Ansley Powell
Professor Stephanie V. Piper
Biology 1103-057
11 October 2018
Spinal Muscular Atrophy
Introduction
Known as the leading genetic cause of infant deaths, spinal muscular atrophy is an autosomal recessive neuromuscular disease that results from the degeneration of motor neurons in the brainstem and spinal cord. (Damico) Although there are different types of spinal muscular atrophy, some general symptoms that characterize it are problems breathing, muscle weakness, involuntary muscle contractions, and tremors. (Kraft, “Spinal Muscular Atrophy – Genetics Home Reference – NIH.”) While those who suffer from this disease may appear to be stable for long periods of time, improvement should not be expected as some forms of spinal muscular atrophy can result in fatality. (“Spinal Muscular Atrophy Fact Sheet.”) The purpose of this paper is to discuss the various types of spinal muscular atrophy, signs and symptoms, causes and predisposing factors, diagnosis, treatment, and prognosis.
Types of Spinal Muscular Atrophy
There are four primary categories of spinal muscular atrophy: type I, type II, type III, and type IV. (“Types of SMA.”) Each category of spinal muscular atrophy is classified on the basis of age of onset and motor function achieved. (Damico) Accounting for 50% of patients diagnosed with spinal muscular atrophy, type I which is also referred to as Werdnig-Hoffmann disease is the most severe and the most frequent form diagnosed. (Damico) Infants are primarily affected by this variety of spinal muscular atrophy. (Kraft) Unable to ever sit or stand, children with type I spinal muscular atrophy typically do not survive beyond the age of two years old. (Kraft) The onset of type II spinal muscular atrophy occurs between 7 and 18 months of age. (Damico) Patients with this diagnosis lack the presence of deep tendon reflexes and usually experience fine tremors in their upper extremities in addition to other side effects. (Damico) The ability to sit unsupported is within reach to those with this form of the condition while learning to stand or walk is considered intangible. Life expectancy for this type of spinal muscular atrophy is dependent upon whether or not the patient develops breathing problems. It is common that most people with this diagnosis survive into adulthood. (Kraft) Type III spinal muscular atrophy, or Kugelberg-Welander disease tends to appear between 2 and 17 years of age. (Kraft) The characteristics of this particular group are milder than those of type I and type II spinal muscular atrophy. These individuals possess the capability to stand and walk independently, nonetheless walking and climbing stairs may become increasingly difficult as wheelchair assistance is often required later in life. (“Spinal Muscular Atrophy – Genetics Home Reference – NIH.”) Obesity and osteoporosis are known complications that occur alongside this diagnosis. (Kraft) The timeframe in which the onset of type IV spinal muscular atrophy transpires is normally after the age of 30 years old, however it is possible to appear as early as 18 years old. (“Spinal Muscular Atrophy – Genetics Home Reference – NIH.”, Kraft) The muscles that are usually affected in patients with type IV spinal muscular atrophy are proximal, or close to the center of the body such as the upper arms and legs. (“Spinal Muscular Atrophy – Genetics Home Reference – NIH.” ) Those with this form of spinal muscular atrophy tend to be ambulatory until about 60 years of age. (“Spinal Muscular Atrophy.”)
Multiple varieties of spinal muscular atrophy in addition to the four main types specified previously do exist, however these other forms differ due to the fact that they are caused by mutations in genes other than the SMN1 gene. (“Types of SMA.”) The four primary forms of spinal muscular atrophy share common mutations of the SMN1 gene which only impacts the susceptibility to muscle weakness and paralysis. (Damico) Secondary varieties of spinal muscular atrophy with mutations in genes other than the SMN1 gene include side effects such as chest deformity, unusually small jaw, drooping of the upper eyelids, and changes in speech. (“Spinal Muscular Atrophy Fact Sheet.”)
Signs and Symptoms
Different forms of spinal muscular atrophy display unique signs and symptoms, however there are several that can be generalized. Muscle weakness and muscle loss are among the main signs and symptoms of spinal muscular atrophy that can be generalized in all its forms. Muscular weakness is the result of denervation, or loss of the signal to contract, that is transmitted from the spinal cord. It is also important to note that the symptoms of spinal muscular atrophy depend on its severity and the individual's age when it starts. Infants with spinal muscular atrophy type I are born with very little muscle tone, weak muscles, and feeding and breathing problems. With spinal muscular atrophy type III, symptoms may not appear until the second year of life. Many of the subsequent symptoms of spinal muscular atrophy relate to secondary complications of muscle weakness. Spinal muscular atrophy type 1 is the most common type of spinal muscular atrophy and is also a severe form of the disease. Muscle weakness, lack of motor development and poor muscle tone are the major clinical manifestations of spinal muscular atrophy type I. A twitching of the tongue is often seen. Intelligence is normal. The onset of weakness in spinal muscular atrophy type 2 patients is usually between 6 and 12 months. A trembling (tremor) of the fingers is almost always seen in spinal muscular atrophy type 2. Patients with spinal muscular atrophy type 3 (Kugelberg-Welander syndrome) The legs are more severely affected than the arms. (Kraft)
Causes and Predisposing Factors
Mutations in the SMN1, UBA1, DYNC1H1, and VAPB genes cause spinal muscular atrophy. Extra copies of the SMN2 gene modify the severity of spinal muscular atrophy.
The SMN1 and SMN2 genes provide instructions for making a protein called the survival motor neuron (spinal muscular atrophy) protein. (“Spinal Muscular Atrophy – Genetics Home Reference – NIH.”) In Spinal Muscular Atrophy, insufficient levels of the Spinal Muscular Atrophy protein lead to the degeneration of the lower motor neurons, producing weakness and wasting of the skeletal muscles. This weakness is often more severe in the trunk and upper leg and arm muscles than in muscles of the hands and feet. (“Spinal Muscular Atrophy Fact Sheet.”) The spinal muscular atrophy protein is important for the maintenance of specialized nerve cells called motor neurons. Motor neurons are located in the spinal cord and the brainstem; they control muscle movement. Most functional spinal muscular atrophy protein is produced from the SMN1 gene, with a small amount produced from the SMN2 gene. Several different versions of the spinal muscular atrophy protein are produced from the SMN2 gene, but only one version is full size and functional. Mutations in the SMN1 gene cause spinal muscular atrophy types I, II, III, and IV. SMN1 gene mutations lead to a shortage of the spinal muscular atrophy protein. Without SMN protein, motor neurons die, and nerve impulses are not passed between the brain and muscles. As a result, some muscles cannot perform their normal functions, leading to weakness and impaired movement.
Some people with type II, III, or IV spinal muscular atrophy have three or more copies of the SMN2 gene in each cell. Having multiple copies of the SMN2 gene can modify the course of spinal muscular atrophy. The additional spinal muscular atrophy proteins produced from the extra copies of the SMN2 gene can help replace some of the spinal muscular atrophy protein that is lost due to mutations in the SMN1 gene. In general, symptoms are less severe and begin later in life as the number of copies of the SMN2 gene increases.
Mutations in the UBA1 gene cause X-linked spinal muscular atrophy. The UBA1 gene provides instructions for making the ubiquitin-activating enzyme E1. This enzyme is involved in a process that targets proteins to be broken down (degraded) within cells. UBA1 gene mutations lead to reduced or absent levels of functional enzyme, which disrupts the process of protein degradation. A buildup of proteins in the cell can cause it to die; motor neurons are particularly susceptible to damage from protein buildup.
The DYNC1H1 gene provides instructions for making a protein that is part of a group (complex) of proteins called dynein. This complex is found in the fluid inside cells (cytoplasm), where it is part of a network that moves proteins and other materials. In neurons, dynein moves cellular materials away from the junctions between neurons (synapses) to the center of the cell. This process helps transmit chemical messages from one neuron to another. DYNC1H1 gene mutations that cause SMA-LED disrupt the function of the dynein complex. As a result, the movement of proteins, cellular structures, and other materials within cells are impaired. A decrease in chemical messaging between neurons that control muscle movement is thought to contribute to the muscle weakness experienced by people with SMA-LED. It is unclear why this condition affects only the lower extremities.
The adult-onset form of spinal muscular atrophy is caused by a mutation in the VAPB gene. The VAPB gene provides instructions for making a protein that is found in
cells throughout the body. Researchers suggest that this protein may play a role in preventing the buildup of unfolded or misfolded proteins within cells. It is unclear how a VAPB gene mutation leads to the loss of motor neurons. An impaired VAPB protein might cause misfolded and unfolded proteins to accumulate and impair the normal function of motor neurons.
Other types of spinal muscular atrophy that primarily affect the lower legs and feet and the lower arms and hands are caused by the dysfunction of neurons in the spinal cord. When spinal muscular atrophy shows this pattern of signs and symptoms, it is also known as distal hereditary motor neuropathy. The various types of this condition are caused by mutations in other genes. (“Spinal Muscular Atrophy – Genetics Home Reference – NIH.”)
Considering the genetics that come into play, types I, II, III, and IV spinal muscular atrophy are inherited in an autosomal recessive pattern, which means both copies of the SMN1 gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. Extra copies of the SMN2 gene are due to a random error when making new copies of DNA (replication) in an egg or sperm cell or just after fertilization.
SMA-LED and the late-onset form of spinal muscular atrophy caused by VAPB gene mutations are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. X-linked spinal muscular atrophy is inherited in an X-linked pattern. The UBA1 gene is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. (“Spinal Muscular Atrophy – Genetics Home Reference – NIH.”)
Diagnosis
The diagnosis of spinal muscular atrophy usually starts when parents or caregivers notice symptoms of spinal muscular atrophy in a child. A physician will carry out a detailed medical history, a family history, and a physical exam. They will see if the muscles are floppy or flaccid, to check for deep tendon reflexes and muscle fasciculation of the tongue muscle.
Tests used to diagnose spinal muscular atrophy can indicate whether there are deletions or mutations of the SMN1 gene. The types of available tests include blood tests, muscle biopsy, genetic tests, and potentially electromyography (EMG). EMG is used to assess the health of muscles and the nerve cells, or motor neurons, that control them. EMG tests record the electrical activity from the brain and/or spinal cord to a peripheral nerve root found in the arms and legs that controls muscles during contraction and at rest. (“Spinal Muscular Atrophy Fact Sheet.”) Amniocentesis or chorionic villus sampling can evaluate the fetus during gestation. (Kraft) The blood test identifies at least 95 percent of spinal muscular atrophy spinal muscular atrophy Types I, II, and III.
Treatment
Spinal muscular atrophy affects 1 in 6,000 to 1 in 10,000 people. There is no cure for spinal muscular atrophy, however treatment that can help people with spinal muscular atrophy live fuller lives do exist. Treatment consists of managing the symptoms and preventing complications. Some of the treatments available to those suffering from spinal muscular atrophy are Physical therapy, occupational therapy, Muscle relaxants such as baclofen, tizanidine, and the benzodiazepines. Even though spinal muscular atrophy cannot be prevented because it is an inherited condition, prospective parents can request genetic testing to determine if they may be carriers. (“Spinal Muscular Atrophy – Genetics Home Reference – NIH.”)
In December 2016 the U.S. Food and Drug Administration approved nusinersen (Spinraza TM) as the first drug approved to treat children and adults with spinal muscular atrophy. The drug is administered by intrathecal injection into the fluid surrounding the spinal cord. It is designed to increase production of the full-length spinal muscular atrophy protein, which is critical for the maintenance of motor neurons. Muscle relaxants such as baclofen, tizanidine, and the benzodiazepines may reduce spasticity. Botulinum toxin may be used to treat jaw spasms or drooling. Excessive saliva can be treated with amitriptyline, glycosylate, and atropine or by botulinum injections into the salivary glands. Antidepressants may be helpful in treating depression. Physical therapy, occupational therapy, and rehabilitation may help to improve posture, prevent joint immobility, and slow muscle weakness and atrophy. Stretching and strengthening exercises may help reduce spasticity, increase range of motion, and keeps circulation flowing. Some individuals require additional therapy for speech, chewing, and swallowing difficulties. Applying heat may relieve muscle pain. Assistive devices such as supports or braces, orthotics, speech synthesizers, and wheelchairs may help some people retain independence. Proper nutrition and a balanced diet are essential to maintaining weight and strength. People who cannot chew or swallow may require insertion of a feeding tube. Non-invasive ventilation at night can prevent apnea in sleep, and some individuals may also require assisted ventilation due to muscle weakness in the neck, throat, and chest during daytime. (“Spinal Muscular Atrophy Fact Sheet.”)
Prognosis
Prognosis varies depending on the type of spinal muscular atrophy. Some forms of spinal muscular atrophy are fatal. (“Spinal Muscular Atrophy Fact Sheet.”)
Conclusion
Although there is not a cure for any form of spinal muscular atrophy existing at the moment, scientists are constantly investigating new treatments. Some scientists are even developing a broad range of model systems in animals and cells to investigate the disease processes and expedite the testing of potential therapies. (“Spinal Muscular Atrophy Fact Sheet.”) The creation of Spinraza TM as the first drug approved to treat children and adults with spinal muscular atrophy is proof that scientists are working towards a cure. I believe that new innovation to attempt to cure spinal muscular atrophy will continue to be made.
Works Cited
1. Damico, Adele, et al. “Spinal Muscular Atrophy.” Orphanet Journal of Rare Diseases, vol. 6, no. 1, 2 Nov. 2011, p. 71., doi:10.1186/1750-1172-6-71.
2. Kraft, Sy. “Spinal Muscular Atrophy (SMA): Types and Treatment.” Medical News Today, MediLexicon International, 16 Oct. 2017, www.medicalnewstoday.com/articles/192245.php.
3. Lunn, Mitchell R, and Ching H Wang. “Spinal Muscular Atrophy.” The Lancet, vol. 371, no. 9630, 21 June 2008, pp. 2120–2133., doi:10.1016/s0140-6736(08)60921-6.
4. “Spinal Muscular Atrophy.” NORD (National Organization for Rare Disorders), rarediseases.org/rare-diseases/spinal-muscular-atrophy/.
5. “Spinal Muscular Atrophy – Genetics Home Reference – NIH.” U.S. National Library of Medicine, National Institutes of Health, 9 Oct. 2018, ghr.nlm.nih.gov/condition/spinal-muscular-atrophy.
6. “Spinal Muscular Atrophy Fact Sheet.” National Institute of Neurological Disorders and Stroke, U.S. Department of Health and Human Services, July 2012, www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Spinal-Muscular-Atrophy-Fact-Sheet.
7. “Types of SMA.” Cure SMA, www.curesma.org/sma/about-sma/types-of-sma/.