Sex, SMN2 Copy Number Influence SMA Type 3 Age of Onset

Sex and the number of copies of the “backup” SMN2 gene influence both the age of symptom onset and the risk of losing the ability to walk in people with spinal muscular atrophy (SMA) type 3, according to a Polish registry study.

The data also confirmed the notion that earlier symptom onset predicts a more severe disease course, which in this patient population was linked to a higher likelihood of becoming unable to walk.

The findings, based mainly on data from untreated patients, add insights to the natural disease course of SMA type 3, which may help inform treatment decisions, the researchers noted.

The study, “Observation of the natural course of type 3 spinal muscular atrophy: data from the polish registry of spinal muscular atrophy,” was published in the Orphanet Journal of Rare Diseases.

SMA is caused by low, or no, production of SMN, a protein key for motor neuron and muscle health, due to mutations in the SMN1 gene. It is historically divided into five types (0, 1, 2, 3, and 4), based on age of onset and maximum motor function achieved.

Notably, the presence of a “backup” gene, SMN2, can partly compensate for the loss of SMN1-produced SMN. Typically, the more SMN2 gene copies a patient has, the less severe the disease, with SMA type 1 patients usually having two copies, those with type 2 carrying three copies, and those with type 3 or 4 disease having three or more copies.

“Registries of patients with rare disorders, such as neuromuscular diseases (NMDs), have an important role in monitoring the course of the disease, defining trial or treatment-ready population,” the researchers wrote.

The Polish Registry for NMDs has been collecting data from people with NMDs, such as SMA, at the Medical University of Warsaw since 2010 — several years before Biogen’s Spinraza, the first SMA disease-modifying therapy, was approved in the country.

While the therapy received European Union approval in June 2017, the Polish National Health Service only decided to reimburse it in December 2018, and the first patients began free Spinraza treatment in April 2019.

Researchers now have described the characteristics of SMA patients enrolled in the Polish registry, with a focus on the disease course of those with SMA type 3, a later-onset form, before the availability of disease-modifying treatments.

Of note, type 3 is usually characterized by symptom onset after 18 months of age (about 1.5 years), and can be divided into types 3a (symptom onset before age 3) and 3b (onset after age 3 and less-severe disease).

At the cut-off date of October 2019, 790 SMA patients (173 with type 1 disease, 218 with type 2, 393 with type 3, and six with type 4) were included in the registry, making it “one of the largest national databases of patients with SMA,” the researchers wrote.

The observed proportion of SMA types, with a predominance of type 3, reflected the real-world prevalence of SMA types, the team noted. A total of 33 patients had received Spinraza, including four with type 3 disease, whose data were excluded in the analysis of disease course, or ability to walk.

More than half of the patients were male (53%) and adults (52%). The mean age was 8.8 years for SMA type 1 patients, 17.5 years for those with type 2, 28 years for type 3 patients, and 44 years for those with type 4, the mildest form of the disease.

In addition, 44% of type 3 patients were still able to walk; the others had lost such ability at a mean of 14 years.

Information on SMN2 gene copy number was available for 672 (85%) patients, and 94% of the 344 type 3 patients with available data had three to four SMN2 copies, while 6% had two copies.

Notably, 59 patients (15%) with type 3 disease had their first symptoms earlier than 18 months of age, consistent with some previous reports. This supports “the continuum of clinical severity” and points out that such cut-off age “can result in about 15% of patients not fitting any traditionally defined type of SMA,” the team wrote.

In SMA type 3 patients, the first symptoms occurred more than three years earlier in those carrying three SMN2 copies than in those with four copies (3 years old vs. 6.7 years).

SMN2 copy number also had a significant impact on disease course, with type 3 patients carrying three or fewer gene copies being two times more likely to lose their ability to walk independently than those with four copies.

“The largest differences in the probability of preserving the ability to walk were noted between patients with SMA3b with four copies of SMN2 and patients with SMA3a with three copies of SMN2,” the researchers wrote.

“Although the number of copies of SMN2 plays an important role in the disease course, there are certainly other SMA-modifying factors,” they added.

Males outnumbered females by about two times among type 3b patients and among individuals with type 3 disease and four SMN2 copies, suggesting that more males had a milder form of this type relative to females.

In agreement, the age of onset of SMA type 3 was significantly lower in girls than in boys (3.1 years vs. 5.7 years), with no new diagnosis occurring in girls older than 16, and female patients lost their ability to walk nearly four years earlier than male patients (11.9 years old vs. 15.7 years).

“All these observations indicate a possible relationship between sex and the course of SMA, as reported in other studies,” the researchers wrote.

Overall, the findings highlight that SMN2 copy number and sex strongly affect the age of onset and walking ability of SMA type 3, and confirmed that age of disease onset also influences the disease course.