WHAT IS SPINAL MUSCULAR ATROPHY? TYPES, TREATMENTS, LATEST ADVANCES AND MORE
Medically Reviewed by Dr. Sony Sherpa (MBBS)
Spinal Muscular Atrophy (SMA) is a sporadic genetic disorder affecting the spinal cord's motor neurons, leading to muscle weakness and atrophy. It is a progressive disease that can impact people of all ages, from infants to adults.
This article sheds light on the different types of SMA, its causes, symptoms, diagnosis, treatment options, and the latest advancements in SMA research.
What is Spinal Muscular Atrophy (SMA)?
Spinal Muscular Atrophy (SMA) is a genetic disorder that causes the destruction of motor neurons (found in the spinal cord), which leads to muscle atrophy and weakness. It is caused by a mutation in the SMN1 gene, which produces a protein essential for healthy muscle function. Without this protein, the motor neurons in the spinal cord degenerate, leading to muscle weakness and atrophy.
How Common is Spinal Muscular Atrophy?
Spinal Muscular Atrophy is a rare disorder, affecting approximately 1 in 10,000 live births. It is one of the leading genetic causes of infantile mortality, with about 1 in every 6,000 to 10,000 babies born with the disease.
Types of SMA
There are five main types of SMA, each with varying degrees of severity and age of onset.[1]
- Type 0 SMA: Type 0 SMA, also known as the prenatal or severe congenital form, is the most severe and rarest form of SMA. It is usually evident before birth or during the first few weeks of life. Babies with Type 0 SMA have feeble muscles and may experience severe respiratory distress, making it difficult for them to breathe without assistance. They may have decreased fetal movements during pregnancy. These babies typically have a very poor prognosis and may have a significantly shortened lifespan.
- Werdnig-Hoffmann Disease (SMA Type 1): Type 1 SMA, also known as Werdnig-Hoffmann Disease, is another severe form of the disease. It is usually diagnosed in infants under six months of age. Patients typically present with hypotonia, weakness, and poor head control early in infancy. The disease progresses rapidly, leading to the inability to sit without support and difficulty feeding due to a lack of swallowing coordination. Respiratory challenges, including weak cough and poor chest expansion, are common.
- Intermediate SMA (SMA Type 2): Intermediate SMA, also called Dubowitz disease, is usually diagnosed in children between 6 and 18 months of age. These patients can sit without support yet may have difficulty standing or walking independently. They often exhibit tremors, decreased deep tendon reflexes, and tongue fasciculations. Respiratory function is compromised but typically not as severely as in Type 1 SMA. They may require respiratory support, such as a cough assist or non-invasive ventilation, to aid in breathing.
- Kugelberg-Welander Disease (SMA Type 3): Type 3 SMA, also known as Kugelberg-Welander Disease, is usually diagnosed in children over 18 months of age. These patients have a later onset of symptoms, typically in childhood or adolescence. They may experience difficulty with running, climbing stairs, or standing from a seated position. While they may have muscle weakness and fatigue, they can generally walk independently. Respiratory function is typically not affected in Type 3 SMA.
- Adult-Onset SMA (SMA Type 4): Adult-Onset SMA is the mildest form and is very rare, accounting for less than 1% of all SMA cases[2]; with symptoms appearing in adulthood. These patients may have a gradual onset of muscle weakness and atrophy, primarily in the proximal muscles of the arms and legs. They may experience difficulty with activities such as lifting objects, walking, or climbing stairs. Respiratory function may be affected in some cases, requiring respiratory support.
There are several other types of rare SMA linked to a broader variety of gene mutations[3]:
- X-linked infantile SMA and UBA1 gene mutations.
- SMA with respiratory distress type 1 (SMARD1) and mutations in the IGHMBP2 gene.
- SMA with lower extremity predominance (SMA-LED) and mutations in the genes DYNC1H1 or BICD2.
- SMA with progressive myoclonic epilepsy (SMA-PME) and mutations in the ASAH1 gene.
- Mutations in the VAPB gene cause finkel-type SMA.
- Several gene mutations, including GARS1, BSCL2, and REEP1, cause distal spinal muscular atrophy (DSMA).
- Kennedy's disease (Spinal and bulbar muscular atrophy, SBMA) arises in response to mutations in the androgen receptor (AR) gene on the X chromosome.
It is important to note that the classification of SMA types may vary slightly between sources, and each patient's experience with the disease can differ. The severity and progression of SMA can also vary within each type.
Causes of SMA
A mutation in the SMN1 gene causes Spinal Muscular Atrophy. SMN stands for the survival motor neuron (SMN) protein, which is multifunctional and necessary for the survival of all organisms.
In the spinal column, lower SMN expression disrupts the formation of various ribonucleoprotein (RNP) complexes involved in RNA metabolism. This disrupts the ability of motor neuron cells to make essential proteins[4] and disturbs vital cellular functions, including processes essential to muscle cell contraction. This process causes damage to anterior horn cells and alpha-motor cells in the spinal cord[5], resulting in muscle weakness, degeneration, and loss. These are hallmark features of spinal muscular atrophy (SMA).
Humans also carry an additional copy of the SMN gene, SMN2. SMN2 produces a shorter version of the protein (SMNΔ7) that can partially compensate for the loss of SMN1. Higher quantities of SMN2 are associated with reduced disease severity in SMA.
Considering the broad roles of the SMN protein, SMN deficiency can contribute to various other health problems. Those with SMA type 1 may present with heart defects from birth and sensory nerve disorders.
In older individuals, SMN1 deficits increase the risk of acquiring inclusion body myositis and osteoarthritis. It is also one of several genetic deficits that play a role in the development of Amyotrophic Lateral Sclerosis (ALS).
How is SMA Inherited?
SMA is an autosomal recessive disorder, meaning both parents must possess a copy of the mutated SMN1 gene for their child to develop the disease. If both are carriers, there is a 25% chance that their children will have SMA, a 50% probability that their children will be carriers, and a 25% likelihood that their children will not have the disease or be carriers.
Spinal Muscular Atrophy Symptoms
The symptoms of SMA vary depending on the type and severity of the disease. Common symptoms include[6]:
- Muscle weakness and atrophy
- Difficulty breathing and swallowing
- Impaired motor skills, such as sitting, standing, and walking, due to weak muscles
- Fatigue and muscle cramps
- Scoliosis (curvature of the spine)
- Trouble with fine motor skills, including the ability to write and grasp objects
- Mild tremors or muscle twitches
- Sensory disturbance, including numbness and tingling sensations
- Slower development
Does Spinal Muscular Atrophy Affect the Brain?
SMA primarily influences the motor neurons in the spinal cord, yet it can also affect the brain in some cases. Children with Type 1 SMA may experience developmental delays and cognitive impairment[7], while adults with Adult-Onset SMA may experience changes in mental function.
What is the Difference Between SMA and ALS?
SMA and ALS (Amyotrophic Lateral Sclerosis) are both motor neuron diseases, but they have different causes and affect different types of motor neurons. A mutation in the SMN1 gene causes SMA, which primarily affects the motor neurons in the spinal cord. In contrast, ALS is the result of multiple genetic and environmental factors and affects both the upper and lower motor neurons.
How is Spinal Muscular Atrophy Diagnosed?
SMA is usually diagnosed through physical exams, medical history, and diagnostic tests. These may include[8]:
- Blood tests revealing high creatine kinase levels, evidence of muscle breakdown
- Nerve conduction studies
- Electromyography (EMG)
- Enzyme and protein blood tests
- Muscle biopsy
Genetic testing can confirm the diagnosis and ascertain the subtype of SMA.
Can Spinal Muscular Atrophy be Diagnosed During Pregnancy?
Yes, SMA is diagnosable during pregnancy through prenatal testing[9]. Two standard prenatal testing methods for SMA are amniocentesis and chorionic villus sampling (CVS).
- Amniocentesis involves analyzing an amniotic fluid sample from the uterus and testing it for the presence of the mutated gene.
- CVS involves removing a sample of cells from the placenta and testing them for the mutated gene.
Spinal Muscular Atrophy Treatment
Currently, there is no foolproof cure for SMA. Treatment options are available that can manage the symptoms and improve the quality of life.
Starting SMA treatment as early as possible offers the best chance of preserving motor neurons and achieving optimal outcomes. Disease-modifying therapies can significantly alter the disease trajectory, allowing children to reach developmental milestones they might not have otherwise.
Treatment often requires a multidisciplinary team, including neurologists, therapists, respiratory specialists, nutritionists, and others, to tailor treatment plans and address the multifaceted needs of individuals with SMA.
Gene Therapy
Gene therapy is a promising SMA treatment that replaces the mutated gene with a healthy copy. Zolgensma is one of the first commercially available gene therapies for SMA patients.
- Zolgensma (Onasemnogene abeparvovec-xioi): This one-time intravenous infusion delivers a usable version of the SMN1 gene into motor neurons using a virus-based delivery system. By replacing the faulty gene, gene therapy aims to restore SMN protein production, potentially halting disease progression and improving motor function[10]. This treatment was approved by the FDA in 2019 for the treatment of SMA in children under 2 years of age[11].
Spinal Muscular Atrophy Modifiers
Spinal Muscular Atrophy Modifiers are medications that can help increase the production of essential proteins and improve muscle function. These include Nusinersen (Spinraza) and Risdiplam (Evrysdi).
- Nusinersen (Spinraza): Injected intrathecally (into the spinal fluid), it modifies the processing of the SMN2 gene, increasing functional SMN protein levels[12]. Nusinersen slows disease progression and can lead to significant gains in motor skills, mainly when initiated early.
- Risdiplam (Evrysdi): A daily oral medication with a similar mechanism to Nusinersen, it targets SMN2 gene function to enhance SMN protein production[13].
Supportive Therapy and Assistive Equipment
Physical and occupational therapy work together to help maximize functional abilities, prevent complications like joint contractures, and boost independence. Physical therapy focuses on muscle strengthening and range of motion, while occupational therapy addresses activities of daily living.
Assistive equipment like wheelchairs, braces, and walkers provide greater mobility and participation[14]. Therapists can help patients to adjust to living with these devices.
Respiratory Support
Due to weakened respiratory muscles, supportive devices may be crucial for breathing support. Respiratory therapy can preserve lung function and improve oxygenation[15].
Many affected individuals do not require invasive respiratory assistance and may only need assistance occasionally (e.g., during sleep or illness). Non-invasive devices, such as BiPAP machines, are often sufficient, delivering oxygen through a facemask.
Invasive ventilation refers to an endotracheal tube that requires surgical insertion into the windpipe. This is useful for severe respiratory collapse, as seen in severe cases where the muscles are too weak to perform the contractions necessary for breathing.
Nutritional Management
Maintaining adequate nutrition is essential in SMA. Nutritionists work closely with individuals and families to address potential challenges with swallowing and ensure sufficient caloric intake. Common suggestions include[16]:
- Consuming smaller meals and a diet low in fat to avoid reflux
- Opting for soft food that is easier to chew and swallow
- Avoiding choking hazards and aspiration risks, such as thin liquids
Enteral nutrition (feeding tubes) or parenteral nutrition (intravenous feeding) may be necessary in severe cases.
Surgery
Surgical intervention can manage spinal curvature (scoliosis), a common complication of SMA. Surgery for scoliosis can improve posture, sitting balance, and respiratory function[17].
Several surgical options exist for treating scoliosis in SMA patients. Spinal fusion surgery involves permanently connecting vertebrae to halt further curvature. This is typically reserved for those that have stopped growing.
For younger patients, growing rods attached to the spine or vertical expandable prosthetic titanium ribs (VEPTRs) attached to the ribs or spine can straighten the spinal column while accommodating growth. However, growing rods and VEPTRs require regular lengthening procedures as the child develops.
In other cases, hip dislocation and congenital heart defects may require surgical intervention to treat as well.
Spinal Muscular Atrophy Prognosis
The prognosis for SMA varies depending on the type and severity of the disease. Children with Type 1 SMA have a shortened life expectancy, while those with Type 2 and Type 3 SMA may have a normal lifespan with adequate treatment and symptom management. Those with Adult-Onset SMA may experience a gradual decline in muscle function over time.
Living with SMA
Living with SMA can be challenging, but with proper treatment and management, many people with the disease can lead fulfilling lives. It is important to work closely with a healthcare team to develop a treatment plan that meets the individual's needs and to address any complications or long-term effects of the disease.
Latest Advancements
Research into SMA is ongoing, and there have been many recent advancements in understanding and treating the disease. Some of the latest advancements include[18]:
- Neuroprotective Therapies are under development to protect motor neurons from degeneration.
- Stem Cell Therapies may be able to replace or regenerate damaged motor neurons.
- Muscle-enhancing therapies in the future may increase muscle mass in those with SMA to compensate for motor neuron loss. Myostatin inhibitors[19] (targeting muscle growth regulation) show promise in animal studies, with some in early clinical trials for SMA.
Conclusion
Spinal Muscular Atrophy (SMA) is a rare genetic disorder that degenerates spinal cord motor neurons, leading to progressive muscle weakness and destruction. It is diagnosable through a combination of physical exams, medical history, and genetic tests. Treatment options can manage the symptoms and improve the quality of the patient’s life. With ongoing research and advancements in treatment, there is hope for a better future for those living with SMA.
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