Fertility issues common in men with SMA, study finds
Those with more severe motor impairments particularly affected
Fertility issues and low sperm counts are common in men with spinal muscular atrophy (SMA), particularly in those with more severe disease, according to a study from France.
Almost two-thirds (65.9%) of SMA patients had fertility disorders. These conditions were particularly common in SMA type 2 patients.
“To our knowledge, this is the first study to demonstrate fertility disorders in relation to [sperm] abnormalities in male SMA patients,” the researchers wrote. The study, “Spinal muscular atrophy is also a disorder of spermatogenesis,” was published in Orphanet Journal of Rare Diseases.
SMA is mostly caused by mutations in the SMN1 gene, leading to limited or no production of SMN. This protein is critical for the health of motor neurons, nerve cells responsible for controlling voluntary movement. Without SMN, motor neurons sicken and die.
SMA patients can be categorized based on the age in which symptoms appear and the highest motor milestone achieved. About one-third of patients have SMA type 2, with SMA symptoms emerging between 6 and 18 months of age. SMA type 3 patients have later disease onset with symptoms appearing between 18 months and the end of adolescence.
SMA treatments and fertility
Prior preclinical studies found that high doses of Evrysdi (risdiplam), an approved daily therapy for SMA, affected the development of sperm in rats and monkeys. The researchers set out to understand whether fertility problems are related to treatment or if they are a pre-existing, underlying symptom of SMA in men.
“Few SMA studies have focused on fertility issues, and little is known about the non-muscular phenotypes [disease-related changes] in SMA patients,” the researchers wrote.
The examined semen analysis data from 33 men with SMA, 20 with SMA type 2 and 13 with SMA type 3.
While an estimated 7.5% of the European population has abnormal sperm concentrations, 95% of SMA type 2 and 61% of SMA type 3 patients had abnormal sperm concentrations, the researchers wrote.
The SMA type 2 group was significantly more likely to have azoospermia, a medical condition in which semen contains no sperm. Azoospermia, a leading cause of male infertility, was found in 45% of SMA type 2 patients and in 7.7% of those with SMA type 3.
Fertility disorders were present in 27 men with SMA with 19 cases of fertility disorders in SMA type 2 patients and eight in men with SMA type 3.
The researchers compared two subgroups of patients. The first had 27 men known to have sperm analysis abnormalities, and the second was composed of 14 men who had children without conception problems or whose sperm analysis was normal.
SMA severity was linked to the presence of fertility disorder. SMA patients with poor motor function and impaired upper-limb movements were more likely to experience fertility issues. More severe disease was associated with lower sperm concentrations.
Disease severity is associated with the number of copies of the SMN2 gene, which encodes a shorter, less stable version of SMN. This shorter version of SMN can partly compensate for the loss of SMN1-encoded SMN. People with SMA with more copies of the SMN2 gene generally have less severe disease.
In line with findings that more severe disease was associated with low sperm production and fertility issues, patients with fewer copies of SMN2 were more likely to have a fertility disorder.
The researchers hypothesized that SMN may play a critical role in male fertility, with its absence affecting diverse aspects of testis development and function. Studies in mouse models of SMA consistently find infertility and related problems.
“The most probable hypothesis is of a specific role linked to the absence of SMN in the genesis of these [fertility] disorders, which is supported by animal studies,” the researchers wrote.
They also called for more research into the long-term effects of Evrysdi.
“A systematic study of spermograms in young adult and adult SMA patients before and after treatment would be appropriate,” the researchers concluded.
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