Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder caused by homozygous absence of the survival motor neuron gene (SMN1). All patients have at least one, usually two to four copies of the related SMN2 gene which, however, produce insufficient levels of functional SMN protein due to the exclusion of exon 7 in the majority of SMN2 transcripts. Here, we show that salbutamol, a beta2-adrenoceptor agonist, determines a rapid and significant increase in SMN2-full length mRNA and SMN protein in SMA fibroblasts, predominantly by promoting exon 7 inclusion in SMN2 transcripts. These data, together with previous clinical findings, provide a strong rationale to investigate further the clinical efficacy of salbutamol in SMA patients.

OBJECTIVE:To assess the efficacy of phenylbutyrate (PB) in patients with spinal muscular atrophy in a randomized, double-blind, placebo-controlled trial involving 10 Italian centers. METHODS:One hundred seven children were assigned to receive PB (500 mg/kg/day) or matching placebo on an intermittent regimen (7 days on/7 days off) for 13 weeks. The Hammersmith functional motor scale (primary outcome measure), myometry, and forced vital capacity were assessed at baseline and at weeks 5 and 13. RESULTS:Between January and September 2004, 107 patients aged 30 to 154 months were enrolled. PB was well tolerated, with only one child withdrawing because of adverse events. Mean improvement in functional score was 0.60 in the PB arm and 0.73 in placebo arm (p = 0.70). Changes in the secondary endpoints were also similar in the two study arms. CONCLUSIONS:Phenylbutyrate was not effective at the regimen, schedule, and duration used in this study.

Spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disease, is caused by homozygous absence of the survival motor neuron (SMN1) gene. A nearly identical copy of SMN1, called SMN2, is present in all patients in at least one, usually two to four copies. This gene produces a small but insufficient amount of functional SMN protein. Higher copy numbers of SMN2 genes are generally associated with milder phenotypes. In this study we have investigated on a possible relationship between the copy number of SMN2 genes and functional ability. To this aim we have assessed motor function of 70 patients with SMA type II or non-ambulant SMA type III and compared with their copy number of SMN2 genes as determined by real-time PCR. The majority of patients (60%) had 3 copies, whereas 36% had 2 and only 4% had 4 copies of the SMN2 gene. Functional ability was assessed by using the Hammersmith scale, a three point scoring system; the total score can range from 0 up to 40. Patients with 2 copies had in general lower scores than those with 3 copies of SMN2 genes. This difference was statistically significant (P = 0.005). In particular, very poor motor function (0–5 scores) was observed in 56% of the patients with 2 copies compared to 21% of those with 3 copies. These data support the hypothesis of a correlation between higher copy number and better motor function but also show that this correlation is not absolute. Therefore, the knowledge of the number of SMN2 genes alone may not be of prognostic value for the individual patients.

The aim of this study was to evaluate tolerability and efficacy of phenylbutyrate (PB) in patients with spinal muscular atrophy (SMA). Ten patients with SMA type II confirmed by DNA studies (age range 2.6-12.7 years, mean age 6.01) were started on oral PB (triButyrate) in powder or tablets. The dosage was 500 mg/kg per day (maximum dose 19 g/d), divided in five doses (every 4 h, skipping one night-dose) using an intermittent schedule (7 days on and 7 days off). Measures of efficacy were the change in motor function from baseline to 3 and 9 weeks, by means of the Hammersmith functional motor scale. In children older than 5 years, muscle strength, assessed by myometry, and forced vital capacity were also measured. We found a significant increase in the scores of the Hammersmith functional scale between the baseline and both 3-weeks (P < 0.012) and 9-weeks assessments (P < 0.004). Our results indicate that PB might be beneficial to SMA patients without producing any major side effect. Larger prospective randomised, double-blind, placebo controlled trials are needed to confirm these preliminary findings.