No cure, no care? Diagnostic and therapeutic challenges in rare neuropathic pain syndromes

Abstract

Abstract body: Children, who are born without any perception of pain, tend to develop a severe phenotype of self-injury. Pain, despite being a dreadful experience, is an important warning signal that prevents us from cutting, biting, or burning ourselves. Neuropathic pain, on the other hand, constitutes an impactful health burden as well. We examined a cohort of 100 idiopathic small fiber neuropathy patients (70% female; mean age: 44.8 years), in whom neuropathic pain was the most abundant symptom (95%) and cause of daily life impairment (72%). As a potential risk factors, we found that metabolic syndrome leads to an increase in neurotoxic 1-deoxy-sphingolipids, which were significantly higher in the “sensory loss” patient cluster compared to ''thermal hyperalgesia'' (p<0.01) or “healthy” (p<0.1) and correlated inversely with the patients’ intraepidermal nerve fiber density (1-deoxy-SA: p<0.05, 1-deoxy-SO: p<0.01). Alongside acquired causes of neuropathic gain or loss of pain, pathogenic variants in genes like SCN9A, SCN10A, or SCN11A can have a significant impact on pain perception. These genes encode voltage-gated sodium channels expressed in C nerve fibers that are important for the generation and upstroke of sensory nerve action potentials. It might sound logic that gain-of-function is associated with gain of pain (examples: specific pathogenic missense mutations in SCN9A and SCN11A, associated with an autosomal dominant inheritance), whereas biallelic loss-of-function mutations in SCN9A cause insensitivity to pain (see above). If a channel's function is extremely increased (specific heterozygous mutations in SCN11A), this can, however, likewise prevent a nerve from demonstrating a regular firing pattern, so that pain perception is reduced. This presentation contains real-life examples of neuropathic pain disorders, illustrating the important balance between too much or too little pain. We will link known pathomechanisms with phenotype details and open a discussion for further treatment considerations, including both aspects on cure and care.