Definition
Spinal muscular atrophies (SMAs) are a wide group of genetic disorders characterized by primary degeneration of anterior horn cells of the spinal cord, resulting in progressive muscle weakness. The most common form of spinal muscular atrophy is childhood proximal SMA. Other forms of SMAs include X-linked recessively inherited bulbospinal SMA, distal SMAs, scapuloperoneal SMAs, and others such as facioscapulohumeral, scapulohumeral, oculopharyngeal, and Ryukyuan SMAs.
Description
SMAs present with diverse symptoms and differ in age of onset, mode of inheritance, distribution of muscle weakness, and progression of symptoms.
Childhood proximal SMA is subdivided into three clinical groups: type I, type II, and type III SMA. SMA type IV designates adult form of proximal SMA. Although it is now apparent that the phenotype of SMA associated with mutations of the survival motor neuron (SMN1) gene spans a continuum without a clear delineation of subtypes, the classification is useful for prognosis and management.
SMA I (acute infantile SMA, Werdnig-Hoffman disease) manifests by decreased fetal movements in the last trimester of pregnancy in about one third of cases. About 65% of affected infants are floppy at birth, while delayed motor milestones are characteristic in all affected children by the age of six months. In addition to muscle weakness, clinical features include head lag, poor sucking and swallowing, weak cry, proximal limb weakness, and lack of reflexes. Affected children never raise their head, roll over, or walk. Sometimes weakness of the face and jaw muscles, finger tremor, and respiratory difficulty occur. Orthopedic abnormalities such as congenital dislocation of the hip, chest wall asymmetries, and flexion contractures are present in 25% of affected newborns.
SMA II (intermediate SMA) usually manifests itself between six and 12 months of age. Although poor muscle tone may be evident at birth or within the first few months of life, patients with SMA II may gain motor milestones slowly. Eighty percent are able to sit independently, although they are not able stand or walk alone. Limb girdle weakness, twitching, lack of reflexes, and weakness of tongue, face, and neck muscles are seen. Tremors affecting the upper extremities, musculoskeletal deformities, and respiratory failure occur.
SMA III (chronic SMA, Kugelberg-Welander disease) presents with the onset of symptoms after the age of 18 months. Patients walk independently, but may fall frequently or have trouble walking up and down stairs between age two to three years. Muscular weakness is present on both sides of the body, and the legs are more severely affected than the arms. Difficulty swallowing and difficulty speaking may occur in later stages of the disorder.
SMA IV manifests as muscle weakness usually in the second or third decade of life. The findings are similar to those described for SMA III.
Bulbospinal muscular atrophy (Kennedy disease) manifests as muscle weakness between the ages of 20 and 40 years. Weakness and atrophy in the lower extremities are usually followed by problems with the pectoral girdle, facial muscles, distal limb, and bulbar muscles. Muscle cramps on exertion often precede the weakness by several years. Fine tremors of the face are present in over 90% of patients. Type 2 diabetes mellitus, hand tremor, and infertility can also occur. Bulbar involvement predisposes the person with spinal muscular atrophy to recurrent aspiration pneumonia, due to weakening of the muscles necessary for efficient swallowing.
Other less common forms of SMAs include distal SMAs (10% of all SMA cases) and scapuloperoneal SMA (7% of all SMA cases). Distal SMAs are a group of disorders that manifest most commonly soon after birth, with muscle wasting in the hands and feet. Later in life, abnormal gait and foot deformities are seen. Similar clinical signs occur in adult-onset forms. Scapuloperoneal SMA has a characteristic pattern of muscle weakness, usually involving the heart and sensory neuropathy (Davidenkow's syndrome).
Demographics
SMAs are one of the most common groups of neuromuscular diseases in children, with an incidence of four to 10 per 100,000 live births. Other SMAs have a lower incidence, as a rule less than one per 100,000 live births.
Causes and symptoms
Spinal muscular atrophies are genetic diseases. Types I, II, and III SMAs have been mapped to chromosome 5q11.2-13.3. In 1994, the survival motor neuron (SMN1) gene was identified as responsible for SMA when mutations occur. The SMN1 gene has a duplicate copy called the SMN2 gene, but it is not able to compensate for the defects in the SMN1 gene. There is evidence that type I SMA is caused by deletion of the SMN1 gene, whereas type III is associated with a conversion event of SMN1 into SMN2, leading to an increased number of SMN2 genes. In addition to bulbospinal muscular atrophy, which has been shown to be caused by a defect in the androgen receptor gene, six other SMAs have already been mapped to corresponding chromosomal locations.
Inheritance pattern for most forms of SMA is autosomal recessive, meaning that both parents are carriers of the disorder, and the chance of having a child affected with the disorder is 25% with each pregnancy. Familial forms of the disorder that occur later in life are usually due to an autosomal recessive or autosomal dominant inheritance pattern.
Diagnosis
Diagnosis is based on the clinical presentation, family history, and genetic testing. The genetic test is based on the fact that approximately 95–98% of individuals with a clinical diagnosis of childhood SMA lack exon 7 in both copies of the SMN1 gene. Likewise, all patients with bulbospinal muscular atrophy have a defect in the androgen receptor gene.
An electromyelogram may reveal damaged nerve impulses secondary to muscle fiber degeneration. Sensory nerve conduction studies are normal in all forms of SMA, the exceptions being bulbospinal muscular atrophy and Davidenkow's syndrome. Muscle biopsy is critical in the diagnosis of childhood SMA. If performed, it reveals atrophy of muscle fibers with a characteristic form of muscle fiber type grouping.
Treatment team
A multidisciplinary approach is essential for providing care and treatment of a person with spinal muscular atrophy, including specialists in the fields of neurology, physical therapy, occupational therapy, respiratory therapy, surgery, and genetic counseling.
Treatment
As no specific treatment is available for spinal muscular atrophies, the resulting complications of muscle deterioration are managed as best as possible. Treatment in severe childhood SMA includes prescription of antibiotics for respiratory infections and tube feeding in children with profound difficulty in sucking and swallowing. In children with SMA II, the goals of conservative therapy include maintaining the sitting posture, preserving or improving function, and reducing progression of deformity. This is achieved by regular active exercise monitored by physical therapists, gentle traction to prevent contractures (stiff muscles near the joints), splinting, bracing, and the use of spinal positioning devices and upright mobility systems. Orthopedic surgical interventions such as tendon transfer or spinal surgery can prevent disability in patients with expected prolonged survival.
Recovery and rehabilitation
As there is no recovery from spinal muscular atrophies, the emphasis is placed upon maintaining muscle function and mobility for as long as possible. Physical therapy is an integral part of maintaining movement in persons with spinal muscular atrophies. In children, range of motion exercises keep muscles and joints moving, while reaching games provide stimulation and aid in coordination. Water therapy also provides an enjoyable medium for working the muscles and joints.
As muscle weakness progresses and affects posture, occupational therapy can provide assistive devices and strategies to maintain positioning and movement, such as specialized wheelchairs and reaching devices. Respiratory therapy is also important to teach parents the chest therapy exercises and maneuvers that are necessary to remove accumulated secretions and mucous from the lungs.
Normal education should be encouraged for children with spinal muscular atrophies, especially in the more slowly progressive forms, as intelligence is preserved and even superior in many children with SMA.
Clinical trials
Riluzole, gabapentin, albuterol, phenylbutyrate, and thyrotropin-releasing hormone have so far been tested and have shown potential effects on improvement of muscle strength in children with SMA. Many different controlled trials are needed to confirm these preliminary findings.
Prognosis
Progressive muscle weakness usually leads to death by age four for persons with SMA I. Muscle weakness progresses at varying rates in SMA II, and many persons survive into adulthood. The life expectancy of patients with SMA III is close to that of the healthy population. Progression of the adult-onset SMAs is usually slow, and patients are ambulatory until late in the disease. Lifespan is only slightly reduced.
Special concerns
Genetic counseling is important in SMA, since prenatal and preimplantation genetic diagnoses offer the parents the possibility to prevent the disease.
Resources
BOOKS
"Disorders of Upper and Lower Motor Neurons," chapter 80 in Neurology in Clinical Practice, edited by Walter G. Bradley, Robert B. Daroff, Gerald Fenichel, and Joseph Jankovic. Burlington, MA: Butterworth Heinemann, 2003.
PERIODICALS
Zerres, K., S. Rudnik-Schoneborn, E. Forrest, et al. "A Collaborative Study on the Natural History of Childhood and Juvenile Onset Proximal Spinal Muscular Atrophy (Type II and III SMA): 569 Patients." J Neurol Sci. 146 (February 1997): 67–72.
OTHER
"NINDS Spinal Muscular Atrophy Information Page." National Institute of Neurological Disorders and Stroke. May 5, 2004 (May 27, 2004). http://www.ninds.nih.gov/health_and_medical/disorders/sma.htm.
"Understanding Spinal Muscular Atrophy: A Comprehensive Guide." Families of Spinal Muscular Atrophy. May 5, 2004 (May 27, 2004). http://www.fsma.org/booklet.shtml#taking.
ORGANIZATIONS
Families of SMA. PO Box 196, Libertyville, IL 60048-0196. (847) 367-7623 or (800) 886-1762. sma@fsma.org. http://www.fsma.org.
Borut Peterlin, MD, PhD
