Diagnosis of SMA

The diagnosis of SMA should be suspected for any infant with unexplained weakness or hypotonia. Additional clues suggesting the diagnosis in infants, children, or adults include a history of motor difficulties, loss of motor skills, proximal muscle weakness, hyporeflexia or areflexia, tongue fasciculations, and signs of lower motor neuron disease on examination. Molecular genetic testing with targeted mutation analysis can confirm the diagnosis of SMA by detection of homozygous deletions of exons 7 of SMN1. The exon 7 deletion is by far the most common mutation in SMA, but point mutations also occur. Thus, sequencing of SMN1 to look for a point mutation should be pursued if the clinical manifestations are typical of SMA and only a single deletion is identified.

The absence of a pathogenic mutation in SMN1 casts serious doubt on the diagnosis. In this situation, it is imperative to consider other conditions in the differential diagnosis (eg, spinal muscular atrophy with respiratory distress type 1).

Electromyography and muscle biopsy were once a standard part of the diagnostic evaluation for SMA but are seldom needed now that molecular genetic testing is widely available. Electromyography in SMA shows abnormal spontaneous activity with fibrillations and positive sharp waves. The mean duration and amplitude of motor unit action potentials are increased, and many are polyphasic. Muscle biopsy reveals large groups of circular atrophic type 1 and 2 muscle fibers interspersed among fascicles of hypertrophied type 1 fibers. The enlarged fibers have been reinnervated by the sprouting of surviving nerves and are three to four times larger than normal. Histologic diagnosis may be more challenging to make in the newborn infant because only widespread atrophy of muscle fibers may be seen, but a later repeat biopsy usually demonstrates the mixture of hypertrophied and atrophic fibers seen after reinnervation occurs.

SMA was added to the Recommended Uniform Screening Panel (RUSP) for newborns in the United States (US) in 2018, and most states in the US now have active newborn screening for SMA. National or pilot newborn screening programs for SMA are also operational in most Canadian provinces, several European countries, Taiwan, and Australia. The feasibility and utility of newborn screening for SMA using different high-throughput molecular techniques is supported by results from several prospective pilot studies. Newborn screening programs identify approximately 95 percent of newborns with SMA through detection of the exon 7 deletion in SMN1 using quantitative PCR (qPCR). Newborns with point mutations in SMN1 will not be detected.