Clinical Features

SMA disorders are characterized by degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem, which results in progressive muscle weakness and atrophy. Cognition is unaffected. These diseases were traditionally classified into types 1 to 3, but now they are classified as types 0 through 4, depending upon the age of onset and clinical course. SMA type 0 (prenatal onset) and SMA type 1 (infantile onset) are the most common and severe types. SMA type 2 and SMA type 3 have a later onset and a less severe course. SMA type 4 (adult onset) is the least severe. While these subtypes are clinically useful for prognostic and therapeutic considerations, it is clear that SMA phenotypes span a spectrum of severity without discrete separation. Disease severity in SMA generally correlates inversely with SMN2 copy number, which varies in the normal population and, to a lesser degree, with the level of SMN protein.

Patients with all forms of SMA have diffuse symmetric proximal muscle weakness that is greater in the lower than upper limbs, and absent or markedly decreased deep tendon reflexes. In addition, SMA is associated with restrictive, progressive respiratory insufficiency, particularly SMA type 0 and type 1.

Less commonly, sleep disturbances can occur in children with SMA, and congenital heart defects may accompany SMA type 0. While there have been occasional reports of heart rhythm abnormalities in SMA types 1, 2, and 3, these may be coincidental associations.

SMA type 0: In the expanded classification, SMA type 0 designates prenatal onset of SMA, although prenatal onset was traditionally classified as SMA type 1. Mothers of affected patients with SMA 0 may recognize a decrease or loss of fetal movement in late pregnancy. At birth, infants with SMA type 0 have severe weakness and hypotonia, often with areflexia, facial diplegia, and congenital heart defects. Arthrogryposis (multiple joint contractures) may be present. No motor milestones are achieved. Death occurs from respiratory failure by age six months, and usually by one month. Infants with SMA of neonatal onset may present with signs of fetal hypokinesia deformation sequence, including polyhydramnios, intrauterine growth retardation, skeletal abnormalities with multiple articular contractures, and pulmonary hypoplasia.

Infants with SMA type 0 generally have only one copy of SMN2.

SMA type 1: SMA type 1 is also known as infantile spinal muscular atrophy or Werdnig-Hoffmann disease. It typically presents after birth but before age six months. Affected infants may appear normal before the onset of symptoms, but soon develop a severe, symmetric flaccid paralysis and never achieve the ability to sit unsupported. Because the upper cranial nerves are mostly spared, patients with SMA type 1 usually have an alert expression, furrowed brow, and normal eye movements. However, weakness of the bulbar muscles results in a weak cry, poor suck and swallow reflexes, pooling of secretions, tongue fasciculations, and an increased risk of aspiration and failure to thrive. Respiratory muscle weakness leads to progressive respiratory failure. The intercostal muscles typically are more affected than the diaphragm, resulting in paradoxical breathing (inspiratory efforts cause the rib cage to move inward and the abdomen to move outward) and the development of a characteristic bell-shaped chest deformity. The severe hypotonic leg weakness often manifests as a "frog-leg" posture when lying. Cardiac muscle does not appear to be affected, since SMA is not associated with dilated cardiomyopathy.

Symptoms progress rapidly, and the majority of infants die before two years of age from respiratory failure. Nevertheless, long-term survivors have been reported. This is perhaps due, in part, to advances in the care of chronic respiratory insufficiency and to more aggressive care.

Patients with SMA type 1 generally have two or three copies of the SMN2 gene.

SMA type 2: SMA type 2 (intermediate form; Dubowitz disease) accounts for approximately 20 percent of cases and has a less severe course than type 1. SMA type 2 most often presents between 3 and 15 months of age. The ability to sit unassisted is attained at some point but may be delayed. However, independent standing and walking are never achieved. Weakness is predominately proximal and affects the legs more than the arms. Common features include sparing of face and eye muscles, tongue atrophy with fasciculations, areflexia, a fine tremor-like form of myoclonus (minipolymyoclonus) affecting distal limbs, dysphagia, and respiratory insufficiency. Muscular weakness leads to progressive scoliosis in nearly all affected individuals; the combination of respiratory muscle weakness and scoliosis may result in restrictive lung disease. Some develop joint contractures and ankylosis of the mandible. The ability to sit independently is usually lost in the teenage years. Life expectancy is variable; one report found that approximately two-thirds of individuals with SMA type 2 were alive at age 25 years.

Patients with SMA type 2 generally have three copies of the SMN2.

SMA type 3: SMA type 3 (juvenile form; Kugelberg-Welander disease) accounts for approximately 30 percent of cases. Onset usually occurs between age 18 months and adulthood. Affected individuals achieve independent ambulation. Presenting symptoms usually reflect proximal weakness affecting the legs more than the arms, such as falls and trouble climbing stairs. Many lose the ability to stand or walk independently with time and progression of weakness, becoming wheelchair dependent. Ambulatory patients may develop foot deformity. However, most do not develop scoliosis or debilitating respiratory muscle weakness. SMA type 3 is associated with a normal lifespan.

Patients with SMA type 3 generally have three or four copies of SMN2.

SMA type 4: SMA type 4 (late onset) accounts for less than five percent of cases. Age of onset is not strictly defined; some experts use onset at age ≥30 years to separate SMA type 4 from SMA type 3, and others accept juvenile onset. SMA type 4 is on the mild end of the SMA spectrum; all motor milestones are achieved, ambulation is usually maintained throughout life, and lifespan is normal. Patients with SMA type 4 generally have four to eight copies of SMN2.