Introduction: Anxiety disorders have a lifetime prevalence of 34% with a similar level of heritability (31%) yet lack objective markers that could differentiate patients with underlying conditions. Up to 60%-70% of patients with Ehlers-Danlos syndrome have anxiety that meets criteria of generalized anxiety disorder, their clinical-DNA findings worth examining as biomarkers for patients with generalized anxiety. Method: Of the 1899 patients diagnosed with Ehlers-Danlos syndrome, 1261 were systematically evaluated for 80 history and 40 physical findings and separated into 826 who reported anxiety and 435 who did not. The most consistently reported or management-directing 60 of these clinical findings were, along with variations in genes relevant to these disorders, examined for association with anxiety. Results: Among the 30 anxiety- associated findings judged most predictive of Ehlers-Danlos syndrome in patients with anxiety were expected ones of adrenergic stimulation (difficulty concentrating-87% frequency and 1.26 anxiety/no anxiety ratio; chronic fatigue-84%, 1.17; sleep issues 69%, 1.52 that are criteria for generalized anxiety disorder) or of cholinergic suppression (e.g., frequent nausea 64%, 1.26). Less associated but more discriminating for underlying disease were those reflective of neuromuscular impact (e.g., chronic daily headaches 76%, 1.12); hypermobility (e.g., awareness of flexibility 72%, 1.03), or skin changes (e.g., elasticity around jaw 71%, 1.06). Anxiety-associated DNA variants included 54 of 88 in collagen type I/V/VII/IX genes, 14 of 16 in sodium channel SCN9A/10A/ 11A genes, 59 of 85 in POLG/MT-DNA genes, and 21 of 28 in profilaggrin- FLG genes that respectively impacted tissue laxity, sensory neural, autonomic-mitochondrial, and autonomic-inflammatory functions. Conclusion: Analysis of pathogenetic mechanisms in Ehlers-Danlos syndrome selected some 50 clinical-DNA findings useful for its diagnosis in those with generalized anxiety disorders.
References
[1]
Gottschalk, M.G. and Domschke, K. (2017) Genetics of Generalized Anxiety Disorder and Related Traits. Dialogues in Clinical Neuroscience, 19, 159-168. https://doi.org/10.31887/dcns.2017.19.2/kdomschke
[2]
Szuhany, K.L. and Simon, N.M. (2022) Anxiety Disorders: A Review. JAMA, 328, 2431-2445. https://doi.org/10.1001/jama.2022.22744
[3]
Kessler, R.C., Chiu, W.T., Demler, O. and Walters, E.E. (2005) Prevalence, Severity, and Comorbidity of 12-Month DSM-IV Disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry, 62, 617-627. https://doi.org/10.1001/archpsyc.62.6.617
[4]
Locke, A.B., Kirst, N. and Shultz, C.G. (2015) Diagnosis and Management of Generalized Anxiety Disorder and Panic Disorder in Adults. American Family Physician, 91, 617-624.
[5]
Yang, X., Fang, Y., Chen, H., Zhang, T., Yin, X., Man, J., et al. (2021) Global, Regional and National Burden of Anxiety Disorders from 1990 to 2019: Results from the Global Burden of Disease Study 2019. Epidemiology and Psychiatric Sciences, 30, e36. https://doi.org/10.1017/s2045796021000275
[6]
Baxter, A.J., Scott, K.M., Vos, T. and Whiteford, H.A. (2012) Global Prevalence of Anxiety Disorders: A Systematic Review and Meta-Regression. Psychological Medicine, 43, 897-910. https://doi.org/10.1017/s003329171200147x
[7]
American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders.
[8]
Penninx, B.W., Pine, D.S., Holmes, E.A. and Reif, A. (2021) Anxiety Disorders. The Lancet, 397, 914-927. https://doi.org/10.1016/s0140-6736(21)00359-7
[9]
Levey, D.F., Gelernter, J., Polimanti, R., Zhou, H., Cheng, Z., Aslan, M., et al. (2020) Reproducible Genetic Risk Loci for Anxiety: Results from ∼200,000 Participants in the Million Veteran Program. American Journal of Psychiatry, 177, 223-232. https://doi.org/10.1176/appi.ajp.2019.19030256
[10]
(2024) Information on Genes and Associated Diseases Can Be Found by Searching on Their Entry Numbers. https://www.omim.org/
[11]
Bamshad, M.J., Ng, S.B., Bigham, A.W., Tabor, H.K., Emond, M.J., Nickerson, D.A., et al. (2011) Exome Sequencing as a Tool for Mendelian Disease Gene Discovery. Nature Reviews Genetics, 12, 745-755. https://doi.org/10.1038/nrg3031
[12]
Malfait, F., Francomano, C., Byers, P., Belmont, J., Berglund, B., Black, J., et al. (2017) The 2017 International Classification of the Ehlers-Danlos Syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 175, 8-26. https://doi.org/10.1002/ajmg.c.31552
[13]
Tinkle, B.T. and Levy, H.P. (2019) Symptomatic Joint Hypermobility. Medical Clinics of North America, 103, 1021-1033. https://doi.org/10.1016/j.mcna.2019.08.002
[14]
Ehlers-Danlos Society (2024) Beighton Maneuvers Illustrated. https://www.ehlers-danlos.com/assessing-joint-hypermobility/
[15]
Bowen, J.M., Sobey, G.J., Burrows, N.P., Colombi, M., Lavallee, M.E., Malfait, F., et al. (2017) Ehlers-Danlos Syndrome, Classical Type. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 175, 27-39. https://doi.org/10.1002/ajmg.c.31548
[16]
Wilson, G.N. and Tonk, V.S. (2024) Clinical-Genomic Analysis of 1261 Patients with Ehlers-Danlos Syndrome Outlines an Articulo-Autonomic Gene Network (Entome). Current Issues in Molecular Biology, 46, 2620-2643. https://doi.org/10.3390/cimb46030166
[17]
McKusick, V.A. (1955) Heritable Disorders of Connective Tissue. Journal of Chronic Diseases, 2, 491-499. https://doi.org/10.1016/0021-9681(55)90148-x
[18]
Yonko, E.A., LoTurco, H.M., Carter, E.M. and Raggio, C.L. (2021) Orthopedic Considerations and Surgical Outcomes in Ehlers-Danlos Syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 187, 458-465. https://doi.org/10.1002/ajmg.c.31958
[19]
Henderson, F.C., Austin, C., Benzel, E., Bolognese, P., Ellenbogen, R., Francomano, C.A., et al. (2017) Neurological and Spinal Manifestations of the Ehlers-Danlos Syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 175, 195-211. https://doi.org/10.1002/ajmg.c.31549
[20]
Cazzato, D., Castori, M., Lombardi, R., Caravello, F., Bella, E.D., Petrucci, A., et al. (2016) Small Fiber Neuropathy Is a Common Feature of Ehlers-Danlos Syndromes. Neurology, 87, 155-159. https://doi.org/10.1212/wnl.0000000000002847
[21]
Labuda, R., Nwotchouang, B.S.T., Ibrahimy, A., Allen, P.A., Oshinski, J.N., Klinge, P., et al. (2022) A New Hypothesis for the Pathophysiology of Symptomatic Adult Chiari Malformation Type I. Medical Hypotheses, 158, Article ID: 110740. https://doi.org/10.1016/j.mehy.2021.110740
[22]
Hugon-Rodin, J., Lebègue, G., Becourt, S., Hamonet, C. and Gompel, A. (2016) Gynecologic Symptoms and the Influence on Reproductive Life in 386 Women with Hypermobility Type Ehlers-Danlos Syndrome: A Cohort Study. Orphanet Journal of Rare Diseases, 11, Article No. 124. https://doi.org/10.1186/s13023-016-0511-2
[23]
Wilson, G.N. (2023) A Clinical Qualification Protocol Highlights Overlapping Genomic Influences and Neuro-Autonomic Mechanisms in Ehlers-Danlos and Long COVID-19 Syndromes. Current Issues in Molecular Biology, 45, 6003-6023. https://doi.org/10.3390/cimb45070379
[24]
Adžemović, T. (2024) Something’s Not Quite Right. JAMA, 331, 1009-1010. https://doi.org/10.1001/jama.2024.1257
[25]
Gazit, Y., Nahir, A.M., Grahame, R. and Jacob, G. (2003) Dysautonomia in the Joint Hypermobility Syndrome. The American Journal of Medicine, 115, 33-40. https://doi.org/10.1016/s0002-9343(03)00235-3
[26]
De Wandele, I., Rombaut, L., Leybaert, L., Van de Borne, P., De Backer, T., Malfait, F., et al. (2014) Dysautonomia and Its Underlying Mechanisms in the Hypermobility Type of Ehlers-Danlos Syndrome. Seminars in Arthritis and Rheumatism, 44, 93-100. https://doi.org/10.1016/j.semarthrit.2013.12.006
[27]
Wang, E., Ganti, T., Vaou, E. and Hohler, A. (2021) The Relationship between Mast Cell Activation Syndrome, Postural Tachycardia Syndrome, and Ehlers-Danlos Syndrome. Allergy and Asthma Proceedings, 42, 243-246. https://doi.org/10.2500/aap.2021.42.210022
[28]
Monaco, A., Choi, D., Uzun, S., Maitland, A. and Riley, B. (2022) Association of Mast-Cell-Related Conditions with Hypermobile Syndromes: A Review of the Literature. Immunologic Research, 70, 419-431. https://doi.org/10.1007/s12026-022-09280-1
[29]
Thwaites, P.A., Gibson, P.R. and Burgell, R.E. (2022) Hypermobile Ehlers-Danlos Syndrome and Disorders of the Gastrointestinal Tract: What the Gastroenterologist Needs to Know. Journal of Gastroenterology and Hepatology, 37, 1693-1709. https://doi.org/10.1111/jgh.15927
[30]
Ehlers-Danlos Society (2024) Criteria for EDS Types. https://www.ehlers-danlos.com/2017-eds-international-classification/
[31]
Thomas, P., Bossan, A., Lacour, J.P., Chanalet, S., Ortonne, J.P. and Chatel, M. (1996) Ehlers-Danlos Syndrome with Subependymal Periventricular Heterotopias. Neurology, 46, 1165-1167. https://doi.org/10.1212/wnl.46.4.1165
[32]
Weerakkody, R.A., Vandrovcova, J., Kanonidou, C., Mueller, M., Gampawar, P., Ibrahim, Y., et al. (2016) Targeted Next-Generation Sequencing Makes New Molecular Diagnoses and Expands Genotype-Phenotype Relationship in Ehlers-Danlos Syndrome. Genetics in Medicine, 18, 1119-1127. https://doi.org/10.1038/gim.2016.14
[33]
Junkiert-Czarnecka, A., Pilarska-Deltow, M., Bąk, A., Heise, M., Latos-Bieleńska, A., Zaremba, J., et al. (2022) Next-Generation Sequencing of Connective Tissue Genes in Patients with Classical Ehlers-Danlos Syndrome. Current Issues in Molecular Biology, 44, 1472-1478. https://doi.org/10.3390/cimb44040099
[34]
Vandersteen, A.M., Weerakkody, R.A., Parry, D.A., Kanonidou, C., Toddie-Moore, D.J., Vandrovcova, J., et al. (2023) Genetic Complexity of Diagnostically Unresolved Ehlers-Danlos Syndrome. Journal of Medical Genetics, 61, 232-238. https://doi.org/10.1136/jmg-2023-109329
[35]
Deer, R.R., Rock, M.A., Vasilevsky, N., Carmody, L., Rando, H., Anzalone, A.J., et al. (2021) Characterizing Long COVID: Deep Phenotype of a Complex Condition. eBioMedicine, 74, Article ID: 103722. https://doi.org/10.1016/j.ebiom.2021.103722
[36]
Wulf Hanson, S., Abbafati, C., Aerts, J.G., Al-Aly, Z., Ashbaugh, C., Ballouz, T., et al. (2022) Estimated Global Proportions of Individuals with Persistent Fatigue, Cognitive, and Respiratory Symptom Clusters Following Symptomatic COVID-19 in 2020 and 2021. JAMA, 328, 1604-1615. https://doi.org/10.1001/jama.2022.18931
[37]
Wyandt, H.E., Wilson, G.N. and Tonk, V.S. (2017) Chromosome Structure and Variation: Heteromorphism, Polymorphism, and Pathogenesis. Chapters 9-10, Springer Nature, New York.
[38]
Retterer, K., Scuffins, J., Schmidt, D., Lewis, R., Pineda-Alvarez, D., Stafford, A., et al. (2015) Assessing Copy Number from Exome Sequencing and Exome Array CGH Based on CNV Spectrum in a Large Clinical Cohort. Genetics in Medicine, 17, 623-629. https://doi.org/10.1038/gim.2014.160
[39]
Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., et al. (2015) Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in Medicine, 17, 405-424. https://doi.org/10.1038/gim.2015.30
Byers, P.H., Belmont, J., Black, J., De Backer, J., Frank, M., Jeunemaitre, X., et al. (2017) Diagnosis, Natural History, and Management in Vascular Ehlers-Danlos Syndrome. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 175, 40-47. https://doi.org/10.1002/ajmg.c.31553
[44]
Wilson, G.N. and Tonk, V.S. (2020) Mitochondrial Dysfunction Contributes to Ehlers-Danlos Syndrome—A Patient Presentation. Journal of Biology and Life Science, 11, 190-202. https://doi.org/10.5296/jbls.v11i2.17756
[45]
Gaudó, P., Emperador, S., Garrido-Pérez, N., Ruiz-Pesini, E., Yubero, D., García-Cazorla, A., et al. (2019) Infectious Stress Triggers a Polg-Related Mitochondrial Disease. Neurogenetics, 21, 19-27. https://doi.org/10.1007/s10048-019-00593-2
[46]
Xu, Y., Zhang, Z., Zhang, P., An, Z. and Sun, C. (2022) FLG Gene Mutation Up-Regulates the Abnormal Tumor Immune Response and Promotes the Progression of Prostate Cancer. Current Pharmaceutical Biotechnology, 23, 1658-1670. https://doi.org/10.2174/1389201023666220413092507
[47]
Jason, L.A., Katz, B.Z., Shiraishi, Y., Mears, C.J., Im, Y. and Taylor, R.R. (2014) Predictors of Post-Infectious Chronic Fatigue Syndrome in Adolescents. Health Psychology and Behavioral Medicine, 2, 41-51. https://doi.org/10.1080/21642850.2013.869176
[48]
Harvey, J.M., Broderick, G., Bowie, A., Barnes, Z.M., Katz, B.Z., O’Gorman, M.R.G., et al. (2016) Tracking Post-Infectious Fatigue in Clinic Using Routine Lab Tests. BMC Pediatrics, 16, Article No. 54. https://doi.org/10.1186/s12887-016-0596-8
[49]
Xie, J., Li, Y. and Jin, J. (2020) The Essential Functions of Mitochondrial Dynamics in Immune Cells. Cellular & Molecular Immunology, 17, 712-721. https://doi.org/10.1038/s41423-020-0480-1
[50]
Lorton, D. and Bellinger, D. (2015) Molecular Mechanisms Underlying Β-Adrenergic Receptor-Mediated Cross-Talk between Sympathetic Neurons and Immune Cells. International Journal of Molecular Sciences, 16, 5635-5665. https://doi.org/10.3390/ijms16035635
[51]
Karalis, K.P., Kontopoulos, E., Muglia, L.J. and Majzoub, J.A. (1999) Corticotropin-Releasing Hormone Deficiency Unmasks the Proinflammatory Effect of Epinephrine. Proceedings of the National Academy of Sciences of the United States of America, 96, 7093-7097. https://doi.org/10.1073/pnas.96.12.7093
[52]
Mitchell, T. and Barlow, C.E. (2011) Review of the Role of Exercise in Improving Quality of Life in Healthy Individuals and in Those with Chronic Diseases. Current Sports Medicine Reports, 10, 211-216. https://doi.org/10.1249/jsr.0b013e318223cc9e
