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Lenz-Majewski hyperostotic dwarfism

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Lenz-Majewski hyperostotic dwarfism. Core disease mechanisms, molecular an...

2026-04-15
Asta MONDO:0007892 Model: Asta Scientific Corpus Retrieval 17 citations

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Lenz-Majewski hyperostotic dwarfism. Core disease mechanisms, molecular an...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 17
  • Snippets retrieved: 20

Relevant Papers

[1] Clinical and Oral Manifestations in a Patient with Lenz-Majewski Syndrome: A Rare Case Report

  • Authors: Merve Bayram, B. B. Akgöl, E. Çetin, Gulsum Ceylan
  • Year: 2025
  • Venue: BMC Oral Health
  • URL: https://www.semanticscholar.org/paper/ff954bf6dd8137f84aa3260205107bb17d260de6
  • DOI: 10.1186/s12903-025-06785-7
  • PMID: 40993826
  • PMCID: 12462183
  • Summary: A 13-year-old male diagnosed with Lenz-Majewski Syndrome is reported through whole exome sequencing, which identified a heterozygous de novo PTDSS1 variant (c.284G > A; p.R95Q), not previously documented in LMS cases, and novel dental findings—particularly taurodontism—in association with a previously unreported PTDSS1 variant are documents.
  • Evidence snippets:
  • Snippet 1 (score: 0.551) > Lenz-Majewski Syndrome (LMS), also referred to as Lenz-Majewski hyperostotic dwarfism, is a rare genetic disorder characterized by a constellation of clinical features, including skeletal dysplasia, craniofacial abnormalities, and intellectual disability. The syndrome is primarily caused by gain-of-function mutations in the Phosphatidylserine Synthase 1 (PTDSS1) gene, which encodes phosphatidylserine synthase 1, an enzyme involved in phospholipid biosynthesis. The clinical presentation of LMS is diverse, with skeletal abnormalities being one of its most prominent features. Patients typically exhibit generalized craniotubular hyperostosis, which leads to progressive skeletal sclerosis and dwarfism [1][2][3]. > The dysplastic changes in the bones are often accompanied by distinctive craniofacial features such as brachycephaly, midface hypoplasia, and a prominent forehead [4]. Oral and dental manifestations in LMS patients include dental enamel dysplasia [4][5][6], and delayed dental eruption [2,4]. Dental enamel dysplasia, a common finding, is characterized by abnormal enamel formation that increases susceptibility to caries and other dental complications [4]. Additionally, delayed tooth eruption is commonly reported, often necessitating early dental interventions to manage potential complications, such as malocclusion or spacing issues [7]. The pathophysiology underlying these dental anomalies is likely linked to the broader developmental disruptions caused by PTDSS1 mutations. The enzyme encoded by PTDSS1 plays a crucial role in lipid metabolism, and its dysregulation can affect cellular processes involved in the development and maintenance of dental tissues [1][2][3]. > LMS is characterized by progressive hyperostosis of craniofacial bones, particularly the skull base and jawbones, which contributes to prognathism and may result in misaligned dentition [1][2][3][4]8].

[2] Cutis laxa and excessive bone growth due to de novo mutations in PTDSS1

  • Authors: J. Piard, J. Lespinasse, M. Vlčková, M. A. Mensah, S. Iurian et al.
  • Year: 2018
  • Venue: American Journal of Medical Genetics. Part a
  • URL: https://www.semanticscholar.org/paper/17ab7d7bdc0c1b44591dcc5816bd11ed88f3ad55
  • DOI: 10.1002/ajmg.a.38604
  • PMID: 29341480
  • PMCID: 5838527
  • Citations: 14
  • Influential citations: 5
  • Summary: Molecular and clinical characterization of three unrelated patients with a very rare phenotype associating cutis laxa, facial dysmorphism, severe growth retardation, hyperostotic skeletal dysplasia, and intellectual disability are provided and it is illustrated that LMS is an unequivocal cuti laxa syndrome and expands the clinical and molecular spectrum of this group of disorders.
  • Evidence snippets:
  • Snippet 1 (score: 0.511) > The cutis laxa syndromes are multisystem disorders that share loose redundant inelastic and wrinkled skin as a common hallmark clinical feature. The underlying molecular defects are heterogeneous and 13 different genes have been involved until now, all of them being implicated in elastic fiber assembly. We provide here molecular and clinical characterization of three unrelated patients with a very rare phenotype associating cutis laxa, facial dysmorphism, severe growth retardation, hyperostotic skeletal dysplasia, and intellectual disability. This disorder called Lenz–Majewski syndrome (LMS) is associated with gain of function mutations in PTDSS1, encoding an enzyme involved in phospholipid biosynthesis. This report illustrates that LMS is an unequivocal cutis laxa syndrome and expands the clinical and molecular spectrum of this group of disorders. In the neonatal period, brachydactyly and facial dysmorphism are two early distinctive signs, later followed by intellectual disability and hyperostotic skeletal dysplasia with severe dwarfism allowing differentiation of this condition from other cutis laxa phenotypes. Further studies are needed to understand the link between PTDSS1 and extra cellular matrix assembly.

[3] Insights into Natural History, Phenotypic, and Molecular Spectrum in a Large Cohort of Osteosclerotic Disorders

  • Authors: Dilek Uludağ Alkaya, Esra Usluer, Zeynep Alp Ünkar, Ali Şeker, Ibrahim Adaletli et al.
  • Year: 2025
  • Venue: Calcified Tissue International
  • URL: https://www.semanticscholar.org/paper/65a0ff0631a0d8ea601a4611820af34f267383b8
  • DOI: 10.1007/s00223-025-01366-w
  • PMID: 40198394
  • PMCID: 11978542
  • Citations: 1
  • Summary: Clinical and radiologic findings improved over time in PHOAR1 patients, whereas they progressed in JPD-5 and trichothiodystrophy-1 patients, and intra- and interfamilial clinical differences were observed in CMD, CED, JPD-5, and GHDD.
  • Evidence snippets:
  • Snippet 1 (score: 0.440) > During follow-up, the patient developed significant difficulty walking and severe hip joint pain at the age of 8.5 years, similar to the previously reported patient [37]. We clearly observed joint stiffness and also sclerosis of the skull, vertebrae and pelvis, which is the characteristic feature of the disease progressing with age, similar to the few patients reported [38]. > Lenz-Majewski hyperostotic dwarfism showed typical clinical findings in one of our patients, including severe prenatal short stature, a dismorphic face, and radiologic features such as short or absent metacarpals and phalanges, diaphyseal thickening, and metaphyseal hypostosis [5,39]. To date, only twenty patients have been documented, 12 of whom received molecular confirmation [40]. > Heterozygosity for a COL1A1 mutation was found in the lung tissue of a fetus with a severe form of prenatal cortical hyperostosis [41]. In our cohort, one fetus was diagnosed with perinatal Caffey disease with typical clinical, radiologic, and histopathologic findings. > Melorheostosis often presents with a classic "dripping candle wax" radiographic appearance. Despite no pathogenic variant detected through exome sequencing, recent studies link melorheostosis to somatic mutations, particularly in the MAP2K1, which plays a crucial role in the RAS-MAPK signaling pathway, implicated in bone remodeling and sclerosis [9]. Our patient, in whom we could not detect mutations in the blood, had unilateral camptodactyly and hyperostosis, which are typical features of the syndrome, as well as dripping waxy lesions on radiographs. The absence of a detectable variant in blood DNA is not unexpected in melorheostosis, as somatic mutations are typically restricted to the affected tissue. This highlights the mosaic nature of the condition and indicates that genetic testing of affected tissue may be required to identify the underlying mutation.
  • Snippet 2 (score: 0.422) > Based on the clinical and radiologic evaluations, nine patients were diagnosed with primary hypertrophic osteoarthropathy type 1, three with primary hypertrophic osteoarthropathy type 2, five with Juvenile Paget's disease-5, four with craniometaphyseal dysplasia, four with Camurati-Engelmann disease, three with Ghosal hematodiaphyseal dysplasia, two with sclerosteosis-1, one with trichothiodystrophy-1, one with Lenz-Majewski hyperostotic dwarfism, one with Caffey disease, and one with melorheostosis. The clinical features of the patients according to the different phenotypes are compared in Table S1. The detailed clinical and radiological features are summarized in Table S2.
  • Snippet 3 (score: 0.410) > Patient 33, diagnosed with Lenz-Majewski hyperostotic dwarfism, was a 6-month-old girl with developmental delay, feeding difficulties, hypotonia and facial dysmorphism including macrocephaly, flattened and broad nasal bridge, hypertelorism, anteverted nostrils, and micrognathia (Fig. 4f). Other features included sagging and wrinkled skin, brachydactyly, partial syndactyly, and rocker bottom feet (Fig. 4g). Radiologic examinations revealed short phalanges, increased bone density in the long bones (Fig. 4h), and hypoplasia of the 5th metatarsal.
  • Snippet 4 (score: 0.369) > Sclerosing bone dysplasias are a heterogeneous group of disorders characterized by increased bone density [1,2]. In the 2023 revised nosology of genetic skeletal disorders, these conditions are categorized into two main groups based on the underlying pathogenic mechanism: Osteopetrosis and related osteoclast disorders, and osteosclerotic disorders [3]. Osteopetrosis and related osteoclastic disorders (group 24) result from impaired bone resorption due to defects in the number or function of osteoclasts while osteosclerotic disorders are mainly caused by excessive bone formation Dilek Uludağ Alkaya and Esra Usluer are joint first authors. > or disruptions in bone remodeling [1]. Osteosclerotic disorders, classified as group 25, combine the previously distinct subcategories of neonatal osteosclerotic dysplasias and other sclerosing bone disorders [3]. This group encompasses various diseases, including sclerosteosis-1, Juvenile Paget's disease (JPD)-5, Ghosal hematodiaphyseal dysplasia (GHDD), primary hypertrophic osteoarthropathy (PHOAR) types 1 and 2, caused by biallelic mutations in SOST/LRP4, TNFRSF11B, TBXAS1, and HPGD/SLCO2A1, as well as craniometaphyseal dysplasia (CMD) and Camurati-Engelmann disease (CED), caused by monoallelic mutations of ANKH and TGFB1, respectively [1][2][3]. Extremely rare osteosclerotic disorders also include Caffey disease, Lenz-Majewski hyperostotic dwarfism, trichothiodystrophy-1 with axial osteosclerosis, and melorheostosis which are caused by mutations in COL1A1, PTDSS1, ERCC2, and MAP2K1, respectively [4][5][6].

[4] New therapeutic targets in rare genetic skeletal diseases

  • Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
  • Year: 2015
  • Venue: Expert Opinion on Orphan Drugs
  • URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
  • DOI: 10.1517/21678707.2015.1083853
  • PMID: 26635999
  • PMCID: 4643203
  • Citations: 37
  • Influential citations: 1
  • Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
  • Evidence snippets:
  • Snippet 1 (score: 0.429) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[5] A Roadmap to Gene Discoveries and Novel Therapies in Monogenic Low and High Bone Mass Disorders

  • Authors: M. Formosa, D. Bergen, C. Gregson, A. Maurizi, A. Kämpe et al.
  • Year: 2021
  • Venue: Frontiers in Endocrinology
  • URL: https://www.semanticscholar.org/paper/be13ff3ea01dc5719f2c63b2cbf5d9f77bafd659
  • DOI: 10.3389/fendo.2021.709711
  • PMID: 34539568
  • PMCID: 8444146
  • Citations: 21
  • Summary: The monogenic forms of rare low and high rare bone Mass disorders known to date are described, a roadmap to unravel the genetic determinants of monogenic rare bone mass disorders is provided, using proper phenotyping and genotyping methods are provided, and different genetic validation approaches paving the way for future treatments are described.
  • Evidence snippets:
  • Snippet 1 (score: 0.418) > Skeletal development is regulated by numerous genetic factors that guide the growth, modeling and remodeling of skeletal structures starting in early fetal development and continuing throughout life. These processes are crucial for attainment of normal height, skeletal patterning, bone shape, and mobility, but also for maintenance of normal bone mass and fracture resistance. Defects in the involved genes result in a large and heterogeneous group of disorders, collectively called skeletal dysplasias, in which the primary features are confined to the skeleton. More than 460 different forms of skeletal dysplasia, most of them monogenic, have been recognized (1). They are estimated to affect approximately 1/5,000 children (2,3), and can have distinct clinical manifestations and course. Clinical outcomes range in severity from neonatal lethality to only mild growth retardation, deformity or fracture risk. Diagnosis is based on growth pattern and other clinical characteristics, skeletal imaging, bone density testing, biochemical diagnostics, and genetic tests. Although the genetic basis has been described and mutations in the responsible genes identified in a significant proportion of these conditions, for several distinct skeletal dysplasia phenotypes the genetic cause is still not known (1). > Within this large group of genetic skeletal disorders, monogenic disorders affecting bone mass comprise an expanding subgroup (1,4). This includes disorders with low bone mass and skeletal fragility, and disorders leading to increased bone mass, both commonly associated with extraskeletal complications (5,6). Due to significant variability in severity, diagnosis can be challenging. Importantly, the underlying molecular genetic mechanisms for these disorders remain inadequately explored and, in several entities, the causative genetic defect, and underlying cellular and molecular pathophysiology are still uncharacterized. > The various skeletal dysplasia delineated to date have provided important information about the molecular pathways governing skeletal health both in these conditions and in the general population, underscoring the significance of new gene discoveries not only for the individuals affected by the monogenic rare bone mass disorder, but also more widely to the musculoskeletal research field (7). Indeed, the large wealth of data generated from monogenic and polygenic bone mass disorders, frailty and other musculoskeletal traits, have led

[6] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

  • Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
  • Year: 2025
  • Venue: Journal of Veterinary Internal Medicine
  • URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
  • DOI: 10.1111/jvim.70139
  • PMID: 40492724
  • PMCID: 12150350
  • Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
  • Evidence snippets:
  • Snippet 1 (score: 0.412) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[7] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

  • Authors: E. Nemutlu, Song Zhang, N. Juranic, A. Terzic, S. Macura et al.
  • Year: 2012
  • Venue: Croatian Medical Journal
  • URL: https://www.semanticscholar.org/paper/880f053c7f060db4b990e447d0a22c4b69372ddb
  • DOI: 10.3325/cmj.2012.53.529
  • PMID: 23275318
  • PMCID: 3541579
  • Citations: 28
  • Summary: The potential use of dynamic phosphometabolomic platform for disease diagnostics currently under development at Mayo Clinic is described and discussed briefly.
  • Evidence snippets:
  • Snippet 1 (score: 0.408) > Living cells represent an integrated and interacting network of genes, transcripts, proteins, small signaling molecules, and metabolites that define cellular phenotype and function. Traditionally the focus of biomedical research was on individual genes, single protein targets, single metabolites, and metabolic or signaling pathways. This "molecular reductionist" paradigm was based on the assumption that identifying genetic variations and molecular components would lead to discovery of cures for human diseases. However, most of diseases are complex and multi-factorial and the disease phenotype is determined by the alterations of multiple genes, pathways, proteins and metabolites (at cellular, tissue, and organismal levels). Therefore, an integrated "omics" approach is more viable direction for uncovering alterations in metabolic networks, disease mechanisms, and mechanisms of drug effects. > Recent advent of large-scale metabolomics and fluxomic (metabolite dynamics and metabolic flux analysis) completed the "omics revolution" (Figure 1), where genomics, transcriptomics, proteomics, metabolomics, and fluxomics all together complement phenotype determination of living organism. Such integrated "omics" cascades provide a framework for advances in system and network biology, integrative physiology, and system medicine as well as system pharmacology and regenerative medicine. Noteworthy is the "reverse omic" approach or "metabolomicsinformed pharmacogenomics, " where discovery of specific metabolite changes have led to discovery of genetic alterations (2). Therefore, bringing new "omics" technologies to clinical practice will improve disease diagnostics and treatment by targeting drugs and procedures for each unique transcriptomic and metabolomic profiles.

[8] Organoids in gastrointestinal diseases: from bench to clinic

  • Authors: Qinying Wang, Fanying Guo, Qinyuan Zhang, Tingting Hu, Yutao Jin et al.
  • Year: 2024
  • Venue: MedComm
  • URL: https://www.semanticscholar.org/paper/9b8880d8b9d45670da950197d7e353794f51d09e
  • DOI: 10.1002/mco2.574
  • PMID: 38948115
  • PMCID: 11214594
  • Citations: 12
  • Summary: A comprehensive and systematical depiction of organoids models is drawn, providing a novel insight into the utilization of organoids models from bench to clinic and clinical adhibition.
  • Evidence snippets:
  • Snippet 1 (score: 0.398) > Organoids models offer a robust platform for investigating the potential mechanisms of GI diseases and evaluating potential therapeutic interventions.By culturing organoids derived from patients' tissues or stem cells, researchers can delve into disease-specific cellular and molecular pathways, encompassing aberrant cell signaling, perturbed immune responses, and dysfunctional metabolic processes.These disease-specific phenotypes enable the study of disease progression, screening of prospective therapeutics, as well as identification of novel drug targets and mechanisms of action for GI diseases in a clinically relevant context.

[9] From Data to Cure: A Comprehensive Exploration of Multi-omics Data Analysis for Targeted Therapies

  • Authors: Arnab Mukherjee, S. Abraham, Akshita Singh, S. Balaji, K. Mukunthan
  • Year: 2024
  • Venue: Molecular Biotechnology
  • URL: https://www.semanticscholar.org/paper/04593d2268ccd7c26b5296d8342b468ca84ae7b1
  • DOI: 10.1007/s12033-024-01133-6
  • PMID: 38565775
  • PMCID: 11928429
  • Citations: 69
  • Influential citations: 2
  • Summary: This review navigates the expansive omics landscape, showcasing tailored assays for each molecular layer through genomes to metabolomes, and aims to illuminate the transformative impact of multi-omics in the big data era, shaping the future of biological research.
  • Evidence snippets:
  • Snippet 1 (score: 0.390) > Biological processes and molecular functions arise from intricate interactions among thousands of molecules, constituting inherent complexity. Integration of metabolomics data with other omics data holds significant promise for achieving a holistic understanding of disease mechanisms. Metabolomics, which focuses on the comprehensive analysis of small molecule metabolites within biological systems, provides unique insights into the functional status and metabolic phenotypes associated with various physiological and pathological conditions [160,161]. The integration of omics datasets with computational models and network analysis tools elucidates the complex interplay between genes, proteins, metabolites, and cellular processes underlying disease phenotypes. > Despite recent progress in omics technologies, the underlying genetic factors contributing to numerous metabolic phenotypes remain elusive. Metabolite biomarkers can be integrated with genomics and clinical parameters to enhance diagnostic accuracy or refine disease risk prediction models. Metabolites can also serve as intermediate phenotypes for genetic investigations, offering insights into underlying genetic mechanisms [162]. The integration of metabolomics data with either whole-exome sequencing or WGS-data presents a promising systematic strategy for pinpointing disease-causing variants and holds potential utility within the framework of a specific pathway under investigation [163]. Furthermore, at a more intricate biological and analytical level, metabolomics can be combined with various omic platforms, facilitating a comprehensive understanding of complex biological systems and interactions (Fig. 4). > The alterations in metabolite levels, perturbations in metabolic pathways, and the onset of disease states can be elucidated by assessing the epigenetic alterations. This approach offers molecular insights into the intricate interplay among genetic, epigenetic, and metabolic factors during the disease progression. Through the integration of epigenomic Fig. 4 The workflow for integration of metabolomics with other omics for a holistic understanding of disease progression and metabolomic data, the intricate relationships between epigenetic alterations and metabolic pathways in disease pathogenesis can be uncovered. In recent years, metabolomics and epigenomics have experienced notable advancement as prominent molecular and analytical methodologies for biomarker identification [164,165].

[10] Drug Repurposing in Rare Diseases: An Integrative Study of Drug Screening and Transcriptomic Analysis in Nephropathic Cystinosis

  • Authors: F. Bellomo, Ester De Leo, A. Taranta, L. Giaquinto, G. di Giovamberardino et al.
  • Year: 2021
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/5e45caf9d574a1dc3ebf53a7fcb57c10bb2373f8
  • DOI: 10.3390/ijms222312829
  • PMID: 34884638
  • PMCID: 8657658
  • Citations: 18
  • Summary: A drug repurposing strategy applied to nephropathic cystinosis, a rare inherited disorder belonging to the lysosomal storage diseases is shown, combining mechanism-based and cell-based screenings, coupled with an affordable computational analysis, which could result very useful to predict therapeutic responses at both molecular and system levels.
  • Evidence snippets:
  • Snippet 1 (score: 0.380) > Diagnosis and cure for rare diseases represent a great challenge for the scientific community who often comes up against the complexity and heterogeneity of clinical picture associated to a high cost and time-consuming drug development processes. Here we show a drug repurposing strategy applied to nephropathic cystinosis, a rare inherited disorder belonging to the lysosomal storage diseases. This approach consists in combining mechanism-based and cell-based screenings, coupled with an affordable computational analysis, which could result very useful to predict therapeutic responses at both molecular and system levels. Then, we identified potential drugs and metabolic pathways relevant for the pathophysiology of nephropathic cystinosis by comparing gene-expression signature of drugs that share common mechanisms of action or that involve similar pathways with the disease gene-expression signature achieved with RNA-seq.

[11] What next-generation sequencing (NGS) technology has enabled us to learn about primary autosomal recessive microcephaly (MCPH).

  • Authors: D. Morris-Rosendahl, A. Kaindl
  • Year: 2015
  • Venue: Molecular and cellular probes
  • URL: https://www.semanticscholar.org/paper/d5c3136364179627c6e534d6e7cb0b6715032dc9
  • DOI: 10.1016/j.mcp.2015.05.015
  • PMID: 26050940
  • Citations: 67
  • Influential citations: 2
  • Summary: Knowing of new genes mutated in MCPH over the last four years has contributed to the understanding of the disorder at both the clinical and cellular levels, and new mechanisms involving kinetochore-associated proteins and chromatin remodelling complexes have been elucidated.
  • Evidence snippets:
  • Snippet 1 (score: 0.377) > The impact that next-generation sequencing technology (NGS) is having on many aspects of molecular and cell biology, is becoming increasingly apparent. One of the most noticeable outcomes of the new technology in human genetics, has been the accelerated rate of identification of disease-causing genes. Especially for rare, heterogeneous disorders, such as autosomal recessive primary microcephaly (MCPH), the handful of genes previously known to harbour disease-causing mutations, has grown at an unprecedented rate within a few years. Knowledge of new genes mutated in MCPH over the last four years has contributed to our understanding of the disorder at both the clinical and cellular levels. The functions of proteins such as WDR62, CASC5, PHC1, CDK6, CENP-E, CENP-F, CEP63, ZNF335, PLK4 and TUBGPC, have been added to the complex network of critical cellular processes known to be involved in brain growth and size. In addition to the importance of mitotic spindle assembly and structure, centrosome and centriole function and DNA repair and damage response, new mechanisms involving kinetochore-associated proteins and chromatin remodelling complexes have been elucidated. Two of the major contributions to our clinical knowledge are the realisation that primary microcephaly caused by mutations in genes at the MCPH loci is seldom an isolated clinical feature and is often accompanied either by additional cortical malformations or primordial dwarfism. Gene-phenotype correlations are being revisited, with a new dimension of locus heterogeneity and phenotypic variability being revealed.

[12] Lateralized and Segmental Overgrowth in Children

  • Authors: A. Mussa, D. Carli, S. Cardaropoli, G. Ferrero, N. Resta
  • Year: 2021
  • Venue: Cancers
  • URL: https://www.semanticscholar.org/paper/1bf068188ceb52b6d570aedc7fc2b9bdfd8c7ca9
  • DOI: 10.3390/cancers13246166
  • PMID: 34944785
  • PMCID: 8699773
  • Citations: 19
  • Summary: Interestingly, some LO shares molecular mechanisms with cancer: recent advances in tumor biological pathway druggability and growth downregulation offer new avenues for the treatment of the most severe and complicated LO.
  • Evidence snippets:
  • Snippet 1 (score: 0.377) > Simple Summary Congenital lateralized or segmental overgrowth (LO) disorders are conditions characterized by excessive tissue growth of a body region often associated with a predisposition to cancer. LOs are caused by mosaic DNA anomalies, that is, they are present only in a part of the cells making up the body. LOs have an extremely heterogeneous clinical presentation: they widely overlap in presentation, are difficult to frame from a clinical point of view and have a diagnostic complexity representing a challenge for the clinician who approaches them. Here we review the key features of the various LOs, expose their molecular causes, and detail the implications for each of them, such as the need for specific cancer screening or the possibility of treatment. The latter represents a recent scientific achievement in medicine, allowed by the development of precision drugs finely tuning cellular pathways involved in growth and tumorigenesis deranged in LO. Abstract Congenital disorders of lateralized or segmental overgrowth (LO) are heterogeneous conditions with increased tissue growth in a body region. LO can affect every region, be localized or extensive, involve one or several embryonic tissues, showing variable severity, from mild forms with minor body asymmetry to severe ones with progressive tissue growth and related relevant complications. Recently, next-generation sequencing approaches have increased the knowledge on the molecular defects in LO, allowing classifying them based on the deranged cellular signaling pathway. LO is caused by either genetic or epigenetic somatic anomalies affecting cell proliferation. Most LOs are classifiable in the Beckwith–Wiedemann spectrum (BWSp), PI3KCA/AKT-related overgrowth spectrum (PROS/AROS), mosaic RASopathies, PTEN Hamartoma Tumor Syndrome, mosaic activating variants in angiogenesis pathways, and isolated LO (ILO). These disorders overlap over common phenotypes, making their appraisal and distinction challenging. The latter is crucial, as specific management strategies are key: some LO is associated with increased cancer risk making imperative tumor screening since childhood. Interestingly, some LO shares molecular mechanisms with cancer: recent advances in tumor biological pathway druggability and growth downregulation offer new avenues for the treatment of the most severe and complicated LO.

[13] Computational drug discovery approaches identify mebendazole as a candidate treatment for autosomal dominant polycystic kidney disease

  • Authors: P. Brownjohn, A. Zoufir, Daniel J O’Donovan, Saatviga Sudhahar, A. Syme et al.
  • Year: 2024
  • Venue: Frontiers in Pharmacology
  • URL: https://www.semanticscholar.org/paper/a595e78572ca02b8cb2897bfc4a989a2b021b279
  • DOI: 10.3389/fphar.2024.1397864
  • PMID: 38846086
  • PMCID: 11154008
  • Citations: 3
  • Summary: It is determined that the anthelmintic mebendazole was a potent anti-cystic agent in human cellular and in vivo models of ADPKD, and is likely acting through the inhibition of microtubule polymerisation and protein kinase activity.
  • Evidence snippets:
  • Snippet 1 (score: 0.373) > Targets and molecules were ultimately filtered for validation based on biological and chemical insights, and the potential for clinical translation.Earlier this year, Wilk et al., 2023 applied a similar transcriptomic approach to us, in that case making use of publicly available transcriptomic datasets to create Pkd2-specific ADPKD disease signatures, from which signature reversion was sought from the Library of Integrated Network-based Cellular Signatures (LINCs) drug signature database in order to identify drug repurposing candidates.While one group has previously made use of a knowledge graph-based approach to prioritise preclinically active compounds with the highest chance of clinical translation (Malas et al., 2019), to our knowledge, the current study provides the first combined application of transcriptomic and machine-learning approaches to identify and prioritise putative treatments for ADPKD, and further deconvolute potential mechanisms of action for experimental validation. > In summary we report, using computational, in vitro and in vivo approaches, that the anthelmintic drug mebendazole ameliorates disease-relevant phenotypes in cellular and animal models of ADPKD.We further show that this effect is likely primarily due to the inhibitory effect of mebendazole on the polymerisation of microtubules, which underlie cellular processes important in ADPKD, including cell proliferation, transport, and cilia signalling, and extends previous work linking the importance of the microtubule network to ADPKD pathophysiology.We also describe the inhibitory profile of mebendazole on known and novel protein kinase targets, some of which have previously been implicated in ADPKD, suggesting mebendazole may be acting via polypharmacology to impact disease mechanisms.We acknowledge that further experimental efforts will be required to confirm the actions of mebendazole on these putative targets in relevant disease model systems.It would be particularly informative to investigate these mechanisms in dedicated in vivo studies, where the effects of mebendazole on a wider range of ADPKD-relevant cell types and phenotypes could be evaluated.

[14] Small molecule metabolites: discovery of biomarkers and therapeutic targets

  • Authors: Shi Qiu, Ying Cai, Hong Yao, Chunsheng Lin, Yiqiang Xie et al.
  • Year: 2023
  • Venue: Signal Transduction and Targeted Therapy
  • URL: https://www.semanticscholar.org/paper/2ad9bd0b205340eea5987fc8a551f2024fa1e977
  • DOI: 10.1038/s41392-023-01399-3
  • PMID: 36941259
  • PMCID: 10026263
  • Citations: 631
  • Influential citations: 6
  • Summary: The metabolic analysis on the potential value of small-molecule candidate metabolites as biomarkers with clinical events, which may lead to better diagnosis, prognosis, drug screening and treatment, and challenges that need to be addressed to fuel the next wave of breakthroughs are summarized.
  • Evidence snippets:
  • Snippet 1 (score: 0.371) > resolve the major challenges with metabolite identification by used various spectroscopy, chromatographic methodology to influence specific constituent, result evaluation by employed different statistical methods and interpretation of clinical significance, all of which could affect experimental or clinical outcome and thus limit the application of small molecule metabolites-based metabolomics into clinical aspects. In the past decade, the significant progress and improvements in technical aspects have been made for small metabolite analysis from metabolic perturbations in tissues and biofluids to further promote understanding of molecular mechanisms to advance meaningful interpretation of metabolic features related to phenotypic variation. Analyzing and revealing metabolic changes in disease response to drugs could provide opportunities to discover the potential targets and biologically meaningful metabolic pathways for metabolism-related diseases therapy. Fortunately, targeted metabolic profiling of some metabolites has been endorsed to be applied in clinical practice for disease markers and potential targets identification for monitoring, diagnosis, and drug efficacy. > The accurate masses, fragment mass spectra and retention time should be provided to identify metabolites via database-based search methods. However, considering that significant amounts of datasets, special statistical software, complexity of computational processing, bioinformatics tool, lead to detecting specific molecules, validate the pathways and associations, analyze data even more difficult. Databases for metabolome analysis with extensive metabolite coverage with help of multivariate analysis have been significantly developed for data identification and visualization. Small metabolites are downstream of transcriptome-proteome and their metabolism were affected by various microbiota in vivo, so that multi-omics can create approach to explore the interactions of proteins, metabolites, genes, and microbiota, and then reveal the pathophysiological mechanisms in both diseased and non-diseased states. Fortunately, integration with other omics could insight into the characteristic metabolic alterations. 824,825 Integrative analysis of omics data by multi-omics technology could provide the mechanistic insights into diseases and bring precision treatment. > One of the biggest challenges is mainly in the realm of data integration still in early stages and needs additional consideration. To achieve this goal, high-throughput integration multi-omics with help improvement of computational and bioinformatics techniques has greatly contributed to accurately identify the relevant smallmetabolites and their biological processes involved in metabolic

[15] Precision Therapeutics in Lennox–Gastaut Syndrome: Targeting Molecular Pathophysiology in a Developmental and Epileptic Encephalopathy

  • Authors: Debopam Samanta
  • Year: 2025
  • Venue: Children
  • URL: https://www.semanticscholar.org/paper/455479c1bfbea7b90b73c109228f67c813d13888
  • DOI: 10.3390/children12040481
  • PMID: 40310132
  • PMCID: 12025602
  • Citations: 19
  • Influential citations: 1
  • Summary: A narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies, receptor and ligand dysfunction, receptor and ligand dysfunction, cell signaling abnormalities, cell signaling abnormalities, synaptopathies, and the repurposing of existing medications with mechanism-specific effects.
  • Evidence snippets:
  • Snippet 1 (score: 0.370) > A key advantage of disease-modifying therapies is their potential to target pathogenic mechanisms early in the disease course, potentially preventing the progression of some infantile epileptic encephalopathies to LGS. > This narrative review explores precision therapeutic strategies based on specific monogenic causes and disease mechanisms relevant to LGS. A comprehensive literature search (PubMed, MEDLINE, ClinicalTrials.gov, conference abstracts from the American Academy of Neurology and American Epilepsy Society, and gray literature) was conducted through 19 February 2025 to identify established ASMs, repurposed and novel drugs, as well as various gene therapy approaches with potential relevance to LGS. Given that over 900 monogenic causes of DEEs have been identified-implicating diverse cellular components such as ion channels, receptors, synaptic proteins, signaling pathways, metabolic processes, and epigenetic regulators-this review discusses current and emerging precision therapeutics based on shared molecular mechanisms and the pathophysiology of select genes associated with LGS [17] (Table 1).

[16] Chromatin modifiers in neurodevelopment

  • Authors: Sarallah Rezazadeh, H. Ji, Cecilia Giulivi
  • Year: 2025
  • Venue: Frontiers in Molecular Neuroscience
  • URL: https://www.semanticscholar.org/paper/7a4d8c063c2b3a908a65bcb637cd818edad8db92
  • DOI: 10.3389/fnmol.2025.1551107
  • PMID: 40469903
  • PMCID: 12133960
  • Citations: 2
  • Summary: This mini review delves into key chromatin modifiers, including the histone methyl transferases NSD1 and ASH1L, the methyl-CpG-binding repressor MeCP2, and the enzymatic repressor EZH2, and spotlight their pivotal roles in early brain development and neurological disorders.
  • Evidence snippets:
  • Snippet 1 (score: 0.368) > Therefore, while epigenetic changes are essential for understanding specific aspects of neurodevelopmental disorders, it is crucial to view these mechanisms as part of a larger, more complex system that encompasses genetic, proteomic, and metabolic factors. Few examples underscore that while epigenetic mechanisms-such as DNA methylation and histone modificationsare essential in regulating gene expression and contribute to neurodevelopmental disorders, they do not fully explain the complex pathophysiology of these diseases. In many cases, the genetic mutations, absence of or dysfunction of protein, or toxic protein aggregation (e.g., Fragile X syndrome, HD) that occur in these disorders play a central role in the clinical phenotypes. Therefore, a comprehensive understanding of neurodevelopmental disorders must integrate epigenetic mechanisms and the broader genetic, proteomic, and cellular pathways that contribute to disease. An integrative approach that considers not only the regulation of gene expression but also the functional consequences of these changes at the protein, metabolic and cellular pathway levels will be essential for advancing our understanding of these intricate disorders and developing effective interventions and treatments. . B., Villate, O., Llano, I., Ocio, I., Martí, I., et al. (2020). Targeted next-generation sequencing in patients with suggestive X-linked intellectual disability. Genes 11:51. doi: 10.3390/genes11010051

[17] The ties that bind: functional clusters in limb-girdle muscular dystrophy

  • Authors: E. Barton, C. A. Pacak, Whitney L. Stoppel, P. Kang
  • Year: 2020
  • Venue: Skeletal Muscle
  • URL: https://www.semanticscholar.org/paper/653422e1a9dc9cc7f16758b10f3f203155bc68c9
  • DOI: 10.1186/s13395-020-00240-7
  • PMID: 32727611
  • PMCID: 7389686
  • Citations: 24
  • Summary: A deeper understanding of these disease pathways could yield a new generation of precision therapies that would each be expected to treat a broader range of LGMD patients than a single subtype, thus expanding the scope of the molecular medicines that may be developed for this complex array of muscular dystrophies.
  • Evidence snippets:
  • Snippet 1 (score: 0.368) > Pyridine nucleotide-disulfide reductase [55] Many of the protein functions listed require further confirmation or are disputed these methodologies. Those patients with moderate disease phenotypes regardless of the underlying causative gene mutation would likely fall into a category where there may be interest in testing a pharmacological treatment (that could be halted) but reduced interest in a more permanent experimental strategy. For all of the above-mentioned reasons, the identification of unifying therapeutic targets applicable to multiple subtypes of > LGMDs is highly desirable. > To identify such targets, we should first consider the question: What binds all of these LGMDs together? The two core phenotypic features are progressive proximal muscle weakness, along with characteristic signs of muscle fiber destruction on biopsy, referred to as "dystrophic" features. Nuances in clinical presentation have helped to distinguish some of the LGMDs, such as the frequent occurrence of difficulty walking on tiptoes in LGMD R2 (LGMD2B), caused by dysferlin deficiency. However, heterogeneity associated with variable ages of onset and ranges of severity makes it generally difficult to distinguish and diagnose LGMD subtypes based on clinical presentation alone. A change in perspective is in order to aid in understanding disease pathways responsible for clinical features even when the genetic mutation is unknown. Further, given the large number of genespecific LGMD subtypes, it could very well be that several major disease mechanisms may be shared across the family of diseases. Yet despite careful studies that have collectively determined the cellular localization of most proteins associated with LGMD (Fig. 1), there is limited knowledge of potentially unifying molecular disease mechanisms. We assert that the identification of functional clusters of these proteins, grouped by such common mechanisms, will streamline our understanding of the disease processes and identify therapeutic targets relevant to individuals in multiple disease subgroups, including individuals whose pathogenic mutations have not been found. By extension, this approach may serve as a tool to not only find common mechanisms, but may also help to distinguish LGMD subtypes that do not share similar functional patterns, and afford further refinement of potential treatments.

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.