A Closer Look at Spinal Muscular Atrophy: Symptoms, Types, and Management

The Rare360 Editorial Team
Sep 17
9 min read

Updated: Sep 18

Young boy in a navy shirt sits on a black wheelchair in a room with beige walls and light curtains, appearing contemplative while living with Spinal Muscular Atrophy.

Spinal Muscular Atrophy (SMA) is a rare genetic neuromuscular disorder that primarily affects the motor neurons in the spinal cord and brainstem. These motor neurons are responsible for muscle movement, and their dysfunction leads to progressive muscle weakness, impacting essential activities like walking, swallowing, and even breathing. SMA is caused by mutations in the survival motor neuron gene 1 (SMN1), which disrupts the production of a critical protein essential for the survival of motor neurons. Without adequate levels of this protein, muscles deteriorate over time.

SMA is inherited in an autosomal recessive pattern, meaning a child must inherit a defective copy of the SMN1 gene from both parents to develop the condition. Parents who carry one defective gene are known as carriers and typically do not exhibit symptom ms. When both parents are carriers, each pregnancy carries:

A 50% chance the child will be a carrier without symptoms.
A 25% chance the child will inherit two functional copies of the gene and experience symptoms.

Despite being the leading genetic cause of infant mortality, SMA affects individuals of all ages, with varying levels of severity. SMA affects approximately one in 15,000 births in the U.S., and about one in every 50 Americans is a genetic carrier.

This article delves into the complexities of Spinal Muscular Atrophy, exploring its causes, symptoms, and the innovative treatments offering hope to patients and families. Whether you're a patient, caregiver, or advocate, this comprehensive guide aims to inform and inspire while promoting awareness of this rare condition.

Types of Spinal Muscular Atrophy (SMA)

Spinal Muscular Atrophy (SMA) is traditionally classified into five types based on the average age of symptom onset and the severity of motor impairment.

A closely related gene, SMN2, also contributes to SMN protein production but is far less efficient than SMN1 due to differences in splicing. However, the number of SMN2 gene copies can vary among individuals and significantly influences the severity of SMA. Additional copies of the SMN2 gene are often associated with milder forms of SMA (Types II-IV), as they partially compensate for the defective SMN1 gene.

The following is a detailed breakdown of the types of SMA based on these genetic and clinical characteristics.

Type 0 (Prenatal SMA)

Age of Onset: Before birth.
Symptoms: Type 0 is the rarest and most severe form of Spinal Muscular Atrophy (SMA). Affected infants exhibit profound muscle weakness in utero, often leading to decreased fetal movement and birth complications. At birth, these newborns commonly present with severe respiratory insufficiency, joint contractures (fixed stiffness in joints), and difficulty feeding. These symptoms result from the extreme loss of motor neurons before delivery.
Prognosis: Infants with Type 0 SMA face critical respiratory failure at birth and typically have a very short life expectancy. Even with supportive care, survival beyond six months is extremely rare. Early intervention and palliative care play a crucial role in providing comfort and improving quality of life for these infants.

Type 1 (Infantile-Onset SMA or Werdnig-Hoffmann Disease)

Age of Onset: Within the first 6 months of life.
Symptoms: Type 1 is the most common form of SMA, affecting approximately 60% of individuals diagnosed with SMA. It is characterized by severe muscle weakness, poor muscle tone, difficulty swallowing, and minimal control of head movements. Infants often exhibit a "floppy baby" appearance and are unable to sit unassisted. Respiratory issues are a prominent concern, frequently necessitating ventilatory support. Most infants with this type have two or three copies of the SMN2 gene, which provides limited compensation for the dysfunctional SMN1 gene.
Prognosis: Without treatment, Type 1 SMA is life-threatening, with the majority of affected children not surviving past their second year. However, advances in treatments have significantly improved both life expectancy and quality of life for these children.

Type 2 (Intermediate SMA or Dubowitz disease)

Age of Onset: Typically manifests between 6 and 18 months of age.
Symptoms: Type 2 SMA is less severe than Type 1 but still leads to significant physical challenges. Children with Type 2 can usually sit independently but are unable to stand or walk without assistance. Over time, muscle weakness progresses, primarily affecting proximal muscles closer to the body’s center, with the lower limbs more severely impacted than the upper limbs. Common complications include scoliosis (spinal curvature), joint contractures, and respiratory difficulties. Facial and eye muscles are typically spared, preserving facial expressions. Most individuals with Type 2 SMA have three copies of the SMN2 gene, providing partial compensation for the loss of SMN1 function.
Prognosis: Life expectancy for individuals with Type 2 SMA varies depending on the severity of respiratory complications and the availability of medical care. Many live into adulthood, with about 70% surviving beyond age 25 and some reaching their 30s or beyond. Respiratory complications remain the leading cause of mortality in Type 2 SMA patients.

Type 3 (Juvenile-Onset SMA or Kugelberg-Welander Disease)

Age of Onset: Typically develops after 18 months, often during childhood or adolescence.
Symptoms: Type 3 SMA is characterized by milder muscle weakness, primarily affecting the legs. Individuals with this type typically achieve independent mobility early in life but may experience difficulty with physical activities such as climbing stairs or running. Proximal muscle weakness can lead to frequent falls. Over time, many individuals lose the ability to walk independently and may require a wheelchair for mobility. Additional complications can include foot deformities, scoliosis, and mild respiratory muscle weakness. Type 3 SMA accounts for about 30% of all SMA cases, with affected individuals typically possessing 3 to 4 copies of the SMN2 gene, offering partial compensation for the loss of SMN1 function.
Prognosis: Type 3 SMA generally does not significantly reduce life expectancy. The progression of symptoms is typically slow, and many individuals maintain relative independence with appropriate interventions, such as physical therapy and assistive devices.

Type 4 (Adult-Onset SMA)

Age of Onset: Typically in the second or third decade of life.
Symptoms: Type 4 SMA is the mildest and rarest form, accounting for less than 5% of all SMA cases. Symptoms include mild muscle weakness, predominantly in proximal muscles such as those in the shoulders and hips. Unlike other types, Type 4 does not typically involve significant respiratory complications or severe physical impairments. Individuals with Type 4 SMA generally have four to eight copies of the SMN2 gene, which provides higher levels of the survival motor neuron protein and mitigates symptom severity.
Prognosis: Life expectancy and overall health are generally unaffected. Most individuals with Type 4 SMA can maintain an active lifestyle, and the progression of muscle weakness is typically slow, allowing for sustained independence and minimal medical intervention.

Non-SMN Related Forms of Spinal Muscular Atrophy

Spinal Muscular Atrophy (SMA) is commonly associated with mutations in the SMN1 gene, but there are other rare types caused by defects in entirely different genes. These forms vary widely in severity, symptoms, and inheritance patterns. Here’s an overview of some of these less common SMA types:

Kennedy’s Disease: While similar to SMA, this condition may affect muscles farther from the center of the body compared to the typical SMA types (0-4).
Distal Spinal Muscular Atrophies (Distal SMA): These forms result from mutations in genes like UBA1, DYNC1H1, TRPV4, PLEKHG5, GARS, and FBXO38. Symptoms can include muscle weakness in the hands and feet and may overlap with Charcot-Marie-Tooth disease (CMT), a condition affecting both motor and sensory nerves. Diagnosis depends on whether motor or sensory symptoms are more prominent.
Spinal Muscular Atrophy with Respiratory Distress (SMARD): Caused by mutations in the IGHMBP2 gene, this rare form of SMA primarily affects respiratory muscles and causes severe breathing difficulties in infants. Many affected babies also experience growth issues and premature birth.
X-Linked Spinal Muscular Atrophy (XL-SMA): Linked to a mutation in the UBA1 gene on the X chromosome, XL-SMA primarily affects males due to its inheritance pattern. It resembles Type 1 SMA, with early-onset muscle weakness, low muscle tone (hypotonia), joint contractures, and minimal response to stimuli.

Diagnosing Spinal Muscular Atrophy (SMA)

Diagnosing Spinal Muscular Atrophy (SMA) requires a comprehensive approach involving clinical evaluation, family history assessment, and specialized diagnostic tests. Early detection is essential, as timely intervention can significantly improve long-term outcomes for individuals with SMA. Below is an overview of the key diagnostic procedures and their significance.

Common Diagnostic Procedures for SMA

Genetic Testing for SMN1 Mutations
The gold standard for diagnosing SMA is genetic testing, which identifies mutations or deletions in the SMN1 gene, the primary cause of SMA. Over 95% of SMA cases involve a homozygous deletion of SMN1. A simple blood test can confirm the diagnosis and is now a routine part of newborn screening in all 50 U.S. states, enabling early detection and treatment.
- Carrier Screening: For families with a history of SMA, genetic testing can identify carriers of the SMN1 mutation, aiding in family planning.
Electromyography (EMG) and Nerve Conduction Studies
EMG measures the electrical activity of muscles, detecting abnormalities associated with nerve damage or dysfunction seen in SMA.Nerve conduction studies complement EMG by assessing the speed and strength of nerve signals, further confirming neuromuscular involvement.
Muscle Biopsy
In rare cases where genetic testing is inconclusive, a muscle biopsy may be performed. This involves removing a small muscle sample to examine its structure and function. In SMA, muscle tissue often shows signs of atrophy and fiber-type grouping, characteristic of the disease.
Creatine kinase blood test
Deteriorating muscles release creatine kinase (CK) enzyme into the bloodstream. While elevated levels of creatine kinase (CK) can indicate muscle damage, CK levels in SMA patients are typically normal, distinguishing it from other neuromuscular disorders.

Prenatal Diagnosis of SMA

For expectant parents with a family history of SMA, prenatal genetic testing can determine whether the developing fetus has the condition. These procedures include:

Amniocentesis: Conducted after the 14th week of pregnancy, this test involves inserting a thin needle into the abdomen to collect a small amount of amniotic fluid. The sample is analyzed for genetic mutations associated with SMA.
Chorionic Villus Sampling (CVS): This procedure, which can be performed as early as the 10th week of pregnancy, involves removing a small tissue sample from the placenta through the cervix or abdomen. The tissue is then examined for SMA-related genetic abnormalities.

Treatment and Management of Spinal Muscular Atrophy (SMA)

Unfortunately, there isn’t a cure for SMA. Treatment for SMA mainly seeks to manage symptoms and prevent complications. Symptom management therapies may include:

FDA-Approved Treatments

Nusinersen (Spinraza): Nusinersen is an intrathecal antisense oligonucleotide therapy that modifies the splicing of the SMN2 gene to increase production of the SMN protein, which is crucial for motor neuron survival. Clinical trials have shown significant improvements in motor function, prolonged survival, and delayed disease progression in patients treated with Spinraza. It is effective for individuals of all ages and SMA types, but it requires regular injections into the spinal fluid.
Onasemnogene Abeparvovec-Xioi (Zolgensma): Zolgensma is a one-time gene therapy that delivers a functional copy of the SMN1 gene via a viral vector (AAV9) to motor neurons, addressing the root cause of SMA. Approved for patients under 2 years old, Zolgensma has demonstrated remarkable results in improving motor milestones, such as sitting and walking, in infants with SMA. Its single-dose administration reduces the treatment burden significantly compared to ongoing therapies.
Risdiplam (Evrysdi): Risdiplam is an oral medication that enhances SMN protein production by targeting the SMN2 gene. It is approved for individuals aged 2 months and older and offers a convenient at-home treatment option. Clinical studies have shown improvements in motor function and reductions in disease progression across various SMA types.

Symptomatic Management Strategies

While disease-modifying therapies address the genetic root of SMA, comprehensive symptomatic management remains vital for improving daily life:

Physical Therapy: Tailored physical therapy programs help maintain mobility, improve muscle strength, and prevent joint contractures. Assistive devices such as braces, wheelchairs, and standing frames can also enhance independence.
Respiratory Care: Individuals with SMA often experience respiratory muscle weakness, making airway clearance and ventilation support crucial. Techniques such as cough-assist devices, suction machines, and non-invasive ventilation can improve breathing and reduce the risk of infections.
Nutritional Support: Swallowing difficulties and reduced muscle tone can lead to nutritional challenges. Dietitians often recommend specialized feeding techniques, high-calorie diets, or feeding tubes to ensure adequate nutrition and prevent weight loss.

Emerging Therapies and Ongoing Research

SMN-Independent Therapies: Researchers are exploring treatments that target pathways other than SMN protein production, such as those promoting muscle strength, neuroprotection, and motor neuron survival.
Stem Cell Therapy: Early-stage studies are investigating the potential of stem cell transplants to regenerate motor neurons or improve their function.
Combination Therapies: Clinical trials are assessing whether combining existing treatments, such as Spinraza and Zolgensma, could further enhance outcomes or address limitations in certain patient populations.

Conclusion

Spinal Muscular Atrophy (SMA) is a complex and challenging condition, but advancements in research, early diagnosis, and innovative treatments are transforming the outlook for patients and their families. From groundbreaking genetic therapies to improved supportive care, the landscape of SMA management continues to evolve, offering renewed hope and better quality of life for those affected.

The courage and resilience of the SMA community—patients, caregivers, researchers, and advocates—serve as a testament to the power of determination and innovation. With continued efforts in awareness, funding, and research, we are moving closer to a future where SMA no longer defines the lives of those impacted. Together, we can strive for a world where every individual with SMA can lead a life of dignity, possibility, and hope.