Biomarkers of disease progression in adolescents and adults with 5q spinal muscular atrophy: a systematic review and meta-analysis

New England Journal of Medicine, 377(18), 1723-1732

Denervation was assessed in 89 spinal muscular atrophy (SMA) 1, 2, and 3 subjects via motor unit number estimation (MUNE) and maximum compound motor action potential amplitude (CMAP) studies, and results correlated with SMN2 copy, age, and function. MUNE and maximum CMAP values were distinct among SMA subtypes (p < 0.05). Changes in MUNE and maximum CMAP values over time were dependent on age, SMA type, and SMN2 copy number. SMN2 copy number less than 3 correlated with lower MUNE and maximum CMAP values (p < 0.0001) and worse functional outcomes. As SMN2 copy number increases, so does functional status (p < 0.0001). Change in MUNE longitudinally over the time intervals examined in this study was not statistically significant for any SMA cohort. However, a decline in maximum CMAP over time was apparent in SMA2 subjects (p = 0.049). Age-dependent decline in MUNE and maximum CMAP was apparent in both SMA 1 (p < 0.0001) and SMA 2 (p < 0.0001) subjects, with age as an independent factor regardless of type. Maximum CMAP at the time of the initial assessment was most predictive of functional outcome (p < 0.0001). Prospective longitudinal studies in four prenatally diagnosed infants demonstrated significant progressive denervation in association with symptomatic onset or functional decline. These data highlight the potential value of such measures in increasing our understanding of pathophysiological factors involved in denervation in SMA.

Abstract Objective To evaluate plasma phosphorylated neurofilament heavy chain (pNF‐H) as a biomarker in spinal muscular atrophy (SMA). Methods Levels of pNF‐H were measured using the ProteinSimple® platform in plasma samples from infants with SMA enrolled in ENDEAR (NCT02193074) and infants/children without neurological disease. Results Median pNF‐H plasma level was 167.0 pg/mL (7.46–7,030; n = 34) in children without SMA (aged 7 weeks–18 years) and was higher in those aged < 1 versus 1–18 years (P = 0.0002). In ENDEAR participants with infantile‐onset SMA, median baseline pNF‐H level (15,400 pg/mL; 2390–50,100; n = 117) was ~10‐fold higher than that of age‐matched infants without SMA (P < 0.0001) and ~90‐fold higher than children without SMA (P < 0.0001). Higher pretreatment pNF‐H levels in infants with SMA were associated with younger age at symptom onset, diagnosis, and first dose; lower baseline Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders score; and lower peroneal compound muscle potential amplitude. Nusinersen treatment was associated with a rapid and greater decline in pNF‐H levels: nusinersen‐treated infants experienced a steep 71.9% decline at 2 months to 90.1% decline at 10 months; sham control–treated infants declined steadily by 16.2% at 2 months and 60.3% at 10 months. Interpretation Plasma pNF‐H levels are elevated in infants with SMA. Levels inversely correlate with age at first dose and several markers of disease severity. Nusinersen treatment is associated with a significant decline in pNF‐H levels followed by relative stabilization. Together these data suggest plasma pNF‐H is a promising marker of disease activity/treatment response in infants with SMA.