Spinal Muscular Atrophy (SMA)

Spinal muscular atrophy (SMA) is a genetic disease that affects the spinal cord and nerves, resulting in muscle wasting and weakness. Untreated, it is a neurodegenerative, progressive disease, which can be fatal in its more severe forms.

In most cases, SMA is an autosomal recessive disease. This means that both males and females are equally affected, and that two mutated copies of the gene, one inherited from each parent, are necessary to have the condition.

SMA is caused by mutations in a gene called survival motor neuron 1 (or SMN1). In more than 95% of cases of SMA, the mutation is a common deletion; less commonly, there are spelling errors, also called point mutations, in SMN1 or other genetic variants. Symptomatic individuals of all ages can be tested through DNA studies typically done from a blood sample.

When both parents are carriers (or they each have one abnormal copy of the gene and one normal copy), there is a one in four (25%) chance, with each pregnancy, to have a child with SMA. Testing to determine if a person is a carrier is being offered more commonly as part of routine prenatal care, but testing still has some limitations, with potential for false negative results, due to the complex genetics of SMA.

Spinal muscular atrophy is sometimes difficult to diagnose, as symptoms can resemble other conditions or medical problems. Each child may experience symptoms differently. There are four types of SMA based on symptoms and age of onset:

• Type I SMA (also called Werdnig-Hoffman or infantile-onset SMA) — This is the most severe type of SMA and may be present at birth or symptom onset may be later, before age 6 months. Infants have problems holding their head, sucking, feeding and swallowing, and they typically move very little. The muscles of the chest are also affected. The motion of the tongue is described as having "worm-like" movements. Untreated patients typically require full-time ventilator support by age 2, and life expectancy is often shortened.
• Type II SMA (juvenile SMA or intermediate SMA) — This form of SMA presents initially in children from 6 months to 18 months of age. Without treatment, these children will not be able to walk independently, and may need respiratory and feeding support when symptoms first appear or later in life. They typically have generalized muscle weakness and may require braces, walkers or a wheelchair for assistance. Life expectancy often extends into adulthood.
• Type III SMA (mild SMA) — This form of SMA affects children older than 18 months of age or as late as adolescence. These children show signs of clumsiness, difficulty walking and mild muscle weakness, and, if untreated, they may lose the ability to walk independently. This type of SMA does not affect life expectancy.
• Type IV SMA — This form of SMA affects adults from age 18 onward and results primarily in a walking disability.

SMA is caused not by an absence of SMN protein, like many other disorders, but by a deficiency. Everyone still makes some SMN protein, from a gene called SMN2. However, each SMN2 gene functions about 10-15% as well as a SMN1 gene. The copy number of SMN2 genes correlates with disease severity, and is responsible for some of the broad variety in clinical presentation.

The symptoms of spinal muscular atrophy may resemble other problems or medical conditions. Always consult your child's doctor for a diagnosis.

Many states, including Pennsylvania and New Jersey have recently mandated screening of all newborn babies for SMA. Other times, the diagnosis of spinal muscular atrophy is made after the sudden or gradual onset of specific symptoms and after diagnostic testing. During a physical examination, your child's doctor will obtain a complete medical history of your child and may ask if there is a family history of any medical problems.

Diagnostic tests that may be performed to confirm the diagnosis of spinal muscular atrophy include:

• Genetic tests (blood or saliva): Diagnostic tests that evaluate for conditions that have a tendency to run in families.
• Electromyogram (EMG)/Nerve conduction studies (NCS): A test that measures the electrical activity of a nerve, muscle or group of muscles. An EMG/NCS can detect abnormal electrical nerve and muscle activity due to diseases and neuromuscular conditions.
• Muscle ultrasound (US): A test to look at the activity and quality of the muscle. This test can help see fasciculations, or abnormal muscle movements, that are classic in spinal muscular atrophy.
• Newborn screening: Newborn screening is testing performed at birth for a variety of treatable inherited disorders. SMA is now on the Recommended Uniform Screening Panel (RUSP), and Pennsylvania and other states are working hard on initiating this process.

Treatment for spinal muscular atrophy is very complex and requires coordinated care from many different subspecialists. Your child’s care team may include experts from neurology, rehabilitation/physical therapy/occupational therapy, pulmonology, orthopaedics, endocrinology, anesthesiology, nutrition/gastroenterology and others.

There are two goals of treatment for SMA. The first goal is to proactively manage anticipated issues that may arise with multi-systemic supportive care. The second goal is targeted treatments to help slow down, and in some cases stop, the progression of SMA.

Specific spinal muscular atrophy treatment will be determined by your child's care team based on:

• Your child's age, overall health and medical history
• The extent of the condition
• The type of spinal muscular atrophy
• Your child's tolerance for specific medications, procedures or therapies
• Expectations for the course of the condition
• Your opinion or preference

There is no cure for spinal muscular atrophy. The key to medically managing the condition is through early detection and proactive management of associated symptoms.

Supportive care for SMA will focus on:

• Physical and occupational therapy, avoiding contractures and enhancing safe independent mobility and daily function
• Maximizing nutritional status
• Improving bone health
• Management of musculoskeletal issues, such as scoliosis
• Breathing supports as needed

In addition to a multidisciplinary approach to care, there are also new specific treatments for SMA, which are described in more detail below.

One of the latest breakthroughs in care for patients with spinal muscular atrophy is the FDA approval of a new medicine called nusinersen (brand name Spinraza^®) for the treatment of SMA in children and adults.

Nusinersen is a medication that is used to increase production of the survival of motor neuron (SMN) protein, increasing the amount of functional protein produced from the SMN2 gene.

Your child’s doctor will determine if your child is a candidate for the drug based on genetic factors, disease type and symptoms. Currently, nusinersen is approved for use in all patients who are confirmed to have the SMN gene mutation that causes the disease.

Early results of SMA treatment with Spinraza are promising. Clinical trials have shown some patients experience improvement in motor skills. Many others will stabilize and not experience any further loss or deterioration of skills. Research trials show that the earlier patients start the medication, the better the results.

Another recent advancement in spinal muscular atrophy treatment is gene replacement therapy. In May 2019, gene replacement therapy for SMA, called onasemnogene abeparvovec-xioi (brand name Zolgensma^®), was approved by the FDA for treatment of children under age 2 years with genetically confirmed SMA.

If your child meets these criteria, we will complete a clinical evaluation and additional testing to determine if they are a candidate to receive SMA gene therapy.

Clinical trials have shown clear efficacy in young children with SMA type 1, resulting in a decreased need for respiratory support as well as improvement in motor skills. Research trials have also shown that the earlier children receive gene therapy, the better the results.

Additional clinical trials with Zolgensma are ongoing. We encourage you to ask your child’s medical team any questions you may have, and we will share new information as it becomes available.

Deformities of the spine, chest wall and hips are common in children with SMA. These deformities can result in decreased space for the lungs and can negatively affect lung function.

Scoliosis is a deformity of the spine that is brought on by the muscular weakness that develops in children with the condition. The age of onset of scoliosis can vary dramatically depending on severity of the disease, but can be as early as age 1 even in newborns who undergo gene therapy treatment.

Children with SMA should be evaluated for a spinal deformity beginning before age 1. Current treatment involves surgically implanting growing rods to control and manage the progressive and detrimental effects of scoliosis. Our surgical team is mindful to leave an area of the child’s spine unfused to allow for genetically-targeted therapy injections, when needed.

Chest wall deformities such as the parasol rib deformity can exist with or without a spinal deformity in children with SMA. In the parasol rib deformity, the ribs are collapsed, preventing proper respiratory mechanics. At CHOP, treatment of this condition involves surgery to reposition the ribs in order to maintain or preserve lung function and prevent further collapse. Ours is one of only a few programs in the country to offer this unique approach to managing this condition.

Pelvic issues in children with SMA can lead to hip deformity and hip dysplasia. Evaluation and management of the condition of the pelvis and the hips is important to preserve a child’s mobility.

In spinal muscular atrophy (SMA) lung infections can cause respiratory difficulty and are a common cause of hospitalization. For this reason it is critical to support a patient’s ability to cough and clear his/her mucus. In addition, as muscle weakness progresses it can become difficult for patients to breathe in oxygen and remove carbon dioxide. This respiratory compromise can first appear during sleep when there is an overall decrease in muscle strength. The pulmonary team works with the child and his/her guardian(s) to assess the muscles involved in breathing and overall lung function regularly through the use of such testing as:

• Pulse oximetry to measure oxygen levels in the blood. Transcutaneous carbon dioxide level to measure carbon dioxide levels in the blood.
• Pulmonary function testing to assess muscle strength and the volume, speed and flow of air exhaled by the lungs.
• Swallow Function Study to determine if any liquids or foods are not cleared from the throat and put the child at risk for aspiration, or are going into the airway or lungs.
• Sleep Study to assess breathing and lung function during sleep by measuring oxygen levels and carbon dioxide levels among other items.

Optimizing lung function and prevention and early treatment of lung infection are the main goals of respiratory management. There are a number of different pieces of equipment and techniques that can be used to clear secretions and support breathing. These techniques may include:

• Cough Assistance Device to mimic coughing in children with weakness or changes in the chest wall that prevents the child from creating a strong effective cough to clear out mucus from the airway and lungs.
• Techniques to expand the lungs and chest wall passively, so as to enhance mobility of the chest wall and reverse small areas of collapse in the lungs.
• Non-invasive Ventilation delivered by a machine through a mask or similar interface, to support the ability of the lungs to fully expand and release carbon dioxide and provide oxygen into the blood.
• Chest physical therapy to loosen and clear lung secretions. This may be done manually by clapping on the chest and back or include devices such as a percussion vest or intrapulmonary percussive ventilator that vibrates the chest and loosens secretions.
• At times inhaled medications may be useful to help remove secretions. These would include bronchodilators or hypertonic saline to assist in keeping the airways clear and to thin secretions as way to increase their ability to be “coughed up.”

For more details please see “Breathing Problems in Children with Neuromuscular Conditions.”

While the approved therapies for SMA are limited at this time, there are many medications currently being studied with the hope that they may also become treatment options. CHOP has long been a site for research studies and clinical trials, continually seeking to find the next breakthrough in the treatment of SMA. In addition to interventional trials, we are a site for natural history studies that allow us to learn more about the disorder and how treatment is altering its natural history. We work with colleagues in pulmonology, orthotics, orthopaedics, endocrinology, and physical and occupational therapy to help learn more about how to best manage this disorder.

A child with spinal muscular atrophy requires frequent medical evaluations throughout their lifespan. Your child’s healthcare team will work closely with your family on how to best care for your child at home. We will also outline specific clinical problems that require immediate medical attention by their doctor.

Being cared for in a top-ranked children’s hospital means your child will have immediate access to the many clinical specialists and pediatric-focused care they need to manage their SMA. We have the experts, support services, facilities and technology in place to ensure your child receives the best possible care.

It is our goal to deliver cutting-edge treatment to as many patients as possible. We have the resources required to provide access to new SMA therapies and medications in a timely manner. We are equipped to tailor dosing to each individual patient and provide the support services that can help make the experience easier on your child and family. These are important factors to look for in any SMA treatment center.