Abstract
BackgroundThe advent of new therapies in spinal muscular atrophy (SMA) has highlighted the need to have natural history data for comparison. Natural history studies using structured assessments in type I however are very limited. We identified and reviewed all the existing longitudinal history data in infants with type I SMA first assessed before the age of 7 months with the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND).Main textThree longitudinal natural history studies, two performed in the United States and one in Italy, were identified. The different study design of these three studies made it possible for the cumulative dataset to include the full spectrum of severity; from infants with neonatal onset to those with a milder phenotype that were not always included in the individual natural history studies. The cumulative analysis confirmed that, even in a larger cohort, there was never an improvement on the CHOP INTEND over time. This was true for all the infants, irrespective of their age or baseline CHOP INTEND scores. Infants with neonatal onset had low CHOP INTEND scores and a fast decline. The relatively large number of patients allowed us to calculate the rate of progression in subgroups identified according to SMN2 copy number and baseline CHOP INTEND scores.ConclusionA detailed understanding of the existing data is important, as it will be difficult to acquire new systematic longitudinal history data because of the availability of disease modifying therapies. The cumulative findings in this review help to better understand the variability of natural history data in untreated patients and will be of use for comparison to the real world patients treated with the recently approved therapies that have shown encouraging results in clinical trials.
Highlights
Three longitudinal natural history studies, two performed in the United States and one in Italy, were identified
The aim of this study was to review and merge all the available data reporting longitudinal changes in the CHOP INTEND scores in type I spinal muscular atrophy (SMA) infants, focusing on those first assessed before the age of 7 months
As this scale has been used in a large clinical trial with a sham group [10], which included infants younger than 7 months of age, we aimed at establishing how the sham data compared to the ones obtained as part of natural history studies
Summary
Search approach A comprehensive search of the following electronic databases was performed: MEDLINE, CINAHL, PsycINFO, and EMBASE. We identified a clinical trial that used the CHOP INTEND in type I SMA infants enrolled below the age of 7 months with a placebo (sham) arm of 41 patients [10]. Data were analyzed looking at changes in all the patients reported in the different natural history studies who were first assessed before the age of 7 months and in subgroups of patients with different SMN2 copy numbers. Patients with 2 SMN2 copies The 30 patients with two copies were subdivided according to their baseline CHOP INTEND score: Seventeen had a score below 25 and included all the severe early onset reported in the Italian group and 8 others with similar low scores but first assessed after the first months. Patient with 4 SMN2 copies The unique patient with 4 copies scored 32 at baseline showing a rate of progression of 3.66 points/month. An increase of at least 1 point was found in none of the 22 NH patients and in one of the 37 in the control group of the ENDEAR study (3%)
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