Genetic Testing in SMA

Tim Hagenacker, MD: Genetic testing is the basis of diagnosis for type 2 SMA [spinal muscular atrophy]. In the years before drugs like nusinersen were available, genetic testing was not performed in every case, especially when patients had a long-term diagnosis. At that time, genetic testing had no consequence on treatment. Often, a diagnosis was made by symptoms, in addition to some electrophysiologic diagnostics. Now that treatment is available, we need the confirmation that it’s really a 5q SMA.

The classical test is the multiplex ligation-dependent probe amplification, or MLPA, to detect the deletion of the SMN gene, and to detect the copy number of the SMN2 gene. Besides that, a classical test can also be performed from a dried-spot blood test. Those are the common tests available.

In most cases, you have homozygous deletion of the SMN1 gene, but there are a few cases that are compound heterozygous. We have a deletion on 1 allele of the SMN1 gene and a point mutation on the other allele. The SMN2 copy number determines the severity of the disease. There is a good correlation between increasing copy number and a less severely impaired patient. Typically you have, for example, 2 SMN2 copies in an SMA type 2 patient, and 4 SMN2 copies in an SMA type 3 patient. This is a correlation in approximately 80% to 90%. There are also other patients in which you don’t have that correlation. We possibly have some other genetic modifiers.