Fibromyalgia is a common, disabling, syndrome that includes chronic widespread pain plus other diverse symptoms. No specific objective abnormalities have been identified, precluding definitive testing, disease-modifying treatments, and identification of causes. In contrast, small-fiber polyneuropathy (SFPN), despite causing similar symptoms, is definitionally a disease caused by dysfunction and degeneration of peripheral small-fiber neurons. SFPN has established etiologies, some diagnosable and definitively treatable, e.g., diabetes. To evaluate the hypothesis that some patients labeled with “fibromyalgia” have unrecognized SFPN causing their illness symptoms, we analyzed SFPN-associated symptoms, signs, and pathological and physiological markers in 27 fibromyalgia patients and 30 matched normal controls. Fibromyalgia subjects had to satisfy American College of Rheumatology criteria plus present documented evidence of a physician’s actual fibromyalgia diagnosis. Study instruments comprised the Michigan Neuropathy Screening Instrument (MNSI), the Utah Early Neuropathy Scale (UENS), distal-leg neurodiagnostic skin biopsies, plus autonomic-function testing (AFT). 41% of skin biopsies from fibromyalgia subjects vs. 3% of biopsies from control subjects were diagnostic for SFPN, and MNSI and UENS scores were higher among fibromyalgia than control subjects (all P ≤ 0.001). Abnormal AFTs were equally prevalent suggesting that fibromyalgia-associated SFPN is primarily somatic. Blood tests from all 13 fibromyalgia subjects with SFPN-diagnostic skin biopsies provided insights into etiologies. All glucose tolerance tests were normal, but eight subjects had dysimmune markers, 2 had hepatitis C serologies, and one family had apparent genetic causality. These findings suggest that some patients with chronic pain labeled as “fibromyalgia” have unrecognized small-fiber polyneuropathy, a distinct disease that can be objectively tested for and sometimes definitively treated.

Background The recently developed composite autonomic symptom score-31 (COMPASS-31) is a questionnaire for assessing symptoms of dysautonomia. It was distilled from the well established autonomic symptom profile questionnaire. COMPASS-31 has not yet been externally validated. To do so, we assessed its psychometric properties and its convergent validity in patients with or without objective diagnosis of small fiber polyneuropathy (SFPN). Methods The internal validity and reliability of COMPASS-31 were assessed in participants with or without SFPN spanning the full autonomic symptoms severity. Convergent validity was assessed by comparing results of the COMPASS-31 and the gold standard autonomic function testing (AFT) which measures cardiovagal, adrenergic, and sudomotor functions. Additionally, relationships between COMPASS-31 and the Short Form McGill pain questionnaire, Short Form Health Survey and a 0-10 numeric pain scale were assessed. COMPASS-31 and all other questionnaires results were compared between patients with or without evidence of SFPN, objectively confirmed by distal-leg PGP9.5-immunolabeled skin biopsy. Results Among 66 participants (28 SFPN+, 38 SFPN-), COMPASS-31 total scores had excellent internal validity (Cronbach's α =0.919), test-retest reliability (rs=0.886; p<0.001), and good convergent validity (rs=0.474; p<0.001). COMPASS-31 scores differed between subjects with or without SFPN (Z=−3.296, p<0.001), and demonstrated fair diagnostic accuracy. Area under the receiver operating characteristic curve was 0.749 (P =0.01, 95% confidence interval 0.627-0.871). Conclusions COMPASS-31 has good psychometric properties in the population of patients being evaluated for SFPN and thus it might be useful as an initial screening tool for the more expensive SFPN objective tests.

Familial dysautonomia (FD) is an autosomal recessive neurodegenerative disease that affects the development and survival of sensory and autonomic neurons. FD is caused by an mRNA splicing mutation in intron 20 of the IKBKAP gene that results in a tissue-specific skipping of exon 20 and a corresponding reduction of the inhibitor of kappaB kinase complex-associated protein (IKAP), also known as Elongator complex protein 1. To date, several promising therapeutic candidates for FD have been identified that target the underlying mRNA splicing defect, and increase functional IKAP protein. Despite these remarkable advances in drug discovery for FD, we lacked a phenotypic mouse model in which we could manipulate IKBKAP mRNA splicing to evaluate potential efficacy. We have, therefore, engineered a new mouse model that, for the first time, will permit to evaluate the phenotypic effects of splicing modulators and provide a crucial platform for preclinical testing of new therapies. This new mouse model, TgFD9; Ikbkap(Δ20/flox) was created by introducing the complete human IKBKAP transgene with the major FD splice mutation (TgFD9) into a mouse that expresses extremely low levels of endogenous Ikbkap (Ikbkap(Δ20/flox)). The TgFD9; Ikbkap(Δ20/flox) mouse recapitulates many phenotypic features of the human disease, including reduced growth rate, reduced number of fungiform papillae, spinal abnormalities, and sensory and sympathetic impairments, and recreates the same tissue-specific mis-splicing defect seen in FD patients. This is the first mouse model that can be used to evaluate in vivo the therapeutic effect of increasing IKAP levels by correcting the underlying FD splicing defect.