A study of genotype/phenotype discordance in the SMAs is very informative

SMA is a degenerative disease of the lower motor neurons, responsible for paralysis of varying severity. A distinction is made between four types (I to IV) depending on the age of onset of the deficit and the maximum motor ability achieved by the patient. In the large majority of cases, one identifies, in the patient, a homozygous deletion of the SMN1 gene, while the number of copies of the paralogous SMN2 gene, which is not mutated, is a predictive factor for severity, with a few exceptions. The number of copies of SMN2 is also given great significance in therapeutic decision algorithms currently being developed.

Spanish researchers have focused on SMA cases in which genotype and phenotype may appear discordant. This involves, for example, cases of SMA with a single copy of the SMN2 gene, without early onset of symptoms, or cases of SMA (type II or III) that are not too severe, despite the presence of two copies of the SMN2 gene. These situations require additional molecular analyses, intended to identify the additional factors involved (rare variants of SMN2, hybrid structures, other modifying genes). The authors also present the particular problem of cases presenting 4 copies of the SMN2 gene, some of which are starting to be detected during the neonatal period, for which there is, as yet, no therapeutic consensus.


Practical guidelines to manage discordant situations of SMN2 copy number in patients with spinal muscular atrophy. I Cuscó, S Bernal, L Blasco-Pérez et al. Neurol Genet. 2020 Nov 18;6(6):e530.