Greater SMA Severity Seen in Men Than Women: Natural History Study
Researchers say sex should be factor predictive of disease severity, progression
Among adults with spinal muscular atrophy (SMA), men show signs of greater disease severity than women, particularly as young adults, according to a recent study.
For patients with SMA type 3, a greater proportion of women were able to maintain their ability to walk compared with men.
“Gender should be considered as a factor predictive of disease severity and progression in SMA patients,” the researchers wrote, noting that future studies should seek to “clarify the gender-related factors contributing to SMA disease progression.”
The study, “Adults with spinal muscular atrophy: a large-scale natural history study shows gender effect on disease,” was published in the Journal of Neurology, Neurosurgery & Psychiatry.
SMA types 0–4 are caused by mutations in the SMN1 gene resulting in little or no production of SMN, a protein critical for the health of muscles and the motor nerve cells that communicate with them. These SMA types are classified based on the age of disease onset and the degree of motor disability.
Another gene, called SMN2, can also produce SMN, albeit less of it. Thus, the number of SMN2 copies a person has can also modify disease severity, with more SMN2 copies generally linked to less severe disease.
While adults comprise a substantial proportion of the overall SMA population, the natural course of SMA into adulthood hasn’t been fully established, including patterns of motor function, risk factors for disease progression, and treatment responses.
“SMA natural history in the adult age has not yet been fully clarified, and the introduction of disease-modifying treatments warrants a better comprehension of factors predicting SMA disease progression and response to treatments,” the researchers wrote.
Moreover, it has been proposed that a patient’s sex could influence disease onset and severity, although the role of sex differences in disease expression remains controversial and poorly understood.
Study examines differences in adult patients with SMA types 2–4
In their study, researchers from Italy examined disease patterns, SMN2 copy numbers, and sex differences among adult patients with SMA types 2–4.
Patients were recruited between July 2019 and June 2020 at 18 SMA care centers in Italy. Of 165 participants, 116 were initially recruited to a clinical study investigating real-world treatment responses to Spinraza (nusinersen), an approved disease-modifying treatment for SMA.
The analysis included 64 women and 101 men. Overall, women experienced SMA onset significantly earlier, with a median onset at age 3 compared with age 4 for male patients.
Gender should be considered as a factor predictive of disease severity and progression in SMA patients
Overall, 21 patients had SMA type 2, 141 had SMA type 3, and three had SMA type 4. A total of 65 people with SMA 3 were considered “sitters,” including patients who never acquired or had lost their ability to walk, while all other type 3 patients were able to walk, with or without assistance.
Among the SMA type 3 population, the ratio of sitters to walkers was significantly higher among male than female patients. Specifically, 46 men were sitters and 38 were walkers, compared with 19 sitters and 38 walkers among women.
Clinical assessments were performed to assess motor function and disability levels. No patients had a normal performance on the Hammersmith Functional Motor Scale Expanded (HFMSE), indicating physical disability, but 49 people did have normal scores on the Revised Upper Limb Module (RULM), a measure of upper limb function.
Male patients had significantly lower median HFMSE scores than female patients, reflecting worse physical disability. RULM scores similarly tended to be worse in the men, although this difference was not significant.
Genetic differences might also contribute to disease severity
Results showed that genetic differences might also contribute to disease severity. The number of SMN2 copies among patients ranged from 2–4. While the number of SMN2 copies didn’t differ between men and women, more men tended to carry four copies of the gene.
Among patients with three or four SMN2 copies, motor performance was lower in male than in female patients at a younger age, but women tended to experience a steeper decline over time.
Likewise, among SMA type 3 patients, females tended to have better motor performance at a younger age, particularly among the subset of sitters.
The age at which SMA type 3 patients lost their ability to walk was strongly associated with SMN2 copy number. Among patients with three or four copies, walking abilities were significantly prolonged in female, but not male, patients.
These findings are overall consistent with previous literature that suggest “a possible higher disease severity in SMA males,” the researchers wrote. “In conclusion, our data suggest a relevant gender effect on motor function in paediatric and adult SMA patients.”