Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (448 page)

Spinal muscular atrophy (SMA) refers to a group of neuromuscular autosomal recessive diseases of the motor nerves that cause muscle weakness and atrophy (wasting). The four types of SMA types I–IV, classified according to the age of onset, muscular activity achieved, and survivorship, are caused by mutations in the SMN1 (survival motor neuron 1) gene:

   SMA type I
MIM #253300
, severe infantile acute SMA, or Werdnig-Hoffman disease

   SMA type II
MIM #253550
or infantile chronic

   SMA type III
MIM #253400
, juvenile SMA, or Wohlfart-Kugelberg-Welander disease

   SMA type IV
MIM #271150
or adult-onset SMA

The copy number of the SMN2 (survival motor neuron 2) gene (homologous to SMN1 but impaired functionally) is known to modify the phenotype of SMA through low level expression of each copy of the SMN2 gene. SMA is the second most common lethal, autosomal recessive disease in Caucasians. Mutations in the SMN1 gene can occur by deletion of SMN1 exon 7, other large deletions, or point mutations.

   Diagnostic Criteria

   Clinical diagnosis: The child’s physical appearance, history of motor difficulties, weakness at birth, a delay in the developmental milestones, such as holding the head up, rolling over, sitting independently, standing, or walking later than, would be expected.

   Molecular genetic diagnosis: The two genes associated with SMA are SMN1 and SMN2. About 95–98% of individuals with SMA are homozygous for a deletion or truncation of SMN1 and about 2–5% are compound heterozygotes for an SMN1 deletion or truncation and an SMN1 intragenic mutation.

   Relevant Tests

   Methods used in molecular diagnostic testing:

   Targeted mutation analysis—to detect deletion of exon 7 of SMN1.

   Sequence analysis of all SMN1 exons and intron/exon borders to identify the intragenic SMN1 mutations.

   Gene dosage analysis—a PCR-based dosage assay, which can determine the number of SMN1 and SMN2 copies.