Spinal Muscular Atrophies (SMAs)

Spinal muscular atrophies (SMA) usually result from autosomal recessive mutations that affect the survival motor neuron 1 (SMN1) gene on the long arm of chromosome 5, most often causing a homozygous deletion of exon 7. Spinal muscular atrophies may involve the central nervous system and thus are not purely peripheral nervous system disorders. SMN2 is a modifier gene; it is 99% identical to the SMN1 gene and is located on 5q; if present in multiple copies, SMN2 may modify the severity of the disease and explain phenotypic differences between children with SMA. Also, there are rare forms of SMA that are not due to 5q mutations.

There are 5 main types of spinal muscular atrophy.

In spinal muscular atrophy type 0, onset is prenatal; it manifests as decreased fetal movement in late pregnancy and severe weakness and hypotonia at birth. Affected neonates have facial diplegia, areflexia, cardiac defects, and sometimes arthrogryposis. Death due to respiratory failure occurs within the first 6 months.

Spinal muscular atrophy type 1 (infantile spinal muscular atrophy, or Werdnig-Hoffmann disease) is also present in utero and becomes symptomatic by about age 6 months. Affected infants have hypotonia (often notable at birth), hyporeflexia, tongue fasciculations, and pronounced difficulty sucking, swallowing, and eventually breathing. Death, usually due to respiratory failure, occurs within the first year in 95% and by age 4 years in all.

In spinal muscular atrophy type 2 (intermediate form, or Dubowitz disease), symptoms usually manifest between 3 and 15 months of age; < 25% of affected children learn to sit, and none walk or crawl. Children have flaccid muscle weakness and fasciculations, which may be hard to see in young children. Deep tendon reflexes are absent. Dysphagia may be present. Most children are confined to a wheelchair by age 2 to 3 years. The disorder is often fatal in early life, frequently resulting from respiratory complications. However, progression can stop spontaneously, leaving children with permanent, nonprogressive weakness and a high risk of severe scoliosis and its complications.

Spinal muscular atrophy type 3 (juvenile form, or Wohlfart-Kugelberg-Welander disease) usually manifests between age 15 months and 19 years. Findings are similar to those of type I, but progression is slower and life expectancy is longer; some patients have a normal lifespan. Some familial cases are secondary to specific enzyme defects (eg, hexosaminidase deficiency). Symmetric weakness and wasting progress from proximal to distal areas and are most evident in the legs, beginning in the quadriceps and hip flexors. Later, arms are affected. Life expectancy depends on whether respiratory complications develop.

Spinal muscular atrophy type 4 (late-onset) can be inherited as a recessive, dominant, or X-linked genetic disorder, with adult onset (age 30 to 60 years) and slow progression of primarily proximal muscle weakness and wasting. Differentiating this disorder from amyotrophic lateral sclerosis that involves predominantly lower motor neurons may be difficult.

X-Linked bulbospinal muscular atrophy (Kennedy disease) typically presents in men (age 30 to 50) with muscle cramps, fasciculations, myalgias, and weakness (1). It is due to a CAG trinucleotide repeat expansion on the androgen receptor gene. Bulbar symptoms, including dysphagia and dysarthria, occur later in the disease process. Fasciculations in the tongue and face are considered pathognomonic. Systemic manifestations are common, including endocrine abnormalities (gynecomastia in 70 to 80% of patients due to androgenic insensitivity), genitourinary issues (sexual dysfunction in 40 to 50% of patients), and cardiac abnormalities (abnormal ECG and ventricular hypertrophy).