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Background: Paraoxonases (PONs) are involved in the detoxification of organophosphate pesticides and chemical nerve agents. Due to a reported possible twofold increased risk of ALS in Gulf War veterans and the associations of PON1 polymorphisms with the neurologic symptom complex of the Gulf War syndrome, the authors investigated the association between sporadic ALS (SALS) and PON gene cluster variants in a large North American Caucasian family–based and case-control cohort (N = 1,891). Methods: Clinically definite and probable ALS was diagnosed according to the revised El Escorial criteria, exclusion of family history of ALS, and SOD1 mutation analysis. Single nucleotide polymorphism (SNP) genotyping was done using Taq Man assays on ABI7900HT. Data were analyzed using SPSS, Haploview, FBAT, and THESIAS. Results: A haploblock of high linkage disequilibrium (LD) spanning PON2 and PON3 was associated with SALS. The SNPs rs10487132 and rs11981433 were in strong LD and associated with SALS in the trio (parents-affected child triad) model. The association of rs10487132 was replicated in 450 nuclear pedigrees comprising trios and discordant sibpairs. No association was found in case-control models, and their haplostructure was different from that of the trios with overall reduced LD. Resequencing identified an intronic variant (rs17876088) that differentiated between detrimental and protective SALS haplotypes. Conclusion: This study demonstrates evidence of significant association of variants in the Paraoxonase gene cluster with sporadic ALS and is compatible with the hypothesis that environmental toxicity in a susceptible host may precipitate ALS.

Exercise is simulated in muscle biopsy preparations by using low concentrations of 2,4-dinitrophenol (DNP), which do not produce contracture or anatomic damage. The validity of this simulation is supported by (1) the biochemical effects of simultaneous muscle contraction and DNP are not additive, suggesting that exercise and DNP stress the same pathways; (2) the effects of increasing concentrations of DNP and increasing levels of stimulation are similar with an early drop in phosphocreatine, increasing lactate and inosine monophosphate (IMP), and a late fall in ATP levels; and (3) DNP provocation in a patient with McArdle's disease demonstrated an absence of lactate and high levels of IMP correlating with clinical findings. DNP provocation may be a simple way of studying metabolic pathways in neuromuscular diseases.