European Network on Inherited Sensory Neuropathies and Insensitivity to Pain (ENISNIP)

Patients with monogenic pain-insensitivity disorders do not respond to painful stimuli and sustain repeated trauma and mutilations with potentially fatal complications, defining a high need for effective prevention and therapy. Limited awareness of these rare conditions, small patient cohorts in individual centres, lack of standardized phenotype information, low diagnostic yield of genetic testing and only partial recognition of disease mechanisms have been largely precluding clinical research. ENISNIP, a European network of clinicians, geneticists and basic scientists will tackle these hurdles and (1) ensure rapid diagnosis by raising awareness for pain- insensitivity disorders, (2) gather harmonized, high quality cross-sectional data by compiling national patient cohorts, (3) advance genetic diagnosis and gene discovery through state-of-the-art genomics and innovative variant filtering procedures integrating additional omics levels, disease modelling in patient-specific cells and regular re-evaluation of variants impact on disease, and (4) track disease mechanisms and relevant phenotypic outcomes in cellular models and genetically modified mice. ENISNIP will bring accurate genetic diagnosis and counselling to individuals with pain-insensitivity disorders and support establishing standards of diagnosis and care. We envision delivering meaningfully sized, well-phenotyped and -genotyped patient cohorts, new insights into the molecular basis of pain-insensitivity disorders and new cellular and animal disease models, paving the way for preclinical experimental treatment trials and clinical research. With regard to further translational capacity, genes and mechanisms related to rare Mendelian pain-insensitivity disorders are exceptional in their potential to uncover novel molecular targets to treat chronic pain, which constitutes one of the major global socioeconomic and health care burdens.

In collaboration with partners from Germany, Czechia and the Switzerland this project focused on the identification of specific, rare subgroups of hereditary neuropathies, particularly those characterized by severe involvement of the peripheral sensory nerves. The resulting insensitivity and reduced or even absent sensation of pain often lead to unrecognized injuries and severe wound healing problems. Infections can be so severe that amputations of particular parts of the extremities may become necessary due to bone involvement (osteonecrosis and osteolysis). Severe sensory neuropathies are found in classic hereditary sensory-autonomic neuropathies (HSN, HSAN), but also in forms characterized by late disease onset with rapid progression (late onset HMSN). The latter group also includes hereditary amyloidosis, for which an early diagnosis has become particularly important in recent years because causal therapies are now available. All patient groups were examined in detail clinically and electrophysiologically. Comprehensive genetic testing was also carried out to achieve the best possible genotypic characterization. For individual forms, functional studies were done to further clarify the pathogenesis. An Austrian-wide epidemiological survey and classification was carried out for the group of hereditary amyloidosis.