For every movement of the body, upper motor nerve cells (neurons) send signals from the brain cortex to the spinal cord where these signals are received by lower motor neurons. Via their long processes (axons) lower motor neurons then pass on the signals to the respective muscle groups and initiate the necessary muscle contraction. In spinal muscular atrophy (SMA), the lower motor neurons in the spinal cord are damaged, and thus, the respective muscles do not receive proper signals from the brain and fail to contract sufficiently. This results in muscle weakness (floppiness, hypotonia) and muscle wasting (atrophy).
The classic and most common form of SMA is caused by deletions or mutations in the “survival motor neuron 1” gene (SMN1). SMA is inherited in an autosomal-recessive manner with 25% recurrence risk for siblings of an affected child from healthy parents.
SMA varies substantially with respect to age at onset and severity. Accordingly, it is defined into four clinical phenotypes: Type I SMA patients (Werdnig-Hoffmann disease) show onset within six months after birth and normally die before two years of age. They are never able to sit or walk. Type II SMA patients (intermediate form) have an onset after six months of age. They are able to sit, but not to stand. Type III SMA patients (Kugelberg-Welander disease) show their first symptoms after 18 months of age. They are able to sit and walk but often become wheel-chair bound in the course of disease progression. Type IV SMA patients (adult form of SMA) are characterized by an age of onset >30 years and only very mild signs of muscle weakness.
Part of this phenotypic variation can be explained by the presence of a copy gene (“survival motor neuron 2”, SMN2) that is highly similar to SMN1. SMN2 can be present in the genome in multiple copies. While SMN2 cannot completely compensate for autosomal-recessive SMN1 gene defects, a higher SMN2 copy number has been associated with less severe disease forms.
Despite the association of SMN2 with severity, the phenotypic variation cannot be fully explained to date. Likewise, a substantial proportion of patients presenting with an SMA-like phenotype (defined as lower motor neuron disease, LMND) no causal SMN1 gene defect can be identified. Thus, the identification of the genetic basis of these LMND phenotypes as well as the elucidation of disease modifying factors is important in order to understand the underlying pathophysiology of SMA and LMND phenotypes and to develop targeted therapies.