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From the Department of Neurology (Drs. Veldink, Kalmijn, Groeneveld, Wokke, Van den Berg), Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht; the Department of Clinical Genetics (Drs. Van der Hout and Lemmink, C. Lummen), University Hospital Groningen; and the Department of Medical Genetics (Dr. Scheffer), University Hospital St. Radboud, Nijmegen, The Netherlands.
* To whom correspondence should be addressed. E-mail: l.h.vandenberg{at}neuro.azu.nl.
Abstract-- Background: ALS is believed to be multifactorial in origin with modifying genes affecting its clinical expression. Childhood-onset spinal muscular atrophy (SMA) is an autosomal recessive disorder of motor neurons, caused by mutations of the survival motor neuron (SMN) gene. The SMN gene exists in two highly homologous variants: SMN1, the causative gene responsible for the production of the majority of functional SMN protein, and SMN2, responsible for the production of less protein but sufficient for modifying the SMA phenotype. Objective: To test whether SMN genotypes are associated with susceptibility to and severity of sporadic ALS. Methods: We performed competitive quantitative PCR analysis for both SMN1 and SMN2 genes in 242 clinically well-defined ALS patients and 175 controls. The combined determination of SMN1 and SMN2 copies also allowed for an estimation of the level of SMN for each patient (estimated SMN protein level = SMN1 copy number + 0.20 x SMN2 copy number). Results: One copy of SMN1 was associated with an increased risk of developing ALS (odds ratio = 4.1, 95% CI = 1.2 to 14.2, p = 0.02) and ALS patients carried fewer SMN2 copy numbers (p < 0.001). Sixty-one percent of patients had an estimated protein SMN level 
2.2 vs only 36% of controls (p = 0.0000004). Multivariate Cox regression analyses showed that lower SMN2 copy numbers and lower levels of estimated SMN protein (hazard ratio = 1.3, 95% CI = 1.1 to 1.6, p = 0.03) were associated with an increased mortality rate. Conclusions: SMN genotypes producing less SMN protein increase susceptibility to and severity of ALS.
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