ALSUntangled No. 35: Hyperbaric Oxygen Therapy*

Fixsen, Emma; Bedlack, Richard; Quinn, Colin; Karam, Chafic; Sherman, Alex; Ostrow, Lyle W.; Hardiman, Orla; Heiman‐Patterson, Terry; Gutmann, Laurie; Bromberg, Mark B.; Kabashi, Edor; Bertorini, Tulio E.; Mozaffar, Tahseen; Andersen, Peter M.; Gámez, Josep; Dimachkie, Mazen M.; Wicks, Paul; Heywood, J. Thomas; Novella, Steven; Rowland, Lewis P.; Pioro, Erik P.; Kinsley, Lisa; Mitchell, Kathy E.; Glass, Jonathan D.; Sathornsumetee, Sith; Baker, Jon; Atassi, Nazem; Forshew, Dallas; Ravits, John; Conwit, Robin; Jackson, Carlayne E.; Dalton, Kate; Tindall, Katherine; Gonzalez, Ginna; Robertson, Janice; Phillips, Larry; Benatar, Michael; Sorenson, Eric J.; Shoesmith, Christen; Nash, Steven; Maragakis, Nicholas J.; Moore, Dan H.; Caress, James B.; Boylan, Khrista; Armon, Carmel; Grosso, Megan; Gerecke, Bonnie; Wymer, Jim; Oskarsson, Björn; Bowser, Robert; Drory, Vivian E.; Shefner, Jeremy M.; Lechtzin, Noah; Leitner, Melanie; Miller, Robert G.; Levine, Todd; Russell, James W.; Sharma, Khema R.; Saperstein, David; McClusky, Leo; MacGowan, Daniel; Licht, J. Hamilton; Verma, Ashok; Strong, Michael J.; Lomen‐Hoerth, Catherine; Tandan, Rup; Rivner, Michael H.; Kolb, Steve; Rudnicki, Stacy A.; Kittrell, Pamela; Quereshi, Muddasir; Sachs, George; Pattee, Gary L.; Weiß, Michael; Kissel, John W.; Goldstein, Jonathan; Rothstein, Jeffrey; Pastula, Dan; Levitsky, Gleb; Ogino, Mieko; Rosenfeld, Jeffrey; Carmi, E; Fournier, Christina; Barkhaus, Paul E.; Morrison, Brett M.; Zinman, Lorne; Valor, Eric; Zach, Neta; Ghavanini, A Alavian; Baker, Yvonne; Salmon, Kristiana; Perrin, Steve; Goldstein, Rob; Vieira, Fernando; Cudkowicz, Merit; Mitsumoto, Hiroshi

doi:10.3109/21678421.2016.1172818

Cited by 2 publications

(1 citation statement)

References 15 publications

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“…4 Such rare ALS Reversal cases have been described since the 1960s. [6][7][8][9][10][11][12][13][14][15][16][17][18] To date, we have identified over 50 such cases with a unique ALS Reversal phenotype, and we have found that this phenotype does not have identifiable common environmental factors. 19 The biological basis for an ALS Reversal is unknown, but in the same way that genetic factors contribute to the etiology of ALS, we have speculated that genetic factors might similarly influence the probability of this unusual reversal of disease course.…”

Section: Introductionmentioning

confidence: 99%

Genetic Associations With an Amyotrophic Lateral Sclerosis Reversal Phenotype

Crayle,

Rampersaud,

Myers

et al. 2024

Neurology

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Background and ObjectivesThe term "ALS Reversal" describes patients who initially meet diagnostic criteria for amyotrophic lateral sclerosis (ALS) or had clinical features most consistent with progressive muscular atrophy (PMA) but subsequently demonstrated substantial and sustained clinical improvement. The objective of this genome-wide association study (GWAS) was to identify correlates of this unusual clinical phenotype. MethodsParticipants were recruited from a previously created database of individuals with the ALS Reversal phenotype. Whole-genome sequencing (WGS) data were compared with ethnicity-matched patients with typically progressive ALS enrolled through the CReATe Consortium's Phenotype-Genotype-Biomarker (PGB) study. These results were replicated using an independent ethnically matched WGS data set from Target ALS. Significant results were further explored with available databases of genetic regulatory markers and expression quantitative trait loci (eQTL) analysis. ResultsWGS from 22 participants with documented ALS Reversals was compared with the PGB primary cohort (n = 103) and the Target ALS validation cohort (n = 140). Two genetic loci met predefined criteria for statistical significance (two-sided permutation p ≤ 0.01) and remained plausible after fine-mapping. The lead single nucleotide variant (SNV) from the first locus was rs4242007 (primary cohort GWAS OR = 12.0, 95% CI 4.1 to 34.6), which is in an IGFBP7 intron and is in near-perfect linkage disequilibrium with a SNV in the IGFBP7 promoter region. Both SNVs are associated with decreased frontal cortex IGFBP7 expression in eQTL data sets. Notably, 3 Reversals, but none of the typically progressive individuals (n = 243), were homozygous for rs4242007. The importance of the second locus, located near GRIP1, is uncertain given the absence of an associated effect on nearby gene transcription. DiscussionWe found a significant association between the Reversal phenotype and an IGFBP7 noncoding SNV that is associated with IGFBP7 expression. This is biologically relevant as IGFBP7 is a reported inhibitor of the insulin growth factor-1 (IGF-1) receptor that activates the possibly neuroprotective IGF-1 signaling pathway. This finding is limited by small sample size but suggests that there may be merit in further exploration of IGF-1 pathway signaling as a therapeutic mechanism for ALS.

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