Peripheral Ion Channel Gene Screening in Painful- and Painless-Diabetic Neuropathy

Ślęczkowska, Milena; Almomani, Rowida; Marchi, Margherita; Greef, Bianca T A de; Sopacua, Maurice; Hoeijmakers, Janneke G. J.; Lindsey, Patrick; Bönhof, Gidon J.; Ziegler, Dan; Malik, Rayaz A.; Waxman, Stephen G.; Lauria, Giuseppe; Faber, Catharina G.; Smeets, Hubert J.M.; Gerrits, Monique M.

doi:10.3390/ijms23137190

Cited by 11 publications

(9 citation statements)

References 55 publications

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“…[29][30][31] Despite extensive investigations 20% will be diagnosed with idiopathic PN. 32 Genetic testing targeting peripheral ion channel and transient receptor potential (TRP) genes has recently shown promise in the evaluation of painful neuropathies, [33][34][35] but is not widely available. There are limited rapid and objective measures of early neurodegeneration 36,37 and DPN may be undiagnosed in 35%-99.8% of patients in Saudi Arabia, 18,22 Qatar, 18,19,38 Kuwait, 18 Germany, 39 United Kingdom, 40 USA, 41,42 Japan, 43 Malaysia, 44 Hong Kong, Philippines, Taiwan and Thailand 45 (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Earlier diagnosis of peripheral neuropathy in primary care: A call to action

Gad,

Kalra,

Pinzon

et al. 2024

J Peripheral Nervous Sys

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Peripheral neuropathy (PN) often remains undiagnosed (~80%). Earlier diagnosis of PN may reduce morbidity and enable earlier risk factor reduction to limit disease progression. Diabetic peripheral neuropathy (DPN) is the most common PN and the 10 g monofilament is endorsed as an inexpensive and easily performed test for DPN. However, it only detects patients with advanced neuropathy at high risk of foot ulceration. There are many validated questionnaires to diagnose PN, but they can be time‐consuming and have complex scoring systems. Primary care physicians (PCPs) have busy clinics and lack access to a readily available screening method to diagnose PN. They would prefer a short, simple, and accurate tool to screen for PN. Involving the patient in the screening process would not only reduce the time a physician requires to make a diagnosis but would also empower the patient. Following an expert meeting of diabetologists and neurologists from the Middle East, South East Asia and Latin America, a consensus was formulated to help improve the diagnosis of PN in primary care using a simple tool for patients to screen themselves for PN followed by a consultation with the physician to confirm the diagnosis.

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Section: Introductionmentioning

confidence: 99%

Earlier diagnosis of peripheral neuropathy in primary care: A call to action

Gad,

Kalra,

Pinzon

et al. 2024

J Peripheral Nervous Sys

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“…Sleczkowska et al [71] investigated the role of ion channels in painful diabetic neuropathy. They analyzed Kv, TRP, ANO, and HCN ion channel genes that are expressed in peripheral nerves.…”

Section: Discussionmentioning

confidence: 99%

Genetic Factors Associated with the Development of Neuropathy in Type 2 Diabetes

Tordai,

Hajdú,

Rácz

et al. 2024

IJMS

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Neuropathy is a serious and frequent complication of type 2 diabetes (T2DM). This study was carried out to search for genetic factors associated with the development of diabetic neuropathy by whole exome sequencing. For this study, 24 patients with long-term type 2 diabetes with neuropathy and 24 without underwent detailed neurological assessment and whole exome sequencing. Cardiovascular autonomic function was evaluated by cardiovascular reflex tests. Heart rate variability was measured by the triangle index. Sensory nerve function was estimated by Neurometer and Medoc devices. Neuropathic symptoms were characterized by the neuropathy total symptom score (NTSS). Whole exome sequencing (WES) was performed on a Thermo Ion GeneStudio S5 system determining the coding sequences of approximately 32,000 genes comprising 50 million base pairs. Variants were detected by Ion Reporter software and annotated using ANNOVAR, integrating database information from dbSNP, ClinVar, gnomAD, and OMIM. Integrative genomics viewer (IGV) was used for visualization of the mapped reads. We have identified genetic variants that were significantly associated with increased (22–49-fold) risk of neuropathy (rs2032930 and rs2032931 of recQ-mediated genome instability protein 2 (RMI2) gene), rs604349 of myosin binding protein H like (MYBPHL) gene and with reduced (0.07–0.08-fold) risk (rs917778 of multivesicular body subunit 12B (MVB12B) and rs2234753 of retinoic acid X receptor alpha (RXRA) genes). The rs2032930 showed a significant correlation with current perception thresholds measured at 5 Hz and 250 Hz for n. medianus (p = 0.042 and p = 0.003, respectively) and at 5 Hz for n. peroneus (p = 0.037), as well as the deep breath test (p = 0.022) and the NTSS (p = 0.023). The rs2032931 was associated with current perception thresholds (p = 0.003 and p = 0.037, respectively), deep breath test (p = 0.022), and NTSS (p = 0.023). The rs604349 correlated with values measured at 2000 (p = 0.049), 250 (p = 0.018), and 5 Hz (p = 0.005) for n. medianus, as well as warm perception threshold measured by Medoc device (p = 0.042). The rs2234753 showed correlations with a current perception threshold measured at 2000 Hz for n. medianus (p = 0.020), deep breath test (p = 0.040), and NTSS (p = 0.003). There was a significant relationship between rs91778 and cold perception threshold (p = 0.013). In our study, genetic variants have been identified that may have an impact on the risk of neuropathy developing in type 2 diabetic patients. These results could open up new opportunities for early preventive measures and might provide targets for new drug developments in the future.

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“…Our research included the sequences of 31 pain-related genes, encompassing 18 pain perception genes: SCN9A , SCN10A , PRDM12 , ANO1 , CCK , MARK1 , MARK2 , RUNX1 , NGF , NTRK1 , CACNA1G , TRPV1 , TRPV4 , P2RX3 , P2RX4 , ASIC1 , ASIC3 and ASIC4 and 13 analgesia genes: CA8 , GRK2 , ARRB2 , KCNA1 , KCNA2 , TRAAK , KCNIP3 , KCNJ10 , ANO3 , OPRM1 , OPRD1 , OPRK1 , and OPRL1 . All the selected genes have been proven to be associated with the pain ( Supplementary Table S1 [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ]). In total, 43 representatives of mammalian species were examined, including: 17 Cetacea, 4 Artiodactyla, 8 Carnivora, 2 Perissodactyla, 3 Chiroptera, 3 Primates, 1 Scandentia, 3 Rodentia, 1 Sirenia, and 1 Proboscidea.…”

Section: Methodsmentioning

confidence: 99%

Rubbing Salt in the Wound: Molecular Evolutionary Analysis of Pain-Related Genes Reveals the Pain Adaptation of Cetaceans in Seawater

Ding

et al. 2022

Animals

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Pain, usually caused by a strong or disruptive stimulus, is an unpleasant sensation that serves as a warning to organisms. To adapt to extreme environments, some terrestrial animals have evolved to be inherently insensitive to pain. Cetaceans are known as supposedly indifferent to pain from soft tissue injury representatives of marine mammals. However, the molecular mechanisms that explain how cetaceans are adapted to pain in response to seawater environment remain unclear. Here, we performed a molecular evolutionary analysis of pain-related genes in selected representatives of cetaceans. ASIC4 gene was identified to be pseudogenized in all odontocetes (toothed whales) except from Physeter macrocephalus (sperm whales), and relaxed selection of this gene was detected in toothed whales with pseudogenized ASIC4. In addition, positive selection was detected in pain perception (i.e., ASIC3, ANO1, CCK, and SCN9A) and analgesia (i.e., ASIC3, ANO1, CCK, and SCN9A) genes among the examined cetaceans. In this study, potential convergent amino acid substitutions within predicted proteins were found among the examined cetaceans and other terrestrial mammals, inhabiting extreme environments (e.g., V441I of TRPV1 in cetaceans and naked mole rats). Moreover, specific amino acid substitutions within predicted sequences of several proteins were found in the studied representatives of cetaceans (e.g., F56L and D163A of ASIC3, E88G of GRK2, and F159L of OPRD1). Most of the substitutions were located within important functional domains of proteins, affecting their protein functions. The above evidence suggests that cetaceans might have undergone adaptive molecular evolution in pain-related genes through different evolutionary patterns to adapt to pain, resulting in greater sensitivity to pain and more effective analgesia. This study could have implications for diagnosis and treatment of human pain.

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Peripheral Ion Channel Gene Screening in Painful- and Painless-Diabetic Neuropathy

Cited by 11 publications

References 55 publications

Earlier diagnosis of peripheral neuropathy in primary care: A call to action

Earlier diagnosis of peripheral neuropathy in primary care: A call to action

Genetic Factors Associated with the Development of Neuropathy in Type 2 Diabetes

Rubbing Salt in the Wound: Molecular Evolutionary Analysis of Pain-Related Genes Reveals the Pain Adaptation of Cetaceans in Seawater

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