Background:As the population ages and more people are affected by multiple chronic conditions, the prevalence of Peripheral Neuropathy (PN) has also rapidly increased. This swift rise in PN leaves clinicians and patients challenged by a lack of consistent diagnosis and treatment guidelines. Purpose:To assist those affected by PN, it is imperative to understand the breadth of symptoms, experiences, and factors related to the quality of life. The primary aims of this study are to (1) characterize the symptoms of PN in a nationwide sample; (2) discern differences in symptom clusters, given perceived causes of PN; and (3) identify significant physiological symptoms related to the quality of life for people with PN. Methods:An online survey of people in online PN support groups. Participants were recruited primarily via an open request sent to recipients of web-based communications from nationally recognized online PN support groups. Inclusion criteria were as follows: Self-reported diagnosis of PN, ability to read English or Spanish, residence in the U.S., and age ≥ 18 years. Results:A total of 608 individuals with PN were included in the analysis. This sample represents 49 U.S. states and the District of Colombia; 221 were male and 387 female. Their disease severity and etiology were similar to previously reported information on this population, with 53.3% of respondents suffering from PN without a known cause. Among known causes, diabetes was the most common (19.6%), followed by chemotherapy (6.9%) and autoimmune diseases (3.6%). Factors affecting the quality of life among people with PN included lower extremity mobility, upper extremity mobility, sleep disturbance, depressive symptoms, and patient activation.
Retinoic acid (RA) is the active form of vitamin A that functions as a ligand for nuclear RA receptors that directly bind genomic control regions to regulate gene expression. However, some studies have suggested that RA may have nongenomic effects outside of the nucleus, particularly with regard to synaptic plasticity. Recent results demonstrate that treatment with pharmacological levels of RA can alter synaptic plasticity which may be useful to treat neurological diseases. However, these results and those reported by others have not shown that endogenous RA is normally required for synaptic plasticity (or any other nongenomic effect) as there are no reports of genetic loss of function studies that remove endogenous RA in adult brain. The implication is that pharmacological levels of RA result in nongenomic effects, some of which may be helpful to treat certain diseases but in other cases this may cause unwanted side effects.
The IQ motif and SEC7 domain-containing protein 2 (IQSEC2) is an X-chromosome gene mutated in both males and females leading to Intellectual Disability (ID) and severe early-onset seizures. The pathogenesis underpinning these mutations remains unknown. Utilizing CRISPR/Cas9 targeted editing, we have generated an Iqsec2 KO mouse model to investigate the molecular and cellular deficits in this gene resulting in disease outcomes, a fundamental step towards the design and implementation of potential treatment options. We confirmed the loss of Iqsec2 mRNA expression and the lack of Iqsec2 protein detected within the brain of founder and progeny mice. Recapitulating the human setting, both male (48%) and female (45%) Iqsec2 KO mice present with frequent and recurrent seizures. There was an increased occurrence of seizures, reabsorption and unsuccessful nurturing of live young in breeding females. Developmentally, the KO mice exhibit significantly increased hyperactivity, altered anxiety and fear responses, decreased social interactions, delayed learning capacity and decreased memory retention/novel recognition; recapitulating the psychiatric issues, autistic-like features and cognitive deficits present in patients with loss-of-function IQSEC2 mutations. Interestingly, the loss of Iqsec2 function not only causes severe ID and seizures in KO male mice, but in agreement with the patient setting, similar severity is also noted in females despite being in a heterozygous state for this X-chromosome gene. We contend this newly generated mouse model provides a highly relevant biological tool required to interrogate IQSEC2/Iqsec2 function in the brain.
