What Is Spinal Muscular Atrophy?

Overview

Many people have heard about motor neuron diseases or know someone affected by them. However, do you know the details about a specific type of motor neuron disease called spinal muscular atrophy?

Spinal muscular atrophy is a rare genetic condition that causes damage to the nerve cells found in the brain and spinal cord. It is a severe condition characterised by symptoms of muscle weakness and movement problems that progressively worsen over time. Although currently incurable, there are treatments available to help manage symptoms.

This article aims to explore all aspects of spinal muscular atrophy so that you can better understand this disease, including the signs and symptoms, how the disease is inherited, how you can get yourself or your child tested, and potential treatment options.

Introduction

Spinal muscular atrophy (SMA) is a type of inherited motor neuron disease characterised by the loss of the specialised nerve cells in the spinal cord known as motor neurons. These cells normally control movement in your body, such as movement of your arms, legs, and face, as well as muscles that control essential functions such as speaking, swallowing, and breathing. The loss of these cells leads to muscle atrophy and symptoms of progressive muscle weakness throughout the body.

SMA affects 1 in 6,000 to 1 in 10,000 individuals worldwide and is the most common genetic cause of infant mortality.¹ However, with early detection and intervention, the mortality risk of SMA can be reduced. Understanding SMA is, therefore, essential to facilitate timely diagnosis and treatment to improve the quality of life for affected individuals. 

What causes spinal muscular atrophy?

SMA is primarily caused by a genetic mutation in the Survival Motor Neuron 1 (SMN1) gene which causes a deficiency of the SMN protein which is a protein normally essential for motor neuron survival. Without sufficient levels of this protein, motor neurons in the spinal cord start to die off and communication between the brain and the muscles is impaired, resulting in the symptoms of SMA. 

SMA is inherited in an autosomal recessive manner, meaning that an individual develops SMA when they receive a copy of the mutated gene from both parents. The parents are usually genetic carriers who do not have SMA themselves and don't show any of the symptoms; they probably would not even know they are carrying this mutation. However, they can still pass on a copy of this defective gene to their child. If both parents are carriers, there is a 50% chance that their child will also be a carrier and a 25% chance that the baby will develop SMA.

Around 1 in 50 people are carriers of this mutation in SMN1 -  it is a very common mutation.² This makes it important to get genetically tested if you or your family have a known history of SMA and are planning to have a child, as the other parent might be a carrier without knowing it.

What are the symptoms of spinal muscular atrophy?

SMA can be classified into different types based on the age of onset of symptoms (the age at which an individual first shows symptoms of SMA), and the severity of the symptoms. Common symptoms include muscle weakness, low muscle tone (hypotonia), and respiratory difficulties, but the severity of these symptoms and how badly they affect an individual vary between the different classifications. Intelligence is never affected in any type of SMA, the symptoms are only physical.³

Types of spinal muscular atrophy

Type 1: Infantile-onset SMA (Werdnig-Hoffmann disease)

Type 1 SMA typically presents in the first few months of life, affecting babies less than 6 months old. It is the most severe form of SMA, with symptoms including:

• Very weak and floppy arms and legs (often described as “floppy babies”)
• Problems moving, eating, breathing and swallowing
• Unable to raise their head by themselves or sit up without support
• Weak breathing muscles can cause difficulties breathing and coughing, increasing the risk of developing life-threatening chest infections.

Type 2: Childhood-onset SMA (Dubowitz disease)

Type 2 SMA is usually diagnosed between 7 months and 2 years of age. Children suffering from this type of SMA present with less severe symptoms than Type 1:

• May be able to sit up without help but not able to stand or walk
• Arm and leg weakness 
• Hand tremors (shaking)
• May develop scoliosis (an unusual curving of the spine)⁴
• Weak breathing muscles can lead to difficulties coughing and increase the risk of chest infections.

Type 3: Juvenile-onset SMA (Kugelberg-Welander disease)

Type 3 SMA is the least severe type of SMA affecting children, with symptoms appearing in childhood or adolescence (after 2 years of age):

• Able to walk and stand without help but may have difficulties running or climbing stairs
• May have balance problems
• Shaking of fingers
• Tendency to become weaker during puberty and growth spurts

These symptoms may get worse as the children age, and some people might lose the ability to walk when they’re older.

Type 4: Adult-onset SMA

The symptoms of Type 4 SMA do not appear until adulthood. This is the mildest form of SMA and generally only causes mild problems:

• Weakness in hands and feet
• Tired, aching or heavy muscles
• Slight shaking or twitching fingers and hands
• Fatigue

Again, these symptoms get progressively worse over time, potentially impacting daily activities such as walking, dressing and bathing. However, affected individuals do not usually develop problems with breathing or swallowing. 

What is the prognosis for people with spinal muscular atrophy?

The life expectancy for an individual with SMA varies between the different types. While the less severe types 3 and 4 do not normally affect life expectancy at all, types 1 and 2 typically cause significant disability and can result in a shortened lifespan due to life-threatening complications (e.g. respiratory infections). 

Many children with type 2 SMA often survive into young adulthood, but in the past, babies with the most severe Type 1 SMA rarely survived to their second birthday. However, recent improvements in new treatments have improved this prognosis and prolonged life expectancy by slowing down or preventing the loss of further motor neurons to slow disease progression.⁵ Now, the life expectancy for some babies with Type 1 SMA who are receiving treatment has increased by years, demonstrating how early diagnosis and intervention can significantly improve the outlook for all individuals with SMA.

How is spinal muscular atrophy diagnosed?

Early diagnosis is crucial for effective management of SMA. If your healthcare providers suspect that you or your child may have or be at risk of being born with SMA based on family medical history or physical examination, they might use a range of tests for its diagnosis:

Prenatal screening

Prenatal testing can help identify SMA in an unborn child, allowing parents to make informed and often difficult decisions before the child is born. There are 2 main tests commonly used:

• Chorionic villus sampling (CVS): A small sample of cells from the placenta are collected and genetically tested between the 11th and 14th weeks of pregnancy.
• Amniocentesis: A sample of amniotic fluid is used for testing between the 15th and 20th weeks of pregnancy.

However, there are risks associated with these tests as they have been reported to slightly increase the risk of miscarriage (0.5-1% risk).^6,7

Genetic testing

If SMA is suspected, a genetic test can be used to confirm a diagnosis of SMA after birth by looking for specific mutations in the SMN1 gene from a blood or saliva sample. Genetic tests can also be used for asymptomatic individuals with a confirmed or suspected family history of SMA to test if they are carriers of the mutation. Testing is approximately 95% accurate.²

Other tests

If any of the genetic tests or physical examinations present atypical results or further investigation is warranted, other diagnostic tests may be used:

• Electromyography and nerve conduction: These tests can be used to record the electrical activity of muscles during movements to look for any abnormalities typically associated with SMA
• Muscle biopsy: A small sample of a muscle can be taken and analysed to look for SMA-specific abnormalities, as well as for markers of other neuromuscular disorders such as myasthenia gravis or muscular dystrophy
• Imaging scans: Non-invasive X-rays and MRI scans may be done to reveal any structural changes in the spinal cord and muscles

Can spinal muscular atrophy be treated?

There is currently no cure for SMA, but there is treatment and support available to manage the symptoms and improve the quality of life for those affected. Recent advancements in novel therapeutics offer the potential to slow disease progression and extend life expectancy in severe cases of SMA. 

Medications

Although there is no cure for SMA, there are a few approved drug treatments (or disease-modifying therapies) that are available and are effective in reducing disease progression to improve symptoms and the quality of life of those affected.^8,9

• Nusinersen (Spinraza): This treatment increases the production of the SMN protein to partially restore the depleted levels in SMA and prevent further loss of motor neurons and muscle function. It is given as an injection into the spine every few months. 
• Risdiplam (Evrysdil): This treatment targets the backup copy of the faulty gene (called Survival Motor Neuron 2 - SMN2) to improve SMN protein production. It is given as a liquid every day. 
• Onasemnogene Abeparvovec (Zolgensma): This is a gene replacement therapy which aims to deliver a healthy copy of the SMN1 gene to replace the faulty gene and restore normal SMN protein production. It is given as an injection and only requires a single treatment.

It is important to note that not all treatments are suitable for everyone. Suitability depends on the type of SMA you have, the symptoms you experience and your current age. Your healthcare treatment team should be able to advise on what treatments are most suitable.

Supportive care

Symptoms can be managed with supportive care to help improve quality of life. Even if medication is being given, supportive care is still important to ensure the best outcomes. 

• Assistive equipment: Mobility equipment (e.g. walking frames or wheelchairs) is useful for those who cannot walk unsupported. Splints or braces can be used to support arms and legs, and back braces for those who also suffer from scoliosis.
• Physical therapy: Exercises and stretches are important to maintain muscle function and strength, and to help prevent joints from becoming stiff to promote mobility. These can be recommended to you by a physiotherapist.
• Respiratory support: Breathing exercises can strengthen breathing muscles and make coughing easier. For more advanced cases, assisted breathing devices, such as a suction machine to clear the throat or ventilators to provide air, can also be provided. 
• Nutritional support: A dietician can offer helpful advice about feeding and diet to maintain an appropriate weight, diet and fluid intake. This is especially important for those who have difficulty feeding or swallowing, and assistive equipment such as feeding tubes can be provided. 

Emerging treatments and research

Ongoing research holds promise for new therapies and potential cures. For example, OAV-101 IT  is a gene therapy currently in Phase 3 clinical trials targeted for older individuals with Type 2 SMA. This treatment has already been shown to be effective in promoting motor function in a trial involving younger Type 2 patients. It now aims to provide treatment options for patients of all ages.

Summary

Spinal muscular atrophy is a complex genetic disorder that affects motor neurons in the spinal cord, leading to muscle weakness and other debilitating symptoms. The mutated gene can be passed on to children from asymptomatic parents who are genetic carriers, with two mutated genes required to cause the disease. Early diagnosis, ongoing research, and advancements in treatment offer hope for improved outcomes in the future. Understanding SMA is vital for healthcare providers, affected individuals, and their families, as it paves the way for better management and support for those with this condition.