SMN1 Duplications Are Associated With Progressive Muscular Atrophy, but Not With Multifocal Motor Neuropathy and Primary Lateral Sclerosis

Abstract

Objective: To assess the association between copy number (CN) variation in the survival motor neuron (SMN) locus and multifocal motor neuropathy (MMN), progressive muscular atrophy (PMA), and primary lateral sclerosis (PLS) susceptibility and to determine the association of SMN1 and SMN2 CN with MMN, PMA, and PLS disease course.

Methods: In this monocenter study, we used multiplex ligation-dependent probe amplification to determine SMN1 and SMN2 CN in Dutch patients with MMN, PMA, and PLS and controls. We stratified clinical parameters for SMN1 and SMN2 CN. We analyzed SMN1 and SMN2 exons 1-6, intron 6, and exon 8 CN to study the genetic architecture of SMN1 duplications.

Results: SMN1 and SMN2 CN were determined in 132 patients with MMN, 150 patients with PMA, 104 patients with PLS, and 956 control subjects. MMN and PLS were not associated with CN variation in SMN1 or SMN2. By contrast, patients with PMA more often than controls carried SMN1 duplications (≥3 SMN1 copies, 12.0% vs 5.0%, odds ratio 2.69 (1.43-4.91), p 0.0020). SMN1 and SMN2 CN status was not associated with MMN, PLS, or PMA disease course. In case of SMN1 exon 7 duplications, exons 1-6, exon 8, and introns 6 and 7 were also duplicated, suggesting full SMN1 duplications.

Conclusions: SMN1 duplications are associated with PMA, but not with PLS and MMN. SMN1 duplications in PMA are balanced duplications. The results of this study highlight the primary effect of altered SMN CN on lower motor neurons.

Figure 1. Clinical Parameters Stratified by SMN1 and SMN2 Copy Number in Patients With MMN and PMA

Boxplots showing median age at onset in years and median MRC sum score at the first visit in patients with MMN, PMA, and PLS. A) Age at onset in years by the SMN1 copy number. B) Age at onset by the SMN2 copy number in patients carrying 2 SMN1 copies. C) MRC sum score at the first visit by the SMN1 copy number. D) MRC sum score at the first visit by the SMN2 copy number in patients carrying 2 SMN1 copies. No association between the clinical parameters and SMN1 or SMN2 copy number status was found in either disease group (all p values > 0.05). MMN = multifocal motor neuropathy; MRC = Medical Research Council; PLS = primary lateral sclerosis; PMA = progressive muscular atrophy; SMN = survival motor neuron.

Figure 2. Survival by the SMN Copy Number in Patients With PMA

Kaplan-Meier curves showing the probability of survival according to disease duration in patients with PMA (panels A and C) and PLS (panels B and D). Panels A and C show overall survival stratified by the SMN1 copy number. Panels B and D show overall survival stratified by the SMN2 copy number in patients carrying 2 SMN1 copies. Because of low numbers, survival curves for patients with SMN1 deletions and SMN2 duplications are not shown. Survival did not differ between patients with PMA carrying 2 or 3 SMN1 copies (log-rank test p 0.16, HR 1.6 [0.83–3.0], p 0.16), nor did the SMN2 copy number have an effect on survival in patients carrying 2 SMN1 copies (log-rank test p 0.44; HR 0 vs 2 copies: 1.7 [0.57–4.8], p 0.35; HR 1 vs 2 copies: 1.3 [0.76–2.1], p 0.38). In patients with PLS, the SMN1 copy number was not associated with survival (log-rank test p 0.22, HR 0.31 [0.04–2.2], p 0.25), nor did the SMN2 copy number affect survival in patients carrying 2 SMN1 copies (log-rank test p 0.52; HR 0 vs 2 copies: 1.4 [0.51–4.1], p 0.49; HR 1 vs 2 copies: 1.4 [0.69–3.0], p 0.33). HR = hazard ratio; PLS = primary lateral sclerosis; PMA = progressive muscular atrophy; SMN = survival motor neuron.