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While it is widely thought that de novo mutations (DNMs) occur randomly, we previously showed that some DNMs are enriched because they are positively selected in the testes of aging men. These "selfish" mutations cause disorders with a shared presentation of features, including exclusive paternal origin, significant increase of the father's age, and high apparent germline mutation rate. To date, all known selfish mutations cluster within the components of the RTK-RAS-MAPK signaling pathway, a critical modulator of testicular homeostasis. Here, we demonstrate the selfish nature of the SMAD4 DNMs causing Myhre syndrome (MYHRS). By analyzing 16 informative trios, we show that MYHRS-causing DNMs originated on the paternally derived allele in all cases. We document a statistically significant epidemiological paternal age effect of 6.3 years excess for fathers of MYHRS probands. We developed an ultra-sensitive assay to quantify spontaneous MYHRS-causing SMAD4 variants in sperm and show that pathogenic variants at codon 500 are found at elevated level in sperm of most men and exhibit a strong positive correlation with donor's age, indicative of a high apparent germline mutation rate. Finally, we performed in vitro assays to validate the peculiar functional behavior of the clonally selected DNMs and explored the basis of the pathophysiology of the different SMAD4 sperm-enriched variants. Taken together, these data provide compelling evidence that SMAD4 , a gene operating outside the canonical RAS-MAPK signaling pathway, is associated with selfish spermatogonial selection and raises the possibility that other genes/pathways are under positive selection in the aging human testis. Activating RAS-MAPK mutations occurring spontaneously in human spermatogonia cause clonal expansion of these stem cells with age, explaining the high birth prevalence of the associated disorders. We show that Myhre syndrome-causing mutations in SMAD4 , a gene operating outside the canonical RAS-MAPK signaling pathway, are positively selected in the male germline. [ABSTRACT FROM AUTHOR]

Marfan syndrome is a rare inherited connective tissue disease, which may be present in patients who have advanced hip pathologies that may require total hip arthroplasty (THA). The postoperative course of patients who have Marfan syndrome following THA has not yet been defined. Adult patients who have and do not have Marfan syndrome and underwent THA were identified in a national database. Patients diagnosed who had infection, trauma, or neoplasms within the 90 days prior to surgery were excluded. Those who have versus those who did not have Marfan syndrome were matched 1:10 based on age, sex, and a comorbidity index. After matching, 144 patients who have Marfan syndrome and 1,440 who do not have Marfan syndrome were identified. The 90-day postoperative adverse events and 5-year revisions were assessed and compared with multivariable analyses and log rank tests, respectively. Multivariable analyses demonstrated that Marfan syndrome was independently associated with greater odds of 90-day adverse events: venous thromboembolic events (odds ratio [OR]: 2.9, P =.001), cardiac events (OR: 4.5, P =.034), pneumonia (OR: 3.5, P <.001), and urinary tract infections (OR: 5.2, P <.001). There was no significant difference in 5-year rates of revision. Following THA, Marfan syndrome was independently associated with greater rates of several 90-day adverse events, but not higher 5-year rates of revision. The identified at-risk adverse events may help guide surgeons to improve perioperative care pathways, while having confidence regarding joint survival of THA in this rare disease population. [ABSTRACT FROM AUTHOR]

Abstract Background Before COVID-19, people with rare diseases (RD) experienced numerous disparities in quality of life and healthcare access and quality, yet little is known about the experiences of this underserved group during the pandemic. Results During the first wave of the COVID-19 pandemic in the United States, spring and summer of 2020, 759 participants representing 231 unique RDs responded to open-ended questions about the impact of the pandemic on life with a RD, healthcare access, and coping. Qualitative conventional content analysis was used to analyze responses. Identified themes represented positive and negative dimensions of change, including a shock to the (health) system, coping with uncertainty, and the value of social support while isolated. Conclusions Limitations in healthcare access and quality were the most frequently described as impacts of COVID-19. Other major negative impacts included exacerbation of symptoms, psychological distress, and a lack of usual social support and reliable information. However, participants also noted silver linings, especially in healthcare. For some, expanded telehealth enhanced their ability to access medical and mental health providers and RD specialists. Finally, many participants hoped that, by highlighting social and health inequities faced by people with RDs and other minorities, the pandemic would prompt greater understanding and policies that could improve the quality of life of the RD community.

Background: Malakoplakia is a rare granulomatous disease that commonly involves the genitourinary tract with the urinary bladder being the most frequently affected site. It is characterized by histiocytes containing distinct basophilic calcified inclusions called Michaelis-Gutmann bodies. It is believed to result from abnormally functioning macrophages, with inclusions representing calcifications around incompletely digested bacteria. Although its pathogenesis remains unknown, it is well-documented that the condition is associated with chronic urinary tract infections and immunosuppression. Grossly, it can present as soft, yellow plaques, nodules, bladder mass, or even without any visible lesion. It poses a huge diagnostic challenge as it tends to mimic malignancy., Case Presentation: Described here is an 86-year-old female with recurrent bladder malakoplakia who presented with foul-smelling urine, hematuria, and dysuria. The clinicopathological features of this rare bladder lesion are described along with a review of the literature., Conclusion: Early identification of malakoplakia's features by pathologists is essential for effective patient management. This condition should be considered in the differential diagnosis of bladder lesions, especially when Escherichia coli is present., Competing Interests: The author declares no conflict of interest., (© 2024 Bladder, All rights reserved.)

RASopathies are rare developmental genetic syndromes caused by germline pathogenic variants in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) signal transduction pathway. Although the incidence of each RASopathy syndrome is rare, collectively, they represent one of the largest groups of multiple congenital anomaly syndromes and have severe developmental consequences. Here, we review our understanding of how RAS/MAPK dysregulation in RASopathies impacts skeletal muscle development and the importance of RAS/MAPK pathway regulation for embryonic myogenesis. We also discuss the complex interactions of this pathway with other intracellular signaling pathways in the regulation of skeletal muscle development and growth, and the opportunities that RASopathy animal models provide for exploring the use of pathway inhibitors, typically used for cancer treatment, to correct the unique skeletal myopathy caused by the dysregulation of this pathway., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

CACNA1A-related disorders are rare neurodevelopmental disorders linked to variants in the CACNA1A gene. This gene encodes the α1 subunit of the P/Q-type calcium channel Cav2.1, which is globally expressed in the brain and crucial for fast synaptic neurotransmission. The broad spectrum of CACNA1A-related neurological disorders includes developmental and epileptic encephalopathies, familial hemiplegic migraine type 1, episodic ataxia type 2, spinocerebellar ataxia type 6, together with unclassified presentations with developmental delay, ataxia, intellectual disability, autism spectrum disorder, and language impairment. The severity of each disorder is also highly variable. The spectrum of CACNA1A-related seizures is broad across both loss-of-function and gain-of-function variants and includes absence seizures, focal seizures with altered consciousness, generalized tonic-clonic seizures, tonic seizures, status epilepticus, and infantile spasms. Furthermore, over half of CACNA1A-related epilepsies are refractory to current therapies. To date, almost 1700 CACNA1A variants have been reported in ClinVar, with over 400 listed as Pathogenic or Likely Pathogenic, but with limited-to-no clinical or functional data. Robust genotype-phenotype studies and impacts of variants on protein structure and function have also yet to be established. As a result, there are few definitive treatment options for CACNA1A-related epilepsies. The CACNA1A Foundation has set out to change the landscape of available and effective treatments and improve the quality of life for those living with CACNA1A-related disorders, including epilepsy. Established in March 2020, the Foundation has built a robust preclinical toolbox that includes patient-derived induced pluripotent stem cells and novel disease models, launched clinical trial readiness initiatives, and organized a global CACNA1A Research Network. This Research Network is currently composed of over 60 scientists and clinicians committed to collaborating to accelerate the path to CACNA1A-specific treatments and one day, a cure., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)