Spinal Muscular Atrophy

What is Spinal Muscular Atrophy?

Spinal muscular atrophy (SMA) is a group of inherited diseases that causes the breakdown of nerve cells in the spinal cord which contributes to muscle weakness and shrinking. Mainly, these diseases damage alpha motor cells, resulting in muscle weakness that usually starts close to the body. SMA is typically caused by a missing piece in a specific gene called SMN1 and this is present in 95% of SMA cases. Ranked behind cystic fibrosis, SMA is the second most common cause of death related to inherited diseases, affecting roughly 1 in every 6000 to 11000 people.

This article will mainly focus on this cause of SMA, while also mentioning other potential causes. SMA varies greatly in how it shows up in different individuals. Symptoms can start as early as birth and be severe, leading to death within weeks, or can appear during adulthood and be milder. The earlier the symptoms appear, the worse the overall health outcomes are likely to be. Different types of SMA are categorized based on the severity of the symptoms and when they first appear in life.

SMA was first identified in the 1890s by Guido Werdnig and Johan Hoffmann who described cases of the disease, including two severe cases amongst brothers. The most severe type of SMA, known as type I, is sometimes called Werdnig-Hoffmann disease after these early researchers. A milder form of SMA (type III) was described by Kugelberg and Welander and is sometimes named after them as Kugelberg-Welander disease.

What Causes Spinal Muscular Atrophy?

Spinal muscular atrophy (SMA) is usually caused by a genetic issue on chromosome 5q13 where a gene called SMN1 is missing. However, this doesn’t fully explain why people with SMA can have symptoms of different severity.

This could be due to the existence of two parts of the SMN gene: the first part (SMN1) and the second part (SMN2). The number of SMN2 that a person has can vary.

SMN1 works to create a complete mRNA, a molecule that carries genetic information. This mRNA can then make the important SMN protein. On the other hand, SMN2 only makes complete mRNA around 10 to 15% of the time. This means that far fewer SMN proteins are made from SMN2.

SMN2 is similar to SMN1, but with one small change. This change sometimes causes a part of the mRNA called exon 7 to be removed during the process of making mRNA, resulting in shortened, non-working proteins.

Patients with SMA don’t have SMN1 and so depend on SMN2 to make the SMN protein to help their motor neurons (nerves controlling muscles) function and continue living. There seems to be a link between the number of SMN2 and how severe the SMA is; type 1 SMA patients usually have 1 to 2 copies of SMN2 and type 4 SMA patients usually have 3 to 5 copies.

However, the link isn’t perfect as people with SMA can have different amounts of SMN protein. This can be because of changes in SMN2, so someone with a small number of SMN2 might have milder symptoms than expected.

Risk Factors and Frequency for Spinal Muscular Atrophy

Spinal Muscular Atrophy (SMA) is a condition that affects around 1 in 6,000 to 11,000 people. Among the general population, 1 in 40 people carry the gene mutation that can cause SMA. However, the frequency of this condition varies depending on one’s ethnicity. For example, it is more common in people of white ethnicity, who have a rate of 8 cases per 100,000 people, compared to people of black or mixed ethnicity, who have approximately 1 case per 100,000 people. Interestingly, there should technically be more live births with SMA based on the number of carriers, but one theory suggests that fetuses with no copies of the SMA-causing genes may not develop, as observed in other species.

Signs and Symptoms of Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) varies clinically and is classified into different types. Importantly, regardless of type, cognitive abilities are generally not affected; patients typically have average or even above-average intelligence. Here’s a brief overview of the main types of SMA:

Type 0 (or Type 1a, congenital SMA) – Patients show signs right from birth, with low muscle tone, severe weakness, rapid breathing problems, and usually decreased fetal movements. It’s a rare condition, and sadly, most infants don’t survive past the first month.
Type I (or Werdnig-Hoffman disease, ‘non-sitters,’ severe SMA) – Symptoms typically start in the first six months of life. Infants have little head control, low muscle tone, and no reflexes. Their weak chest muscles and stronger diaphragm lead to unusual breathing patterns. Swallowing can be difficult, leading to problems like malnutrition and choking. Over time, they may develop facial muscle weakness, but their thinking ability remains unaffected. Sadly, without breathing assistance, many children do not live past the age of two.
Type II (or Dubowitz disease, ‘sitters,’ intermediate SMA) – This type shows up between 6 to 18 months and affected children can sit but not walk. They have weak muscle tone, absent reflexes, and they lose muscle strength over time. Notably, their leg muscles weaken more than their arm muscles. As they get older, they may suffer from curvature of the spine and difficulty breathing; these problems are key contributors to early death. Most survive well into their 20s, with some living even longer.
Type III (or Kugelberg-Welander disease, ‘walkers,’ mild SMA) – Symptoms start to show after 18 months. Patients can walk but may need a wheelchair as their disease progresses. Their leg muscles are more affected than their arms, similar to Type II. However, they generally don’t suffer from breathing difficulties, and their lifespan is typically normal.
Type IV (or adult SMA) – This is the mildest form of SMA and starts in adulthood (21 years or older). Patients can walk but will develop progressive weakness in their legs over time. Like Type III, their lifespan typically isn’t affected.

Testing for Spinal Muscular Atrophy

If a doctor suspects that someone may have Spinal Muscular Atrophy (SMA) after closely reviewing their medical history and doing a thorough physical exam, they usually rely on genetic testing to confirm this diagnosis.

Two methods used for genetic testing include the Polymerase Chain Reaction (PCR) or Multiplex Ligation Probe Amplification (MLPA). These methods can identify a particular type of abnormality called a homozygous exon 7 deletion in the SMN1 gene, which is associated with SMA. This test is pretty reliable – it can diagnose with SMA about 95% of the time and misdiagnose SMA in only 0-5% of cases.

However, around 5% of individuals with SMA show a different type of abnormality and have one exon 7 deletion in the SMN1 gene along with another unusual point mutation. In these cases, an additional process called SMN2 detection is usually performed at the same time. This method gives doctors additional information about the patient’s prognosis – in general, more copies of SMN2 are associated with less severe forms of SMA.

If for some reason the initial genetic testing doesn’t detect a homozygous SMN1 gene exon 7 deletion, there are other types of diagnostic tests available:

* Creatinine kinase – looks at muscle damage. The result is usually normal, although sometimes it can be slightly elevated.

* Nerve conduction studies – these check the nerves’ ability to send electrical signals. While the sensory nerves (those that manage sensation) usually show normal action potentials, motor nerves (those that control movements) may show reduced motor action potentials.

* Needle electromyography (EMG) – this test measures the electrical activity within muscle cells. In SMA type I, this test shows that nerve cells are lost without any restoration. In SMA types II and III, the test shows a pattern of nerve disease with action potentials of longer duration, increased amplitude, and reduced recruitment.

* Muscle biopsy – this involves taking a small sample of muscle to examine under a microscope. This test has become quite outdated as a diagnostic tool for SMA due to improvements in genetic testing and less invasive testing methods. However, when performed in a patient with SMA, it reveals a pattern indicating nerve disease.

Treatment Options for Spinal Muscular Atrophy

Historically, there have not been any specific treatments for SMA (spinal muscular atrophy). The care provided to patients, especially for types 0, I, and II, was largely supportive and often required early involvement of pediatric palliative care specialists. However, new therapies have been developed recently, showing significant promise in greatly improving the quality of life and survival rates of patients with SMA I and II.

In SMA, due to a condition known as ‘restrictive lung disease’, patients have difficulty breathing, which often leads to respiratory failure and can even be fatal. This condition is commonly seen in SMA types 0, I, and II. One intervention that significantly increases quality of life and survival rate is a non-invasive method of ventilation called BiPAP (bilevel positive airway pressure). Patients who require this treatment tend to have a weak cough and are at an increased risk of respiratory problems like severe lung infections and subsequent low levels of oxygen in the blood. Physiotherapists who specialize in respiratory care are key to this process because they help with cough assessments, clear mucus, and monitor lung function in children over 5 years old. In certain situations, when non-invasive ventilation is not enough, there may be difficult discussions about the need for a tracheostomy (a surgical procedure that involves creating an opening in the neck in order to place a tube into a person’s windpipe) and permanent invasive ventilation.

SMA can also impact a patient’s digestive system. Due to the weakness in their muscles, patients may become tired quickly and have difficulty swallowing which can lead to failure to grow or gain weight and worsen muscle weakness. Other symptoms they may experience include constipation, delayed gastric emptying, and acid reflux. For type I SMA patients, doctors might consider performing laparoscopic gastrostomy (a procedure that involves the placement of a tube through the abdomen into the stomach for feeding) and Nissen fundoplication (surgery to stop acid reflux). This can improve nutritional status and decrease the occurrence of aspiration (inhaling food or drink into the lungs). Nutritionists play a crucial role for type II patients as they can help ensure optimal nutrition even if they appear to be within the normal growth range for their age.

SMA can also lead to orthopedic complications such as scoliosis (a sideways curvature of the spine), hip subluxation (partial dislocation of the hip), and a higher likelihood of fractures. Physical therapy can be crucial in preserving and optimizing function and mobility. Use of orthopedic aids like frames, wheelchairs, and orthotics can improve the quality of life and mobility of patients.

Recently, thanks to advances in our understanding of the disease and breakthroughs in genetic therapeutics, several promising drugs have emerged. For example, Nusinersen is a medication delivered into the spinal cord that enhances the functioning of the SMN2 gene, thereby increasing the levels of functional SMN protein. Clinical trials have shown that Nusinersen improves lifespan and decreases disease severity.

Another promising treatment is Onasemnogene abeparvovec. This one-time intravenous injection gene therapy uses a virus to transport the SMN1 gene into cells, allowing the body to produce the functioning SMN protein. Trials have shown that all patients treated with Onasemnogene abeparvovec were alive at 20 months, compared to an expected 8% in historical cohorts.

A drug named Risdiplam is currently under trial. This oral medication works by modifying the functioning of the SMN2 gene, which increases levels of functional SMN protein. Phase II/III trials have shown improvements in motor function for patients with type II and III SMA. This drug is currently under review for approval in the US, Europe, and the UK.

If doctors suspect Spinal Muscular Atrophy (SMA) but can’t confirm it through genetic testing, there are numerous rare conditions that could show similar symptoms. Most of these are due to genetic disorders and they can manifest with unique features not found in SMA. These are sometimes called non-5q13-associated-SMAs.

Different medical examinations like taking a detailed medical history, physical examination, testing for creatine kinase (CK), electromyography (EMG), nerve conduction tests, muscle biopsy, and MRI scans can all be crucial to reach the right diagnosis. Being referred to a geneticist can also be really helpful.

There is a broad range of potential alternative diagnoses, depending on the patient’s age. Though a detailed overview is beyond the scope here, a summarized list grouped by age is given as per GeneReviews:

Congenital (<6 months): Pompe disease, Prader-Willi syndrome, Myotonic dystrophy type 1, Sellweger spectrum disorder, Congenital myasthenic syndromes, X-linked infantile spinal muscular atrophy. Disorders regarding congenital muscles, metabolism, and mitochondria should also be taken into account.
Childhood: Botulism, hexosaminidase A deficiency, Guillain-Barré, Duchenne muscular dystrophy, Fazio-Londe syndrome, Hirayama disease
Adulthood: Amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy

What to expect with Spinal Muscular Atrophy

In the past, the prognosis of Spinal Muscular Atrophy (SMA), a condition that affects the nerve cells controlling muscle movement, was determined by its type. Type 0 was the most severe, with affected individuals typically passing away within the first months of life, while Type IV was milder and didn’t affect life expectancy.

However, new treatments have been introduced, such as Onasemnogene Abeparvovec, which can modify the course of the disease. Due to this, people with Type I SMA have been reported to live longer than in the past. So, it’s possible that the future prognosis of people with SMA could be much better with these advances in treatment. This is an area that medical professionals continue to actively study.

Possible Complications When Diagnosed with Spinal Muscular Atrophy

People with SMA (Spinal Muscular Atrophy) often face complications related to their breathing, digestion, and bone structure. These issues can significantly impact their quality of life and may even be life-threatening. For instance, they might get chest infections due to swallowing difficulties and muscle weakness which can lead to food or liquid entering the lungs. In addition, those with SMA stand a higher risk of developing metabolic acidosis, which is an excess of acid in the body that can occur during illness or fasting. While the reason for this susceptibility is not clearly understood, some believe that problems with glucose metabolism due to abnormalities in the pancreas might be contributing factors.

Common Effects on People with SMA:

Respiratory issues
Gastrointestinal complications
Orthopedic complications
Chest infections due to swallowing difficulties
Metabolic acidosis during illness or fasting

Preventing Spinal Muscular Atrophy

Genetic counseling is particularly important for diseases, like Spinal Muscular Atrophy (SMA), that largely come from inherited genes. Genetic counseling can help patients and their families make informed decisions. Since SMA follows an ‘autosomal recessive inheritance pattern’, meaning it’s one of the types of inheritance patterns for genetic diseases, siblings have a 25% chance of having the disease, 50% chance of carrying the gene without being sick, and 25% chance of neither having the disease nor carrying the gene.

Statistically, 98% of parents with a child suffering from SMA carry the gene. The remaining 2% of cases occur as a result of a new or ‘de novo’ mutation, meaning a change in a gene that happens spontaneously in the child without being inherited. Therefore, it can be beneficial for those affected by SMA and their future spouses to receive counseling before conception, and the prospective spouse should be offered gene testing.

Frequently asked questions

The prognosis for Spinal Muscular Atrophy (SMA) varies depending on the type of SMA. In the past, the prognosis was determined by the type, with Type 0 being the most severe and Type IV being milder. However, new treatments have been introduced that can modify the course of the disease, potentially improving the prognosis. With advances in treatment, people with Type I SMA have been reported to live longer than in the past, suggesting that the future prognosis for SMA could be much better.

Spinal muscular atrophy (SMA) is usually caused by a genetic issue on chromosome 5q13 where a gene called SMN1 is missing.

Signs and symptoms of Spinal Muscular Atrophy (SMA) vary depending on the type of SMA. Here is an overview of the signs and symptoms for each type: 1. Type 0 (or Type 1a, congenital SMA): - Signs appear right from birth - Low muscle tone - Severe weakness - Rapid breathing problems - Decreased fetal movements - Rare condition, with most infants not surviving past the first month 2. Type I (or Werdnig-Hoffman disease, 'non-sitters,' severe SMA): - Symptoms typically start in the first six months of life - Little head control - Low muscle tone - No reflexes - Unusual breathing patterns due to weak chest muscles and stronger diaphragm - Swallowing difficulties leading to malnutrition and choking - Facial muscle weakness may develop over time - Thinking ability remains unaffected - Without breathing assistance, many children do not live past the age of two 3. Type II (or Dubowitz disease, 'sitters,' intermediate SMA): - Symptoms appear between 6 to 18 months - Children can sit but not walk - Weak muscle tone - Absent reflexes - Progressive loss of muscle strength, particularly in leg muscles - Curvature of the spine and difficulty breathing may occur as they get older - Most survive well into their 20s, with some living even longer 4. Type III (or Kugelberg-Welander disease, 'walkers,' mild SMA): - Symptoms start to show after 18 months - Patients can walk but may need a wheelchair as the disease progresses - Leg muscles are more affected than arm muscles, similar to Type II - Generally, no breathing difficulties - Lifespan is typically normal 5. Type IV (or adult SMA): - Mildest form of SMA - Starts in adulthood (21 years or older) - Patients can walk but develop progressive weakness in their legs over time - Lifespan is typically not affected It is important to note that regardless of the type of SMA, cognitive abilities are generally not affected, and patients typically have average or even above-average intelligence.

The types of tests needed for Spinal Muscular Atrophy (SMA) include: 1. Genetic testing: This is the primary method used to diagnose SMA. It can identify a homozygous exon 7 deletion in the SMN1 gene, which is associated with SMA. Two methods commonly used for genetic testing are Polymerase Chain Reaction (PCR) and Multiplex Ligation Probe Amplification (MLPA). 2. SMN2 detection: In cases where genetic testing does not detect a homozygous SMN1 gene exon 7 deletion, SMN2 detection is performed. This additional process provides information about the patient's prognosis by determining the number of copies of the SMN2 gene, which is associated with the severity of SMA. 3. Additional diagnostic tests: If the initial genetic testing is inconclusive, other tests may be ordered, including: - Creatinine kinase: This test looks at muscle damage. - Nerve conduction studies: These check the nerves' ability to send electrical signals. - Needle electromyography (EMG): This test measures the electrical activity within muscle cells. - Muscle biopsy: This involves taking a small sample of muscle to examine under a microscope. However, this test is less commonly used now due to improvements in genetic testing.

The doctor needs to rule out the following conditions when diagnosing Spinal Muscular Atrophy (SMA): - Pompe disease - Prader-Willi syndrome - Myotonic dystrophy type 1 - Sellweger spectrum disorder - Congenital myasthenic syndromes - X-linked infantile spinal muscular atrophy - Botulism - Hexosaminidase A deficiency - Guillain-Barré - Duchenne muscular dystrophy - Fazio-Londe syndrome - Hirayama disease - Amyotrophic lateral sclerosis - Spinal and bulbar muscular atrophy

When treating Spinal Muscular Atrophy (SMA), there can be several side effects or complications that patients may experience. These include: - Respiratory issues, such as difficulty breathing, respiratory failure, and the need for non-invasive ventilation or, in some cases, a tracheostomy and permanent invasive ventilation. - Gastrointestinal complications, including difficulty swallowing, failure to grow or gain weight, constipation, delayed gastric emptying, and acid reflux. - Orthopedic complications, such as scoliosis, hip subluxation, and an increased risk of fractures. - Chest infections due to swallowing difficulties and muscle weakness, which can lead to food or liquid entering the lungs. - Metabolic acidosis, which is an excess of acid in the body that can occur during illness or fasting. The reason for this susceptibility is not clearly understood, but abnormalities in the pancreas and problems with glucose metabolism may be contributing factors.

A geneticist.

Spinal Muscular Atrophy affects around 1 in 6,000 to 11,000 people.

Spinal Muscular Atrophy (SMA) is historically treated with supportive care, especially for types 0, I, and II, which often involves early involvement of pediatric palliative care specialists. However, recent advancements in treatment have shown significant promise in improving the quality of life and survival rates for patients with SMA I and II. Non-invasive ventilation methods like BiPAP (bilevel positive airway pressure) can greatly increase the quality of life and survival rate for patients with SMA, particularly those with weak coughs and an increased risk of respiratory problems. Physiotherapists specializing in respiratory care play a key role in this process by assisting with cough assessments, mucus clearance, and monitoring lung function. In some cases, when non-invasive ventilation is insufficient, discussions about the need for a tracheostomy and permanent invasive ventilation may arise. SMA can also impact the digestive system, and treatments such as laparoscopic gastrostomy and Nissen fundoplication may be considered to improve nutritional status and decrease the occurrence of aspiration. Orthopedic complications like scoliosis, hip subluxation, and fractures can be managed with physical therapy and the use of orthopedic aids. Additionally, there are promising drugs like Nusinersen, Onasemnogene abeparvovec, and Risdiplam that have shown improvements in lifespan, disease severity, and motor function in clinical trials.

Spinal muscular atrophy (SMA) is a group of inherited diseases that cause the breakdown of nerve cells in the spinal cord, resulting in muscle weakness and shrinking. It is typically caused by a missing piece in a specific gene called SMN1, present in 95% of SMA cases. SMA is the second most common cause of death related to inherited diseases.

Muscle Atrophy Muscle Weakness Neurology Spine