Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Hailey-Hailey Disease. Core disease mechanisms, molecular and cellular pat...

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

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Yeast-Based Screen to Identify Natural Compounds with a Potential Therapeutic Effect in Hailey-Hailey Disease

• Authors: Graziella Ficociello, Azzurra Zonfrilli, S. Cialfi, C. Talora, D. Uccelletti
• Year: 2018
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/1ed1d0caa401181feca8112bb119d2edc7e218d8
• DOI: 10.3390/ijms19061814
• PMID: 29925776
• PMCID: 6032253
• Citations: 4
• Summary: The results indicated that the activation of these pathways might provide protection to the HHD-skin cells, as oxidative stress plays pivotal roles in promoting the skin lesions of Hailey-Hailey, the NRF2 pathway could be a viable therapeutic target for HHD.
• Evidence snippets:
• Snippet 1 (score: 0.557) > As lesions became recalcitrant to SOC treatment, several possible treatments have been proposed, including: Botulinum toxin injection and photodynamic therapy [8]. However, evidence for the above indicated treatments of HHD is limited to case reports, case series, and expert opinion. The development of causal treatment strategies (i.e., molecular therapy-based) is highly desirable and could be reached through intensified efforts to elucidate the various molecular mechanisms underlying the disorder. HHD is associated with the loss of a single copy of the ATP2C1 gene. ATP2C1 is likely essential in humans, as more severe phenotypes are found in patients who suffer clonal loss of both copies of the gene [9]. Consistently, mice embryos homozygous for null mutations in ATP2C1 die with defects in neural tube closure, while heterozygotes show susceptibility to squamous cell tumors, a phenotype observed rarely in humans with Hailey-Hailey; [10,11] and our personal observation); however, this mouse model fails to reproduce the clinical manifestation of the disease, unfortunately opposing the applicability of this mouse model in HHD. Yeast has been increasingly used as a model and tool for biomedical research [12,13], based on the observation that basic cellular functions are conserved from yeast to humans and that disease's key players are often evolutionarily conserved. Indeed, about 30% of the genes known to be involved in human diseases have a yeast ortholog [14,15]. For these reasons, this simple organism is widely used for high-throughput genetic and small-molecule screens to find possible pharmacological drugs for many human diseases. This is still true in the study of Hailey-Hailey disease. Indeed, both the budding yeasts Saccharomyces cerevisiae (S. cerevisiae) and Kluyveromyces lactis (K. lactis) express the orthologous gene of ATP2C1, PMR1 (plasma membrane ATPase related) [16][17][18].

[2] Upadacitinib successfully treats Hailey-Hailey disease: a cases report and literature review

• Authors: Zhuochen Wu, Qing Zhu, Xu Yang, Xiaoyu Xie, Guoqiang Zhang
• Year: 2026
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/53c68fed9a2dfa4feddd036a36e4383d003528f9
• DOI: 10.3389/fimmu.2025.1676459
• PMID: 41613125
• PMCID: 12847405
• Summary: The efficacy and safety of the JAK inhibitor upadacitinib as a novel therapeutic regimen for Hailey-Hailey disease is investigated and a reference for the clinical treatment of refractory cases is provided.
• Evidence snippets:
• Snippet 1 (score: 0.501) > The mechanism of HHD treatment with upadacitinib, a highly selective JAK1 inhibitor, can be analyzed from multiple dimensions. On the one hand, JAK1 plays a key role in the signaling of proinflammatory cytokines such as IL-4, IL-13, and IL-31 (13), which are abnormally overexpressed in HHD lesions and further exacerbate inflammatory responses and barrier damage by stimulating the release of chemokines (e.g., eotaxin-3) from keratinocytes (14). By inhibiting JAK1, upadacitinib can directly block the above inflammatory signaling pathway and alleviate the symptoms of skin erythema, itching and exudation (14). On the other hand, recent studies have shown that type 2 inflammatory factors (IL-4, IL-13) inhibit free calcium release and actin polymerization in keratinocytes, two processes that are central to maintaining intercellular adhesion (15). The selective inhibition of JAK1 by upadacitinib may indirectly restore calcium-dependent cellular junction stability and promote the repair of spiny loosening, which explains the rapid improvement of the patients' lesions within a short period of time in the present study. > In recent years, in addition to JAK inhibitors, monoclonal antibody drugs have also demonstrated promising therapeutic potential for refractory Hailey-Hailey disease. Dupilumab, a human monoclonal antibody that blocks interleukin-4 and interleukin-13 receptors, has been successfully used in multiple clinical studies to treat refractory Hailey-Hailey disease. Relevant research indicates that all 11 patients treated with dupilumab achieved significant clinical improvement, with 64% achieving sustained disease remission lasting 5 to 24 months. No drugrelated adverse reactions were observed. Its mechanism of action may involve suppressing Th2-mediated inflammatory responses (20)(21)(22)(23)(24)(25)(26), offering another important therapeutic option for this condition. > Here we conducted a systematic review of Janus kinase inhibitors treatment regimens in Hailey-Hailey disease and summarized five papers to explore the characteristics of their treatment regimens (Table 1).

[3] Efficacy of the melanocortin analogue Nle4-D-Phe7-α-melanocyte-stimulating hormone in the treatment of patients with Hailey–Hailey disease

• Authors: G. Biolcati, C. Aurizi, L. Barbieri, S. Cialfi, Isabella Screpanti et al.
• Year: 2013
• Venue: Clinical and Experimental Dermatology
• URL: https://www.semanticscholar.org/paper/8f16f076bb5091847e1c9d546e27d9d6f884c69a
• DOI: 10.1111/ced.12203
• PMID: 24256215
• PMCID: 4255790
• Citations: 33
• Influential citations: 4
• Summary: Oxidative stress plays a specific role in the pathogenesis of HHD, by regulating the expression of factors playing an important role in keratinocyte proliferation and differentiation.
• Evidence snippets:
• Snippet 1 (score: 0.427) > Familial benign chronic pemphigus or Hailey-Hailey disease (HHD; OMIM 169600) is a rare, autosomal dominant genodermatosis. The prevalence of HHD is unknown. HHD is characterized by development of relapsing and recurrent blisters, erosions and crusts in the intertriginous areas. Although lesions generally first appear after adolescence, with peak onset around the age of 30-40 years, they can develop at any age. Lesions can be complicated by heat, rubbing or superinfection, and they can have a substantial negative effect on patients' quality of life (QOL). 1 sing linkage analysis, the HHD candidate region has been localized to chromosome 3q21-q24. 2 Within this region resides an expressed sequence tag sequence (EST) that has been identified as the orthologue of a yeast gene, ATP2C1, which encodes a calcium ATPase. 2 A complex interplay of genetic and environmental factors is thought to play a crucial role in the pathogenesis of HHD, with keratinocytes and inflammatory mediators most likely playing a cooperative role in the formation of HHD lesions. However, the exact molecular mechanisms regulating the complex interactions between resident skin cells and additional extrinsic signals are still not fully elucidated. > To gain a better understanding of the molecular pathways involved in the initiation and progression of the disease, we previously conducted an exploratory study to identify candidate genes involved in HHD development. 3 Our findings clearly support a role for reactive oxygen species (ROS) in HHD symptoms. 3,4 e identified ROS accumulation in keratinocytes derived from the cutaneous lesions of patients with HHD. 3,4 Interestingly, we also found that Notch1 expression was negatively regulated by ATP2C1mediated ROS induction in keratinocytes, both in vivo and in vitro. 3,4 Our results also implicated a critical cellular factor, p63, in the response to disease progression. These factors participate in and often regulate, a variety of cellular functions, including cell growth, survival and proliferation. 3,4

[4] Novel and recurrent variants of ATP2C1 identified in patients with Hailey-Hailey disease

• Authors: J. Sawicka, A. Kutkowska-Kaźmierczak, K. Woźniak, A. Tysarowski, Katarzyna Osipowicz et al.
• Year: 2020
• Venue: Journal of Applied Genetics
• URL: https://www.semanticscholar.org/paper/a6641e967ebcbf3ea9dccc2112306066cd591584
• DOI: 10.1007/s13353-020-00538-8
• PMID: 31983024
• PMCID: 7148260
• Citations: 4
• Summary: The results broaden the knowledge about genetic heterogeneity in Central European patients with ATP2C1 mutations and also give further evidence that careful and multifactorial evaluation of variant pathogenicity status is essential.
• Evidence snippets:
• Snippet 1 (score: 0.427) > Hailey-Hailey disease (HHD, OMIM 16960, or Benign Chronic Pemphigus.) is a rare (incidence 1:50000) autosomal dominant genodermatosis. The symptoms, aggravating periodically, onset in third-fourth decade include blisters, vesicular lesions, crusted erosions, and erythematous scaly plaques, which occur mainly on groins, axillae, neck, and other intertriginous areas, and mucosa may also be involved. Lesions may be odorous and painful and lead to mobility affecting fissures (Li et al. 2016;Zamiri and Munro 2016). In histopathological findings, suprabasalar and intraepidermal keratinocyte acantholysis with a "dilapidated brick wall" appearance is due to abnormal epidermal Ca 2+ distribution by secretory pathway Ca(2+) ATPase 1 (hSPCA1) caused by mutation in its gene: calcium-transporting ATPase type 2C member 1 (ATP2C1) (Cheng et al. 2010;Micaroni et al. 2016;Cialfi et al. 2016). Importantly, ATP2C1 is expressed in all tissues, although HHD clinical symptoms are solely isolated to the skin. Four isoforms differing by alternative processing of the C-terminus are produced, but only few of ATP2C1 mutations localized beyond the core of 26 exons are present in each transcript (Nellen et al. 2017). The majority of ATP2C1 mutations lead to a premature termination codon (PTC); thus the dominant inheritance pattern of HHD seems to result from haploinsufficiency. Nevertheless, as around 1/3 of mutations lead to missenses or in-frame rearrangements, other mechanisms may be involved (Dobson-Stone et al. 2002;Kitajima 2002). Thus, to understand the pathophysiological molecular mechanism of HHD, further investigation is required. Worldwide, only about 300 individuals have been described so far with 179 distinct ATP2C1 variants (Nellen et al. 2017).

[5] Disruption of genes associated with Charcot-Marie-Tooth type 2 lead to common behavioural, cellular and molecular defects in Caenorhabditis elegans

• Authors: M. S. Soh, Xinran Cheng, Jie Liu, Brent Neumann
• Year: 2019
• Venue: PLoS ONE
• URL: https://www.semanticscholar.org/paper/edcd66d1a6090f52f2fe2703b8cc89d1c9892194
• DOI: 10.1371/journal.pone.0231600
• PMID: 32294113
• PMCID: 7159224
• Citations: 20
• Influential citations: 2
• Summary: By comparing the consequences of mutating numerous CMT2-related genes, this study reveals common deficits in muscle structure and function, as well as NMJ signalling when these genes are disrupted.
• Evidence snippets:
• Snippet 1 (score: 0.426) > Conversely, HSPB1, the gene involved in CMT2F, encodes a heat shock protein with molecular chaperone functions (Ackerley S et al., 2006). Other causative genes are involved in protein translation (GARS, AARS MARS, HARS), osmotic regulation (TRPV4), signalling pathways and cell adhesion (LRSAM1), and neuroprotection (TRIM2). To further complicate matters, advancements in genetic screening has led to the discovery of additional CMT2 causal genes, with the latest one, ATP1A1, encoding a sodium/potassium-transporting ATPase, identified in 2018 (Lassuthova et al.). This results in a constant modification of the disease classification system in order to include the newer members, making the nomenclature imprecise and confusing (Patzkó and Shy, 2012). Besides causal genes, the age and mechanisms of onset, disease progression and severity also vary from one CMT2 subtype to another, and from patient to patient within the same subtype (Bird, 1993(Bird, -2018)). Due to its genetic and clinical heterogeneity coupled with the relative neoteric discovery of causal genes, it remains to be determined how mutations in a vast range of proteins with distinct functions all lead to CMT2. This has hindered the development of therapeutics for the disease. To aid our understanding of CMT2 pathophysiology, development of animal models which carry the mutant causal genes has played a crucial role. Unfortunately, unlike CMT1, the scarcity of CMT2 animal models has caused the study of underlying molecular mechanism of the axonal neuropathy to trail behind its demyelinating counterpart (Cartoni and Martinou, 2009). > C. elegans has emerged as one of the most widely used animal model systems to address questions regarding cellular and molecular aspects of human disease in vivo.

[6] Novel Approaches to Studying SLC13A5 Disease

• Authors: Adriana S. Beltran
• Year: 2024
• Venue: Metabolites
• URL: https://www.semanticscholar.org/paper/8469c534cd81d96f84b61e2d963dead12088feb7
• DOI: 10.3390/metabo14020084
• PMID: 38392976
• PMCID: 10890222
• Citations: 2
• Summary: Current technologies for generating patient-specific induced pluripotent stem cells (iPSCs) and their inherent advantages and limitations are discussed, followed by a summary of the methods for differentiating iPSCs into neurons, hepatocytes, and organoids.
• Evidence snippets:
• Snippet 1 (score: 0.416) > The precise pathophysiology underlying how SLC13A5 loss-of-function results in epilepsy refractory to treatment is a subject of open and ongoing research. Several hypotheses suggest SLC13A5 alters metabolic pathways, leading to neuronal dysfunction. Conversely, therapeutic inhibition of NaCT in the liver is a target to improve metabolic diseases, including non-alcoholic fatty liver disease, obesity, and insulin resistance. Thus, functionally accurate modeling and characterization of the mechanisms involved in citrate transport disruption are critical for understanding its role in human disease. > IPSC-derived cellular systems are a powerful tool for modeling rare human genetic diseases, such as SLC13A5 (Figure 5). IPSCs derived from patients containing the genetic information of the disease can overcome the limitations of animal models, providing access to relevant human cell types that recapitulate the disease phenotype. For instance, patient-derived iPSCs differentiated into neurons or hepatocytes can be used to investigate molecular and cellular mechanisms, including citrate transport and accumulation, energy metabolism, oxidative stress, and other cellular processes. They can also be used to define the spectrum of the disease and how different mutations might lead to various disease severities, screen for potential therapeutic compounds that can restore the transporter function or ameliorate the symptoms, and enable personalized medicine approaches that can tailor treatments to individual patients based on their genetic background and disease severity. > transport disruption are critical for understanding its role in human disease. > IPSC-derived cellular systems are a powerful tool for modeling rare human genetic diseases, such as SLC13A5 (Figure 5). IPSCs derived from patients containing the genetic information of the disease can overcome the limitations of animal models, providing access to relevant human cell types that recapitulate the disease phenotype. For instance, patient-derived iPSCs differentiated into neurons or hepatocytes can be used to investigate molecular and cellular mechanisms, including citrate transport and accumulation, energy metabolism, oxidative stress, and other cellular processes.

[7] 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: 39
• 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: 0.414) > 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.

[8] From molecular signatures to predictive biomarkers: modeling disease pathophysiology and drug mechanism of action

• Authors: A. Heinzel, P. Perco, G. Mayer, R. Oberbauer, A. Lukas et al.
• Year: 2014
• Venue: Frontiers in Cell and Developmental Biology
• URL: https://www.semanticscholar.org/paper/36d6c03a528c1358c0ae5b667cca5ce73b2fbee5
• DOI: 10.3389/fcell.2014.00037
• PMID: 25364744
• PMCID: 4207010
• Citations: 27
• Summary: This work exemplifies a computational workflow for expanding from statistics-based association analysis toward deriving molecular pathway and process models for characterizing phenotypes and drug mechanism of action, in turn providing precision medicine hypotheses utilizing predictive biomarkers.
• Evidence snippets:
• Snippet 1 (score: 0.408) > Omics profiling significantly expanded the molecular landscape describing clinical phenotypes. Association analysis resulted in first diagnostic and prognostic biomarker signatures entering clinical utility. However, utilizing Omics for deepening our understanding of disease pathophysiology, and further including specific interference with drug mechanism of action on a molecular process level still sees limited added value in the clinical setting. We exemplify a computational workflow for expanding from statistics-based association analysis toward deriving molecular pathway and process models for characterizing phenotypes and drug mechanism of action. Interference analysis on the molecular model level allows identification of predictive biomarker candidates for testing drug response. We discuss this strategy on diabetic nephropathy (DN), a complex clinical phenotype triggered by diabetes and presenting with renal as well as cardiovascular endpoints. A molecular pathway map indicates involvement of multiple molecular mechanisms, and selected biomarker candidates reported as associated with disease progression are identified for specific molecular processes. Selective interference of drug mechanism of action and disease-associated processes is identified for drug classes in clinical use, in turn providing precision medicine hypotheses utilizing predictive biomarkers.

[9] 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
• Citations: 2
• 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: 0.404) > 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.

[10] Genetics of Darier’s Disease: New Insights into Pathogenic Mechanisms

• Authors: Barbara Moschella, Sabrina Busciglio, Enrico Ambrosini, Sofia Cesarini, L. Caramanna et al.
• Year: 2025
• Venue: Genes
• URL: https://www.semanticscholar.org/paper/8faec234894d6c3877c742f15d7c98c85c84b9cf
• DOI: 10.3390/genes16060619
• PMID: 40565511
• PMCID: 12191890
• Citations: 9
• Summary: A broad overview of the pathology is provided, from intracellular dysfunction to the clinical manifestations, elucidating the molecular effects of SERCA2 variants found in DD patients and exploring the potential cell signaling pathways that may contribute to disease progression.
• Evidence snippets:
• Snippet 1 (score: 0.399) > If ER stress persists, as in the pathological context of Darier's disease, a cellular response shifts from adaptation to apoptosis, through the expression of the pro-apoptotic factor CHOP (Figure 7) [63]. Studies have shown that DD skin lesions display an enhanced expression of ER stress markers, such as CHOP, GRP78, calreticulin, and BiP, suggesting that the keratinocyte apoptosis in DD is mediated by the mitochondrial apoptosis pathway (Figure 7) [64]. > However, another study suggests that DD keratinocytes may undergo apoptosis through a mitochondria-independent mechanism. In fact, this study observed an increased expression of poly (ADP-ribose) polymerase (PARP) and caspase 2 in DD keratinocytes, while the levels of the pro-apoptotic proteins BAK and BAX remained unchanged [5]. > Other signaling pathway alterations have been investigated in DD patients, such as ERK hyper-activation in skin biopsies from DD patients compared to healthy individuals, supporting the hypothesis that MAPK pathway activation via ERK may be a result of SERCA2b dysfunction, highlighting it as a potential pathogenic driver in DD [58]. > Darier's disease is commonly misdiagnosed as eczema, seborrheic dermatitis, Hailey-Hailey disease (HHD), or acanthosis nigricans. Interestingly, HHD is associated with pathogenic variants in ATP2C1, which encodes the secretory pathway Ca 2+ -ATPase 1 (SPCA1) which is a calcium pump transporting Ca 2+ and Mn 2+ ions into the Golgi apparatus, where they are stored until needed. Although both DD and HHD involve abnormalities in calcium pumps and may share certain histologic similarities, their clinical and molecular characteristics are unique [65]. The haploinsufficiency of SPCA1 results in reduced Ca 2+ sequestration in the Golgi, and impaired N-linked glycosylation, protein trafficking, and desmosome assembly.

[11] Neurodegenerative Diseases in Children: A Comprehensive Review

• Authors: C. Ailioaie, Laura Marinela Ailioaie, C. Stan, Anca Sava, D. Chiran
• Year: 2026
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/1c4d5233587a486d27c1fc791a6b8173084f6669
• DOI: 10.3390/ijms27094096
• PMID: 42123674
• PMCID: 13163766
• Summary: This comprehensive review synthesizes current knowledge regarding the epidemiology, molecular classification, pathophysiology, and emerging therapeutic strategies of major pediatric neurodegenerative disorders to refine disease classification, improve prognostication, and expand access to targeted therapies.
• Evidence snippets:
• Snippet 1 (score: 0.396) > This article was designed as a narrative, comprehensive review of pediatric neurodegenerative diseases, with a particular focus on disorders characterized by progressive neurological decline, developmental regression, and genetically determined disruption of essential cellular pathways. The review was based on the assumption that pediatric neurodegenerative diseases, although clinically heterogeneous, can be meaningfully ana-lyzed within an integrated framework combining epidemiology, molecular classification, pathophysiology, diagnosis, and therapeutic strategies. > A structured literature search was performed in PubMed/MEDLINE, Scopus, and Google Scholar to identify relevant publications addressing neurodegenerative diseases in children. Additional articles were identified through manual screening of reference lists from key reviews, consensus statements, and original research papers. The search strategy included combinations of the following keywords: pediatric neurodegeneration, childhood neurodegenerative diseases, lysosomal storage disorders, leukodystrophies, mitochondrial diseases, peroxisomal disorders, developmental regression, neuroinflammation, oxidative stress, gene therapy, precision medicine, diagnosis, and treatment. Emphasis was placed on articles published in English, with particular attention to studies published in the last 10 years, while older landmark articles were included when considered essential for historical context or mechanistic understanding. > The inclusion criteria comprised original research articles, systematic or narrative reviews, consensus statements, clinical guidelines, epidemiological studies, and translational studies relevant to pediatric neurodegenerative diseases. Publications were selected if they addressed at least one of the following domains: epidemiology, molecular or genetic classification, pathophysiological mechanisms, diagnostic approaches, or therapeutic interventions in children. Studies focusing predominantly on adult-onset neurodegenerative diseases were excluded unless they provided mechanistic insights directly relevant to pediatric disorders. Case reports with limited generalizability, non-peer-reviewed sources, and articles lacking sufficient methodological or clinical detail were also excluded, except where rare disorders required illustrative citation of limited pediatric data. > The final selection of references was based on clinical relevance, methodological quality, recency, and their contribution to the conceptual scope of the review. Priority was given to studies with clear diagnostic definitions, recognized disease classifications, robust clinical or molecular data, and direct applicability to pediatric populations.

[12] Cellular reprogramming and inherited peripheral neuropathies: perspectives and challenges

• Authors: M. Saporta
• Year: 2015
• Venue: Neural Regeneration Research
• URL: https://www.semanticscholar.org/paper/8c3dabb1b4abf93506e2026564b8a329c0ec37c6
• DOI: 10.4103/1673-5374.158345
• PMID: 26199602
• PMCID: 4498347
• Citations: 4
• Summary: iPSC-based models of neuromuscular disorders, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and inherited peripheral neuropathies, have successfully reproduced pathophysiological findings from previous animal and cellular models and have also identified new disease mechanisms with potential therapeutical implications.
• Evidence snippets:
• Snippet 1 (score: 0.396) > Inherited peripheral neuropathies (or Charcot-Marie-Tooth disease, CMT) are a phenotypically and genetically heterogeneous group of disorders, which are currently untreatable. They are the most common inherited neuromuscular disorder, affecting around 1 in every 2,500 people (over 120,000 people in the US). Based on clinical neurophysiological and histopathological features, inherited neuropathies can be divided into two major forms: demyelinating (type 1) and axonal (type 2) CMT (Saporta, 2014). From a biological standpoint, these two major forms of CMT are associated with mutations in different sets of genes, affecting Schwann cell development and myelination (type 1) or peripheral axon physiology (type 2), although some overlap does exist (Figure 1). To date, over 70 genes have been associated with a CMT phenotype, making CMT an attractive natural model to study peripheral nervous system biology. Despite significant advances made in our knowledge of disease mechanisms in CMT, findings from animal models have so far translated poorly in clinical trials, underscoring the need for innovative methods to investigate the pathophysiology of these human disorders. Induced pluripotent stem cells (iPSCs) offer an unlimited source of patient specific, disease-relevant cell lines that can be used as a platform for identification of disease mechanisms, discovery of molecular targets and development of phenotypic screens for drug discovery (Saporta et al., 2011). iPSC-based models of neuromuscular disorders, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and inherited peripheral neuropathies, have successfully reproduced pathophysiological findings from previous animal and cellular models and have also identified new disease mechanisms with potential therapeutical implications.

[13] The Puzzle of Hereditary Spastic Paraplegia: From Epidemiology to Treatment

• Authors: A. Meyyazhagan, Haripriya Kuchi Bhotla, Manikantan Pappuswamy, A. Orlacchio
• Year: 2022
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/cbd3b2183e6ecd030d4a6aa543bf521a34b8058f
• DOI: 10.3390/ijms23147665
• PMID: 35887006
• PMCID: 9321931
• Citations: 37
• Influential citations: 1
• Summary: The current work briefly explains the causative genes, epidemiology, underlying mechanism, and the management approach undertaken to date for hereditary spastic paraplegia, and mentioned the latest approved drugs to summarise the available knowledge on therapeutic strategies.
• Evidence snippets:
• Snippet 1 (score: 0.395) > HSP lacks a straightforward genotypic-phenotypic association due to the sudden onset of manifestations irrespective of age. The symptoms can be triggered as early as infancy or late adulthood with various clinical presentations at different progressive and disability rates within the same families with similar mutations [8]. > Advancing technologies such as next-generation sequencing have paved the way for creating genetic panels for the most rare diseases, including HSP. However, due to the lack of suspected cases, the molecular diagnosis is limited [9]. Though advancing genetic testing has increased the identification of patients in the past few years, managing and determining is still challenging. The current era focuses on providing the benefits of using gene editing methodology as personalized drugs in patients with specific genotypes. This is not possible with HSP as the drug should target 80 genes. Some individuals can have one of many causative alterations or two confound heterozygous recessive states. Hence, we need therapy pointed towards the molecular mechanism of the HSP genotypes associated with cellular structure, dysfunction, and altered pathways as it can be useful for multiple genotypes. The cellular functions related to HSP pathophysiology are linked to defects in the metabolism of lipid molecules, organelles morphology, endo-lysosomal functioning, and axons transportation [10]. Though the unravelling of the pathophysiological aspect of HSP is progressing continuously, the specific clinical management and cure are still lagging due to the overlapping similarity between the pathways and clinical manifestations with other neurological deteriorating diseases. So far, HSP management majorly includes physiotherapy, antispastic drugs, and botulinum toxin [10,11]. Hence, the current necessity is to find a cure or effective management therapy for HSP. Our present review sums up the available therapeutics for HSP treatment to date and other possible medicaments.

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

• Authors: E. Barton, Christina 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: 0.395) > 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.

[15] Therapies for Mitochondrial Disease: Past, Present, and Future

• Authors: Megan Ball, Nicole J. Van Bergen, A. Compton, David R. Thorburn, S. Rahman et al.
• Year: 2025
• Venue: Journal of Inherited Metabolic Disease
• URL: https://www.semanticscholar.org/paper/196ee50a950f29bc4134cfb8fe6bdfa9a3a1468b
• DOI: 10.1002/jimd.70065
• PMID: 40714961
• PMCID: 12301291
• Citations: 13
• Summary: The latest developments in the pursuit to identify effective treatments for mitochondrial disease are examined and the barriers impeding their success in translation to clinical practice are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.394) > Mitochondrial disease is a diverse group of clinically and genetically complex disorders caused by pathogenic variants in nuclear or mitochondrial DNA‐encoded genes that disrupt mitochondrial energy production or other important mitochondrial pathways. Mitochondrial disease can present with a wide spectrum of clinical features and can often be difficult to recognize. These conditions can be devastating; however, for the majority, there is no targeted treatment. In the last 60 years, mitochondrial medicine has experienced significant evolution, moving from the pre‐molecular era to the Age of Genomics in which considerable gene discovery and advancement in our understanding of the pathophysiology of mitochondrial disease have been made. In the last decade, in response to the urgent need for effective treatments, a wide range of emerging therapies have been developed, driven by innovative approaches addressing both the genetic and cellular mechanisms underpinning the diseases. Emerging therapies include dietary intervention, small molecule therapies aimed to restore mitochondrial function, stem cell or liver transplantation, and gene or RNA‐based therapies. However, despite these advances, translation to clinical practice is complicated by the sheer genetic and clinical complexity of mitochondrial disease, difficulty in efficient and precise delivery of therapies to affected tissues, rarity of individual genetic conditions, lack of reliable biomarkers and clinically relevant outcome measures, and the dearth of natural history data. This review examines the latest developments in the pursuit to identify effective treatments for mitochondrial disease and discusses the barriers impeding their success in translation to clinical practice. While treatment for mitochondrial disease may be on the horizon, many challenges must be addressed before it can become a reality.

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

• Authors: E. Barton, Christina A. Pacak, Whitney L. Stoppel, Peter B. Kang
• Year: 2020
• Venue: Skeletal Muscle
• URL: https://www.semanticscholar.org/paper/3493c658bb8716d789a05ddf292162832e064e47
• DOI: 10.1186/s13395-020-00240-7
• 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: 0.393) > 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.

[17] Recent advances in modelling of cerebellar ataxia using induced pluripotent stem cells

• Authors: M. M. Wong, L. Watson, Esther B. E. Becker
• Year: 2017
• Venue: Journal of neurology & neuromedicine
• URL: https://www.semanticscholar.org/paper/49e96be489c11f06a20c2ff2647320709a3328c8
• DOI: 10.29245/2572.942x/2017/7.1134
• PMID: 28825058
• PMCID: 5558869
• Citations: 10
• Summary: This review focuses on recent breakthroughs in generating human iPSC-derived Purkinje cells and highlights the future challenges that will need to be addressed in order to fully exploit these models for the modelling of the molecular mechanisms underlying cerebellar ataxias and the development of effective therapeutics.
• Evidence snippets:
• Snippet 1 (score: 0.392) > dominant polyglutamine spinocerebellar ataxias (SCAs) are the most studied forms of ataxias. Despite significant clinical and genetic heterogeneity, emerging evidence points to the existence of common pathogenic mechanisms that may be shared by several genetically distinct forms of cerebellar ataxias (reviewed in5-8). However, it is still unclear how the proposed pathological pathways ultimately result in cerebellar dysfunction and degeneration, predominantly affecting Purkinje cells. > Understanding disease mechanisms is key to treating neurodegenerative disorders. The heterogeneous nature of the cerebellar ataxias combined with the unavailability of human brain tissue and the lack of reliable disease models have, however, hampered our understanding of the molecular disease mechanisms underlying cerebellar ataxias and thus, the development of effective therapies. Although mouse models of several cerebellar ataxias, including FRDA and SCAs, have provided valuable insights into the pathophysiology of these disorders (reviewed in9), many questions remain about the observed species differences in disease phenotypes and the effectiveness of potential drugs in clinical trials. > To help translate research from animal models into novel treatments for ataxia patients, it is essential to validate findings in the relevant affected human cell types, particularly in cerebellar Purkinje cells. The current obstacles might be overcome by exploiting recently developed human induced pluripotent stem cell (iPSC) technology and neuronal differentiation protocols.

[18] Pathophysiology of childhood polycystic kidney diseases: new insights into disease-specific therapy

• Authors: W. Sweeney, E. Avner
• Year: 2013
• Venue: Pediatric research
• URL: https://www.semanticscholar.org/paper/7cdcda7801317bb9421bd1953219a73f8b62a435
• DOI: 10.1038/pr.2013.191
• PMID: 24336431
• PMCID: 3953890
• Citations: 59
• Influential citations: 3
• Summary: This review will focus on the molecular and cellular bases of the abnormal cystic phenotype and discuss the clinical translation of such basic data into new therapies that promise to alter the natural history of disease for children with genetic PKDs.
• Evidence snippets:
• Snippet 1 (score: 0.391) > Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are significant causes of morbidity and mortality in children and young adults. ADPKD, with an incidence of 1:400 to 1:1,000, affects more than 13 million individuals worldwide and is a major cause of end-stage renal disease in adults. However, symptomatic disease is increasingly recognized in children. ARPKD is a dual-organ hepatorenal disease with an incidence of 1:20,000 to 1:40,000 and a heterozygote carrier rate of 1 in 70. Currently, no clinically significant disease-specific therapy exists for ADPKD or ARPKD. The genetic basis of both ADPKD and ARPKD have been identified, and delineation of the basic molecular and cellular pathophysiology has led to the discovery that abnormal ADPKD and ARPKD gene products interact to create “polycystin complexes” located at multiple sites within affected cells. The extracellular matrix and vessels produce a variety of soluble factors that affect the biology of adjacent cells in many dynamic ways. This review will focus on the molecular and cellular bases of the abnormal cystic phenotype and discuss the clinical translation of such basic data into new therapies that promise to alter the natural history of disease for children with genetic PKDs.

[19] Protein kinases in neurodegenerative diseases: current understandings and implications for drug discovery

• Authors: Xiaolei Wu, Zhang-zhong Yang, Jinjun Zou, Huile Gao, Zhenhua Shao et al.
• Year: 2025
• Venue: Signal Transduction and Targeted Therapy
• URL: https://www.semanticscholar.org/paper/57c532f807605e5181ca30a675ad0d79e3625453
• DOI: 10.1038/s41392-025-02179-x
• PMID: 40328798
• PMCID: 12056177
• Citations: 59
• Influential citations: 2
• Summary: The role and complexity of kinase–kinase networks in the pathogenesis of neurodegenerative diseases are discussed, and the advances of clinical applications of protein kinase inhibitors or novel kinase-targeted therapeutic strategies for effective prevention and early intervention are illustrated.
• Evidence snippets:
• Snippet 1 (score: 0.390) > Neurodegenerative diseases (e.g., Alzheimer’s, Parkinson’s, Huntington’s disease, and Amyotrophic Lateral Sclerosis) are major health threats for the aging population and their prevalences continue to rise with the increasing of life expectancy. Although progress has been made, there is still a lack of effective cures to date, and an in-depth understanding of the molecular and cellular mechanisms of these neurodegenerative diseases is imperative for drug development. Protein phosphorylation, regulated by protein kinases and protein phosphatases, participates in most cellular events, whereas aberrant phosphorylation manifests as a main cause of diseases. As evidenced by pharmacological and pathological studies, protein kinases are proven to be promising therapeutic targets for various diseases, such as cancers, central nervous system disorders, and cardiovascular diseases. The mechanisms of protein phosphatases in pathophysiology have been extensively reviewed, but a systematic summary of the role of protein kinases in the nervous system is lacking. Here, we focus on the involvement of protein kinases in neurodegenerative diseases, by summarizing the current knowledge on the major kinases and related regulatory signal transduction pathways implicated in diseases. We further discuss the role and complexity of kinase–kinase networks in the pathogenesis of neurodegenerative diseases, illustrate the advances of clinical applications of protein kinase inhibitors or novel kinase-targeted therapeutic strategies (such as antisense oligonucleotides and gene therapy) for effective prevention and early intervention.

[20] Renal ciliopathies: promising drug targets and prospects for clinical trials

• Authors: L. Devlin, Praveen Dhondurao Sudhindar, J. Sayer
• Year: 2023
• Venue: Expert Opinion on Therapeutic Targets
• URL: https://www.semanticscholar.org/paper/ab2155b6e12caba53d57ac0e8ce28860d69ec9fd
• DOI: 10.1080/14728222.2023.2218616
• PMID: 37243567
• Citations: 12
• Summary: The advances in basic science and clinical research into renal ciliopathies which have yielded promising small compounds and drug targets are reviewed, within both preclinical studies and clinical trials.
• Evidence snippets:
• Snippet 1 (score: 0.387) > Although renal ciliopathies can be classified into distinct syndromes, causative mutations in genes encoding proteins involved in the primary cilium or centrosome mean they may share overlapping mechanisms of disease, which may be amenable for therapeutic intervention (Figure 2). Abnormal functioning of proteins involved in ciliogenesis, such as CEP164, can prevent proper cilia formation, which will effect a myriad of downstream ciliary signaling pathways. Additionally, mutations in genes encoding for proteins involved in cargo trafficking or regulation, such as CEP290, will have implications for signal pathway transduction, as well as mutations in components of signaling pathways themselves, such as PKD1. In regard to renal ciliopathies, abnormalities in signaling pathways such as cAMP, Shh, Wnt, mTOR, and AMPK, likely cause misoriented cellular divisions, increased proliferation, increased fluid secretion and subsequent cystogenesis, consequently leading to further kidney damage. Ciliary and centriolar proteins which have roles in DDR and cell cycle regulation may also be driving a renal cystogenesis phenotype alongside increased fibrosis and apoptosis. Increased inflammation and dysfunctional mitochondria are also byproducts of dysregulated signaling pathways have been shown to contribute to the progression of renal ciliopathies. Extensive reviews of mechanisms of renal ciliopathy diseases have recently been performed [23,24]. Importantly, due to the wide range of cellular processes that primary cilia regulate, it is likely that in each syndrome there are multiple pathogenic drivers of disease. In some ways, this is advantageous as it offers many points for potential therapeutic targets. However, the cross talk between pathways and feedback loops introduces complications of changing one pathway without negatively affecting another. Further challenges arise with core biological pathways, such as Shh signaling, in which modification in vitro may be beneficial, but systemic treatment is unrealistic due to the expected severe side effects [18,24,116].

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