Models of Distal Arthrogryposis and Lethal Congenital Contracture Syndrome

Distal arthrogryposis and lethal congenital contracture syndromes describe a broad group of disorders that share congenital limb contractures in common. While skeletal muscle sarcomeric genes comprise many of the first genes identified for Distal Arthrogyposis, other mechanisms of disease have been demonstrated, including key effects on peripheral nerve function. While Distal Arthrogryposis and Lethal Congenital Contracture Syndromes display superficial similarities in phenotype, the underlying mechanisms for these conditions are diverse but overlapping. In this review, we discuss the important insights gained into these human genetic diseases resulting from in vitro molecular studies and in vivo models in fruit fly, zebrafish, and mice.

Ethoxyquin is neuroprotective and partially prevents somatic and autonomic neuropathy in db/db mouse model of type 2 diabetes

Ethoxyquin (EQ), a quinolone-based antioxidant, has demonstrated neuroprotective properties against several neurotoxic drugs in a phenotypic screening and is shown to protect axons in animal models of chemotherapy-induced peripheral neuropathy. We assessed the effects of EQ on peripheral nerve function in the db/db mouse model of type II diabetes. After a 7 week treatment period, 12-week-old db/db-vehicle, db/+ -vehicle and db/db-EQ treated animals were evaluated by nerve conduction, paw withdrawal against a hotplate, and fiber density in hindlimb footpads. We found that the EQ group had shorter paw withdrawal latency compared to vehicle db/db group. The EQ group scored higher in nerve conduction studies, compared to vehicle-treated db/db group. Morphology studies yielded similar results. To investigate the potential role of mitochondrial DNA (mtDNA) deletions in the observed effects of EQ, we measured total mtDNA deletion burden in the distal sciatic nerve. We observed an increase in total mtDNA deletion burden in vehicle-treated db/db mice compared to db/+ mice that was partially prevented in db/db-EQ treated animals. These results suggest that EQ treatment may exert a neuroprotective effect in diabetic neuropathy. The prevention of diabetes-induced mtDNA deletions may be a potential mechanism of the neuroprotective effects of EQ in diabetic neuropathy.

The Effects of Insulin on Immortalized Rat Schwann Cells, IFRS1

Schwann cells play an important role in peripheral nerve function, and their dysfunction has been implicated in the pathogenesis of diabetic neuropathy and other demyelinating diseases. The physiological functions of insulin in Schwann cells remain unclear and therefore define the aim of this study. By using immortalized adult Fischer rat Schwann cells (IFRS1), we investigated the mechanism of the stimulating effects of insulin on the cell proliferation and expression of myelin proteins (myelin protein zero (MPZ) and myelin basic protein (MBP). The application of insulin to IFRS1 cells increased the proliferative activity and induced phosphorylation of Akt and ERK, but not P38-MAPK. The proliferative potential of insulin-stimulated IFRS1 was significantly suppressed by the addition of LY294002, a PI3 kinase inhibitor. The insulin-stimulated increase in MPZ expression was significantly suppressed by the addition of PD98059, a MEK inhibitor. Furthermore, insulin-increased MBP expression was significantly suppressed by the addition of LY294002. These findings suggest that both PI3-K/Akt and ERK/MEK pathways are involved in insulin-induced cell growth and upregulation of MPZ and MBP in IFRS1 Schwann cells.

Chemotherapy-induced peripheral neuropathy: longitudinal analysis of predictors for postural control

Impaired postural control is often observed in response to neurotoxic chemotherapy. However, potential explanatory factors other than chemotherapy-induced peripheral neuropathy (CIPN) have not been adequately considered to date due to primarily cross-sectional study designs. Our objective was to comprehensively analyze postural control during and after neurotoxic chemotherapy, and to identify potential CIPN-independent predictors for its impairment. Postural control and CIPN symptoms (EORTC QLQ-CIPN20) were longitudinally assessed before, during and three weeks after neurotoxic chemotherapy, and in three and six months follow-up examinations (N = 54). The influence of peripheral nerve function as determined by nerve conduction studies (NCS: compound motor action potentials (CMAP) and sensory action potentials (SNAP)), physical activity, and muscle strength on the change in postural control during and after chemotherapy was analyzed by multiple linear regression adjusted for age and body mass index. Postural control, CIPN signs/symptoms, and CMAP/SNAP amplitudes significantly deteriorated during chemotherapy (p < .01). During follow-up, patients recovered from postural instabilities (p < .01), whereas CIPN signs/symptoms and pathologic NCS findings persisted compared to baseline (p < .001). The regression model showed that low CMAP and high SNAP amplitudes at baseline predicted impairment of postural control during but not after chemotherapy. Hence, pre-therapeutically disturbed somatosensory inputs may induce adaptive processes that have compensatory effects and allow recovery of postural control while CIPN signs/symptoms and pathologic peripheral nerve function persist. Baseline NCS findings in cancer patients who receive neurotoxic chemotherapy thus might assist in delineating individual CIPN risk profiles more precisely to which specific exercise intervention programs could be tailor-made.

Cardiometabolic risk factors as determinants of peripheral nerve function: the Maastricht Study

Aims/hypothesis We aimed to examine associations of cardiometabolic risk factors, and (pre)diabetes, with (sensorimotor) peripheral nerve function. Methods In 2401 adults (aged 40–75 years) we previously determined fasting glucose, HbA1c, triacylglycerol, HDL- and LDL-cholesterol, inflammation, waist circumference, blood pressure, smoking, glucose metabolism status (by OGTT) and medication use. Using nerve conduction tests, we measured compound muscle action potential, sensory nerve action potential amplitudes and nerve conduction velocities (NCVs) of the peroneal, tibial and sural nerves. In addition, we measured vibration perception threshold (VPT) of the hallux and assessed neuropathic pain using the DN4 interview. We assessed cross-sectional associations of risk factors with nerve function (using linear regression) and neuropathic pain (using logistic regression). Associations were adjusted for potential confounders and for each other risk factor. Associations from linear regression were presented as standardised regression coefficients (β) and 95% CIs in order to compare the magnitudes of observed associations between all risk factors and outcomes. Results Hyperglycaemia (fasting glucose or HbA1c) was associated with worse sensorimotor nerve function for all six outcome measures, with associations of strongest magnitude for motor peroneal and tibial NCV, βfasting glucose = −0.17 SD (−0.21, −0.13) and βfasting glucose = −0.18 SD (−0.23, −0.14), respectively. Hyperglycaemia was also associated with higher VPT and neuropathic pain. Larger waist circumference was associated with worse sural nerve function and higher VPT. Triacylglycerol, HDL- and LDL-cholesterol, and blood pressure were not associated with worse nerve function; however, antihypertensive medication usage (suggestive of history of exposure to hypertension) was associated with worse peroneal compound muscle action potential amplitude and NCV. Smoking was associated with worse nerve function, higher VPT and higher risk for neuropathic pain. Inflammation was associated with worse nerve function and higher VPT, but only in those with type 2 diabetes. Type 2 diabetes and, to a lesser extent, prediabetes (impaired fasting glucose and/or impaired glucose tolerance) were associated with worse nerve function, higher VPT and neuropathic pain (p for trend <0.01 for all outcomes). Conclusions/interpretation Hyperglycaemia (including the non-diabetic range) was most consistently associated with early-stage nerve damage. Nonetheless, larger waist circumference, inflammation, history of hypertension and smoking may also independently contribute to worse nerve function.