heart defects. Respiratory failure usually occurs within the first month of life. ^{1, 4}
• Type 1 (infantile Spinal Muscular Atrophy): This is the most common subtype, affecting about 60% of infants born with Spinal Muscular Atrophy. Symptoms usually appear within the first six months of life and include poor head control, low muscle tone (hypotonia), and difficulty swallowing or breathing. ^{1, 4}
• Type 2 (intermediate Spinal Muscular Atrophy): This subtype affects around 30% of infants born with Spinal Muscular Atrophy, with symptoms usually appearing between six and 18 months of age. They include decreased muscle tone, worsening muscle weakness, curvature of the spine (scoliosis), trembling of the fingers (tremor), and difficulty swallowing or breathing. ^{1, 4}
• Type 3 (juvenile Spinal Muscular Atrophy): Type 3 accounts for about 10% of cases and appears after 18 months of age, sometimes as late as teenage years. Individuals may initially be able to walk but often lose this ability over time, becoming wheelchair dependent. Unlike other types, breathing difficulties are uncommon in Type 3. ^{1, 4}
• Type 4 (late-onset Spinal Muscular Atrophy): This rare and mild form of the disease usually starts after the age of 35. Muscle weakness symptoms progress slowly, so most individuals retain the ability to walk throughout their lives.It affects fewer than 1% of people with Spinal Muscular Atrophy ^{1, 4}

Diagnosis of Spinal Muscular Atrophy

To diagnose Spinal Muscular Atrophy, physicians typically start by reviewing the patient’s family history and symptoms, followed by neurological and physical examinations. ^{4, 9}

If Spinal Muscular Atrophy is suspected, genetic testing is the primary method used to confirm the diagnosis. A simple blood test can identify changes in the SMN1 gene, confirming about 95% of Spinal Muscular Atrophy cases. ^{4, 12}

In cases where Spinal Muscular Atrophy is not immediately suspected, the physician may order a blood test to measure creatine kinase (CK), an enzyme that leaks from damaged muscles. A high CK level suggests that the muscles are being harmed. ^{4, 9} While CK levels are usually standard in patients with Spinal Muscular Atrophy Type 1, they may be slightly elevated in individuals with other types, such as Types 2 and 3. ⁹

Additional tests, such as electromyography (EMG) and nerve conduction studies, may also be used to measure electrical activity in muscles and nerves. These tests can help determine whether symptoms are caused by problems with muscles, nerves, or motor neuron loss. ⁴

Treatment for Spinal Muscular Atrophy

While there is no cure for this disease at the moment, some Spinal Muscular Atrophy therapies are available to help manage symptoms, improve quality of life and prevent complications ⁴

Over the past decade, three medications have been approved by the FDA (U.S. Food and Drug Administration) and the EMA (European Medicines Agency). These medications — Nusinersen (Spinraza®), Risdiplam (Evrysdi®), and Onasemnogene abeparvovec (Zolgensma®) — are designed to address the underlying cause or mechanisms of the disease, with the goal of slowing its progression and potentially altering its course. ¹³

• Nusinersen and Risdiplam act on the SMN2 gene. Normally, this gene produces a shorter and less effective version of the SMN protein compared to the SMN1 gene. These medications help the SMN2 gene produce a complete and functional SMN protein, aiming to replace as much as possible the missing protein caused by the mutated SMN1 gene. ^{4, 15} Nusinersen is administered as an injection into the spine, whilst Risdiplam is taken orally, allowing for at-home treatment. ^{4, 15}
• Zolgensma works by replacing the mutated SMN1 gene with a functioning one, which can produce the SMN protein on its own. This is a one-time gene therapy that can be administered directly into a vein. ^{4, 16}

The effectiveness of these Spinal Muscular Atrophy treatments often depends on how early they are started. Beginning treatment as soon as possible — even before symptoms appear — offers the best chance of slowing disease progression and preserving motor function. This highlights the importance of early diagnosis through newborn screening programs, which allows the start of the treatment in the early stages of the disease. 4, [15] Today at the time of this blog’s publication, all 50 U.S. states include Spinal Muscular Atrophy in routine newborn screening. ^{4, 17}

Besides medication, a treatment plan for Spinal Muscular Atrophy usually includes supportive care to manage complications and help improve quality of life. This can include:

• Physical therapy: Activities such as swimming, aquatic therapy, and adaptive sports can help improve posture, prevent joint immobility and slow down muscle weakness. ^{4, 12, 18}
• Assistive devices: Equipment like orthopedic braces, crutches, walkers, or wheelchairs can provide mobility and independence for those with mobility challenges. ^{4, 12, 18}
• Nutrition support: Some people with Spinal Muscular Atrophy may have trouble chewing and swallowing their food. Nutritionists may suggest easy-to-swallow meals or supportive feeding tubes if needed. ^{4, 12, 18}
• Respiratory care: Specific exercises or ventilators can help those people with breathing difficulties. Routine vaccinations against influenza, pneumococcus, and respiratory syncytial virus are also important to reduce the risk of respiratory infections. ^{4, 12, 18}

Investigational treatments

Researchers are exploring investigational treatments for Spinal Muscular Atrophy with the aim of managing symptoms and slowing disease progression. Some of the therapies being evaluated in clinical trials include:

• Riluzole: This medication, already approved for treating amyotrophic lateral sclerosis (ALS) by both the FDA (Food and Drug Administration) in the U.S. and EMA (European Medicines Agency) in Europe, aims to reduce the levels of glutamate, a chemical that can damage nerve cells in ALS. Clinical trials are now exploring whether it could help slow the progression of Spinal Muscular Atrophy. ^{13, 15}
• Myostatin Inhibitors: Myostatin is a protein that limits muscle growth. By blocking it, these inhibitor drugs aim to improve muscle strength and reduce muscle loss. ^{13, 15} However, since people with Spinal Muscular Atrophy often already have low levels of myostatin, especially as they age, it’s uncertain whether these treatments will benefit those with advanced stages of the disease. ¹³
• Therapies targeting neuromuscular transmission: Research suggests that changes in the connection between nerves and muscles play a significant role in the progression of Spinal Muscular Atrophy. Treatments aimed at improving neuromuscular transmission may help alleviate symptoms and are currently being studied in clinical trials for Spinal Muscular Atrophy. ¹³
• Other medications: Drugs originally used in the treatment of Multiple Sclerosis (Dalfampridine), Lambert-Eaton myasthenic syndrome (Amifampridine) and asthma (Salbutamol) are now being studied in clinical trials for Spinal Muscular Atrophy. ¹⁵

Additionally, other investigational approaches are being studied in preclinical research, meaning they are being tested in laboratory settings but have not yet progressed to human trials. These include mechanisms aiming at protecting the SMN protein from breaking down, regulating gene activity to boost SMN protein levels and using gene-editing tools like CRISPR to fix or replace the mutations that cause Spinal Muscular Atrophy.¹³

Conclusions

Spinal Muscular Atrophy (SMA) is a group of genetic neurological disorders that affect motor neurons, causing them to lose function and eventually die. This leads to a progressive loss of the ability to control movements like walking, swallowing or breathing. While there is no cure, recently approved medicines — Nusinersen, Risdiplam and Zolgensma — allow symptoms to be managed more effectively. Early diagnosis, often through newborn screening, is important for maximizing the potential benefits of these treatments. In addition, supportive care, including physical therapy, respiratory care, and nutrition support, is often recommended for people with Spinal Muscular Atrophy. There are several investigational treatments for Spinal Muscular Atrophy being explored in clinical trials, including the use of the ALS medication Riluzole, Myostatin Inhibitors or therapies targeting neuromuscular transmission.

At myTomorrows, we have a team of Patient Navigators, who are multi-lingual professionals with a medical background, who can help you to explore your treatment options and support you through your journey.