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Proximal hereditary spinal muscular atrophy (SMA) is caused by homozygous deletion of the survival motor neuron (SMN) 1 gene and has a wide range of severity.1 Onset may occur prenatally up to the fourth decade of life, and motor deficits range from neonatal hypotonia to mild weakness in adulthood. The current classification of SMA distinguishes five SMA types (ie, type 0–4) based on the combination of age at onset and two acquired gross motor milestones.1 ,2 Distinction of additional subtypes based on differences in the age at onset, first for SMA type 3 (ie, 3a and 3b) and more recently for type 1 (ie, 1a–1c), has been proposed. This may help to further clarify differences in prognosis within SMA types and to balance baseline characteristics in clinical trials. We aimed to gain further insight into the added predictive value of motor milestones for the occurrence of SMA outcome or common complications, that is, death, respiratory insufficiency, scoliosis surgery and loss of ambulation. We included SMN2 copy number in our analysis, since this is the most important genetic biomarker of severity.3
Patients and methods
We enrolled patients with SMA types 1–4 between September 2010 and August 2014.
Methods are described in the online supplementary file.
The clinical diagnosis of SMA was genetically confirmed in 200 patients. SMN2 copy number varied from 1 to 5 and overlapped between SMA types. SMN2 copy number correlated inversely with SMA type (p<0.001; table 1). Clinical characteristics are summarised in table 1.
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Motor milestones defined SMA type 1–3 in case of discrepancies with age of onset. SMA classification was eventually changed in 18 patients (9%) because of acquisition of new motor milestones.
We included 42 patients with SMA type 1 (table 1). Three patients had the most severe phenotype, type 0/1a, …
Contributors RIW contributed to the drafting of the manuscript for content, study concept and design, analysis or interpretation of data, study supervision, acquisition of data, statistical analysis. HHL contributed to the revising of the manuscript for content, study concept or design and analysis of data. MS, MG, INS, CAW, MAGCS, KPJB, DD contributed to the revising of the manuscript for content and acquisition of data. LHvdB contributed to the revising of the manuscript for content, study concept and design and interpretation of data. W-LvdP contributed to the drafting and revising of the manuscript for content, including writing for content, analysis or interpretation of data revising of the manuscript for content, study concept and design, interpretation of data, statistical analysis, study supervision and obtaining funding. W-LvdP and RIW had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Funding This study was supported by grants from the Prinses Beatrix Spierfonds (WAR08-24) and the Stichting Spieren voor Spieren.
Disclaimer The funders had no role in study design, data collection, data analysis or interpretation, writing the report or decisions in submitting this manuscript.
Competing interests LHvdB serves on scientific advisory boards for the Prinses Beatrix Spierfonds, Thierry Latran Foundation, Biogen Idec and Cytokinetics; received an educational grant from Baxter International; serves on the editorial board of Amyotrophic Lateral Sclerosis and the Journal of Neurology, Neurosurgery and Psychiatry; and receives research support from the Prinses Beatrix Spierfonds, Netherlands ALS Foundation, the European Community's Health Seventh Framework Programme (grant agreement number 259867), the Netherlands Organization for Health Research and Development (Vici Scheme, JPND (SOPHIA, STRENGTH)). W-LvdP receives research support from the Prinses Beatrix Spierfonds, Netherlands ALS Foundation and Stichting Spieren voor Spieren.
Ethics approval Medical Ethical Committee of the University Medical Centre Utrecht.
Provenance and peer review Not commissioned; externally peer reviewed.