Fibromyalgia, mood disorders, and intense creative energy: A1AT polymorphisms are not always silent

Neurotoxicology. 2012 Dec;33(6):1454-1472. doi: 10.1016/j.neuro.2012.03.001. Epub 2012 Mar 10.


Persons with single copies of common alpha-1-antitrypsin polymorphisms such as S and Z are often considered "silent carriers". Published evidence however supports a complex behavioral phenotype or trait - intense creative energy ("ICE")-associated with A1AT polymorphisms. We now confirm that phenotype and present an association of fibromyalgia syndrome (FMS) and A1AT in a consecutive series of neurological patients. This is a retrospective case control series of 3176 consecutive patients presenting to Duke University Memory Clinic (747 patients) and to regional community-based Caldwell Hospital Neurology and Memory center (2429 patients). Work-up included medical history and examination, psychological evaluation, and genetic analysis. Chronic widespread pain (CWP) or FMS were diagnosed according to clinical guidelines, mostly as secondary diagnoses. Neurological patients carrying A1AT polymorphisms were common (ca 16% prevalence) and carriers had significantly higher use of inhaler and anxiolytic medications. Patients with ICE phenotype had a significantly higher proportion of A1AT polymorphisms (42%) compared to non-ICE patients (13%). Presence of CWP or FMS was common (14-22%) with average age at presentation of 56 years old and mostly female gender (82%). Patients with CWP/FMS had again significantly higher proportion of A1AT polymorphisms (38%) compared to other neurological patients (13%). Patients with anxiety disorders, bipolar I or bipolar II disorders or PTSD also had increased proportion of A1AT polymorphisms and significant overlap with ICE and FMS phenotype. Significant reductions in CWP/FMS prevalence are seen in apolipoprotein E4 carriers and methylene tetrahydrofolate reductase (MTHFR) mutation homozygotes. Since ICE phenotype is reported as a lifelong behavioral attribute, the presumption is that A1AT carriers have fundamental differences in brain development and inflammatory response. In support of this concept is finding those persons reporting a diagnosis of juvenile rheumatoid or idiopathic arthritis (JRA, JIA) had a significantly high proportion of A1AT polymorphisms (63%), suggesting a spectrum for JRA to later FMS presentations. Likewise, persons reporting a history of attention deficit disorder (ADD) had an increased proportion of A1AT polymorphisms (26%) compared to non-ADD persons (13%). Toxic environmental exposures are common (23%) and associated with diagnoses of PSP, PPA, FTD, FTD-PD, PD and ADVD. A1AT carriers were increased in cases of toxic exposure and PSP, PPA and FTD-PD. Our findings support the ICE behavioral phenotype for A1AT polymorphism carriers and the reported association with anxiety and bipolar spectrum disorders. We now extend that phenotype to apparent vulnerability to inflammatory muscle disease in a spectrum from JRA to fibromyalgia (FMS) and specific behavioral subsets of ADD, PTSD, and specific late onset neurological syndromes (FTD-PD and PPA). High and low risk FMS subsets can be defined using A1AT, MTHFR and APOE genotyping. Clinical diagnoses associated with A1AT polymorphisms included fibromyalgia, JRA/JIA, bipolar disorder, PTSD, primary progressive aphasia and FTDPD, but not most Alzheimer Disease subtypes. These results support an extended phenotype for A1AT mutation carriers beyond liver and lung vulnerability to selective advantages: ICE phenotype and disadvantages: fibromyalgia, affective disorders, and selected late onset neurological syndromes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Affect
  • Aged
  • Aged, 80 and over
  • Analysis of Variance
  • Arthritis, Juvenile / enzymology
  • Arthritis, Juvenile / genetics
  • Chi-Square Distribution
  • Creativity*
  • Environmental Pollutants / adverse effects
  • Female
  • Fibromyalgia / chemically induced
  • Fibromyalgia / diagnosis
  • Fibromyalgia / enzymology
  • Fibromyalgia / genetics*
  • Fibromyalgia / psychology
  • Gene Frequency
  • Gene-Environment Interaction
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Middle Aged
  • Mood Disorders / chemically induced
  • Mood Disorders / diagnosis
  • Mood Disorders / enzymology
  • Mood Disorders / genetics*
  • Mood Disorders / psychology
  • Neurotoxicity Syndromes / diagnosis
  • Neurotoxicity Syndromes / enzymology
  • Neurotoxicity Syndromes / genetics*
  • Neurotoxicity Syndromes / psychology
  • North Carolina
  • Occupational Exposure
  • Odds Ratio
  • Phenotype
  • Polymorphism, Genetic*
  • Retrospective Studies
  • Risk Factors
  • alpha 1-Antitrypsin / genetics*


  • Environmental Pollutants
  • SERPINA1 protein, human
  • alpha 1-Antitrypsin