Spinal Muscular Atrophy: Clinical Aspects

Spinal muscular atrophy (SMA) is the most common genetic disease of the motor neuron and results in degeneration of motor neurons in both the spinal cord and the brain stem. Patients have diffuse, symmetric muscle weakness that is greater proximally and in the lower limbs; hyporeflexia or areflexia; and progressive respiratory insufficiency. Non-motor manifestations are rare, although sensory involvement, cardiac defects, gastrointestinal and autonomic dysfunction, and endocrine abnormalities have been reported. The impact of these atypical features is not well-defined.¹

Clinically, SMA is often divided into five types, primarily based on age of clinical onset:

• Infants with type 0 (prenatal onset) SMA are profoundly weak and require respiratory support at birth. Life expectancy is less than 6 months.

• The clinical presentation of type 1 SMA (Werdnig-Hoffmann disease) begins after birth but before age 6 months. Affected infants are not expected to be able to meet sitting, standing, or walking milestones, and most die before the age of 2 years from respiratory failure.

• SMA type 2 usually manifests between 6 and 18 months of age. These children may grow to sit unassisted but are often unable to stand or walk. The range of life expectancy is broad at 10 to 40 years.

• Children with type 3 SMA (Kugelberg-Welander disease) and those with type 4 SMA present after age 18 months and after 5 years, respectively. These children usually meet gross motor milestones (sitting, standing, and walking). Patients with type 4 SMA are typically less affected than those with type 3 SMA and are less likely to require assistance with ambulation as the disease progresses. Both SMA type 3 and type 4 are associated with a normal lifespan.

Known genetic alterations linked to SMA

Approximately 95% of SMA cases are chromosome 5q-related and have an autosomal recessive inheritance pattern. Homozygous deletions in exon 7 of the survival motor neuron 1 gene (SMN1, located on chromosome 5q13.2) account for 95% of 5q-related SMA. According to Arnold and colleagues, “essentially all other patients with SMN-related SMA will be compound heterozygotes with a single SMN1 deletion and a frameshift, nonsense or missense mutation in the other SMN1 copy.”¹ These alterations in the SMN1 gene result in deficiency of the SMN protein. The cell loss in SMA is related to low, but not absent, levels of SMN protein. This protein is believed to play a role in motor neuron mRNA synthesis, a critical cell function.²

In SMA, the survival motor neuron 2 gene (SMN2) acts as a modifying gene. The SMN1 and SMN2 genes are more than 99% identical, with the main difference of a C to T transition in the SMN2 gene within exon 7. Because of this transition, the majority of mRNA from the SMN2 gene will code for a truncated and non-functional SMN protein. However, because of alternative splicing events, about 10% of SMN2 mRNA will contain exon 7 and code for a full-length, functional SMN protein. These SMN2-derived proteins partially compensate for the loss of the SMN1 coded protein and contribute to the differences in SMN protein activity and phenotypic expression among individuals with SMA.

In general, the predicted SMN2 copy number is higher for later onset and less severe cases of SMA. For example, infants with type 0 (prenatal onset) SMA generally have 1 copy of the SMN2 gene, while patients with type 4 (late onset) are expected to have 4 or more copies.

The non-5q spinal muscular atrophies form a small minority of SMA cases (4% to 5%) and are clinically and genetically heterogeneous. The non-5q spinal muscular atrophies are generally classified by distribution of weakness and mode of inheritance.³