Kellen Winden, E Martina Bebin, Shafali Jeste, Darcy A Krueger, Elahna Paul, Mustafa Sahin
{"title":"Tuberous sclerosis complex.","authors":"Kellen Winden, E Martina Bebin, Shafali Jeste, Darcy A Krueger, Elahna Paul, Mustafa Sahin","doi":"10.1038/s41572-026-00688-9","DOIUrl":"10.1038/s41572-026-00688-9","url":null,"abstract":"<p><p>Tuberous sclerosis complex (TSC) is a rare genetic disease caused by heterozygous loss-of-function variants in TSC1 or TSC2. Patients present with benign tumours known as hamartomas in the brain, eyes, lungs, kidneys, heart and skin. Many hamartomas contain mosaic second hit variants in TSC1 or TSC2. The most disabling features of TSC include epilepsy and TSC-associated neuropsychiatric disorders (TAND) such as intellectual disability and autism spectrum disorder. Remarkable progress has been made both in understanding the pathogenesis of TSC and in its clinical management, largely due to the discovery of the link between TSC1 and TSC2 and the mechanistic target of rapamycin (mTOR) signalling pathway. TSC1 and TSC2 form a protein complex that inhibits mTOR. Naturally occurring inhibitors of mTOR (rapamycin) and its analogues, collectively known as rapalogues, have been used to test various hypotheses in preclinical models and are approved for the treatment of several manifestations of TSC. Approved drug treatments (rapalogues) exist for subependymal giant cell astrocytomas, renal angiomyolipomas, pulmonary lymphangioleiomyomatosis, facial angiofibromas and refractory seizures. However, there is still an unmet need for effective treatment of TAND and refractory epilepsy, despite the available medical and surgical options.</p>","PeriodicalId":18910,"journal":{"name":"Nature Reviews Disease Primers","volume":"12 1","pages":""},"PeriodicalIF":79.8,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147443917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Clare L Scott, Susana Banerjee, Florence Joly, Jung-Min Lee, Asima Mukhopadhyay, David S Tan, Elise C Kohn
{"title":"Ovarian cancer.","authors":"Clare L Scott, Susana Banerjee, Florence Joly, Jung-Min Lee, Asima Mukhopadhyay, David S Tan, Elise C Kohn","doi":"10.1038/s41572-026-00686-x","DOIUrl":"10.1038/s41572-026-00686-x","url":null,"abstract":"<p><p>Epithelial ovarian cancer (EOC) describes a group of diseases characterized by differing pathogeneses, molecular profiles, histologies and prognoses. The low incidence of each distinct histological type of EOC poses challenges for obtaining an accurate diagnosis, robust evidence to guide management, and a mechanistic understanding to ensure availability of effective therapies. Most EOCs, including high-grade serous ovarian cancer, predominantly originate from the fimbriated ends of the fallopian tube, whereas low-grade serous, clear cell, endometrioid and mucinous EOCs are thought to originate from other tissues. Despite recognized genetic susceptibilities for the disease, no effective screening is available and late-stage diagnosis remains common. Known genetic susceptibilities are addressed by risk reduction surgery including removal of both fallopian tubes and both ovaries. Management is predominantly based on adequate surgery and chemotherapy with carboplatin and paclitaxel, with the addition of anti-angiogenic therapy as indicated. The incorporation of poly(ADP-ribose) polymerase inhibitors into first-line therapy has considerably altered outcomes in some women with EOC who have defective homologous recombination DNA repair, including in those with BRCA1 and/or BRCA2 mutations. Other molecular characteristics are important in distinct types of EOC, but the use of matched targeted therapies remains under investigation, as does the role of immunotherapy for EOC, for which trial data have been disappointing to date. Translationally enriched clinical trials will be important to further explore and validate accurate biomarkers to better guide clinical care.</p>","PeriodicalId":18910,"journal":{"name":"Nature Reviews Disease Primers","volume":"12 1","pages":""},"PeriodicalIF":79.8,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147365594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Liesl Zühlke, Andrea Beaton, Mark Engel, Anu Gomanju, Raman Kirshna Kumar, James Marangou, Neema Minja, Nicole J Moreland, Emmy Okello, Jafesi Pulle, Joselyn Rwebembera, David Watkins, Chris Yilgwan, Jonathan Carapetis
{"title":"Acute rheumatic fever and rheumatic heart disease.","authors":"Liesl Zühlke, Andrea Beaton, Mark Engel, Anu Gomanju, Raman Kirshna Kumar, James Marangou, Neema Minja, Nicole J Moreland, Emmy Okello, Jafesi Pulle, Joselyn Rwebembera, David Watkins, Chris Yilgwan, Jonathan Carapetis","doi":"10.1038/s41572-026-00685-y","DOIUrl":"10.1038/s41572-026-00685-y","url":null,"abstract":"<p><p>Acute rheumatic fever (ARF), the acute autoimmune sequela of group A Streptococcus infection, and its chronic life-threatening manifestation, rheumatic heart disease (RHD), which causes permanent heart valve damage, remain major drivers of preventable cardiovascular mortality and disability in low-income and middle-income countries. Since the mid-1990s, multidisciplinary and international collaborative research has yielded new insights into the role of superficial skin infections such as impetigo in ARF pathogenesis and the disease mechanisms that underlie the progression from ARF to RHD, and has explored novel treatments and delivery mechanisms in clinical trials and progressed the development of Strep A vaccines. Early detection and patient care have advanced, with revised echocardiographic screening criteria and the 2024 WHO guidelines, which provide a framework for evidence-based management and therapeutic strategies. Notwithstanding these advancements, considerable disparity persists in the care, control and treatment of advanced disease, necessitating coordinated programmes, prioritization by global agencies and local governments, and substantial involvement of those with RHD. Of note, few to no cardiac surgery programmes exist in some countries most burdened by RHD. Future research must encompass implementation studies for validated evidence-based therapies, translational technologies and applications, together with a definitive pathway to direct patient effect, to achieve the WHO target of eliminating RHD as a public health problem.</p>","PeriodicalId":18910,"journal":{"name":"Nature Reviews Disease Primers","volume":"12 1","pages":""},"PeriodicalIF":79.8,"publicationDate":"2026-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147308170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bradley T Hammoor, Christopher S Lai, Grace X Xiong, Dawn M Elliott, Brian Snyder, Edward Vresilovic, Christopher M Bono, Benjamin R Freedman
{"title":"Intervertebral disc degeneration.","authors":"Bradley T Hammoor, Christopher S Lai, Grace X Xiong, Dawn M Elliott, Brian Snyder, Edward Vresilovic, Christopher M Bono, Benjamin R Freedman","doi":"10.1038/s41572-025-00681-8","DOIUrl":"10.1038/s41572-025-00681-8","url":null,"abstract":"<p><p>Intervertebral disc (IVD) degeneration is a naturally occurring process that is a consequence of biological ageing and exposure to normal physiological loading over a lifetime and is characterized by loss of IVD tissue structural integrity. The nucleus pulposus changes with loss of pressurization, decreased collagen concentration and loss of distinction from annulus fibrosus. The annulus fibrosus and cartilaginous endplate suffer delamination, tears, fractures and clefts of their respective extracellular matrix at both microscopic and macroscopic scales. This loss of structural integrity generally follows a predictable pattern of degeneration, and it predisposes the IVD to pathological states. As the disc degenerates, the likelihood of functional failure to protect the neural elements and/or to provide stable spine motion and support increases. Functional failure takes the degenerated IVD to a state of disc pathology that has various phenotypes: the most common forms are disc herniation, mechanical instability, spinal stenosis, degenerative spondylolisthesis and degenerative scoliosis. IVD pathology is commonly self-limited and non-operative treatment remains the mainstay of treatment in most patients. For patients with refractory disease, surgical intervention focuses on neural decompression and, when indicated, motion segment stabilization. Future therapies for prevention of disc degeneration, targeted disc regeneration and biological modification of the degenerative cascade might prevent or reverse pathological changes across all spinal regions.</p>","PeriodicalId":18910,"journal":{"name":"Nature Reviews Disease Primers","volume":"12 1","pages":"5"},"PeriodicalIF":79.8,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146125930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Charcot-Marie-Tooth disease and related neuropathies.","authors":"","doi":"10.1038/s41572-026-00683-0","DOIUrl":"10.1038/s41572-026-00683-0","url":null,"abstract":"<p><p>This PrimeView summarizes the clinical manifestations and diagnosis of Charcot-Marie-Tooth disease, and accompanies the Primer article by Burns and colleagues.</p>","PeriodicalId":18910,"journal":{"name":"Nature Reviews Disease Primers","volume":"12 1","pages":"4"},"PeriodicalIF":76.9,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Joshua Burns, Vincent Timmerman, Matilde Laurá, Eppie M Yiu, Maurizio D'Antonio, Bipasha Mukherjee-Clavin, Jonathan De Winter, Steven S Scherer
{"title":"Charcot-Marie-Tooth disease and related neuropathies.","authors":"Joshua Burns, Vincent Timmerman, Matilde Laurá, Eppie M Yiu, Maurizio D'Antonio, Bipasha Mukherjee-Clavin, Jonathan De Winter, Steven S Scherer","doi":"10.1038/s41572-025-00679-2","DOIUrl":"10.1038/s41572-025-00679-2","url":null,"abstract":"<p><p>Charcot-Marie-Tooth disease (CMT) subsumes many different inherited neuropathies. CMT and related neuropathies are among the most common inherited neurological disorders, affecting ~1 in 2,500 people globally and including both sexes. Mutations in genes that cause demyelinating forms of CMT often affect the proteins of the myelin sheath, the unfolded protein response, endosomal signalling and recycling, or key transcription factors. Mutations in genes that cause axonal forms often affect mitochondrial biology, aminoacyl-tRNA synthetases, molecular chaperones or the axonal cytoskeleton. All forms of CMT result in length-dependent, progressive axonal loss that correlates with clinical impairments such as distal upper and lower limb weakness, musculoskeletal deformity, absent deep tendon reflexes and distal sensory deficits. Compared with the general population, children and adults with CMT have reduced quality of life across physical, emotional and social domains, with the physical domain being the most disabling. Disease-modifying therapies are not yet available for any form of CMT. Management includes rehabilitative approaches such as muscle strength training and orthotic devices, surgical interventions, symptom relief and anticipatory monitoring of associated complications. The investigation of genetically authentic cellular, organoid and animal models will enable the development of rational therapies. Natural history studies and biomarkers will enable potential therapies to be critically evaluated.</p>","PeriodicalId":18910,"journal":{"name":"Nature Reviews Disease Primers","volume":"12 1","pages":"3"},"PeriodicalIF":79.8,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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