A Novel KIDINS220 Pathogenic Variant Associated with the Syndromic Spastic Paraplegia SINO: An Expansion of the Brain Malformation Spectrum and a Literature Review.

BACKGROUND/OBJECTIVES: Identifying novel variants in very rare disease genes can be challenging when patients exhibit a complex phenotype that expands the one described, and we provide such an example here. A few terminal truncating variants in KIDINS220 cause spastic paraplegia (SP), intellectual disability (ID), nystagmus, and obesity (SINO, MIM #617296). Prompted by the result of next-generation sequencing on a patient referred for SP associated with complex brain dysmorphisms, we reviewed the phenotype of SINO patients focusing on their brain malformations, mainly described in prenatal age and first years of life, and tried to understand if the predicted effect of the mutant kidins220 may have caused them. METHODS: We performed whole exome sequencing (WES) and a literature and mutation databases review. RESULTS: We report a young adult with SP, severe ID, strabismus, and macrocephaly exhibiting brain malformations at follow-up, partially overlapping with those described in TUBB3 tubulinopathy. WES analysis of the proband and parents identified the heterozygous de novo variant (NM_020738.4: c. 4144G > T) p. Glu 1382* in KIDINS220 that was predicted to be causative of SINO. CONCLUSIONS: The progression of myelination and the development of brain structures turned out to be crucial for identifying, at follow-up, the whole KIDINS220-related brain malformations. The truncated proteins associated with SINO lack a portion fundamental for the interaction of kidins220 with tubulins and microtubule-associated proteins. The complexity of the brain malformations displayed by our patient, and possibly by other reported SINO patients, could result from an impaired dynamic modulation of the microtubule cytoskeleton during embryogenesis. Brain malformations must be considered as part of the SINO spectrum phenotype.

Self-care behaviors and their individual-level determinants in Italian adults with Marfan syndrome: A single-center cross-sectional study.

AIM: This study aimed to describe the levels of self-care behaviors and self-care self-efficacy in patients with Marfan syndrome and to identify the individual-level determinants of self-care behaviors. BACKGROUND: The behaviors aimed at maintaining health stability (self-care maintenance), monitoring signs and symptoms (self-care monitoring), and taking action when signs and symptoms occur (self-care management) are key aspects of the care for addressing the complexity of care of patients with Marfan syndrome. However, the description of self-care behaviors and their determinants in patients with Marfan syndrome are highly under-described. METHODS: The adopted design was descriptive observational with a cross-sectional data collection on 111 patients with MFS in a single Italian specialized and reference center for this disease between 2020 and 2021. RESULTS: Performing healthy activities and managing illness, therapies, and follow-ups to maintain health over time (self-care maintenance) was almost adequate (mean score = 67.87 ± 13.17), as well as the ability to recognize signs and symptoms promptly (self-care monitoring, mean score = 67.95 ± 26.70). The ability to respond to symptoms when they occur (self-care management, mean score = 54.17 ± 19.94) was sub-optimal. The stronger positive predictor of each self-care behavior was self-care self-efficacy. CONCLUSIONS: This study suggested prioritizing educational activities focused on enhancing self-care management in patients with Marfan syndrome and strengthening their self-care self-efficacy. Researchers should develop and validate evidence-based educational approaches to enhance self-care in patients with Marfan syndrome, and clinical nurses should strengthen their focused educational activities to improve the self-care management of these patients.

Coding and Non-Coding Transcriptomic Landscape of Aortic Complications in Marfan Syndrome.

Marfan syndrome (MFS) is a rare congenital disorder of the connective tissue, leading to thoracic aortic aneurysms (TAA) and dissection, among other complications. Currently, the most efficient strategy to prevent life-threatening dissection is preventive surgery. Periodic imaging applying complex techniques is required to monitor TAA progression and to guide the timing of surgical intervention. Thus, there is an acute demand for non-invasive biomarkers for diagnosis and prognosis, as well as for innovative therapeutic targets of MFS. Unraveling the intricate pathomolecular mechanisms underlying the syndrome is vital to address these needs. High-throughput platforms are particularly well-suited for this purpose, as they enable the integration of different datasets, such as transcriptomic and epigenetic profiles. In this narrative review, we summarize relevant studies investigating changes in both the coding and non-coding transcriptome and epigenome in MFS-induced TAA. The collective findings highlight the implicated pathways, such as TGF-ß signaling, extracellular matrix structure, inflammation, and mitochondrial dysfunction. Potential candidates as biomarkers, such as miR-200c, as well as therapeutic targets emerged, like Tfam, associated with mitochondrial respiration, or miR-632, stimulating endothelial-to-mesenchymal transition. While these discoveries are promising, rigorous and extensive validation in large patient cohorts is indispensable to confirm their clinical relevance and therapeutic potential.

Marfan Syndrome: Enhanced Diagnostic Tools and Follow-up Management Strategies.

Marfan syndrome (MFS) is a rare inherited autosomic disorder, which encompasses a variety of systemic manifestations caused by mutations in the Fibrillin-1 encoding gene (FBN1). Cardinal clinical phenotypes of MFS are highly variable in terms of severity, and commonly involve cardiovascular, ocular, and musculoskeletal systems with a wide range of manifestations, such as ascending aorta aneurysms and dissection, mitral valve prolapse, ectopia lentis and long bone overgrowth, respectively. Of note, an accurate and prompt diagnosis is pivotal in order to provide the best treatment to the patients as early as possible. To date, the diagnosis of the syndrome has relied upon a systemic score calculation as well as DNA mutation identification. The aim of this review is to summarize the latest MFS evidence regarding the definition, differences and similarities with other connective tissue pathologies with severe systemic phenotypes (e.g., Autosomal dominant Weill-Marchesani syndrome, Loeys-Dietz syndrome, Ehlers-Danlos syndrome) and clinical assessment. In this regard, the management of MFS requires a multidisciplinary team in order to accurately control the evolution of the most severe and potentially life-threatening complications. Based on recent findings in the literature and our clinical experience, we propose a multidisciplinary approach involving specialists in different clinical fields (i.e., cardiologists, surgeons, ophthalmologists, orthopedics, pneumologists, neurologists, endocrinologists, geneticists, and psychologists) to comprehensively characterize, treat, and manage MFS patients with a personalized medicine approach.

Case report: Complex arterial findings in vascular ehlers-danlos syndrome with a novel COL3A1 variant and death at young age.

Vascular Ehlers-Danlos syndrome (vEDS) is a genetic disease caused by a pathogenic mutation in the COL3A1 gene. Despite its severe course, the rarity and extreme clinical variability of the disease can pose significant obstacles to a timely diagnosis. Early and accurate diagnosis may lead to improved patient outcomes by providing access to targeted pharmacological treatments like celiprolol and enhancing the management of vEDS-related complications. Herein, we report a patient harboring a novel de novo COL3A1 missense variant, in which the diagnosis was only possible belatedly due to delayed referral for genetic evaluation. The patient developed pulmonary complications, aneurysms, and vascular malformations, and died at the age of 26 years due to massive pulmonary bleeding.

COVID-19 Vaccine Hesitancy in Italian Adults with Marfan Syndrome: Insights from a Secondary Analysis of a Cross-Sectional Study.

Although vaccine hesitancy has been reported in many patient groups and countries, there is a lack of data on vaccine hesitancy in patients with Marfan syndrome (MFS). MFS is a rare genetic disorder that can lead to cardiovascular, ocular, and musculoskeletal issues. Because MFS patients may face an increased risk of COVID-19 complications, vaccination is crucial for this population. This brief report aims to describe vaccine hesitancy rates in MFS patients and compare the characteristics of patients who are hesitant and those who are not to gain a better understanding of this specific population. This study analyzes previously published cross-sectional data that examined mental health, sociodemographic, and clinical factors associated with PTSD, depression, anxiety, and insomnia in MFS patients during the third wave of the COVID-19 pandemic in Lombardy, Italy. Of the 112 MFS patients who participated, 26 (23.9%) reported vaccine hesitancy. Vaccine hesitancy may be associated mainly with younger age and not be related to other patient characteristics. Therefore, this report found no differences in individual-level variables, such as sex, education, comorbidities, and mental health symptoms, between those who were hesitant and those who were not. The study findings are insightful and suggest that interventions to address vaccine hesitancy in this population may need to focus on attitudes and beliefs related to vaccination rather than targeting specific sociodemographic or clinical factors.

Describing post-traumatic stress disorder and its associations with depression, anxiety and insomnia: a descriptive study in Italian adults with Marfan syndrome during the COVID-19 third wave.

OBJECTIVE: The evaluation of post-traumatic stress disorder (PTSD), depression, anxiety and insomnia in patients with Marfan syndrome (MFS) during the third wave of the COVID-19 pandemic in a region of northern Italy (Lombardy) and the investigation of which mental health, sociodemographic and clinical factors were associated with PTSD. DESIGN: Descriptive observational design with cross-sectional data collection procedure. SETTING: A single Italian MFS-specific specialised and reference centre in Lombardy (Italy) between February and April 2021. PARTICIPANTS: 112 adults with MFS. The majority of participants were female (n=64; 57.1%), with a high school diploma (n=52; 46.4%) and active workers (n=66; 58.9%). The mean age was 41.89 years (SD=14.00), and the mean time from diagnosis was 15.18 years (SD=11.91). PRIMARY AND SECONDARY OUTCOMES: Descriptive statistics described PTSD, which was the primary outcome, as well as depression, anxiety and insomnia, which were the secondary outcomes. Four linear regression models described the predictors of PTSD total score and its three domains: avoidance, intrusion and hyperarousal. RESULTS: One out of 10 patients with MFS had mild psychological symptoms regarding depression, anxiety and insomnia, and scores of PTSD that indicated clinical worries about the mental health status. The presence of PTSD was mainly predicted by anxiety (ß=0.647; p<0.001), being older, taking psychoactive medication and being unemployed. CONCLUSION: Depression, anxiety and insomnia should be monitored in patients with MFS in order to minimise PTSD insurgence. Specific psychosocial interventions should be developed and tested for this population and adopted in clinical practice, given the relevance of mental health outcomes during the pandemic.