Spinal Muscular Atrophy Diagnosis and Tests
Clinical Diagnosis and Classification of Spinal Muscular Atrophy
Physicians encountering children with hypotonia and weakness should maintain a high index of suspicion for the diagnosis of spinal muscular atrophy. Certain physical characteristics are readily identifiable. The weakness is usually symmetrical and more proximal than distal. Sensation is preserved. Tendon reflexes are absent or diminished. Weakness in the legs is greater than in the arms. The severity of weakness generally correlates with the age of onset. The most severe type presents in infancy. The infant may appear normal at birth. Weakness evolves within the first few months of life. Occasionally, decreased intrauterine movements suggest prenatal onset of the disease and present with severe weakness and joint contractures at birth. Milder types of spinal muscular atrophy present with later onset, and the course is more insidious. Some children sit but never walk, whereas others show delayed walking but may be able to maintain walking until adult years. For the purpose of clinical care and discussion, individuals manifesting different levels of weakness due to spinal muscular atrophy have been divided into 4 groups defined by functional ability. We list typical clinical features of spinal muscular atrophy in Table 1. The first 3 types are classified according to criteria established by the International Spinal Muscular Atrophy Consortium. Type 4 spinal muscular atrophy is a mild form that presents in adulthood. It can be expected that some patients will manifest features that are at the margins between groups.
In addition to these defining criteria, unique clinical features of each spinal muscular atrophy type include the following:
- Type 1 spinal muscular atrophy. This type is also called Werdnig-Hoffmann disease. Children with this disease have impaired head control, with a weak cry and cough. Swallowing, feeding, and handling of oral secretion are affected before 1 year of age. The tongue may show atrophy and fasciculation. Weakness and hypotonia in the limbs and trunks are eventually accompanied by intercostal muscle weakness. Combining intercostal weakness with initial sparing of the diaphragm, the infants exhibit characteristic paradoxical breathing and a bell-shaped trunk with chest wall collapse and abdominal protrusion. Early morbidity and mortality are most commonly associated with bulbar dysfunction and pulmonary complications.
- Type 2 spinal muscular atrophy. These children have delayed motor milestones. Some learned to achieve independent sitting, whereas others need help to sit up. The defining characteristic is an ability to maintain a sitting position unsupported. At the strongest end of this category are those who can stand with a standing frame or long leg braces but are not able to walk independently. Bulbar weakness with swallowing difficulties may lead to poor weight gain in some children. Intercostal muscles are weak, and some are also diaphragmatic breathers. They have difficulty coughing and clearing tracheal secretion. They have fine tremors with extended fingers or when attempting hand grips. Kyphoscoliosis eventually develops, and bracing or spinal surgery is needed. Joint contractures commonly evolve over years.
- Type 3 spinal muscular atrophy. This type is also called Kugelberg-Welander disease or juvenile spinal muscular atrophy. These patients have later but variable age of onset. All achieve independent walking. Some patients lose the ability to walk in childhood, yet others maintain walking until adolescence or adulthood. Scoliosis can develop in these patients. Swallowing, cough, and nocturnal hypoventilation are less common than in type 2 spinal muscular atrophy but may occur. Muscle aching and joint overuse symptoms are common.
- Type 4 spinal muscular atrophy. The onset of weakness is usually in the second or third decade of life. Motor impairment is mild without respiratory or gastrointestinal problems.
Within each spinal muscular atrophy type, subclassifications have been proposed and can add to prognostic significance. For example, only 22% of patients with type 3a, with onset of symptoms before age 3 years, were still ambulatory at age 40 years, whereas 58.7% of the patients with type 3b, with onset after age 3 years, were still walking by age 40 years. Type 1 patients have also been subclassified into types 1a (neonatal or antenatal onset), 1b (typical Werdnig-Hoffmann disease with onset after neonatal period), and 1c (later onset, better head control in supported sitting, mild feeding or respiratory difficulties during the first 6 months of life). However, these subclassifications have not been widely used among clinicians.
Other Forms of Spinal Muscular Atrophy
There are other inherited motor neuron disorders, not caused by mutation of the SMN gene (non-5q spinal muscular atrophy), that present with early denervation weakness but different clinical symptoms than those stated above. These atypical symptoms include joint contractures, distal rather than proximal weakness, diaphragmatic paralysis with early respiratory failure, and pontocerebellar degeneration. DNA testing has become available for some but not all of these disorders. If a child with clinical features of spinal muscular atrophy is found not to have an SMN deletion on either chromosome 5, the child should be reexamined and receive additional diagnostic testing. (Please see the next section for the diagnostic strategies for these patients.) Table 2 lists some spinal muscular atrophy variants that exhibit early symptoms overlapping with 5q spinal muscular atrophy. Several later-onset motor neuron diseases overlap with milder 5q spinal muscular atrophy. These are beyond the scope of this document and are not listed here.
The stepwise algorithm of the diagnostic procedure is summarized in Figure 1. Briefly, the first diagnostic test for a patient suspected to have spinal muscular atrophy should be the SMN gene deletion test. This test is currently performed by several diagnostic laboratories, and the result can be obtained within 2 to 4 weeks. The test achieves up to 95% sensitivity and nearly 100% specificity. A homozygous deletion of SMN1 exon 7 (with or without deletion of exon 8 ) confirms the diagnosis of SMN-associated spinal muscular atrophy (5q spinal muscular atrophy). The next group of tests following a negative SMN test result includes repeat clinical examination of the patient for atypical clinical features as listed in Table 2. Laboratory tests should include muscle enzyme creatine kinase, electrophysiological testing such as electromyography (EMG), and nerve conduction study with repetitive stimulation. This will help to identify muscle diseases, motor neuropathies, and disorders of neuromuscular junctions. If EMG suggests a motor neuron disease, then further testing for SMN mutations should be pursued. Some laboratories are currently offering SMN1 gene copy number testing. If the patient possesses only a single copy of SMN1 (missing 1 copy), then it is possible that the remaining copy contains subtle mutations, including point mutations, insertions, and deletions, rendering homozygous dysfunction of the gene. Sequencing of the coding region of the remaining SMN1 copy may identify the mutation on the remaining copy and confirm the diagnosis of 5q spinal muscular atrophy. Unfortunately, sequencing the coding region of SMN is currently not widely available and is usually performed only in a few diagnostic or research laboratories. If the patient possesses 2 copies of SMN1, then other motor neuron disorders such as spinal muscular atrophy with respiratory distress, X-linked spinal muscular atrophy, distal spinal muscular atrophy, and juvenile amyotrophic lateral sclerosis should be considered. If EMG, nerve conduction study, and repetitive stimulation reveal characteristic patterns associated with diseases in muscle, nerve, or neuromuscular junction, then further diagnostic tests, including muscle or nerve biopsy and edrophonium test, may be performed. When disease of the neuromuscular system is ruled out, then one should pursue diagnostic tests to identify spinal cord or brain anomalies by imaging studies such as magnetic resonance imaging or computed tomography scans. Other diagnostic tests should then be performed to identify systemic diseases, such as metabolic disorders or other genetic disorders.
Four key elements to establishing a firm diagnosis of spinal muscular atrophy
Written for FightSMA by Robert T. Leshner, M.D., Professor, Neurology and Pediatrics, Children’s National Medical Center
Genetic Testing for Spinal Muscular Atrophy
The past few years have witnessed remarkable advances in our understanding of the genetic defects underlying SMA. The gene determining SMA has been localized to a small region of chromosome #5. The actual identification of the gene has been hindered by the extreme complexity of this portion of the chromosome. At least two different genes in this area have been proposed as the "offenders" producing SMA. One is termed the "survival motor neuron gene" (SMN) and the other is the "neuronal apoptosis inhibitory protein gene" (NAIP). These genes are located next to each other; in fact, there are copies of each of these genes forming a near mirror image of one another. The major candidate gene is the SMN gene. This very complex picture has hampered a full and complete understanding of how the genes work and how their malfunction may produce SMA. Although we do not fully understand how the gene abnormality produces the disease, the discovery of the SMN gene has proved extremely helpful in both establishing a diagnosis of SMA, and offering precise genetic counseling.
In over 95% of patients with SMA, changes in the SMN gene are identified which confirm the diagnosis and allow screening for the carrier state in parents and asymptomatic relatives.
Clinical Tests for Spinal Muscular Atrophy
The initial step in diagnosing SMA begins with parental concerns about their children’s strength and gross motor abilities. These concerns usually occur early in life in children with SMA Type I and II, where as children with SMA III may not show any clinical symptoms for many years. It is important that a physician knowledgeable about pediatric neuromuscular diseases examine these youngsters. Many other neuromuscular diseases can present with clinical symptoms identical to those expressed by children with SMA. Some of these alternative diagnoses required different diagnostic tests and may warrant different forms of treatment. Typically, the child with SMA Type I and II will exhibit his or her most dramatic weakness in the proximal muscles of the legs and arms. A quivering tongue (fasciculations of the motor units in the tongue muscle), is a very important clinical sign and often guides the physician to the diagnosis of SMA. Most children with SMA lose their deep tendon reflexes (the reflexes physicians check when they strike the knees or ankles with a rubber hammer). Sensation is normal and children always appreciate feelings like tickling and light touch.
Although the clinical examination is critically important, the fact that other neuromuscular disease can present with the same symptoms and show some of the same physical features makes additional diagnostic testing necessary. Often the physician will order a blood test such as a muscle enzyme test (creatine kinase – CPK), to distinguish SMA and Muscular Dystrophy. Most children with muscular dystrophy have very high CPK levels, where as children with SMA have normal or only slightly elevated CPK levels.
Electromyography Testing (EMG) for Spinal Muscular Atrophy
The EMG test consists of two parts. The physician administers a small electrical stimulus to the nerves of a child’s arm and legs to determine how quickly electrical messages are carried by the motor and sensory nerves. This test is necessary to differentiate some forms of nerve disease from SMA. The second part of the test requires the insertion of a very fine electrical probe into several muscles. Characteristic abnormalities show that the muscle has lost nerve supply because of the malfunction of the motor neuron. These EMG findings are called “abnormalities of denervation” and are found in all children with symptomatic SMA. The testing is very sensitive, but should be performed by an electromyographer experienced in pediatric neuromuscular disease. This test involves a small amount of discomfort; an experienced electromyographer can minimize the pain of the procedure with a rapid and skillful interpretation of the results.
Muscle Biopsy Tests for Spinal Muscular Atrophy
The examination of muscle tissue is commonly used to confirm the diagnosis of SMA. Muscle tissue may be obtained in one of two ways: A surgeon may make a one or two inch incision in the skin to remove a piece of muscle for microscopic examination. Alternatively, a less invasive technique termed a punch muscle biopsy has become popular among many pediatric neuromuscular specialists. This involves a skin incision of only a few millimeters and can often be done without general anesthesia. Many experts believe that this is the biopsy procedure of choice for infants and younger children because it avoids the risk of heavy sedation or anesthesia. Although the muscle biopsy may be highly specific for SMA, many authorities feel comfortable in deferring a biopsy when the clinical, EMG findings, and genetic studies all confirm the diagnosis of SMA. When the genetic investigations are not confirmatory, muscle biopsy is absolutely essential.
It is our hope that additional understanding of the gene and its functions will provide insights into SMA and clues for future treatments.
American College of Medical Genetics – Find a Geneticist
Carrier Testing Now Available For Spinal Muscular Atrophy (June 2, 1997)
GeneReviews – Spinal Muscular Atrophy (February 24, 2000)
Genzyme Corporation – Spinal Muscular Atrophy Carrier Testing
Athena Diagnostics – SMA Awareness: SMA Carrier Testing