Adults with spinal muscular atrophy: a large-scale natural history study shows gender effect on disease

Abstract

BackgroundNatural history of spinal muscular atrophy (SMA) in adult age has not been fully elucidated yet, including factors predicting disease progression and response to treatments. Aim of this retrospective, cross-sectional study, is to investigate motor function across different ages, disease patterns and gender in adult SMA untreated patients.MethodsInclusion criteria were as follows: (1) clinical and molecular diagnosis of SMA2, SMA3 or SMA4 and (2) clinical assessments performed in adult age (>18 years).ResultsWe included 64 (38.8%) females and 101 (61.2%) males (p=0.0025), among which 21 (12.7%) SMA2, 141 (85.5%) SMA3 and 3 (1.8%) SMA4. Ratio of sitters/walkers within the SMA3 subgroup was significantly (p=0.016) higher in males (46/38) than in females (19/38). Median age at onset was significantly (p=0.0071) earlier in females (3 years; range 0–16) than in males (4 years; range 0.3–28), especially in patients carrying 4 SMN2 copies. Median Hammersmith Functional Rating Scale Expanded scores were significantly (p=0.0040) lower in males (16, range 0–64) than in females (40, range 0–62); median revised upper limb module scores were not significantly (p=0.059) different between males (24, 0-38) and females (33, range 0–38), although a trend towards worse performance in males was observed. In SMA3 patients carrying three or four SMN2 copies, an effect of female sex in prolonging ambulation was statistically significant (p=0.034).ConclusionsOur data showed a relevant gender effect on SMA motor function with higher disease severity in males especially in the young adult age and in SMA3 patients.

Clinical Phenotype of Pediatric and Adult Patients With Spinal Muscular Atrophy With Four SMN2 Copies: Are They Really All Stable?

“…We also observed that the imbalance in gender representation was more obvious in patients with onset of clinical signs after puberty than in those with earlier onset. These findings are in agreement with the hypothesis that there may be other female patients who do not come to our observation because of a milder phenotype and that the number of overall 4 or more SMN2 copies may be therefore underestimated 16 . The relatively high incidence of 4 SMN2 copies found in some neonatal screening programs appears to support this hypothesis 20 …”

“…The ongoing discussion on if and when treatment should be started in patients with 4 SMN2 copies identified through neonatal screening has highlighted the need to better understand the variability of phenotypes associated with 4 SMN2 copies and the risk of developing a severe phenotype over the years. The phenotypic variability associated with 4 copies in the literature [16][17][18][19] partly reflects the cohorts studied, with studies focusing on adults more often reporting milder phenotypes and studies including pediatric cohorts also showing more severe phenotypes.…”

“…The main concern is generated by the relative paucity of information on the natural history and by the variable phenotypes and SMA progression associated with 4 copies. Whereas studies focusing on or including pediatric patients report early signs of clinical involvement, 15 those in adult cohorts report a high percentage of late onset of relatively mild clinical signs 16–19 . Because of this, even in countries where treatment is available for all the infants identified by NBS, irrespective of the copy number, not all clinicians or families opt for early treatment 20 …”

Sex and Gender Differences in Neurodegenerative Diseases: Challenges for Therapeutic Opportunities

“…This change produces a truncated and unstable protein in around 90% of cases. SMN2 can be present in multiple copies and acts as a genetic modifier of disease severity [ 99 ].…”

“…However, motor function impairment seemed to occur more predominantly in male patients. Even if the median Hammersmith Functional Rating Scale Expanded (HFRSE) score were significantly lower in males than in females (16 vs. 40), the upper limb segment of the battery did not reveal a statistically significant difference between the sexes [ 99 ]. Of interest, the presence of gender differences in the growth pattern of SMA children has been described.…”