Spinal muscular atrophy (SMA) is a disease characterized by degradation of the anterior horn cells of the spinal cord and has similar characteristics to Spinobulbar muscular atrophy (SBMA). SBMA differs from SMA in its mode of inheritance, the disease-determining gene, the mutational events that trigger disease and the cellular specificity of the disease pathology.
Description
The anterior horn cells control the voluntary muscle contractions from large muscle groups such as the arms and legs. For example, if an individual wants to move his/her arm, electrical impulses are sent from the brain down the anterior horn cells to the muscles of the arm, which then stimulates the arm muscles to contract allowing the arm to move. Degradation is a rapid loss of functional motor neurons. Loss of motor neurons results in progressive symmetrical atrophy of the voluntary muscles. Progressive symmetrical atrophy refers to the loss of function of muscle groups from both sides of the body. For example, both arms and both legs are equally effected to similar degrees of muscle loss and the inability to be controlled and used properly. Progressive loss indicates that muscle loss is not instantaneous, rather, muscle loss occurs consistantly over a period of time. These muscle groups include those skeletal muscles that control large muscle groups such as the arms, legs and torso. The weakness in the legs is generally greater than the weakness in the arms.
Spinal muscular atrophy (SMA) arises primarily from degradation of the anterior horn cells of the spinal cord, resulting in proximal weakness and atrophy of voluntary skeletal muscle. Proximal weakness effects the limbs positioned closer to the body, such as arms and legs, rather than more distant body parts such as hands, feet, fingers, or toes.
Spinal muscular atrophy only affects the motor neurons of the spinal cord and voluntary muscles of the limb and trunk. Patients do not display sensory loss, heart problems, or mental retardation. There are numerous secondary complications seen in SMA, including bending of the legs and arms and pneumonia. SMA development involves an initial substantial loss of motor units, followed by a stabilization of the surviving motor units. Motor units refer to an entire motor neuron and the connections within a muscle required for neuronal function.
Clinical subgroups
The childhood form of SMA is subdivided into three main clinical subgroups, Type I, II, and III, depending upon the age of onset and severity. A fourth subgroup, Type O, was recently discovered in London.
Type I
Type I SMA, or Werdnig-Hoffmann disease, is the acute or severe form, characterized by severe muscle atrophy. Guido-Werdig, an Austrian doctor, first identified the disease in 1891. He described two brothers displaying progressive muscle weakness from the age of 10 months, starting in the legs and progressing to the back and arms. The first brother died at the age three years with respiratory problems. The second brother survived to the age of six years.
Symptoms emerge in the first three months of life with the affected children never gaining the ability to sit, stand, or walk. Swallowing and feeding may be difficult and the child may show difficulties with their own secretions. There is general weakness in the intercostals and accessory respiratory muscles (the muscles situated between the ribs). The chest may appear concave (sunken in) due to the diaphragmatic (tummy) breathing.
Type II
Type II SMA was first described in 1964. It is less severe than type I, with clinical symptoms emerging between three and 15 months of age. Most patients can sit but are unable to stand or walk unaided. Feeding and swallowing problems are uncommon in patients with Type II SMA. Again, as with patients diagnosed with type I SMA, the intercostal muscles are affected, with diaphragmatic breathing a main characteristic of children with type II. Most patients will survive beyond the age of four years and, depending upon how their respiratory system is affected, may live through adolescence.
Type III
The chronic form of SMA, Type III (Kugelberg-Welander disease) was first described in 1956. The clinical symptoms manifest after the age of four. It produces proximal muscle weakness, predominantly in the lower body. Affected individuals can walk unaided and have a normal life span depending upon the extent of respiratory muscles loss.
Type O
Clinicians in London have recently identified a fourth form of the childhood disease; Type 0 SMA. This form appears to have a fetal-onset in that affected individuals display reduced movement within the uterus and are born with severe muscular atrophy with massive motor neuronal cell death. Therefore, these patients have very few functional motor neurons and motor units.
Diagnosis
One of the main diagnostic tools is electromyography (EMG). Contraction of voluntary muscle is controlled by electrical impulses originating from the brain. These impulses pass down the motor neurons of the spinal cord to the connecting muscles, where it triggers the contraction. The EMG records this electrical impulse and determines whether the electric current is the same as in normal individuals. Metal needles are inserted into the arms and thigh and the electrical impulse is recorded.
In addition, the speed at which the electric impulse passes down the motor neuron can also be used as a diagnostic test. In SMA patients, both the nerve conduction velocity (NVC) and the EMG readings are reduced.
The third test is an invasive procedure called a muscle biopsy. This involves a surgeon removing a small section of muscle. This is then tested for signs of degradation.
Genetic profile
All forms of childhood SMA are autosomal recessive, with both parents needing to be carriers to pass the disease on. If both parents are carriers, there is a 25% chance of their child being affected.
All three forms are caused by a decrease in the production of a protein, termed Survival of Motor Neuron (SMN). The SMN protein is encoded by two nearly identical genes located on chromosome 5; SMN-1 and SMN-2 (previously referred to as telomeric and centomeric SMN, respectively). Remarkably, only mutations or deletions of SMN-1 result in disease development.
In most individuals who do not have SMA, each chromosome (maternal and paternal) contains one copy of SMN-1 and one copy of SMN-2. Therefore, in most unaffected individuals, there are two SMN-1 and two SMN-2 genes. Importantly, a subset of SMA-causing mutations are intragenic SMN-1 single amino acid substitutions. Intragenic indicates that mutations are within an otherwise intact SMN gene, but that there is a small and very subtle mutation that is only found within the SMN gene. This is in contrast to large genomic deletions that can delete the SMN gene and also neighboring genes. The intragenic or small mutations thereby confirms SMN-1 as the SMA-determining gene.
Signs and symptoms
Research shows that, in SMA, the reduced SMN protein levels result in motor neuronal cell degradation. How, and why this occurs is still not known.
Demographics
Approximately, one in 10,000 live births are affected with SMA, which is slightly lower than expected since the carrier frequency is between one in 40 and one in 50. Since this is a recessive disease, meaning two copies of the abnormal gene must be present for the disease to occur, carriers are unaffected because only one copy of the abnormal gene is present.
The genomic SMN region is remarkably unstable, and de novo mutations (mutations that are new and not inherited from the parents) are quite frequent, accounting for nearly 2% of all SMA cases. In 90% of patients, death occurs before the age of two due to respiratory failure. In North America and Europe, type I SMA accounts for one in every 25,000 infant mortalities. SMA is the leading genetic cause of infantile death and is the second most common autosomal recessive disorder behind cystic fibrosis. Carrier frequencies and disease frequencies are similar throughout the world, although slight variations can exist. Asian populations have a slightly reduced carrier frequency although it is not known why this discrepancy has occurred.
Treatment and management
To date, there is no treatment for childhood SMA. However, there are possible mechanisms through which treatment could be developed. Gene therapy could be used for SMA to replace the abnormal SMN-1 gene. Such treatment is not yet available or possible at this time though.
Prognosis
In Type I SMA, eating and swallowing can become difficult as the muscles of the face are affected. Due to the degradation of the respiratory muscles breathing can also be labored. It is therefore essential for patients to undergo chest physiotherapy (CPT). CPT is a standard set of procedures designed to trigger and aid coughing in patients. Coughing is important as it clears the patients lungs and throat of moisture and prevents secondary problems, such as pneumonia.
As symptoms progress, patients may require a ventilator to aid breathing. There are two main forms of ventilation systems. Negative Pressure Ventilation can be achieved by placing the patient in a Port-A-Lung. This machine ensures that the air pressure around the patient is lower than the air pressure within the patient's lungs, enabling easier breathing. The pressure can be raised or lowered if the patients ventilation rate increases or decreases.
The second method is called Bi-Pap (Biphasic Positive Airway Pressure). This procedure involves the insertion of a small tube down the nose into the patient's lungs, through which oxygen is pumped into the lungs and waste carbon dioxide is removed. This system allows maximum inspiration and expiration levels to be reached.
Of all the forms of childhood SMA, Type II is the most diverse. It is therefore hard to tell when muscle weakness will occur and how severe the disease will be. With the aid of leg braces and walking devices, some children may gain the ability to stand. Unlike Type I SMA, not all children with Type II are affected by respiratory weakness. The main cause of death in patients with Type II is respiratory failure resulting from a respiratory infection. It is therefore important to ensure that mucus does not build up in patients respiratory tracts as this could aid viral and bacterial infections.
PERIODICALS
Crawford, T. O., and C. A. Pardo. "The neurobiology of childhood spinal muscular atrophy." Neurobiology of Disease 3 (1996): 97-110.
ORGANIZATIONS
Muscular Dystrophy Association. 3300 East Sunrise Dr., Tucson, AZ 85718. (520) 529-2000 or (800) 572-1717. <http://www.mdausa.org>.
