141P Spinal muscular atrophy is also a disorder of spermatogenesis

Abstract

Spinal muscular atrophy (SMA) patients benefit from pre-mRNA splicing modifiers targeting the SMN2 gene, which aims to increase functional SMN production. The animal toxicity affecting spermatogenesis associated with one such treatment raised questions about male SMA patients’ spermatogenesis. This descriptive, cross-sectional study was conducted from June 2022 to July 2023. The study involved adult male patients with genetically confirmed SMA type 2 (SMA2) or SMA3 from 13 French neuromuscular centers. The patients’ general data, motor severity, urological history, exposure to certain factors, parenthood, and spermogram results were obtained. Sixty-eight patients were enrolled (33 SMA2 and 35 SMA3 patients). The two patient cohorts had significantly different motor severity, wheelchair usage duration, weight, and height. Forty-one patients had fertility data (parenthood history and spermogram analyses) and involved 33 spermograms. Fertility disorders were identified in 27 of the 41 patients (65·9%, SMA2: 19 cases (90,4%), SMA3: 8 cases (40%)). Among the patients with available spermograms, 81% (27/33) had abnormal sperm concentration; 40% presented azoospermia. These abnormalities were significantly associated with SMA type (more prevalent in SMA2 patients, p<0·001), disease motor severity, which included age at the loss of walking ability and wheelchair use duration (p<0·001). The Motor Function Measure (MFM) determined that the sperm counts were correlated with disease severity (p<0·01). The fertility disorders were correlated with SMA severity and were particularly evident in SMA2 patients. In SMA2 patients, sperm concentration positively correlated with MFM. The potential contributing factors included prolonged sitting (influencing testicular thermoregulation or hormonal dysfunction) and the role of SMN in germ cell development. This study is the first to link fertility disorders with spermogram abnormalities in SMA males. Understanding spermatogenesis in SMA is crucial, especially with new therapies (e.g. risdiplam). Consequently, conducting systematic spermogram studies prior to SMA treatment is recommended.