SMN1 gene mutation
Related Terms
Adult onset spinal muscular atrophy, Autosomal recessive disorder, chronic SMA, hypotonia, infantile-onset SMA, intermediate SMA, juvenile SMA, Kugelberg-Welander disease, mild SMA, muscle weakness, muscular dystrophy, progressive muscle degeneration, SMARD1, SMN1 gene mutation, type I SMA, type II SMA, type III SMA, Werdnig-Hoffman disease, Wolhlfart-Kugelberg-Welander disease, X-linked infantile spinal-muscular atrophy, XL-SMA.
Background
Spinal muscular atrophy (SMA) is a group of inherited diseases that cause muscles to lose function. The progressive muscle deterioration causes weakness and eventually leads to death.
SMA affects the motor neurons, especially those in the spinal cord and brain stem. Motor neurons help convey electrical and chemical signals to and from the voluntary muscles in the body that are used for physical activities such as crawling, walking, head and neck control, and swallowing.
There are four types of SMA, which are distinguished by the age of disease onset and specific motor functions that the patient is capable of performing, indicating the severity of the disease.
SMA disorders are caused by a genetic mutation (abnormal gene) or deletion (missing gene). The gene affected is known as the survival motor neuron gene (SMN1), which is normally responsible for creating a protein necessary for motor neurons to function correctly. When SMN1 is mutated or missing, this protein is not produced, causing motor neurons to degenerate and die. When motor neurons die, they no longer signal the muscle cells, and then the muscle cells cannot function properly. When muscle cells are not being used, they become very small and begin to break down (atrophy). This is what causes the muscle weakness associated with SMA.
SMA is inherited through autosomal recessive genetic transmission, meaning that two abnormal genes are needed to result in the disease.
There are a number of diseases that involve loss of function in motor neurons. SMA is considered a rare disorder, but is more common than other disorders in this category, such as Werdnig-Hoffmann disease. About one out of every 15,000-20,000 babies born in the United States is affected by SMA. Infants, children, and adults are affected worldwide.
Various muscles throughout the body may be affected by SMA. The proximal muscles, those closest to the trunk of the body, such as in the neck, back, shoulders, or hips, are the most severely affected by the disease. The legs are generally more severely affected than the arms.
Muscle degeneration causes weakness and eventually loss of function. SMA patients experience more weakness in the legs than the arms. If the muscles in the neck or throat are affected, feeding and swallowing may become difficult. Respiratory muscles may also be affected, causing difficulties breathing and coughing and increasing the patient's risk of developing pneumonia and other lung problems.
There is currently no known cure for SMA. Generally, the younger the onset of disease, the shorter the patient's life expectancy. Treatment consists of managing the symptoms and preventing complications.
Signs and symptoms
General: Spinal muscular atrophy (SMA) affects the motor neurons, especially those in the spinal cord and brain stem. Motor neurons help convey electrical and chemical signals to and from the voluntary muscles in the body. Voluntary muscles are used for physical activities such as crawling, walking, head and neck control, and swallowing. In people with SMA, a deficiency of the survival motor neuron (SMN) protein causes motor neurons to die. This causes the voluntary muscles to atrophy, or become progressively smaller and weaker, until they can no longer perform their normal functions.
Generally, the younger a patient is when their symptoms first appear, the shorter his or her life span will be. The onset of SMA is usually sudden and dramatic. Once symptoms are observed, it can be expected that motor neuron cells will quickly deteriorate shortly after. Age of onset varies and depends on the type of SMA. Unfortunately, SMA is usually fatal and currently has no known cure.
All types of SMA include muscle weakness and poor muscle tone. SMA does not affect sensation, intellectual activity, or sexual function in patients. It is commonly observed that patients with SMA are unusually bright and sociable.
Type I: Type I (also known as Werdnig-Hoffman disease or infantile-onset SMA) is evident at birth or within the first few months of life. This is the most severe form. Symptoms include floppy limbs and trunk, feeble movements of the arms and legs, absence of reflexes, inability to move joints or lift the head. Upper body muscle weakness also creates feeding and swallowing difficulties, a weak sucking reflex, impaired breathing, and a weak cry. Type I SMA patients also experience accumulation of secretions in the lungs or throat and increased susceptibility to respiratory tract infections. Infants with type 1 SMA have a life expectancy of less than two years. However, some do survive into adulthood.
Type II: In type II (also known as juvenile SMA, intermediate SMA, or chronic SMA), symptoms are observed beginning between six and 18 months. The legs are usually weaker than the arms. Children with type II are usually capable of sitting without support, but must be placed in position. Some patients may be able to stand or walk with help.
Type III: In type III (also called Wolhlfart-Kugelberg-Welander disease or mild SMA), symptoms may begin as early as the toddler years or as late as adolescence. Children are usually able to stand alone and walk, but may have difficulty getting up from a sitting position.
Type IV: Spinal muscular atrophy Type IV, also known as adult onset spinal muscular atrophy, begins in adulthood. Symptoms, usually mild to moderate, tend to begin after age 35, and may include muscle weakness, tremors, and twitching. Adult-onset SMA is typically characterized by a slow progression, does not usually result in a complete loss of mobility, and patients usually have a normal life expectancy. Most patients with Type IV SMA do not require wheelchair assistance.
Diagnosis
General: Spinal muscular atrophy (SMA) causes progressive muscle degeneration (breakdown that leads to loss of function) and weakness. Diagnosis is made based on the onset and severity of symptoms and may be confirmed through a genetic test called the SMN gene test.
There are four diagnostically different types of SMA, which are generally determined from the physical examination evaluating the patient's degree of weakness and ability to perform normal motor functions such as sitting independently or walking. A genetic test may be performed if there is a family history of SMA, but the disease is usually discovered through routine physical examinations. Types I and II are the most commonly observed.
Clinical examination: At the onset of symptoms indicating SMA, a doctor will compile a detailed family medical history to determine the likelihood of SMA. He or she will also perform a physical examination to look for characteristic symptoms of SMA. Symptoms will vary depending on the stage of development of the patient, but generally may include muscle weakness, lack of muscle tone, and inability to perform normal motor functions. Most cases of SMA will present with some form of breathing, walking, and/or feeding difficulties.
Genetic testing: SMA is caused by genetic mutations (abnormalities) in the survival motor neuron gene (SMN1) or the absence of this gene. The SMN gene test determines whether there is at least one copy of the SMN1 gene. This is performed by taking a blood sample and using man-made gene sequences called genetic markers to examine the genetic makeup for the unique sequences on SMN1 that distinguish it from the almost identical SMN2 gene. Ninety five percent of SMA patients are missing at least one normal SMN gene sequence. Some patients inherit a mutated SMN1 gene.
The number of copies of the SMN2 gene can be used to predict the severity of the disease, since SMN2 may produce a protein that partially compensates for the loss of SMN1. The more copies of SMN2 a patient has, the less severely they will experience the symptoms and degeneration of SMA.
Other diagnostic tests: If the SMN gene test does not show abnormalities or cannot be performed, other tests may be used for diagnosis. Electromyography (EMG) involves using electrodes that measure the electrical activity of muscle. This helps distinguish SMA from other nerve or muscle disorders that may have similar symptoms. A nerve conduction velocity test (NCV) measures responses to an electrical stimulus using small shocks, which can determine how well the nerves are functioning. A muscle biopsy (sample) may also be taken and examined for the presence of degeneration. However, these tests have rarely been used since the development of genetic testing.
Type I diagnosis: Type I is the most severe and is usually diagnosed before an infant is three months old. These patients are generally unable to perform the motor functions that infants are normally capable of; they cannot lift their own heads or sit without support and do not kick their legs with the strength of a normal infant. They usually have difficulty swallowing and feeding and have rippling movements (fasciculations) of the tongue. Infants with this type of SMA have weak muscles between their ribs (intercostal muscles) and therefore breathe using the diaphragm muscles, giving the appearance that the stomach performs the breathing function and that the chest is concave (caved in).
Fifty percent of children with type I SMA do not live past two years of age.
Type II diagnosis: Type II SMA is almost always diagnosed before two years of age. Type II patients differ in motor function from type I patients in that they may be able to sit without support, though only if they are placed in position, and some may even be able to stand with support. Difficulty swallowing is not usually characteristic of this type. Children with type II SMA also have tongue fasciculations, weak intercostal muscles, and breathe with their diaphragms. They may have tremors in their fingers when they are outstretched. Most type II patients also have scoliosis (side-to-side spinal curvature).
Type III diagnosis: Type III SMA is the mildest form of childhood-onset SMA and diagnosis is usually made before age three. Unlike patients with types I and II, type III patients are able to walk, although most experience weakness. Early motor development is often normal. However, they may fall frequently when walking, have difficulty standing up from a seated or bent position, and may be incapable of running. Type III patients also have tremors in their outstretched fingers, but do not usually have tongue fasciculations. Feeding or swallowing difficulties in childhood are rare in type III patients.
Type IV diagnosis: Type IV SMA is the adult form of the disease and the most uncommon. Symptoms tend to begin after age 35. Onset of type IV SMA is usually without warning signs and the disease progresses slowly. In contrast to types I, II, and III, the muscles used for swallowing and breathing are rarely affected in type IV.
Complications
General: Spinal muscular atrophy (SMA) is a group of inherited genetic disorders that cause the muscles to degenerate (break down), leading to weakness and loss of function. While SMA does not affect sensation, intellectual ability, or sexual function in patients, complications due to muscle degeneration are severe and eventually lead to death.
SMA is caused by a genetic mutation (abnormality) that prevents the body from producing an important protein called SMN. SMN is necessary for motor neurons to function correctly. Motor neurons are cells in the spinal cord and brain stem that carry chemical and electrical signals to muscles of the body that perform functions that a person can control, such as swallowing, walking, crawling, and head and neck control. These are called voluntary muscles and are the ones most affected by SMA.
SMA disorders can have a devastating physical and emotional impact. There are some problems, however, such as feeding, breathing, and walking difficulties, which can be anticipated and addressed before they become serious concerns for SMA patients.
Pain: While most muscle degeneration associated with SMA is not physically painful, loss of muscle function decreases a patient's ability to move, which may result in painful muscle cramps.
Bone problems: The most common forms of SMA occur in young children who are still developing. As a result, the body of a child with SMA is doubly stressed during growth, first because of the loss of motor neurons and second because of the increased demands normal growth places on the nerve and muscle cells. The resulting muscle atrophy (shrinkage) often causes bone and spinal deformities that may lead to further loss of function. Almost all children with type II SMA develop scoliosis (side-to-side curvature of the spine) as they grow, resulting in need for spinal surgery or bracing. Severe scoliosis may restrict breathing and pulmonary functions. Also, SMA patients have decreased bone density, which increases their risk of fractures.
Breathing and feeding difficulties: Degeneration and death of the motor neurons cause muscle weakness and atrophy and can lead to loss of the ability to breathe or swallow. In type I and some type II patients, the intercostal muscles (muscles between the ribs), which are responsible for expanding the chest, are very weak. Therefore, patients must use the diaphragm muscle to perform most breathing functions. As a result, the lungs may not fully develop, the cough is very weak, and it may be difficult to take deep enough breaths while sleeping to maintain normal oxygen and carbon dioxide levels. Those patients who breathe with their diaphragms have an increased risk for complications from respiratory infections.
Children with types I and II SMA also suffer degeneration of the muscles involved with chewing and swallowing. This creates feeding difficulties and may make these children more susceptible to aspiration (inhalation of material into the windpipe and lungs) and pneumonia.
Morbidity/Mortality: SMA disorders can be fatal, causing the deaths of more infants and young children than any other genetic disease. Although most cases of SMA are fatal during childhood, some SMA patients do survive into adulthood and even old age.
The lifespan of an SMA patient depends greatly on the severity of the disorder in each individual. Of the four types of SMA, the first two types occur most often and at the youngest ages. Of all children with type I SMA, 50% do not live past two years of age.
Treatment
General:
Spinal muscular atrophy (SMA) is a group of fatal genetic disorders that cause progressive muscular degeneration and loss of function. There is currently no known cure for SMA. Treatment consists of managing the symptoms and preventing complications. Each type of SMA has variability among patients. This should be considered when planning an individual's care.
Caregivers are encouraged to raise children with SMA in the same way that they would a child not affected with the disorder. It is important to engage children in as many age-appropriate activities as possible. While this may require adapting activities to a child's ability, it helps children with SMA to reach their full potential of development. Adult-onset cases of SMA generally progress more slowly and may not require as serious a degree of medical care.
Gene replacement strategies have been researched preliminarily in animals. The current treatment for SMA consists of prevention and management of symptoms and complications. It is likely that gene replacement for SMA will require many more years of investigation before it may be applicable to humans. Research approaches have been aimed at searching for drugs that increase survival motor neuron (SMN) protein levels, enhance residual SMN function, or compensate for its loss. While several promising drugs have been identified in laboratory experiments, there is currently no drug known to alter the course of SMA.
Feeding difficulties:
Diet: Children with types I and II SMA often experience feeding difficulties because the muscles involved in chewing and swallowing are affected. Dietary management is important for patients of all types of SMA in order to promote physical development and potential for mobility. When the body is deprived of calories and protein, it begins to feed on its own muscles for nourishment. For this reason, maintaining adequate nutrition is very important for children with SMA.
A speech pathologist may be able to identify whether certain foods may be particularly hazardous to a patient with SMA. To do this, a special X-ray called a "swallowing study and cine esophagram" is used. This allows the specialist to observe how a child swallows various forms of food substances such as solids, liquids, and purees. Based on these observations, a special diet may be created to ensure optimal safety and nutrition for the child.
Alternative feeding methods: Children who cannot swallow liquids or semisolids may be fed through alternative methods, such as nasogastric (NG) tubes or gastrostomy tubes (PEG). An NG tube is inserted through the nose, down the esophagus (food pipe), and into the stomach. These can be inserted by trained caregivers at home. A PEG tube is inserted by a surgeon and allows liquids to be placed directly into the stomach. Alternative feeding methods are a fairly simple and very effective means of dealing with a potentially serious problem.
Mobility:
Progressive weakness and loss of function of the arms and legs in SMA patients may create other problems such as tightness of the joints (contractures) and painful muscle cramps. Range of motion techniques as part of a physical therapy program may help prevent these problems. A physical therapist can train caregivers and patients in these techniques. Contractures may also be treated or prevented through splinting of the ankles and/or wrists during sleep.
It is important to assist children in getting into an upright position at the earliest possible age. Standing is important in development because it allows for better breathing, improved bowel function, and greater mobility. This may be achieved through the use of standing aids.
Children with types I or II SMA almost never achieve independent standing or walking. Sitting or standing with special supports may therefore be an important part of a daily therapy program.
There are several options available for standing aids. These may include a standing frame and/or parapodium or weight-bearing braces for feet and ankles. Use of the appropriate type of assistive device or walker with braces is important and various options should be explored with a physical therapist. Independent mobility usually requires the use of a power wheelchair. This enables patients to participate in age-appropriate activities with their family and peers.
Scoliosis (side-to-side curvature of the spine) usually occurs in children with types I and II SMA and in some children with type III. The degree of severity of scoliosis is a factor in treatment, but precautions must be taken early in the development of scoliosis in order to prevent complications such as breathing restriction and loss of pulmonary function. Options for managing scoliosis may include custom seating systems, seating aids, and a body jacket. Spinal fusion surgery may be necessary.
Patients with adult-onset SMA are more aware of their physical weaknesses and limitations. It is important for these patients to work together with a physician and physical and occupational therapist to work out the best possible treatment program.
Breathing support:
Children with type I and type II SMA are especially vulnerable to breathing complications. A regular program of respiratory therapy and breathing exercises may be very helpful for these patients. Precautions to avoid illness, including yearly immunizations, are important. Prevention and early treatment of respiratory infections are a major issue, especially in patients with type 1 SMA, since pneumonia is the cause of death in the majority of cases.
In severe cases, doctors may opt to start aggressive mechanical support for the patient when their breathing muscles begin to fail. This usually entails using a ventilator. Although medically mechanical breathing support is not complicated, it can be emotionally distressing for a child. Advances in technology have made using a mechanical ventilator considerably easier and more convenient. A ventilator may be set to deliver a specific size breath at a set number of breaths per minute. Mechanical ventilation can be delivered with a nose mask, a mouthpiece while awake, or through a tracheostomy tube. A tracheostomy tube is inserted through a surgical hole in the neck to the large airway (trachea). This tube bypasses the mouth and vocal cords and goes directly from the skin to the trachea (wind-pipe). A negative pressure ventilator is another option that may also be set to deliver a specific number of breaths per minute.
A less invasive method of breathing support includes a device called a "negative pressure" ventilator and external positive airway pressure support system or Bi-level Positive Airway Pressure (BI-PAP). The use of a BI-PAP machine has been especially helpful for many children with SMA. Air is mechanically directed through the nostrils through a fitted mask and gives the same benefits as a mechanical ventilator. BiPAP provides a higher volume of air into the lungs during inhalation and inflates the lung greater than the person can on their own. During exhalation, the BiPAP pressure drops so that air can passively leave the lungs. The BiPAP machine can sense when the person is taking a breath and can synchronize with the individual. A respiratory rate is also set so that the BiPAP gives a minimum number of breaths per minute. If a person breathes above that rate, the BiPAP will deliver more breaths. CPAP (continuous positive air pressure) should never be used in patients with SMA.
Other options for treating respiratory problems include simple chest physiotherapy (CPT) to help ease symptoms of coughs and colds. CPT is a method of clearing the lungs of accumulated mucus by using positioning and clapping on the chest to assist in loosening secretions.
Supplemental oxygen may be given through a small nasal tube, usually at night. This is beneficial for children with weak respiratory muscles who breathe using the muscles of the diaphragm, which decreases their oxygen intake. Respiratory distress can be monitored by measuring the level of oxygen saturation in the blood using a tool called a pulse oximeter. A small clip or tape with a red light and a sensor is placed on the patient's finger or toe to determine the oxygen saturation. Before giving oxygen treatment, it must be determined that the brain is not using low concentrations of oxygen in the blood in order to determine how rapidly a child must breathe. Treatment should be preceded by an evaluation by a pulmonary specialist.
Cognitive support:
Intellectual ability is unaffected by SMA, and while motor development is limited, a number of techniques may be used to cognitively and emotionally stimulate infants with SMA. Using balloons and feathers as toys allows children a feeling of independence and accomplishment. Reaching games are a form of physical or occupational therapy that can be very helpful.
Adults with SMA benefit greatly from the use of assistive technology, such as speech recognition software. These devices allow people with even very limited mobility to use a computer to read, write, communicate, play video games, and access environmental controls.
Medications:
Some drugs may be able to increase the amount of SMN protein available to the body in SMA patients. These drugs have not yet been shown to be effective in SMA patients and may have serious side effects. Further research is needed in this area.
Integrative therapies
Note: Currently, there is insufficient evidence available on the safety and effectiveness of integrative therapies for the prevention or treatment of spinal muscle atrophy (SMA). The integrative therapies listed below should be used only under the supervision of a qualified healthcare provider and should not be used in replacement of other proven therapies or preventive measures.
Good scientific evidence:
Vitamin D: Vitamin D is found in numerous dietary sources such as fish, eggs, fortified milk, and cod liver oil. The sun is also a significant contributor to our daily production of vitamin D, and as little as 10 minutes of daily exposure is thought to be enough to prevent deficiencies. The term vitamin D refers to several different forms of this vitamin. Two forms are important in humans: ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). Vitamin D2 is synthesized by plants. Vitamin D3 is synthesized by humans in the skin when it is exposed to ultraviolet-B (UVB) rays from sunlight, or it is supplied in the diet. Vitamin D deficiency has been associated with muscle weakness and pain in both adults and children. Limited research has reported vitamin D deficiency in patients with low-back pain.
Avoid if allergic or hypersensitive to vitamin D or any of its components. Vitamin D is generally well-tolerated in recommended doses. Doses higher than recommended may cause toxic effects. Individuals with hyperparathyroidism (overactive thyroid), kidney disease, sarcoidosis, tuberculosis, or histoplasmosis are at a higher risk of experiencing toxic effects. Vitamin D is generally considered safe for pregnant women. It may be necessary to give infants vitamin D supplements along with breast milk. The recommended intake of vitamin D for normal infants, children, and adolescents is 200 IU daily.
Unclear or conflicting scientific evidence:
Hydrotherapy: Water has been used medicinally for thousands of years, with traditions rooted in ancient China, Japan, India, Rome, Greece, the Americas, and the Middle East. There are references to the therapeutic use of mineral water in the Old Testament. During the Middle Ages, bathing fell out of favor due to health concerns, but by the 17th century, "taking the waters" at hot springs and spas became popular across Europe (and later in the United States). Water therapy may be very helpful in treating SMA as the buoyancy of the water allows movement of the arms and legs that may not otherwise be possible. It is important to ensure that the water temperature is at least 90?F and that the patient's head does not go under the water.
Sudden or prolonged exposure to extreme temperatures in baths, wraps, saunas, or other forms of hydrotherapy should be avoided, particularly with heart disease, lung disease, or if pregnant. Avoid with implanted medical devices like pacemakers, defibrillators, or hepatic (liver) infusion pumps. Vigorous use of water jets should be avoided with fractures, known blood clots, bleeding disorders, severe osteoporosis, open wounds, or during pregnancy. Use cautiously with Raynaud's disease, chilblains, acrocyanosis, erythrocyanosis, and impaired temperature sensitivity, such as neuropathy. Use cautiously if pregnant or breastfeeding. Hydrotherapy should not delay the time to diagnosis or treatment with more proven techniques or therapies and should not be used as the sole approach to illnesses. Patients with known illnesses should consult their physician(s) before starting hydrotherapy.
Physical therapy: According to the American Physical Therapy Association, the goal of physical therapy or physiotherapy is to improve mobility, restore function, reduce pain, and prevent further injury by using a variety of methods, including exercises, stretches, traction, electrical stimulation, and massage. Special tools are used, such as hot or cold packs, crutches, braces, treadmills, prosthetics, compression vests, computer-assisted feedback, lasers, and ultrasound. Patients range in age from newborns to the elderly. There is insufficient evidence for the treatment of SMA with physical therapy. Additional research is needed in this area.
Not all physical therapy programs are suited for everyone, and patients should discuss their medical history with a qualified healthcare professional before beginning any treatments. Based on the available literature, physical therapy appears generally safe when practiced by a qualified physical therapist. However, complications are possible. Treatment options should be considered carefully. Physical therapy may aggravate pre-existing conditions. Persistent pain and fractures of unknown origin have been reported. Physical therapy may increase the duration of pain or cause limitation of motion. Pain and anxiety may occur during the rehabilitation of patients with burns. Both morning stiffness and bone erosion have been reported in the literature, although causality is unclear. Erectile dysfunction has also been reported. Physical therapy has been used in pregnancy, specifically to treat women with pelvic girdle pain during pregnancy and at three, six, and 12 months postpartum. Reports of major adverse effects are lacking in the available literature, but caution is advised nonetheless. All therapies during pregnancy and breastfeeding should be discussed with a licensed obstetrician/gynecologist before initiation.
Traditional or theoretical uses lacking sufficient evidence:
Acupuncture: Acupuncture originated 5,000 years ago in China. Today, it is commonly used throughout the world. Chinese medicine theory holds that the human body contains a network of energy pathways through which vital energy, called "chi" (also spelled "qi"), circulates. These pathways are called "meridians." The meridians contain specific "points" that function like gates, allowing chi to flow through the body. Needles are inserted into these points to regulate the flow of chi. Illnesses and symptoms are thought to be caused by problems in the circulation of chi through the meridians. Acupuncture has been shown to effectively treat some health conditions, including pain. However, the mechanism of action remains unclear. There is evidence from several studies suggesting that laser acupuncture therapy may be beneficial for musculoskeletal conditions. However, due to weaknesses in study methods, as well as the wide variety of conditions in this category, it is difficult to make specific recommendations for acupuncture as a potential treatment method for SMA.
Needles must be sterile in order to avoid disease transmission. Avoid with valvular heart disease, infections, bleeding disorders or with drugs that increase the risk of bleeding (anticoagulants), medical conditions of unknown origins, and neurological disorders. Avoid on areas that have received radiation therapy and during pregnancy. Use cautiously with pulmonary disease (like asthma or emphysema). Use cautiously in elderly or medically-compromised patients, diabetics, or patients with a history of seizures. Avoid electroacupuncture with arrhythmia (irregular heartbeat) or in patients with pacemakers.
Creatine: Multiple studies suggest that creatine may improve muscle mass and strength in men and women, particularly when accompanied by increased physical activity. However, studies of creatine in athletes have found conflicting results. Scientific evidence to support the effectiveness of creatine in the treatment of SMA is currently lacking in the available literature.
Avoid if allergic to creatine or with diuretics (like hydrochlorothiazide, furosemide (Lasix?)). Use cautiously with asthma, diabetes, gout, stroke, and kidney, liver, or muscle problems, or a history of these conditions. Avoid with dehydration. Avoid if pregnant or breastfeeding.
Prevention
Spinal muscular atrophy (SMA) is the cause of more deaths in young children than any other genetic disorder. While treatment is available to manage symptoms and prevent complications, there is currently no known method of prevention for SMA.
SMA is inherited as an autosomal recessive disorder, meaning that two copies of a specific abnormal gene must be inherited from parents in order for a child to have SMA. Individuals with only one copy of the abnormal gene are called carriers. Anyone with a closely related family member affected by SMA is at an increased risk of being a carrier and may want to seek the advice of a genetic counselor in order to better understand the risks and chances of having a child affected by SMA.
Preventative measures for respiratory complications, nutritional deficiency, and loss of mobility are central treatment methods for SMA.
Author information
This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).
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Causes
Spinal muscular atrophy (SMA) disorders are inherited and they all have a common genetic factor. SMA disorders are caused by the inheritance of an abnormal or absent copy of a specific gene known as the survival motor neuron gene (SMN1).
SMN1 is located on chromosome 5 and is normally responsible for creating a protein called survivor motor neuron (SMN). SMN is necessary for the survival of motor neurons, which are nerve cells in the spinal cord that control muscles and movement. The muscles that are most affected by SMA are the ones that a person controls. These muscles, called voluntary muscles, control actions such as swallowing, walking, and crawling.
When the SMN1 gene is mutated (abnormal) or missing, the SMN protein is not produced. This protein deficiency causes motor neurons to degenerate and die, which means they no longer signal the muscle cells. As a result, muscle cells cannot function properly. When muscles are not being used, they atrophy, or become very small and weak. This is what causes the muscle weakness associated with SMA.
SMA is an autosomal recessive genetic disease, meaning that two abnormal genes are needed to cause the disease. Genetic research confirms that most children and adults with SMA have inherited the disorder by receiving one mutated SMN1 gene, or no SMN1 gene at all, from each parent. This means that both parents had an abnormal or missing copy of the gene linked to SMA, which makes them carriers. The child of two carriers has a 25% chance of developing SMA.
Even though there are several different types of SMA, most of them are due to mutations (abnormalities) in the SMN1 gene. However, the severity of SMA can depend on a second gene, SMN2.
Normally, people have two copies of the SMN1 gene and at least two copies of the SMN2 gene in each cell. In people with SMA, both copies of SMN1 are mutated or missing and little or no SMN protein is produced. In some cases, however, an individual affected by SMA may have three or more copies of SMN2, which can partially compensate for the loss of SMN protein. Therefore, the severity of SMA is partially the result of how well SMN2 compensates for the absence of SMN1 and creates the necessary protein. The more copies of SMN2 a patient has, the less severe the effect of SMA will be.
A severe infantile form of the disease can also occur in boys because of mutations on the X chromosome. This is called X-linked infantile spinal-muscular atrophy (XL-SMA). Researchers have identified a gene interval where the mutation is believed to occur in XL-SMA, although no specific gene is currently known. Male children of females who are carriers generally have a 50% chance of having the disease. Female children of females who are carriers have a 50% chance of being carriers, but are not affected by the disease.
There is no evidence that confirms that SMN1 mutation occurs spontaneously, although some observations in SMA research may be explained by this theory.
Risk factors
General: Spinal muscular atrophy (SMA) is considered a rare genetic disorder, but is one of the most common genetic disorders affecting motor neurons. SMA occurs worldwide and can affect people of any age, gender, or race. However, incidence is reported to be low in black African individuals.
The ratio of males to females with SMA is 2 to 1. Males generally experience a more severe form of the disease, although life expectancy tends to be similar among males and females. Females generally experience disease onset before age eight.
About one of every 15,000-20,000 babies born in the United States has some form of SMA, and 50% of children diagnosed before age two do not live up to their second birthday. SMA is the most common genetic cause of infant deaths.
Family history: SMA is an inherited condition, so people with a family history of the disorder are at a higher risk of inheriting the condition. SMA disorders are inherited through an autosomal recessive inheritance pattern. SMA is caused by a defect (mutation) in the survival motor neuron gene (SMN1), which contains the instructions for creating a protein necessary for motor neurons to function correctly. Individuals who receive two copies of the mutation (one from each parent) develop SMA. The child of two carriers has a 25% chance of developing SMA.
Individuals who inherit only one copy of the mutation are known as "carriers." One of every 80 people in the Unites States is a carrier for SMA. Carriers do not show symptoms of the disease. Most carriers are only tested for the gene because a family member is affected.
Types of the disease
General: Spinal muscular atrophy (SMA) patients are classified into having one of four main types of disorders. Classification is based on the age of onset of the disease and specific motor functions that the patient is capable of performing, which indicate the severity of SMA. Type I and II are the most commonly observed types.
Patients with SMA typically lose muscle function over time. This may occur rapidly in association with a growth spurt or illness, or much more gradually, as seen in adult-onset SMA. Patients have been observed to maintain stable motor and muscle function for prolonged time periods, sometimes over the course of several years. However, almost all cases of SMA experience continued loss of function as they age.
Type I: Type I is also called Werdnig-Hoffmann Disease and is the most severe form of SMA. This type is first apparent in infants between birth and six months of age. Diagnosis is usually made before three months and mothers may even note that the child has decreased movement during the final months of pregnancy. Fifty percent of children with type I SMA do not live past two years of age.
Most children with type I SMA do not achieve normal motor skill milestones. Patients with SMA are not able to lift their own heads or sit up without support. They do not usually kick their legs with as much strength as healthy infants do and they cannot hold up any weight using their legs.
Type I patients may have difficulties swallowing and feeding and as the tongue weakens, it may show rippling movements (fasciculations). They may also have trouble breathing, as type I patients may have a smaller than usual sized chest, which may appear caved in (concave) and the muscles between the ribs (intercostal muscles) that expand the chest are generally weak.
Type II: Type II SMA is also called juvenile SMA, intermediate SMA, or chronic SMA. This type of SMA typically affects infants between seven and 18 months of age, and diagnosis is almost always made before two years of age. Type II patients differ in motor function from type I patients in that they may be able to sit without support, though only if they are placed in position. Some patients with type II SMA may even be able to stand with support.
Although difficulty swallowing is not usually characteristic of type II SMA, some patients may require a feeding tube because it is difficult to consume the quantity of food by mouth that is necessary to maintain weight and to grow. Children with type II SMA also have tongue fasciculations.
Children with type II have weak intercostal muscles and breathe with their diaphragms. They are at increased risk for complications from respiratory infections.
Type II SMA patients are also at increased risk of bone fractures due to decreased bone density. As children with type II SMA grow, almost all patients develop scoliosis (side-to-side spinal curvature). This requires either bracing, spinal surgery, or both.
Type III: Type III SMA is also known as Kugelberg-Welander disease or juvenile SMA and is the mildest form of childhood-onset SMA. Type III usually becomes apparent in children as early as the age of eighteen months, but may develop as late as adolescence. Diagnosis is usually made before age three. Unlike patients with types I and II, type III patients are able to walk, although most experience weakness. Eventually, most type III patients require the use of a wheelchair.
Early motor development is often normal in type III SMA. However, once the patient begins walking, they may fall frequently, have difficulty standing up from a seated or bent position, and may be incapable of running. These individuals often lose their ability to walk later in childhood, adolescence, or even adulthood. This is usually associated with a growth spurt.
Type III patients also have a tremor in their outstretched fingers, but do not usually have tongue fasciculations.
Feeding or swallowing difficulties in childhood are very uncommon in type III patients.
Type IV (adult onset): Type IV SMA is the adult form of the disease and the most uncommon. Symptoms tend to begin after age 35. It is rare for SMA symptoms to develop between ages 18 and 30.
Adult-onset SMA is typically characterized by onset without warning signs and very slow progression.
In contrast to types I, II, and III, the muscles used for swallowing and respiratory function are rarely affected in type IV.