Introduction
Spinal muscular atrophy (SMA) is an inherited condition affecting muscles and nerves, making them increasingly weak. It usually affects infants and children but can also affect adults. Most of the nerves that control the muscles are in the spinal cord, so the name spinal is in the disease. Muscular is because it affects the muscle, which does not receive signals from these nerve cells. Atrophy means getting smaller, which happens when the nerves do not stimulate them.
What Is Spinal Muscular Atrophy?
Spinal muscular atrophy is a genetic neuromuscular condition that weakens the muscles. People with this condition lose the motor neurons (the type of nerve cell in the spinal cord) that control muscle movements. Without these motors, muscles do not receive signals that make them move. The age at which spinal muscular atrophy symptoms begin correlates with the degree to which motor function is affected. The earlier the symptoms occur, the greater the impact on motor functions.
Who Is Affected by Spinal Muscular Atrophy?
A person affected by spinal muscular atrophy inherits two copies of the missing or mutated survival motor neuron 1 (SMN1) gene. One mutated gene is inherited from the mother, and the other from the father. A person can have a single copy of the defective gene that results in spinal muscular atrophy and not know it. The spinal muscular atrophy carriers will contain one healthy SMN1 gene and one defective or mutated SMN1 gene; they do not develop spinal muscular atrophy. There is one in four chances that two carrier parents may have a child with spinal muscular atrophy.
What Are the Types of SMA?
There are four types of spinal muscular atrophy; these are
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Type 1 (Severe):
About 60% of people are affected by type 1, known as Werdnig-Hoffman disease. Symptoms of spinal muscular atrophy appear at birth or in the first six months. Type 1 spinal muscular atrophy affects infants who show difficulty swallowing and sucking. They do not achieve typical milestones like holding up their heads or sitting. As the muscle weakens, the children become more prone to respiratory infections and pneumothorax (collapsed lungs). Most infants with spinal muscular atrophy die within a year.
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Type 2 (Intermediate):
It is also called Dubowitz disease, where symptoms appear in infants between six to eighteen months. Type 2 spinal muscular atrophy usually affects the lower limbs. Infants affected with type 2 can sit but can not walk, and they live into adulthood.
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Type 3 (Mild):
It is also called Kugelberg-Welander or juvenile-onset of spinal muscular atrophy. The symptoms of type 3 spinal muscular atrophy appear after the first eighteen months. However, some have signs and symptoms of the disease in adulthood. The symptoms of type 3 include mild muscle weakness, difficulty walking, and frequent respiratory infections over time; symptoms can affect the tendency to walk or sit. Type 3 does not shorten life expectancy.
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Type 4 (Adult):
It is a rare type of spinal muscular atrophy, where symptoms do not appear until the mid-thirties. The symptoms of muscle weakness progress slowly, and people affected with type 4 will be active and live throughout their lives.
What Are the Causes of Spinal Muscle Atrophy?
The cause of spinal muscular atrophy is missing part of the SMN1 gene or mutated gene. A healthy SMN1 gene produces SMN proteins that are significant for motor neuron survival and proper functioning. People affected by spinal muscular atrophy do not make sufficient SMN proteins, so the motor neurons shrink and die. Due to this, the brain can not control voluntary movements, especially in the head, neck, arms, and legs. People also contain the SMN2 gene, which produces a small amount of SMN proteins, whereas some may contain eight copies of SMN2 genes. Many copies of the SMN2 gene reduce symptoms of spinal muscular atrophy as the extra gene compensates for the missing SMN1 protein. Rarely, non-SMN mutated genes cause spinal muscular atrophy.
What Are the Signs and Symptoms?
The primary symptom of SMN-related spinal muscular atrophy is the weakness of the voluntary muscles. The muscles present close to the center of the body, such as the shoulder, hips, thighs, and upper back, are usually affected. The upper limbs are less affected, and the deep tendon reflexes are reduced. People with SMA experience muscle control, movement, and strength loss, which worsens with age.
Some complications occur if the muscles responsible for breathing and swallowing are affected, which results in abnormal functioning. In addition, spinal curvature occurs if the back muscles weaken. There is a great deal of difference in the age when the symptoms occur and the extent of motor function achieved in SMN-related spinal muscular atrophy. This gives information about the functional SMN protein in the motor neurons, which relates to the copies of SMN2 genes present. Sensory, mental, and emotional functions are normal in SMN-related spinal muscular atrophy. The non-SMN-related spinal muscular atrophy affected the distal muscles.
What Is the Diagnosis of Spinal Muscular Atrophy?
Initially, a physical examination is performed by the doctor; in addition, some of the tests performed are:
Blood Test:
An enzyme and protein blood test is done to check for increased levels of creatine kinase, as deteriorating muscles release the enzymes into the bloodstream.
Genetic Test:
This blood test rules out the issues with the SMN1 gene. A genetic tool is 95 % effective, which helps to find the altered SMN1 gene.
Nerve Conduction Test:
An electromyogram (EMG) is used to measure the electrical activity of the nerve muscles and the nerve.
Muscle Biopsy:
It is a rare procedure where a small amount of muscle tissue is removed and sent to the lab for examination, which can show atrophy or muscle loss.
How Is Spinal Muscular Atrophy Diagnosed During Pregnancy?
If there is a family history of spinal muscular atrophy, a prenatal test can be performed to determine whether the developing fetus is affected by the condition. This procedure increases the risk of miscarriage or pregnancy loss. Prenatal tests include:
- Amniocentesis: In this procedure, a small amount of fluid is collected from the amniotic sac with the help of a thin needle, after which a lab test is done to check for the presence of SMA. This procedure is carried out after the 14th week of pregnancy.
- Chorionic Villus Sampling (CVS): In this procedure, a small sample from the placenta is removed through the cervix or stomach and proceeded with the laboratory tests. This procedure is performed during the 10th week of pregnancy.
How Is Spinal Muscular Atrophy Treated?
There is no permanent cure for spinal muscular atrophy. Supportive care and management are based on the severity of the symptoms that are caused. Many people get help from physical and occupational therapy and assistive devices like orthopedic braces, crutches, walkers, and wheelchairs. Some treatment interventions include -
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Disease-Modifying Therapy - Some drugs stimulate the production of SMN protein. The doctor injects the drug around the spinal canal.
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Nusinersen is the first FDA-approved drug for children (aged 2 to 12 years) and adults having SMA. It increases SMN protein production, which is essential for maintaining motor neurons.
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The medication Risdiplam is recommended for adults and children who are older than two months. This medication is taken orally daily.
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Genetic Replacement Therapy - This FDA-approved gene therapy replaces a missing or faulty SMN1 gene with a functional gene in children younger than two (infantile-onset SMA).
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Children (less than two years of age) benefit from a single-time intravenous injection of a drug named Onasemnogene abeparvovec-xioi. Here, a functionally competent human SMN gene is delivered to the target-specific motor neurons through a safe viral vector, which subsequently enhances muscular movement, restores function, and improves survival.
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Rehabilitation Therapy - This includes physical therapy and occupational therapy to minimize postural deformities, improve mobility in joints, and reduce the progression of muscle weakness, thereby delay atrophy.
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Strengthening exercises such as stretching activities prevent contractures, enhance the range of motion, and improve blood circulation. Therapies for speech improvement and to aid swallowing dysfunction are also recommended.
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Supportive Care - Proper nutritional intake and adequate calories should be maintained for optimal weight and physical strength. Prolonged fasting should be avoided. Feeding assistance, such as feeding tube insertion, should be given to individuals who are not able to chew and swallow their food.
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Non-invasive ventilation assistance, particularly at night, improves breathing at sleep and prevents suffocation. In severe conditions like extreme weakness of the chest, throat, and neck muscles, assisted ventilation is also extended in the daytime.
What Are the Recent Treatment Advances on Spinal Muscle Atrophy?
Animal Studies
The National Institute of Neurological Disorders and Stoke and, a component of the National Institutes of Health, performed the basic study and clinical research on SMA. The scientists have formed a model system for animals to know about the disease and to enhance the testing of potential therapies, which includes:
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In mouse models and individuals affected by SMA, gene therapy and specific medications have been shown to prevent motor neuron destruction and reduce the pace of disease progression. Clinical trials based on SMA are an ongoing process.
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For developing new therapies for SMA, animal models represent critical tools. Scientists develop zebrafish, mouse, and pig models that can help to find new therapeutic targets and candidate therapies.
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Scientists have gathered data on pre-symptomatic or recently diagnosed children afflicted with SMA type I, II, and III and their healthy siblings. The aim of this study is to educate the parents based on the possible clinical trial opportunity.
Recent Advances
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Muscle Growth Upregulation - These therapeutic interventions target enhancing muscle mass and its function. Fast Skeletal-Muscle Troponin Activators (FSTA) and Myostatin-inhibitors are two such compounds used in current therapies.
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SMA Biomarkers - Phosphorylated neurofilament heavy chain (pNF-H) levels are higher in SMA (type 1) individuals. Such biomarkers are used for the early detection of SMA and prompt initiation of Nusinersen therapy.
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Electrophysiological biomarkers such as cyclic muscle action potential (CMAP) and estimation of motor unit number (MUNE) are under clinical trials.
What Are the Complications?
Over time, people with spinal muscular atrophy experience muscle weakness and muscle control. Some complications are:
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Bone fracture.
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Hip dislocation.
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The curvature of the spine (scoliosis).
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Malnutrition and dehydration caused due to eating and swallowing problems that require a feeding tube.
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Pneumonia and respiratory infection.
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Breathing problems due to weak lungs.
Conclusion:
Spinal muscular atrophy is a genetic or inherited condition that affects the muscles by weakening them. It usually affects children and infants. It is caused due to the loss of motor neurons that regulate muscle movements. It varies with signs and symptoms, which worsens with age. It is not completely curable but can be managed by some physical and occupational therapies.
