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CFTR-deficient pigs display peripheral nervous system defects at birth.

ABSTRACT: Peripheral nervous system abnormalities, including neuropathy, have been reported in people with cystic fibrosis. These abnormalities have largely been attributed to secondary manifestations of the disease. We tested the hypothesis that disruption of the cystic fibrosis transmembrane conductance regulator (CFTR) gene directly influences nervous system function by studying newborn CFTR(-/-) pigs. We discovered CFTR expression and activity in Schwann cells, and loss of CFTR caused ultrastructural myelin sheath abnormalities similar to those in known neuropathies. Consistent with neuropathic changes, we found increased transcripts for myelin protein zero, a gene that, when mutated, can cause axonal and/or demyelinating neuropathy. In addition, axon density was reduced and conduction velocities of the trigeminal and sciatic nerves were decreased. Moreover, in vivo auditory brainstem evoked potentials revealed delayed conduction of the vestibulocochlear nerve. Our data suggest that loss of CFTR directly alters Schwann cell function and that some nervous system defects in people with cystic fibrosis are likely primary.

SUBMITTER: Reznikov LR

PROVIDER: S-EPMC3581923 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Purpose of reviewPeripheral nervous system vasculitides (PNSV) are a heterogeneous group of disorders with a clinical subset that may differ in prognosis and therapy. We provide a comprehensive update on the clinical assessment, diagnosis, complications, treatment, and follow-up of PNSV.Recent findingsProgress in neuroimaging, molecular testing, and peripheral nerve biopsy has improved clinical assessment and decision-making of PNSV, also providing novel insights on how to prevent misdiagnosis and increase diagnostic certainty. Advances in imaging techniques, allowing to clearly display the vessel walls, have also enhanced the possibility to differentiate inflammatory from non-inflammatory vascular lesions, while recent histopathology data have identified the main morphological criteria for more accurate diagnosis and differential diagnoses. Overall, the identification of peculiar morphological findings tends to improve diagnostic accuracy by defining a clearer boundary between systemic and non-systemic neuropathies. Therefore, the definition of epineurium vessel wall damage, type of vascular lesion, characterization of lymphocyte populations, antibodies, and inflammatory factors, as well as the identification of direct nerve damage or degeneration, are the common goals for pathologists and clinicians, who will both benefit for data integration and findings translation. Nevertheless, to date, treatment is still largely empiric and, in some cases, unsatisfactory, thus often precluding precise prognostic prediction. In this context, new diagnostic techniques and multidisciplinary management will be essential in the proper diagnosis and prompt management of PNSV, as highlighted in the present review. Thirty to fifty percent of all patients with vasculitis have signs of polyneuropathy. Neuropathies associated with systemic vasculitis are best managed according to the guidelines of the underlying disease because appropriate workup and initiation of treatment can reduce morbidity. Steroids, or in severe or progressive cases, cyclophosphamide pulse therapy is the standard therapy in non-systemic vasculitic neuropathies. Some patients need long-term immunosuppression. The use of novel technologies for high-throughput genotyping will permit to determine the genetic influence of related phenotypes in patients with PNSV.

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CFTR-deficient pigs display peripheral nervous system defects at birth.

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