Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder that causes muscle weakness and degeneration over time. There are five main types of SMA that account for 95 percent of cases – types 0, 1, 2, 3, and 4.
Type 0 is the most severe form of SMA and begins before birth. Type 4 is the mildest and begins in adulthood. Depending on the type of SMA a person has, symptoms can include respiratory weakness, problems swallowing and chewing, lack of motor function, inability to walk, or mild muscle weakness. Life expectancy is often reduced in more severe SMA types. The recent introduction of new therapies for SMA may influence the course of the disease, longevity, and disability.
Because SMA is mostly driven by genetic factors, rather than environmental, the potential use of gene therapy has been of great interest in the SMA medical community. SMA is an autosomal recessive disorder. This means that a child needs to inherit a mutant copy of the gene from both parents to display the condition. In the case of SMA, this mutation is almost always a deletion of the survival motor neuron (SMN) 1 gene on chromosome 5.
This SMN1 gene normally provides the body with instructions to make the messenger RNA (mRNA) for SMN protein. Your body needs mRNA to make proteins. Without the proper genetic instructions to make SMN protein, cells in the spinal cord begin to break down. This breakdown leads to the symptoms of SMA, including worsening motor function, muscle weakness, spine curvature (scoliosis), and other progressive SMA symptoms. Another gene related to SMN protein, SMN2, also plays a role in SMA. The more copies of the SMN2 gene a person has, the less severe their symptoms will likely be.
Keya was diagnosed with SMA Type 2 at a very early age of 10 months. Spinal Muscular Atrophy or better known as SMA is caused due to a missing human gene (or SMN 1 deletion) in the infant / adult body leading to the degeneration of nerves and muscles ( Motor neurons ) leading to gradual loss of body movements.
For SMA types 0-4, a person must inherit a mutated survival motor neuron 1 gene (SMN1) from each parent. The SMN1 gene, located on chromosome 5, is responsible for the production of survival motor neuron (SMN) protein. SMN protein is essential for the function of motor neurons – nerve cells that send signals from the brain and spinal cord to the muscles.
If motor neurons can’t signal the muscles, the muscles atrophy. Depending on the severity of the SMA type, muscle atrophy can lead to compromised respiratory and motor function. The type of SMA a person develops can be influenced by a second gene on chromosome 5 called SMN2. The SMN2 gene produces some survival motor neuron protein, but not enough for normal muscle function.
People without SMA usually have one or two copies of SMN2, though they may have more. Among people with SMA, having more copies of the SMN2 gene is associated with a less severe form of the condition. Other spinal muscular atrophy types are caused by different gene mutations.
Cases of SMA were first described in the early 1890s by Austrian scientist Guido Werdnig and German scientist Johan Hoffmann, leading to the name Werdnig-Hoffmann disease for what is now known as SMA type 1. The first cases of severe SMA in babies were identified around the same time, in 1899 and 1903. Milder forms of SMA, what might now be considered types 3 or 4, were first described in the 1950s.
The classification system used today to describe SMA types 0-4 was developed in 1991. Scientific understanding of SMA improved greatly in 1995 when researchers led by French geneticist Judith Melki discovered that 95 percent of all SMA cases are caused by a mutated or deleted SMN1 gene. The same research team discovered the SMN2 gene, which is sometimes referred to as the SMA “back-up gene.”
Discovering the role of the SMN genes opened the door for new diagnostic tools and research. Before identifying the SMN1 gene, SMA was diagnosed based on signs and symptoms of disease, rather than genetic testing that can confirm the presence of a genetic mutation. The SMN gene breakthrough also allowed scientists to begin animal experiments to expand research on the genetic factors that influence SMA. Improved understanding of the genetic pathology of SMA opened the doors for clinical trials, which were rare before the 1990s.
Clinical trials for SMA have led to improvements in treatment options, including the first SMA treatment approved by the U.S. Food and Drug Administration (FDA) in 2016 – Spinraza (nusinersen). A second treatment for SMA in children under age 2, Zolgensma (onasemnogene abeparvovec-xioi), was approved in 2019. Finally the third treatment, with an oral tonic called Risdiplam ( Evrysdi) released in 2020.
SMA is a rare disease. It occurs in about 1 out of every 11,000 births world over. About 1 in 54 people in this world, is a carrier for SMA, though this rate varies by ethnic background. While SMA impacts a small number of people, it is the top genetic cause of infant mortality.
There are five main types of SMA – types 0,1,2,3, and 4 – that comprise 95 percent of SMA cases. These types of SMA are all caused by a mutation on the SMN1 gene. Types 0-4 are differentiated by age of onset and severity.
Type 0 is among the rarest and severest forms of SMA. It affects babies before they’re born. Infants with type 0 have profound muscle weakness and significant breathing difficulties, which can severely curtail life expectancy.
Type 1, also called Werdnig-Hoffmann disease, comprises about 45 percent of all SMA cases. Type 1 usually impacts babies before they reach 6 months of age. Babies with type 1 have significant muscle weakness and problems breathing, sucking, and swallowing. Breathing problems contribute to a diminished lifespan – babies with type 1 SMA often do not live past age 2.
Type 2 accounts for about 20 percent of SMA cases. Symptoms generally appear in early childhood, between 6 months and 2 years old. Children with type 2 often develop the ability to sit up on their own but they rarely develop the ability to stand and do not develop the ability to walk. People with type 2 can live into young adulthood or longer with the right treatment and therapies.
Type 3 (Kugelberg-Welander disease) develops between 18 months and 30 years old. This less severe form of SMA accounts for 30 percent of cases. The first indications of SMA type 3 may be muscle weakness in the legs that causes falls and makes stair climbing difficult. Type 3 does not usually cause respiratory problems. While people with type 3 experience muscle degeneration, they have an average life expectancy.
Type 4 develops in adulthood, usually after age 35, and causes mild impairment. The first symptoms adults who develop type 4 may notice include tremors in the hands, a feeling of heaviness in the muscles, numbness, and muscle cramping. People with SMA type 4 have a normal life span and tend to remain mobile into their older age.
There are several other very rare types of SMA, including SMA with respiratory distress (SMARD) and distal SMA.
Spinal muscular atrophy is usually diagnosed through genetic testing. The genetic test for SMA looks for mutations on the SMN1 gene on chromosome 5. Until recently, genetic testing was usually only conducted if a person showed symptoms of SMA or if there was a family history of the condition.
Beginning in 2018, the United States Department of Health and Human Services added SMA to their list of conditions newborns should be screened for in their first 48 hours of life. As of January 2020, 17 states include SMA as part of routine newborn screening.
Before genetic testing was available, SMA was diagnosed via a muscle biopsy. If SMA was suspected, doctors would remove a tiny piece of muscle tissue for evaluation in a lab and perform an electromyogram (EMG) to evaluate the electrical activity of muscles. Muscle biopsy and EMG may still be used on occasion if genetic testing is inconclusive.
Muscle weakness (hypotonia) is the primary symptom of every type of SMA. Muscle weakness can impact several functions. Sucking, Chewing and Swallowing Difficulty sucking, chewing, and swallowing are most prevalent in babies and children with severe forms of SMA. Eating difficulties are the result of muscle weakness in the throat and mouth. A feeding tube may be necessary to ensure infants and children with SMA receive adequate nutrition.
Motor Skills and Mobility Motor skill development and mobility is depending on SMA type. Babies and children with SMA type 0 and type 1 will never develop the ability to sit up unsupported. Children with type 2 may learn to sit up but may lose that ability as SMA progresses. Occasionally, children with SMA type 2 develop the ability to stand.
Depending on age of onset, those with SMA type 3 can develop the ability to stand and walk, though these abilities may be compromised over time. Adults with type 4 generally only experience muscle weakness that impacts mobility in their older age. Respiratory Function Respiratory weakness can make it difficult for people with SMA to effectively cough to clear secretions from the lungs and can also put them at risk for aspiration. Inability to cough and aspiration increase the risk of chest infections like pneumonia.
Other Symptoms There are many other SMA symptoms that can impact function and quality of life. They include: Scoliosis (curvature of the spine) Hand tremors Tongue fasciculations (tongue quivering) Joint contractures (joint shortening and tightening) Bone fractures Depression.
There are three disease-modifying therapies available for SMA — Spinraza (nusinersen) and Zolgensma (onasemnogene abeparvovec-xioi). The FDA approved Spinraza in 2016 and Zolgensma in 2019. Both drugs are forms of gene therapy. Finally the third treatment, with an oral tonic called Risdiplam ( Evrysdi) released in 2020.
People with SMA may be eligible to participate in clinical trials to receive access to new treatments. Respiratory Support Breathing support can be critical for people with more severe forms of SMA. Breathing problems can be addressed with noninvasive or invasive ventilation support. Noninvasive forms of ventilation support are used as needed and can be removed. A bilevel positive airway pressure (BiPAP) machine is a noninvasive option often used for breathing support while sleeping. Ventilation supports that penetrate the body are available if noninvasive options aren’t sufficient. Examples include an endotracheal tube (tube that goes through the trachea to the lung) that can be used short-term and a tracheostomy (surgical placement of a breathing tube in the trachea).
In addition to breathing support machines, respiratory therapy can help strengthen weak intercostal muscles. Feeding Support Feeding tubes may be necessary in cases where muscle weakness impacts a person’s ability to chew or swallow. Some feeding tubes are placed surgically through the skin and some are placed through the nose. They may go to the stomach or the small intestine.
Other Treatments Physical therapy can help people with SMA maximize physical function and strength, prevent falls, learn to use mobility aids, prevent or manage contractures, and improve range of motion. Occupational therapy can help people with SMA perform daily activities. Scoliosis treatment, such as braces or surgery, can help address breathing problems that may result from the curvature of the spine.
Spinal muscular atrophy has its most profound effects on the muscles, and SMA symptoms like muscle weakness (hypotonia) can lead to serious complications in the musculoskeletal system.
Scoliosis is a complication of SMA so common that it is often considered a symptom. Scoliosis is most common in SMA type 1 (Werdnig-Hoffmann disease) and type 2 and also affects people with type 3 (Kugelberg-Welander disease). In people with SMA, the muscles are too weak to hold the spine in the correct alignment, and gravity slowly pulls the curve of the spine into a side-to-side conformation. About 90 percent of children with SMA develop scoliosis. In children with SMA, scoliosis develops on average between ages 6 and 8, but onset can be as early as 8 or 9 months of age. Age of onset is later in children who continue to be able to walk. Scoliosis may be treated with bracing, surgery, or an implanted vertical expandable prosthetic titanium rib (VEPTR) device.
Scoliosis can cause or worsen respiratory dysfunction, affect balance while sitting, interfere with use of the arms, and change appearance. Other disorders of spinal conformation can occur along with scoliosis. In kyphosis, the upper section of the spine curves back, forming a hunched shape. In lordosis, the spine curves forward or inward. The pelvis can also become tilted, a condition known as pelvic obliquity. About one-third of people with SMA have kyphosis, lordosis, or pelvic obliquity as well as scoliosis. Pelvic obliquity can, in turn, lead to hip dislocation or subluxation (partial dislocation).
Hip dislocation is less prevalent in people with SMA who continue to stand or walk. Some people with SMA who experience hip dislocation have hip surgery to reduce pain and pressure and improve balance.
If people with SMA lack the muscle tone to move their joints through the full range of motion, they may develop joint contractures – a situation where joints become too tight to move. Joint contracture can become permanent and limit movement. Splints, braces, and physical therapy or occupational therapy may help prevent joint contractures.
In some people with SMA type 2, problems with the jaw may develop. If range of motion is lost in the mandibular joints (hinges of the jaw), opening of the mouth may be limited. Respiratory Complications in SMA In cases of SMA type 1 and SMA type 2, weak intercostal muscles (located between the ribs) and a relatively stronger diaphragm can lead to the development of a bell-shaped chest and pectus excavatum (sunken chest). Scoliosis can also contribute to distorting the shape of the chest.
Changes to the shape of the chest compromise breathing and can lead to chronic respiratory failure, which can become life-threatening without treatment. Recurrent respiratory infections are common complications of SMA due to compromised respiratory function and impaired coughing ability. Treatments for respiratory complications in SMA include noninvasive breathing support, invasive breathing support, respiratory therapy, and the implantation of a VEPTR device.
Cardiovascular Conditions Apart from complications related to the muscles and skeleton, abnormalities of the cardiovascular system (heart and blood vessels) are some of the most frequently reported comorbidities in people with SMA. Some researchers suspect that the genetic mutation on the survival motor neuron (SMN1) gene that results in deficiency in SMN protein — the cause of SMA symptoms — may also lead to effects in the cardiovascular system.
Cardiovascular disorders differ by spinal muscular atrophy type. People with type 1 are more likely to have structural abnormalities of the heart such as changes to heart valves or septa (walls dividing the heart chambers). Arrhythmias – disturbances to heart rhythm – are seen in SMA types 1, 2, and 3.
Managing Related Conditions To Improve Quality of Life There are ways to manage most complications of spinal muscular atrophy. Treating complications and comorbidities can help people with SMA maintain function and quality of life. If there are signs that you or your child may be developing a complication of SMA, talk to your doctor as soon as possible.
KHYPHOSCOLIOSIS is derived from (kyphosis + scoliosis). Its a spinal deformity resulting Keya's case from SMA and is of neuromuscular in origin.
The neuromuscular degeneration in SMA children, causes the spine to buckle, like in Keya’s case and is called Kyphoscoliosis. Which is an abnormal curvature of the spine, both from side to side and back to front. If not Surgically corrected, it would affect her internal organ function and transform a sitter child into a vegetable for whatever little life is left in them.
This surgery is a high risk one with 25% of chances the child might not make it out of operation theatre , as its conducted on General anesthesia and SMA children like Keya have weaker lungs compared to normal children.
On the brighter side, if carried out by the best, will help lived ahead with dignity and superior quality of life along with the drug Risdiplam , hoping newer better drugs are on the way.
What Is Gene Therapy?
Gene therapy is any technique that changes someone’s genetic code in order to treat a disease. Gene therapy can include replacing a mutant gene with one that is healthy, “turning off” a gene that is not working right, or introducing a new or modified gene into the body. These genetic therapies can be delivered in several ways, including using a modified version of a virus, called viral vector technology, which is sometimes used in vaccines.
How Can People With SMA Benefit From Gene Therapy?
Gene therapy has the potential to change the lives of individuals with SMA, particularly if the treatment is given early. People with SMA can benefit from gene therapy because SMA is a genetic disorder.
How Does SMA Gene Therapy Work?
SMA gene therapy works by targeting one of the major genes associated with the disease, notably SMN1 and SMN2. There are three SMA gene therapy methods currently approved by the U.S. Food and Drug Administration (FDA): Spinraza (nusinersen) Evrysdi (risdiplam) Zolgensma (onasemnogene abeparvovec-xioi)
Both Spinraza and Evrysdi target a process for cutting up genetic material, called gene splicing, at the SMN2 gene. Zolgensma is a replacement gene therapy that works by replacing an SMN1 gene that doesn’t work with a new, fully functional SMN1 gene.
Spinraza The FDA approved Spinraza for use in December 2016.
It can be used to treat all types of SMA. Spinraza is a piece of RNA genetic material that blocks the process that creates a dysfunctional SMA protein and allows the cells to make the functional SMN protein instead. By increasing the production of this normal SMN protein in the cell, it prevents the loss of cells in the central nervous system. Spinraza is administered by injection into fluid surrounding the spinal cord. Injections are done at a hospital or clinic. After the initial four-dose treatment regimen, Spinraza is given every four months. The most common side effects found in the clinical trials on Spinraza were upper respiratory infection, lower respiratory infection, and constipation.
Evrysdi Evrysdi is the newest gene therapy and the first FDA-approved oral drug to treat SMA. The FDA approved it for use in August 2020 for people with SMA types 1, 2, and 3.
Similar to Spinraza, Evrysdi contains an SMN2-directed RNA splicing modifier and promotes the formation of functional SMN protein. However, this newer formulation has more widespread effects throughout the body than Spinraza. Research in animals has shown that the levels of SMN protein in the blood may be a biomarker (a molecule that represents the effect of a disease or treatment) of Evrysdi function. This is because levels of SMN protein in the blood are increased by Evrysdi in a similar manner to other tissues and organs in the body, including the brain, heart, and spinal cord. This means that a blood draw might be used to monitor the effectiveness of Evrysdi for each individual with SMA. This drug is given orally at home, once per day. The most common side effects of Evrysdi include fever, diarrhea, rash, ulcers of the mouth area, joint pain (arthralgia), and urinary tract infections.
Zolgensma The FDA approved Zolgensma in May 2019
for use as gene therapy for all types of SMA in children under the age of two. Zolgensma uses a viral vector and targets the SMN1 gene. This viral vector is used to deliver a fully functional copy of the human SMN1 gene into the motor neuron cells. Zolgenesma is a one-time, intravenous treatment. The most common side effects of Zolgensma are elevated liver enzymes and vomiting.
Outlook for Gene Therapy Methods in SMA
The future is promising for SMA gene therapy methods. Just a few years ago, there were no preventive treatments for SMA. Now, children with known genetic risks can be treated, and the harmful symptoms associated with SMA can be partially prevented or delayed. Although gene therapy isn’t a cure, it is a promising step in the right direction.
Recent interview with Jacqueline Glascock, Ph.D., the director of research programs at Cure SMA, an nonprofit organization in Elk Grove, Illinois, that funds research into spinal muscular atrophy (SMA) and advocates for families and patients.
In this video, Glascock discusses SMA and her organization, the three current therapies for the disease, and a combination therapy approach to the disease.
#RepublicTV #RepublicTVLive #LiveTV Cure SMA India Fights For Easy Access To Treatment, Campaigners Seek Govt Intervention.
Keya's life-saving SMA treatment costs INR 80 lacs / year for life. Thanks to your valuable support, Keya is receiving treatment since Jan 2022.
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