Before understanding SMA it is very necessary to know about the Survival Motor Neuron (SMN1) gene. This gene is responsible for making the SMN protein, which is found throughout the body, with the highest levels in the spinal cord. The protein belongs to a group of a protein called a SMN complex, which is important for the maintenance of specialized nerve cells called motor neurons. These neurons transmit signals from the brain and spinal cord that tell skeletal muscles to tense (contract) for body movement. Mutation in the SMN1 gene results in Spinal Muscular Atrophy (SMA) disorder.
About 95 percent of individuals with spinal muscular atrophy have mutations that delete a piece of the SMN1 gene in both copies of the gene in each cell. As a result, SMN protein production is impaired. In about 5 percent of people with this disorder, one copy of the SMN1 gene is missing a section, and the other copy has a different kind of mutation that disrupts the production or function of the SMN protein. In addition, a small amount of SMN protein is produced from a gene similar to SMN1 called SMN2. Several different versions of the SMN protein are produced from the SMN2 gene, but only one version is functional; the other versions are smaller and quickly broken down.
This disorder is characterized by a loss of motor neurons that leads to weakness and wasting (atrophy) in muscles used for movement (skeletal muscles) that worsens with age. It has a wide range of severity. There are several types of spinal muscular atrophy that differ in age of onset and level of muscle functioning; however, there is overlap among the types. It has been discovered that a shortage of SMN protein leads to the inefficient assembly of the machinery needed to process pre-mRNA. A lack of mature mRNA, and subsequently the proteins needed for normal cell functioning, has damaging effects on motor neuron development and survival. The loss of motor neurons leads to the signs and symptoms of spinal muscular atrophy.
Types of SMA
Spinal muscular atrophy type 0 is apparent before birth and is the rarest and most severe form of the condition. Affected infants move less in the womb, and as a result, they are often born with joint deformities (contractures). They have extremely weak muscle tone (hypotonia) at birth. Their respiratory muscles are very weak and they often do not survive past infancy due to respiratory failure. Some infants with spinal muscular atrophy type 0 also have heart defects that are present from birth (congenital).
Spinal muscular atrophy type I (also called Werdnig-Hoffmann disease) is the most common form of SMA. The muscle weakness is marked at birth or within the first few months of life. Most affected children cannot control their head movements or sit unassisted. Children with this type may have swallowing problems that can lead to difficulty feeding and poor growth. Similarly, they can also have breathing problems due to the weakness of respiratory muscles and an abnormally bell-shaped chest that prevents the lungs from fully expanding. Unfortunately, most children with spinal muscular atrophy type I do not survive past early childhood due to respiratory failure.
Spinal muscular atrophy type II (also called Dubowitz disease) is characterized by muscle weakness that develops in children between ages 6 and 12 months. Children with this type cannot sit without support. However, as the muscle weakness worsens later in childhood, affected individuals may need support to sit. They often have involuntary trembling (tremors) in their fingers, a spine that curves side-to-side (scoliosis) and respiratory muscle weakness that can be life-threatening.
Spinal muscular atrophy type III (also called Kugelberg-Welander disease) typically causes muscle weakness after early childhood. Individuals with this condition can stand and walk unaided, but over time, walking and climbing stairs may become increasingly difficult. Many affected individuals require wheelchair assistance later in life. People with spinal muscular atrophy type III typically have a normal life expectancy.
Spinal muscular atrophy type IV is rare and often begins in early adulthood. Affected individuals usually experience mild to moderate muscle weakness, tremors, and mild breathing problems. People with spinal muscular atrophy type IV have a normal life expectancy.
Spinal muscular atrophy (SMA) should be suspected in individuals with the following:
- History of motor difficulties, especially with the loss of skills
- Proximal muscle weakness
- Tongue fasciculations
- Evidence of motor unit disease on physical examination
The diagnosis of SMA is established in a proband with a history of motor difficulties, evidence of motor unit disease on physical examination, and identification of biallelic pathogenic variants in SMN1 on molecular genetic testing.
- Creatine Kinase (CPK) Test
- Electromyography (EMG) Test that measures the electrical activity of a muscle or a group of muscles
- Genetic Blood Tests
Creatine kinase (CPK) test includes blood testing for an enzyme called creatine kinase (CK), an enzyme that leaks out of muscles that are deteriorating. This is a nonspecific test because CK levels are elevated in many neuromuscular diseases, but it’s often useful anyway. High blood CK levels aren’t harmful in and of themselves, but they do indicate that muscle damage has occurred.
Electromyography (EMG) is used to diagnose SMA in terms of nerve conduction velocity — the speed with which signals travel along nerves and one that measures the electrical activity in the muscle called an electromyogram or EMG. Nerve conduction velocity tests involve sensations that feel like mild electric shocks, and EMGs require that short needles be inserted in the muscles.
Genetic Blood Test
This involves drawing around 3-4 ml of blood from a patient in EDTA vials which takes for 5- 10 minutes and will be sent to the laboratory for testing. Genetic testing will be performed, if SMA is suspected because this is the least invasive and most accurate way to diagnose mutations within genes on chromosome 5 where the presence of the SMN1 gene will be detected. However, this gene will be missing in about 95 percent of those with SMN-related SMA. In the other 5 percent, the gene will appear mutated.
Gene-targeted deletion/duplication analysis to determine the dosage of SMN1 is performed first for the SMN1 exon 7. If exon 7 is deleted from one copy of SMN1, perform sequence analysis of SMN1. If exon 7 is present in both copies of SMN1, consider other diagnoses.
This includes SMN1 and SMN2 and other genes of interest may also be considered. The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time.
Comprehensive Genomic Testing
This includes exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if serial single-gene testing (and/or use of a multigene panel) fails to confirm the diagnosis in an individual with features of SMA.