Browsing by Author "Francomano, Clair A."
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Item A qualitative study of pain and related symptoms experienced by people with Ehlers-Danlos syndromes(Frontiers Media, 2024-01-03) Schubart, Jane R.; Mills, Susan E.; Francomano, Clair A.; Stuckey-Peyrot, Heather; Medical and Molecular Genetics, School of MedicineIntroduction: Individuals with Ehlers-Danlos syndromes (EDS) often have complex and multi-faceted symptoms across the lifespan. Pain and the related symptoms of fatigue and sleep disorders are common. The objective of this qualitative study was to understand how participants manage their pain and related symptoms. Methods: The design was a qualitative thematic content analysis. Twenty-eight interviews were conducted to collect data from individuals who were participants in a prior quantitative longitudinal study. A semi-structured interview guide was designed to focus on and understand the trajectory of pain, sleep, fatigue, and general function. The interview continued with questions about coping mechanisms and obstacles to maintaining a sense of well-being. Results: Symptoms reported by participants were widespread and often interwoven. Pain was universal and often resulted in fatigue and disordered sleep which impacted physical function. Most participants reported that their symptoms worsened over time. Participants reported a wide range of effective interventions and most reported developing self-care strategies to adapt to their disabilities/limitations. Solutions included complementary interventions discovered when conventional medicine was unsuccessful. Very few relied on a "system" of health care and instead developed their own strategies to adapt to their disabilities/limitations. Discussion: EDS symptoms are often debilitating, and their progression is unknown. For most participants, symptoms worsened over the time. Even though participants in our study, by experience, were self-reliant, the importance of knowledgeable medical providers to help guide self-care should be emphasized.Item Arterial Elasticity in Ehlers-Danlos Syndromes(MDPI, 2020-01-04) Miller, Amanda J.; Schubart, Jane R.; Sheehan, Timothy; Bascom, Rebecca; Francomano, Clair A.; Medical and Molecular Genetics, School of MedicineEhlers-Danlos Syndromes (EDS) are a group of heritable disorders of connective tissue (HDCT) characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Orthostatic intolerance (OI) is highly prevalent in EDS however mechanisms linking OI to EDS remain poorly understood. We hypothesize that impaired blood pressure (BP) and heart rate control is associated with lower arterial stiffness in people with EDS. Orthostatic vital signs and arterial stiffness were assessed in a cohort of 60 people with EDS (49 female, 36 ± 16 years). Arterial elasticity was assessed by central and peripheral pulse wave velocity (PWV). Central PWV was lower in people with EDS compared to reference values in healthy subjects. In participants with EDS, central PWV was correlated to supine systolic BP (r = 0.387, p = 0.002), supine diastolic BP (r = 0.400, p = 0.002), and seated systolic BP (r = 0.399, p = 0.002). There were no significant correlations between PWV and changes in BP or heart rate with standing (p > 0.05). Between EDS types, there were no differences in supine hemodynamics or PWV measures (p > 0.05). These data demonstrate that increased arterial elasticity is associated with lower BP in people with EDS which may contribute to orthostatic symptoms and potentially provides a quantitative clinical measure for future genotype-phenotype investigations.Item Clinician-associated traumatization from difficult medical encounters: Results from a qualitative interview study on the Ehlers-Danlos Syndromes(Elsevier, 2023) Halverson, Colin M. E.; Penwell, Heather L.; Francomano, Clair A.; Medicine, School of MedicinePatients with hypermobile Ehlers Danlos Syndrome often experience psychological distress resulting from the perceived hostility and disinterest of their clinicians. We conducted 26 in-depth interviews with patients to understand the origins of this trauma and how it could be addressed in practice. We found that the cumulative effects of numerous negative encounters lead patients to lose trust in their healthcare providers and the healthcare system, and to develop acute anxiety about returning to clinic to seek further care. We describe this as clinician-associated traumatization. Ultimately, our interviewees described the result of this traumatization as worse – but preventable – health outcomes.Item Combination of common mtDNA variants results in mitochondrial dysfunction and a connective tissue dysregulation(National Academy of Science, 2022) Schaefer, Patrick M.; Scherer Alves, Leonardo; Lvova, Maria; Huang, Jessica; Rathi, Komal; Janssen, Kevin; Butic, Arrienne; Yardeni, Tal; Morrow, Ryan; Lott, Marie; Murdock, Deborah; Song, Angela; Keller, Kierstin; Garcia, Benjamin A.; Francomano, Clair A.; Wallace, Douglas C.; Medical and Molecular Genetics, School of MedicineMitochondrial dysfunction can be associated with a range of clinical manifestations. Here, we report a family with a complex phenotype including combinations of connective tissue, neurological, and metabolic symptoms that were passed on to all surviving children. Analysis of the maternally inherited mtDNA revealed a novel genotype encompassing the haplogroup J - defining mitochondrial DNA (mtDNA) ND5 m.13708G>A (A458T) variant arising on the mtDNA haplogroup H7A background, an extremely rare combination. Analysis of transmitochondrial cybrids with the 13708A-H7 mtDNA revealed a lower mitochondrial respiration, increased reactive oxygen species production (mROS), and dysregulation of connective tissue gene expression. The mitochondrial dysfunction was exacerbated by histamine, explaining why all eight surviving children inherited the dysfunctional histidine decarboxylase allele (W327X) from the father. Thus, certain combinations of common mtDNA variants can cause mitochondrial dysfunction, mitochondrial dysfunction can affect extracellular matrix gene expression, and histamine-activated mROS production can augment the severity of mitochondrial dysfunction. Most important, we have identified a previously unreported genetic cause of mitochondrial disorder arising from the incompatibility of common, nonpathogenic mtDNA variants.Item Consensus clinical management guidelines for Alström syndrome(BMC, 2020-09-21) Tahani, Natascia; Maffei, Pietro; Dollfus, Hélène; Paisey, Richard; Valverde, Diana; Milan, Gabriella; Han, Joan C.; Favaretto, Francesca; Madathil, Shyam C.; Dawson, Charlotte; Armstrong, Matthew J.; Warfield, Adrian T.; Düzenli, Selma; Francomano, Clair A.; Gunay-Aygun, Meral; Dassie, Francesca; Marion, Vincent; Valenti, Marina; Leeson-Beevers, Kerry; Chivers, Ann; Steeds, Richard; Barrett, Timothy; Geberhiwot, Tarekegn; Medical and Molecular Genetics, School of MedicineAlström Syndrome (ALMS) is an ultra-rare multisystem genetic disorder caused by autosomal recessive variants in the ALMS1 gene, which is located on chromosome 2p13. ALMS is a multisystem, progressive disease characterised by visual disturbance, hearing impairment, cardiomyopathy, childhood obesity, extreme insulin resistance, accelerated non-alcoholic fatty liver disease (NAFLD), renal dysfunction, respiratory disease, endocrine and urologic disorders. Clinical symptoms first appear in infancy with great variability in age of onset and severity. ALMS has an estimated incidence of 1 case per 1,000,000 live births and ethnically or geographically isolated populations have a higher-than-average frequency. The rarity and complexity of the syndrome and the lack of expertise can lead to delayed diagnosis, misdiagnosis and inadequate care. Multidisciplinary and multiprofessional teams of experts are essential for the management of patients with ALMS, as early diagnosis and intervention can slow the progression of multi-organ dysfunctions and improve patient quality of life. These guidelines are intended to define standard of care for patients suspected or diagnosed with ALMS of any age. All information contained in this document has originated from a systematic review of the literature and the experiences of the authors in their care of patients with ALMS. The Appraisal of Guidelines for Research & Evaluation (AGREE II) system was adopted for the development of the guidelines and for defining the related levels of evidence and strengths of recommendations. These guidelines are addressed to: a) specialist centres, other hospital-based medical teams and staffs involved with the care of ALMS patients, b) family physicians and other primary caregivers and c) patients and their families.Item Craniocervical instability in patients with Ehlers-Danlos syndromes: outcomes analysis following occipito-cervical fusion(Springer, 2024-01-02) Henderson, Fraser C.; Schubart, Jane R.; Narayanan, Malini V.; Tuchman, Kelly; Mills, Susan E.; Poppe, Dorothy J.; Koby, Myles B.; Rowe, Peter C.; Francomano, Clair A.; Medical and Molecular Genetics, School of MedicineCraniocervical instability (CCI) is increasingly recognized in hereditary disorders of connective tissue and in some patients following suboccipital decompression for Chiari malformation (CMI) or low-lying cerebellar tonsils (LLCT). CCI is characterized by severe headache and neck pain, cervical medullary syndrome, lower cranial nerve deficits, myelopathy, and radiological metrics, for which occipital cervical fusion (OCF) has been advocated. We conducted a retrospective analysis of patients with CCI and Ehlers-Danlos syndrome (EDS) to determine whether the surgical outcomes supported the criteria by which patients were selected for OCF. Fifty-three consecutive subjects diagnosed with EDS, who presented with severe head and neck pain, lower cranial nerve deficits, cervical medullary syndrome, myelopathy, and radiologic findings of CCI, underwent open reduction, stabilization, and OCF. Thirty-two of these patients underwent suboccipital decompression for obstruction of cerebral spinal fluid flow. Questionnaire data and clinical findings were abstracted by a research nurse. Follow-up questionnaires were administered at 5-28 months (mean 15.1). The study group demonstrated significant improvement in headache and neck pain (p < 0.001), decreased use of pain medication (p < 0.0001), and improved Karnofsky Performance Status score (p < 0.001). Statistically significant improvement was also demonstrated for nausea, syncope (p < 0.001), speech difficulties, concentration, vertigo, dizziness, numbness, arm weakness, and fatigue (p = 0.001). The mental fatigue score and orthostatic grading score were improved (p < 0.01). There was no difference in pain improvement between patients with CMI/LLCT and those without. This outcomes analysis of patients with disabling CCI in the setting of EDS demonstrated significant benefits of OCF. The results support the reasonableness of the selection criteria for OCF. We advocate for a multi-center, prospective clinical trial of OCF in this population.Item Editorial: Research advances in understanding the etiology, epidemiology, pathophysiology, clinical features, and management of the Ehlers Danlos syndrome disorders(Frontiers Media, 2024-07-22) Francomano, Clair A.; Maitland, Anne; Krakow, Deborah; Maier, Cheryl L.; Medical and Molecular Genetics, School of MedicineItem Estimates of the excess cost burden of Ehlers-Danlos syndromes: a United States MarketScan® claims database analysis(Frontiers Media, 2024-07-03) Schubart, Jane R.; Schaefer, Eric W.; Knight, Dacre R. T.; Mills, Susan E.; Francomano, Clair A.; Medical and Molecular Genetics, School of MedicineIntroduction: Patients with Ehlers-Danlos syndromes (EDS) and hypermobility spectrum disorders (HSD) have significant health challenges that are well-documented, however their impact in terms of cost is not known. Our research objective was to examine the cost burden of EDS and HSD in the United States. We focused this analysis on those with commercial insurance plans. Methods: We queried the MarketScan® database for year 2021 for claims that contained an ICD-10 diagnosis code for EDS or hypermobility. Excess costs for patients in the EDS and HSD cohorts were determined by matching each patient to one patient in the database that did not have a claim for EDS or HSD and comparing total costs for the calendar year. We determined whether patients had claims for selected comorbid conditions likely to impact costs during the calendar year. Results: Sample sizes were 5,113 for adult (age ≥ 18) patients with EDS, 4,880 for adult patients with HSD, 1,059 for child (age 5-17) patients with EDS, and 2,427 for child patients with HSD. The mean excess costs were $21,100 for adult EDS patients, $11,600 for adult HSD patients, $17,000 for child EDS patients, and $11,000 for child HSD patients. EDS and HSD cohorts, both adults and children, with any of the comorbidities had greater healthcare costs. The largest difference was found in the EDS cohort with gastrointestinal comorbid conditions, with more than double the costs for adults. Discussion: We found that patients in the MarketScan database, adults and children, who had EDS or HSD had substantially higher associated excess healthcare costs than patients without EDS or HSD when considering age, sex, geographic location, and comorbidities. These disproportionate healthcare costs in this population have health policy and economic implications, including the need for rapid diagnosis, access to treatment, and accelerated research to advance treatments.Item Evolving Attitudes Toward Numeric Pain Assessment Among Patients with Hypermobile Ehlers-Danlos Syndrome: A Qualitative Interview Study(Oxford University Press, 2023) Halverson, Colin M. E.; Kroenke, Kurt; Penwell, Heather L.; Francomano, Clair A.; Medicine, School of MedicineItem Hereditary alpha-tryptasemia modifies clinical phenotypes among individuals with congenital hypermobility disorders(Elsevier, 2022-02-22) Vazquez, Maribel; Chovanec, Jack; Kim, Jiwon; DiMaggio, Thomas; Milner, Joshua D.; Francomano, Clair A.; Gurnett, Christina A.; Ritelli, Marco; Colombi, Marina; Lyons, Jonathan J.; Medical and Molecular Genetics, School of MedicineHereditary alpha-tryptasemia (HαT) is an autosomal dominant (AD) genetic trait characterized by elevated basal serum tryptase ≥8 ng/mL, caused by increased α-tryptase-encoding TPSAB1 copy number. HαT affects 5% to 7% of Western populations and has been associated with joint hypermobility. Hypermobility disorders are likewise frequently AD, but genetic etiologies are often elusive. Genotyping of individuals with hypermobility spectrum disorder (n = 132), hypermobile Ehlers-Danlos syndrome (n = 78), or axial skeletal abnormalities with hypermobility (n = 56) was performed. Clinical features of individuals with and without HαT were compared. When analyzing our combined cohorts, dysphagia (p = 0.007) and retained primary dentition (p = 0.0003) were significantly associated with HαT, while positive associations with anaphylaxis (p = 0.07) and pruritus (P = 0.5) did not reach significance likely due to limited sample size. Overall, HαT prevalence is not increased in individuals with hypermobility disorders, rather linked to a unique endotype, demonstrating how HαT may modify clinical presentations of complex patients.