Cerebrospinal fluid characteristics of patients treated with intrathecal nusinersen for spinal muscular atrophy.

INTRODUCTION/AIMS: There is limited information on the potential effects of repeated intrathecal antisense oligonucleotide drug delivery on cerebrospinal fluid (CSF) biochemical and blood cell profiles. This study aimed to examine longitudinal changes in the biochemical components (glucose, protein) and blood cell counts in the CSF of spinal muscular atrophy (SMA) patients treated with intrathecal nusinersen. METHODS: We collected and analyzed clinical and CSF parameters (cell count, protein, glucose, culture) of 50 individuals with SMA during nusinersen treatment (22 type 1, 17 type 2, and 11 type 3). RESULTS: The median protein concentration at baseline and during treatment was within the normal range but rose during treatment and was significantly above baseline at the time of the ninth intrathecal injection (p = 0.02, two-tailed Wilcoxon matched-pairs test, and p = 0.0015, Friedman test for repeated measures). Further analysis showed that the increase in CSF protein concentration was evident for SMA types 2 and 3 patients, but not for type 1. This observation was also demonstrated by a significant correlation between the SMN2 gene copy number and the increase in CSF protein concentration (Spearman rank correlation test). DISCUSSION: Our results demonstrate that a delayed increase in CSF protein concentration is expected during nusinersen treatment for SMA types 2 and 3. This might reflect the medication's effect and a possible therapeutic biochemical marker.

Insulin-like growth factor-1 status is associated with insulin resistance in young patients with spinal muscular atrophy.

Insulin-like growth factor-1 (IGF-1) is an anabolic hormone with myotrophic effects on muscle tissue. Patients with spinal muscular atrophy (SMA) sustain early-onset sarcopenia, which contributes to an increased prevalence of insulin resistance. Our aim was to determine the IGF-1 status in 5q-SMA patients and its association with insulin resistance. Real-life clinical and laboratory data of 34 patients (15 males; age 3 months-24 years) included: anthropometric measurements [weight, height/length, body mass index or weight-to-length ratio, delta-height standard deviation score (∆Ht SDS) as the difference between height/length SDS and mid-parental height (MPHt) SDS] and laboratory measurements [Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and IGF-1]. HOMA-IR levels categorized patients as insulin-resistant [HOMA-IR ≥1.9 (n = 20)] or insulin-sensitive [HOMA-IR <1.9 (n = 14)]. The collective height/length SDS was -0.29±1.34 and ∆Ht SDS was -0.11±1.47. IGF-1 levels were within the normal population range for all patients. Insulin-resistant patients had higher IGF-1 SDS levels compared to insulin-sensitive patients (0.87±0.78 vs. -0.67±0.96, respectively, P<0.001). The IGF-1 SDS was significantly associated with HOMA-IR for all subjects (r = 0.547, P = 0.001), and linear growth parameters (height/length SDS, ∆Ht SDS) were significantly associated with IGF-1 SDS in the insulin-resistant subgroup (r = 0.649, P = 0.002 and r = 0.605, P = 0.005, respectively). Our findings suggest that IGF-1 status is associated with insulin resistance in patients with early-onset sarcopenia.

The endocrine manifestations of spinal muscular atrophy, a real-life observational study.

The introduction of nusinersen, the first therapeutic modality for Spinal Muscular Atrophy (SMA) patients has raised hopes and led to construction of a multi-professional medical SMA service, including pediatric endocrinology. Our study aimed to provide a comprehensive description of the endocrine manifestations of SMA patients with variable degree of sarcopenia. Real-life clinical and laboratory data of 62 SMA patients (age range 3 months to 31 years, 24 type 1, 21 type 2, 17 type 3) were collected including: weight-status, self-reported information on puberty, current pubertal stage, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), basal gonadotropin and androgen levels. Precocious pubarche (mean age at onset 3.9 ±â€¯2.8 years) was found in 24% (15/62) of the SMA cohort [45.9%(11/24) type 1 and 19%(4/21) type 2]. A higher HOMA-IR predicted precocious pubarche after adjustment for SMA type and age (OR=1.42; 95% CI, 1.05, 1.93, P = 0.025). Bilateral cryptorchidism was found in 60% of type 1 and 30% of type 2 boys; type 3 young adult males attained full puberty. Most of the young women had normal pubertal development and regular menses, regardless of degree of obesity. Our findings suggest that isolated precocious pubarche is associated with early-onset insulin resistance linked to severity of muscular atrophy.