Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Isolated Sedoheptulokinase Deficiency. Core disease mechanisms, molecular...

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

• Papers retrieved: 19
• Snippets retrieved: 20

Relevant Papers

[1] 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: 0.435) > 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.

[2] Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight

• Authors: F. Iheagwam, A. J. Joseph, E. D. Adedoyin, Olawumi Toyin Iheagwam, Samuel Akpoyowvare Ejoh
• Year: 2025
• Venue: Pathophysiology
• URL: https://www.semanticscholar.org/paper/dbf8042761c1a5fc50f8cd894cc498505abac7cb
• DOI: 10.3390/pathophysiology32010009
• PMID: 39982365
• PMCID: 12077258
• Citations: 38
• Influential citations: 1
• Summary: This review aims to elucidate the complex link between mitochondrial dysfunction and diabetes, covering the spectrum of diabetes types, the role of mitochondria in insulin resistance, highlighting pathophysiological mechanisms, mitochondrial DNA damage, and altered mitochondrial biogenesis and dynamics.
• Evidence snippets:
• Snippet 1 (score: 0.427) > The landscape of DM research is continuously evolving, with emerging technologies and approaches offering new insights into the pathophysiology of the disease and potential therapeutic targets. Advancements in omics technologies, encompassing genomes, transcriptomics, proteomics, and metabolomics, have transformed the molecular mechanisms underlying DM [134]. High-throughput sequencing techniques enable comprehensive analysis of genetic variants, gene expression profiles, protein abundance, and metabolite levels associated with DM and its complications [135]. Single-cell omics approaches provide unprecedented resolution and granularity, allowing researchers to dissect cellular heterogeneity and identify novel cell types, subpopulations, and signalling pathways involved in DM pathogenesis. Integrating multi-omics data sets offers a systems-level perspective of DM, unravelling complex networks of molecular interactions and regulatory circuits underlying disease progression [136]. > In addition to omics technologies, advances in imaging modalities, such as MRI, PET, and optical imaging, enable non-invasive visualisation and quantification of metabolic, functional, and structural changes. Molecular imaging probes targeting specific biomarkers and metabolic pathways provide valuable insights into disease mechanisms and treatment responses in preclinical and clinical settings [85]. Despite significant progress in DM research, numerous unanswered questions and knowledge gaps persist, hindering the ability to develop effective prevention and treatment strategies. Key areas requiring further investigation include the role of epigenetics, environmental factors, and the microbiome in DM susceptibility and progression. Moreover, the interaction between environmental cues and genetic predisposition remains incompletely understood, highlighting the need for comprehensive multi-omics studies and large-scale epidemiological analyses to identify gene-environment interactions and modifiable risk factors for DM [137]. Furthermore, the heterogeneity of DM phenotypes and clinical outcomes poses a challenge for personalised medicine approaches, necessitating robust biomarkers and predictive models to stratify patients based on disease subtypes, prognosis, and treatment response [138].

[3] 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: 0.426) > 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.

[4] Global and Targeted Metabolomics for Revealing Metabolomic Alteration in Niemann-Pick Disease Type C Model Cells

• Authors: Masahiro Watanabe, Masamitsu Maekawa, Keitaro Miyoshi, Toshihiro Sato, Yu Sato et al.
• Year: 2024
• Venue: Metabolites
• URL: https://www.semanticscholar.org/paper/27c7aa8f74e2997a59b92b38aec1fb9ff9cbb608
• DOI: 10.3390/metabo14100515
• PMID: 39452896
• PMCID: 11509386
• Citations: 3
• Summary: Several metabolite characteristics of Niemann-Pick disease type C that may fluctuate in a cellular model of the disease are identified using both global and targeted metabolomic analyses by liquid chromatography/tandem mass spectrometry.
• Evidence snippets:
• Snippet 1 (score: 0.424) > Background: Niemann-Pick disease type C (NPC) is an inherited disorder characterized by a functional deficiency of cholesterol transport proteins. However, the molecular mechanisms and pathophysiology of the disease remain unknown. Methods: In this study, we identified several metabolite characteristics of NPC that may fluctuate in a cellular model of the disease, using both global and targeted metabolomic analyses by liquid chromatography/tandem mass spectrometry (LC-MS/MS). Three cell lines, HepG2 cells (wild-type[WT]) and two NPC model HepG2 cell lines in which NPC1 was genetically ablated (knockout [KO]1 and KO2), were used for metabolomic analysis. Data were subjected to enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Results: The enrichment analysis of global metabolomics revealed that 8 pathways in KO1 and 16 pathways in KO2 cells were notably altered. In targeted metabolomics for 15 metabolites, 4 metabolites in KO1 and 10 metabolites in KO2 exhibited statistically significant quantitative changes in KO1 or KO2 relative to WT. Most of the altered metabolites were related to creatinine synthesis and cysteine metabolism pathways. Conclusions: In the future, our objective will be to elucidate the relationship between these metabolic alterations and pathophysiology.

[5] Molecular Genetics of Bartter Syndrome: Bridging Genotype–Phenotype Correlations and Precision Therapeutics

• Authors: Lina Zhu, Yang Li, Yiyao Bao
• Year: 2026
• Venue: Current Issues in Molecular Biology
• URL: https://www.semanticscholar.org/paper/a5e1ddccfa7d333834c4d32be123c71bfd573f83
• DOI: 10.3390/cimb48040422
• PMID: 42042082
• PMCID: 13114623
• Summary: A comprehensive framework to provide a comprehensive framework to facilitate precise diagnosis and individualized treatment strategies, ultimately advancing precision medicine in the management of Bartter syndrome is provided.
• Evidence snippets:
• Snippet 1 (score: 0.417) > Molecular genetic research on Bartter syndrome has made remarkable strides, elucidating the principal BS genes SLC12A1, KCNJ1, CLCNKB, BSND, and MAGED2 and their corresponding protein defects, thereby refining the molecular framework of disease classification while separating CaSR-associated Bartter-like disease from the core canonical BS spectrum. This progress has significantly deepened our understanding of the underlying pathophysiology and provided an essential framework for correlating genotypes with clinical phenotypes. However, the intricate relationship between genetic mutations and clinical manifestations remains complex and multifaceted, reflecting the profound heterogeneity of the syndrome. Addressing these diagnostic challenges and refining disease classification beyond traditional clinical criteria requires an integrative approach that seamlessly balances high-throughput sequencing technologies with rigorous functional studies. > The mechanisms by which these genetic mutations lead to protein dysfunction are diverse, encompassing critical defects in protein expression, impaired membrane localization, and direct functional impairments. Notably, aberrant protein folding, endoplasmic reticulum-associated degradation (ERAD), and splicing abnormalities have emerged as critical pathogenic pathways. These mechanistic insights not only enhance our fundamental understanding of the disease but also highlight highly promising therapeutic targets. While current treatments remain predominantly symptomatic, focusing primarily on managing electrolyte imbalances and associated complications, they inherently fail to address the underlying molecular defects driving the disease. > The precise identification of specific molecular defects opens innovative avenues for the development of targeted interventions aimed at correcting or compensating for specific protein abnormalities. For instance, molecular chaperones that assist in protein folding, agents that modulate aberrant splicing, and future gene-based strategies represent important experimental directions for mechanism-based therapy. Consequently, the future of Bartter syndrome management may increasingly move toward precision medicine tailored to the molecular pathology of individual patients. However, the transition from concept to clinical implementation will require substantial additional functional, translational, and trial-level evidence. Such mechanism-based strategies promise not only to alleviate clinical symptoms but to fundamentally modify disease progression, thereby drastically improving long-term prognosis and quality of life for patients.

[6] Clinical metabolomics in type 2 diabetes mellitus: from pathogenesis to biomarkers

• Authors: Chuanxin Liu, Hetao Chen, Yujin Ma, Lei Zhang, Lulu Chen et al.
• Year: 2025
• Venue: Frontiers in Endocrinology
• URL: https://www.semanticscholar.org/paper/36f8d26a208b7b96763df2e9aa3211e440031c0e
• DOI: 10.3389/fendo.2025.1501305
• PMID: 40070584
• PMCID: 11893406
• Citations: 16
• Influential citations: 1
• Summary: The results facilitate understanding the pathophysiology and mechanism of type 2 diabetes mellitus and supports research in accurate diagnosis, risk prediction, curative effect, distinct stages, and prognosis judgment of T2DM.
• Evidence snippets:
• Snippet 1 (score: 0.407) > T2DM is a chronic disease characterized by two primary pathophysiological mechanisms: ① a reduction in the mass and function of pancreatic b cells, ranging from 20% to 65%, which leads to impaired insulin secretion; ② insulin resistance, where cells in muscles, fat, and liver tissues fail to respond adequately to insulin (9). Consequently, higher levels of insulin are required to maintain normal blood glucose concentrations by inhibiting hepatic glucose production and promoting glucose uptake in muscle and adipose tissues. Prolonged exposure to elevated levels of circulating insulin leads to the development of insulin resistance in peripheral tissues, and over time, the pancreas fails to produce sufficient insulin to overcome this cellular resistance (10). However, due to the long latent period and absence of obvious symptoms initially, reversing T2DM with drug intervention is difficult after the symptoms are exposed or clinically confirmed in light of clear diagnostic criteria. According to the literature, the pathogenesis and process of metabolic syndromes such as diabetes and its complications are mainly reflected in the metabolite network, and the mechanism changes at the gene level are also found in the network. Studies have shown that some related metabolites in patients with diabetes have changed before the occurrence of obvious organic damage (11). Therefore, it is necessary to scientifically prevent T2DM in the early stages of disease onset. Fortunately, clinical metabolomics were employed to understand the progression pathologies of T2DM and its corresponding complications in detail (12). Studies have demonstrated that metabolomic analysis enables the exploration of metabolic disorders associated with T2DM, thereby deepening our understanding of disease progression (13,14). This approach has the potential to facilitate novel clinical diagnoses and the development of effective treatment strategies. Moreover, identifying specific metabolites may provide promising biomarkers for the early prediction, prevention, and management of hyperglycemia and its complications (15). In recent years, excellent progress has been made in the study of T2DM and its complications through High throughput sequencing method, i.e., a discipline specifically focused on metabolic small molecules. > Clinical metabolomics is a type of systems biology research closely linked to phenotype.
• Snippet 2 (score: 0.406) > The metabolome is sensitive to a variety of genetic and environmental stimuli and susceptible to genetic, environmental, and gut microbiome pressures, so subtle differences between individuals can lead to large perturbations in metabolite concentrations and fluxes (15, 24). At present, cystatin C has become an ideal endogenous marker for evaluating glomerular filtration function because it is not affected by sex, age or muscle mass (25). In addition, more and more evidence shows that serum CysC is involved in the pathological process of vascular remodeling and neovascularization, which is closely related to the occurrence and development of diabetic microangiopathy (26). > Eighty-four papers were included in this review and obtained through database searches, namely, PubMed, Cochrane Library, China national knowledge internet(CNKI), General Purpose, and VIP Database. The keywords for the searches were "metabolomics" and "type 2 diabetes mellitus" and its complications. The papers were incorporated by reading and summarizing the literature according to the classification standards (27). The profound analysis of clinical differential metabolites identified in type 2 diabetes and its complications were conducted concerning composition, frequency of category, sample type, and pathways to explore the pathological mechanism of type 2 diabetes and its complications to provide a systematic basis for clinical diagnosis, risk stratification, comprehending disease progression, prognosis assessment, and drug efficacy. Our goal is to apply metabolomics to clinical diagnostic biomarkers, metabolic mechanisms, and prognostic observations, and early diagnosis can be made through metabolites to avoid progression to more serious complications.

[7] 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: 11
• 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: 0.403) > 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.

[8] F0F1 ATP Synthase: A Fascinating Challenge for Proteomics

• Authors: F. Dabbeni-sala, A. Rai, G. Lippe
• Year: 2012
• Venue: Unknown venue
• URL: https://www.semanticscholar.org/paper/1552961080b5c0cc551fac0da8a3e63be58104e8
• DOI: 10.5772/31082
• Citations: 5
• Summary: This book covers four important and diverse areas of current proteomic research: Proteomic Discovery of Disease Biomarkers, proteomic Analysis of Protein Functions, Proteome Approaches to Dissecting Disease Processes, and Organelles and Secretome Proteomics.
• Evidence snippets:
• Snippet 1 (score: 0.402) > In both types of ATP synthase disorders, hyperpolarization due to decreased ATP synthesis promotes ROS production by the respiratory chain, an event that can contribute to the clinical phenotypes as suggested by the beneficial effect of antioxidants observed in NARP cells (Mattiazzi et al,. 2004). This finding is quite important, considering that, in spite of the considerable progress in understanding of the molecular mechanisms of ATP synthase disorders, the available therapeutic approaches are still extremely limited (Kucharczyk et al., 2009). It has been proposed that other secondary effects possibly involved in the pathogenic pathways of ATP synthase deficiency could be changes in mitochondrial cristae morphology, which is mediated by ATP synthase oligomerization (Couoh-Cardel et al., 2010;Paumard et al., 2002), and/or a concomitant impairment of an ectopic function of ATP synthase localized on cell surface (see paragraph 4) (Kucharczyk et al., 2009). Microarray analyses have been performed in an attempt to gain a more global view of the cellular consequences of ATP synthase deficiency. In fibroblast cell lines from 13 genetically heterogeneous patients, 1632 human genes involved in mitochondrial biology, cell cycle regulation, signal transduction and apoptosis have been analysed. Surprisingly, only minor changes in expression of ATP synthase related genes were shown. Moreover, the cellular gene expression phenotypes were different depending on the site (mtDNA vs nuclear DNA) and the severity (ATP synthase content) of the underlying defect, indicating the need for further investigation of these pathways in other ATP synthase disorders (Cížková et al,. 2008). As far as our knowledge is concerned, the proteomic profiles of ATP synthase-related diseases have not yet been reported. > Other intriguing examples of ATP synthase-related diseases are Batten disease in man or ceroid lipofuscinosis in sheep. Both are storage diseases with abnormal accumulation of subunit c in lysosomes occurring in the brain and liver, respectively. MS and protein sequencing have shown that the stored protein is structurally identical to the normal mitochondrial subunit c (Chen et al,. 2004).

[9] 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: 0.401) > 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.

[10] Modelling Mitochondrial Disease in Human Pluripotent Stem Cells: What Have We Learned?

• Authors: Cameron L. McKnight, Y. C. Low, D. Elliott, D. Thorburn, Ann E. Frazier
• Year: 2021
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/bf41f9d980522896fcd2284bd630fbb418e55941
• DOI: 10.3390/ijms22147730
• PMID: 34299348
• PMCID: 8306397
• Citations: 21
• Summary: Mitochondrial diseases disrupt cellular energy production and are among the most complex group of inherited genetic disorders. Affecting approximately 1 in 5000 live births, they are both clinically and genetically heterogeneous, and can be highly tissue specific, but most often affect cell types with high energy demands in the brain, heart, and kidneys. There are currently no clinically validated treatment options available, despite several agents showing therapeutic promise. However, modell...
• Evidence snippets:
• Snippet 1 (score: 0.401) > Mitochondrial disease hPSC models provide a system to study disease gene-or mutation-related pathomechanisms in tissues relevant to the clinical phenotype. Ultimately, the long-term goal of these models would be to identify a phenotype in a clinically relevant cell type that could be used to validate efficacy of targeted treatments, or for use in highthroughput treatment trials [94][95][96] (Figure 2). > There are now a wide range of endpoints that have been validated in terminally differentiated cell types to investigate the underlying cellular mechanisms of disease and efficiently identify targetable pathways. Many of these approaches can also be adapted to suit different cell types and even organoids at scale. The tissue specific nature of mitochondrial diseases means that mitochondrial function post-differentiation can be distinct to that from the undifferentiated stem cells or original fibroblast line, often greatly exaggerating any underlying defects [97]. Additionally, detailed transcriptomic and proteomic analyses can elucidate cellular compensation mechanisms and potential target pathways to inform downstream treatment studies [98,99]. Other approaches include microscopic visualization of key cellular features to determine a mutation's impact on cell structure or function [100]. For cardiomyocytes and neurons, electrophysiology can provide highly sensitive data to identify even subtle functional changes [101]. Calcium imaging can be particularly informative in the context of mitochondrial diseases, since calcium handling is a key role of mitochondria [102,103].

[11] 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: 30
• 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: 0.400) > 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.

[12] The Emerging Application of Itaconate: Promising Molecular Targets and Therapeutic Opportunities

• Authors: Jiaqi Lin, Jinxuan Ren, Dave Schwinn Gao, Yi Dai, Lina Yu
• Year: 2021
• Venue: Frontiers in Chemistry
• URL: https://www.semanticscholar.org/paper/975a5f0a1c927d09167f7b8d2d56d52d8b9acefb
• DOI: 10.3389/fchem.2021.669308
• PMID: 34055739
• PMCID: 8149739
• Citations: 61
• Influential citations: 1
• Summary: The structural characteristics and classical pathways of itaconate and its derivatives are summarized, with special emphasis on its promising role in future clinical application, in order to provide theoretical basis for future research and treatment intervention.
• Evidence snippets:
• Snippet 1 (score: 0.400) > Metabolites have recently been found to be involved in significant biological regulation and changes. Itaconate, an important intermediate metabolite isolated from the tricarboxylic acid cycle, is derived from cis-aconitate decarboxylation mediated by immune response gene 1 in mitochondrial matrix. Itaconate has emerged as a key autocrine regulatory component involved in the development and progression of inflammation and immunity. It could directly modify cysteine sites on functional substrate proteins which related to inflammasome, signal transduction, transcription, and cell death. Itaconate can be a connector among immunity, metabolism, and inflammation, which is of great significance for further understanding the mechanism of cellular immune metabolism. And it could be the potential choice for the treatment of inflammation and immune-related diseases. This study is a systematic review of the potential mechanisms of metabolite associated with different pathology conditions. We briefly summarize the structural characteristics and classical pathways of itaconate and its derivatives, with special emphasis on its promising role in future clinical application, in order to provide theoretical basis for future research and treatment intervention.

[13] Succinic Semialdehyde Dehydrogenase: Biochemical–Molecular–Clinical Disease Mechanisms, Redox Regulation, and Functional Significance

• Authors: Kyung-Jin Kim, P. Pearl, K. Jensen, O. Snead, P. Malaspina et al.
• Year: 2011
• Venue: Antioxidants & Redox Signaling
• URL: https://www.semanticscholar.org/paper/d95101b74cd56d93c2af4e68057a48c55fd6ff4a
• DOI: 10.1089/ars.2010.3470
• PMID: 20973619
• Citations: 80
• Influential citations: 6
• Summary: The current review summarizes some 30 years of research on this protein and disease, addressing pathological mechanisms in human and mouse at the protein, metabolic, molecular, and whole-animal level.
• Evidence snippets:
• Snippet 1 (score: 0.398) > Succinic semialdehyde dehydrogenase (SSADH; aldehyde dehydrogenase 5a1, ALDH5A1; E.C. 1.2.1.24; OMIM 610045, 271980) deficiency is a rare heritable disorder that disrupts the metabolism of the inhibitory neurotransmitter 4-aminobutyric acid (GABA). Identified in conjunction with increased urinary excretion of the GABA analog gamma-hydroxybutyric acid (GHB), numerous patients have been identified worldwide and the autosomal-recessive disorder has been modeled in mice. The phenotype is one of nonprogressive neurological dysfunction in which seizures may be prominently displayed. The murine model is a reasonable phenocopy of the human disorder, yet the severity of the seizure disorder in the mouse exceeds that observed in SSADH-deficient patients. Abnormalities in GABAergic and GHBergic neurotransmission, documented in patients and mice, form a component of disease pathophysiology, although numerous other disturbances (metabolite accumulations, myelin abnormalities, oxidant stress, neurosteroid depletion, altered bioenergetics, etc.) are also likely to be involved in developing the disease phenotype. Most recently, the demonstration of a redox control system in the SSADH protein active site has provided new insights into the regulation of SSADH by the cellular oxidation/reduction potential. The current review summarizes some 30 years of research on this protein and disease, addressing pathological mechanisms in human and mouse at the protein, metabolic, molecular, and whole-animal level. Antioxid. Redox Signal. 15, 691–718. I. Historical Perspectives and Background A. Identification of succinic semialdehyde dehydrogenase deficiency B. Human SSADH deficiency: early clinical, metabolic, and enzymatic findings C. Pharmacology of GABA and GHB II. Molecular Genetics of SSADH Deficiency and Functional Polymorphisms of the SSADH Gene A. SSADH protein characterization B. Molecular genetics of SSADH deficiency–cDNA cloning and pathogenic mutations C. Variation

[14] Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response

• Authors: P. Mesdom, R. Colle, É. Lebigot, S. Trabado, Eric Deflesselle et al.
• Year: 2020
• Venue: Current Neuropharmacology
• URL: https://www.semanticscholar.org/paper/79368e365458486de96794333613c12a6063bf54
• DOI: 10.2174/1570159X17666191021141057
• PMID: 31631822
• PMCID: 7327943
• Citations: 15
• Summary: This review highlights the great and still underused potential of HDF, which stands out as a very promising tool in the understanding of MDD and AD mechanisms of action.
• Evidence snippets:
• Snippet 1 (score: 0.398) > Background: Human dermal fibroblasts (HDF) can be used as a cellular model relatively easily and without genetic engineering. Therefore, HDF represent an interesting tool to study several human diseases including psychiatric disorders. Despite major depressive disorder (MDD) being the second cause of disability in the world, the efficacy of antidepressant drug (AD) treatment is not sufficient and the underlying mechanisms of MDD and the mechanisms of action of AD are poorly understood. Objective The aim of this review is to highlight the potential of HDF in the study of cellular mechanisms involved in MDD pathophysiology and in the action of AD response. Methods The first part is a systematic review following PRISMA guidelines on the use of HDF in MDD research. The second part reports the mechanisms and molecules both present in HDF and relevant regarding MDD pathophysiology and AD mechanisms of action. Results HDFs from MDD patients have been investigated in a relatively small number of works and most of them focused on the adrenergic pathway and metabolism-related gene expression as compared to HDF from healthy controls. The second part listed an important number of papers demonstrating the presence of many molecular processes in HDF, involved in MDD and AD mechanisms of action. Conclusion The imbalance in the number of papers between the two parts highlights the great and still underused potential of HDF, which stands out as a very promising tool in our understanding of MDD and AD mechanisms of action

[15] Transcriptional profiling of Hutchinson-Gilford progeria patients identifies primary target pathways of progerin

• Authors: Sandra Vidak, Sohyoung Kim, Tom Misteli
• Year: 2026
• Venue: Nucleus
• URL: https://www.semanticscholar.org/paper/4bd99b0875508364d8672b6da5a50d024d485a53
• DOI: 10.1080/19491034.2025.2611484
• PMID: 41489464
• PMCID: 12773485
• Citations: 1
• Summary: To probe the clinical relevance of previously implicated cellular pathways and to address the extent of gene expression heterogeneity between patients, transcriptomic analysis of a comprehensive set of HGPS patients finds misexpression of several cellular pathways, including multiple signaling pathways, the UPR and mesodermal cell fate specification.
• Evidence snippets:
• Snippet 1 (score: 0.397) > Oxidative stress represents another key pathogenic mechanism in HGPS, as impaired NRF2 activity or increased reactive oxygen species (ROS) levels are sufficient to recapitulate HGPSassociated phenotypes [17,32,60]. Collectively, these findings underscore the multifactorial nature of HGPS pathogenesis, implicating interconnected signaling cascades involved in inflammation, oxidative stress, proteostasis, and vascular remodeling. Reassuringly, our findings indicate that many of the major pathways that have been described to contribute to HGPS phenotypes in mouse and cellular disease models are also misregulated in progeria patients, and targeting these pathways may provide therapeutic avenues to mitigate disease severity and improve outcomes in HGPS. > Although individuals with HGPS typically exhibit a characteristic set of clinical features, such as craniofacial abnormalities, growth retardation, and cardiovascular complications, there is notable variability in the age of onset, severity, and progression of symptoms between patients [7,9]. At the cellular level, HGPS is associated with several hallmark abnormalities, including nuclear envelope defects, decreased expression of several nuclear proteins and epigenetic marks, mitochondrial dysfunction, and increased cellular senescence [1,11,30,31,61]. These cellular phenotypes also exhibit considerable variation between patients, possibly contributing to differences in clinical outcomes. Our results indicate that even though some degree of transcriptional heterogeneity between the individual patients exists, the majority of patients exhibit misregulation of a set of shared pathways, suggesting that these pathways are universal driver mechanisms in HGPS. Further work is needed to understand the molecular and genetic factors that underlie inter-individual variability in disease expression and progression. > A limitation of pathway analysis of HGPS patient samples is to distinguish the pathways which are directly targeted by the disease-causing progerin protein and the emergence of adaptive secondary response pathways during progression of the disease in patients during their lifetime. The same caveat applies to the use of cell-based models used in the study of HGPS disease mechanisms.

[16] Computational modelling of TNFα related pathways regulated by neuroinflammation, oxidative stress and insulin resistance in neurodegeneration

• Authors: Hemalatha Sasidharakurup, Shyam Diwakar
• Year: 2020
• Venue: Applied Network Science
• URL: https://www.semanticscholar.org/paper/aea95bfe3c4303f1361a8ea72828d2926ea0d03e
• DOI: 10.1007/s41109-020-00307-w
• Citations: 9
• Summary: Simulations suggest insulin may be an important factor identifying neurodegeneration in AD and PD, through its action along with the neuroinflammation and oxidative stress.
• Evidence snippets:
• Snippet 1 (score: 0.397) > Modelling complex biological pathway networks including their cellular and molecular components, and interactions (Ji et al. 2017) can help connect critical factors statistically relevant as common signaling mechanisms or phentotypic functions to both disorders. Developing computational models can aid reproducing disease pathways and predicting dynamical behaviours essential for approprite protocol design and experimental testing and to map clinical symptoms to molecular processes going through cellular and circuit functions (Conradi et al. 2007;Bartocci and Lió 2016). Using biochemical systems theory (BST), sub-cellular reactions and biochemical pathways were modeled using ordinary differential equations (ODE) for reconstructing signalling dynamics in this study (Savageau et al. 1987). All biochemical reactions involved in disease-related signalling pathways were expressed mathematically using ODE and rate equations were computed using computational tools (Bartocci and Lió 2016). > The objective of this modeling exercise was to map major genes or proteins involved in disease mechanism, the reactions affected by the mutation of these genes and the difference in reactions when compared with healthy controls, action ofpotential drugs. In literature, BST models on oxidative stress and inflammation in insulin resistance were already available for PD condition (Braatz and Coleman 2015). These models explore some of the important pathways involved in PD and the treatment options. Most of the initial conditions for the model parameters were assigned as relative values rather than real data. With the need to model crosstalk and critical networks relevant to neurodegeneration identified by more recent studies, we have incorporated the crosstalk between insulin resistance, oxidative stress and neuroinflammation related to TNFα signalling in normal, AD and PD conditions (Fallahi-Sichani et al. 2011;Sasidharakurup et al. 2020;Su and Wu 2020). The parameteric values relating to biological states and initial conditions for this model were manually extracted from literature on disease models. In a previous study, we had modelled the role of TNFα mediated glutamate excitotoxicity and neuroinflammation (Sasidharakurup et al. 2020) and the variations in TNFα levels during both healthy and diseased conditions were analyzed.

[17] Oxidative Stress in Healthy and Pathological Red Blood Cells

• Authors: Florencia Orrico, Sandrine Laurance, Ana C. Lopez, S. Lefevre, L. Thomson et al.
• Year: 2023
• Venue: Biomolecules
• URL: https://www.semanticscholar.org/paper/5ea67232d5288f7e47b3304da16c315738a09419
• DOI: 10.3390/biom13081262
• PMID: 37627327
• PMCID: 10452114
• Citations: 146
• Influential citations: 3
• Summary: The most relevant oxidant species involved in RBC damage, the enzymatic and low molecular weight antioxidant systems that protect RBCs against oxidative injury, and the role of oxidative stress in different red cell diseases are discussed, highlighting the underlying mechanisms leading to pathological RBC phenotypes are highlighted.
• Evidence snippets:
• Snippet 1 (score: 0.396) > Red cell diseases encompass a group of inherited or acquired erythrocyte disorders that affect the structure, function, or production of red blood cells (RBCs). These disorders can lead to various clinical manifestations, including anemia, hemolysis, inflammation, and impaired oxygen-carrying capacity. Oxidative stress, characterized by an imbalance between the production of reactive oxygen species (ROS) and the antioxidant defense mechanisms, plays a significant role in the pathophysiology of red cell diseases. In this review, we discuss the most relevant oxidant species involved in RBC damage, the enzymatic and low molecular weight antioxidant systems that protect RBCs against oxidative injury, and finally, the role of oxidative stress in different red cell diseases, including sickle cell disease, glucose 6-phosphate dehydrogenase deficiency, and pyruvate kinase deficiency, highlighting the underlying mechanisms leading to pathological RBC phenotypes.

[18] Exploring the design of clinical research studies on the efficacy mechanisms in type 2 diabetes mellitus

• Authors: Huifang Guan, Shuang Zhao, Jiarui Li, Ying Wang, P. Niu et al.
• Year: 2024
• Venue: Frontiers in Endocrinology
• URL: https://www.semanticscholar.org/paper/9d2373b41c891753172645f7d59f817036dd0bf5
• DOI: 10.3389/fendo.2024.1363877
• PMID: 39371930
• PMCID: 11449758
• Citations: 12
• Summary: This review examines the complexities of Type 2 Diabetes Mellitus, focusing on the critical role of integrating omics technologies with traditional experimental methods, and highlights the indispensable role of non-omics experimental techniques in comprehending and managing T2DM.
• Evidence snippets:
• Snippet 1 (score: 0.396) > Discussing clinical research and therapeutic mechanisms for T2DM underscores the importance of an integrated cross-omics approach, particularly in identifying new regulators of metabolic pathways, biomarkers, and novel drug mechanisms related to the condition. Omics technologies have revealed metabolic and lipid changes during the progression of T2DM, providing a deeper understanding of its pathophysiology. However, current studies have not yet reached a consensus on identifying core dysregulated metabolic pathways and potential biomarkers. Future research should focus on standardizing experimental procedures, using validation cohorts, and considering the openness of research data to generate more replicable and robust outcomes. > Applying various omics techniques and molecular biology can help us understand the metabolic dysregulation and treatment opportunities for T2DM more comprehensively. As these technologies advance, the future management of glycolipid metabolic diseases will increasingly emphasize individualized treatment strategies. Drug development will also increasingly depend on individuals' genetic and metabolic characteristics to enhance therapeutic effects and minimize side effects. Exploring multi-target drugs is crucial for developing new treatment strategies, particularly those that synergistically target multiple biological processes in T2DM. These drugs may offer therapeutic effects on various aspects of the condition, such as improving insulin sensitivity, regulating blood sugar levels, and reducing complications. Management of individuals with T2DM involves not just customizing drugs and treatment plans based on their genetic backgrounds and biomarkers but also integrating lifestyle interventions, such as diet, exercise, and behavioral changes, to optimize treatment outcomes. These technologies also provide opportunities for early diagnosis and prevention of glycolipid metabolic diseases, enabling interventions before clinical symptoms manifest by identifying early biomarkers and risk factors. This comprehensive and personalized management model not only improves treatment efficacy but also enhances the quality of life for patients and reduces overall healthcare system costs. Therefore, the application of omics and non-omics technologies in optimizing chronic disease management is a key factor in advancing the treatment and prevention of glycolipid metabolic diseases. > Clinical trial validation and improvement of existing treatment methods, as well as the development of new treatment strategies, will be crucial in advancing personalized medicine. Furthermore, integrating multi-omics data will aid in comprehensively understanding the metabolic dysregulation and treatment opportunities in T2DM.

[19] Mitochondrial Dysfunction in Glycogen Storage Disorders (GSDs)

• Authors: Kumudesh Mishra, O. Kakhlon
• Year: 2024
• Venue: Biomolecules
• URL: https://www.semanticscholar.org/paper/beabb5e517ed40ea3f0c149e40bdc2bf857a591f
• DOI: 10.3390/biom14091096
• PMID: 39334863
• PMCID: 11430448
• Citations: 9
• Influential citations: 1
• Summary: The intertwining of mitochondrial dysfunction and GSDs underscores the complexity of these disorders and has significant clinical implications, and potential strategies include antioxidants to mitigate oxidative stress, compounds that enhance mitochondrial biogenesis, and gene therapy to correct the underlying mitochondrial enzyme deficiencies.
• Evidence snippets:
• Snippet 1 (score: 0.392) > Mitochondrial dysfunction in glycogen storage disorders (GSDs) represents a critical aspect of these metabolic diseases, underscoring the complex interplay between cellular energy management and glycogen metabolism. GSDs, characterized by deficiencies in enzymes involved in glycogen synthesis or degradation, lead to the accumulation or improper utilization of glycogen in tissues such as the liver and muscle. This metabolic dysregulation often results in impaired energy production within mitochondria. Studies have shown that mitochondrial dysfunction in GSDs manifests through various mechanisms including altered mitochondrial biogenesis, disturbed ROS activity, increased oxidative stress, and impaired OXPHOS. These anomalies resulted in impaired structure and function of the mitochondria and contributed to clinical symptoms such as muscle weakness, exercise intolerance, and hepatic dysfunction, which are very common in GSDs. Furthermore, the intricate relationship between mitochondrial function and glycogen metabolism suggests that targeting mitochondrial pathways could offer therapeutic potential for managing GSDs. Advancements in molecular biology and genetics have provided deeper insights into the mitochondrial disturbances in GSDs, highlighting the need for comprehensive diagnostic and therapeutic strategies that address both glycogen metabolism and mitochondrial health. Interventions aiming to restore mitochondrial function, such as antioxidant therapy, gene therapy, and enzyme replacement therapy, hold promise but require further research and clinical validation. In conclusion, mitochondrial dysfunction plays a pivotal role in the pathophysiology of glycogen storage disorders, significantly influencing disease outcomes and patient quality of life. A multidisciplinary approach that integrates metabolic, genetic, and mitochondrial-targeted therapies is essential for developing effective treatments for GSDs, ultimately aiming to improve clinical outcomes and enhance the well-being of affected individuals.

Notes

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

Isolated Sedoheptulokinase Deficiency (SHPK Deficiency) — Comprehensive Research Report

Prepared: 2026-08-08 · Target: Isolated sedoheptulokinase deficiency · MONDO:0014969 · Category: Mendelian (autosomal recessive inborn error of metabolism)

⚠️ Framing note for knowledge-base curation (read first)

This is an unusual entry: the existence of a clinical disease is explicitly disputed in the defining primary literature. The only paper reporting isolated (non-contiguous-gene) SHPK deficiency is titled "First two unrelated cases of isolated sedoheptulokinase deficiency: A benign disorder?" and states verbatim:

"It is questionable whether SHPK deficiency is a causal factor for the clinical phenotypes of our patients. This study illustrates the necessity of extensive functional and clinical workup for interpreting a novel variant, including nonsense variants." — Wamelink et al., J Inherit Metab Dis 2015 (PMID:25647543)

Three independent lines of evidence support the "benign biochemical phenotype" reading: (i) the two reported patients had discordant, non-overlapping clinical presentations; (ii) SHPK loss-of-function alleles are present in population databases at frequencies higher than expected for a pathogenic recessive allele; (iii) Shpk^-/- mice reproduce the biochemical abnormality with no clinical or histological phenotype. Every clinical phenotype below should be curated with that caveat attached, and any supports: field should reflect the uncertainty rather than asserting causation.

Also flagged for curators: no ontology term ID in this report has been passed through just validate-terms. IDs marked ✅ were retrieved directly from the authoritative source (OLS4/ChEBI, HPO API, UniProt, NCBI); IDs marked ⚠️ are suggestions requiring OAK verification before commit.

1. Disease Information

1.1 Overview

Isolated sedoheptulokinase deficiency is an autosomal recessive inborn error of the non-oxidative branch of the pentose phosphate pathway (PPP) caused by biallelic loss-of-function variants in SHPK (formerly CARKL). The enzyme sedoheptulokinase (EC 2.7.1.14) phosphorylates free sedoheptulose to sedoheptulose-7-phosphate; its loss produces a characteristic urinary metabolite signature — elevated sedoheptulose and elevated erythritol, with low-to-normal sedoheptulose-7-phosphate.

Orphanet definition (verbatim, ORPHA:440713):

"A rare, hereditary disorder of pentose phosphate metabolism characterized by increased urine levels of sedoheptulose and erythritol, and low-to-normal excretion of sedoheptulose-7P."

The term "isolated" is load-bearing. Sedoheptulokinase deficiency occurs far more often as part of a contiguous gene deletion: the common 57-kb founder deletion causing nephropathic cystinosis removes CTNS and the adjacent SHPK, plus the 5′ non-coding exons of TRPV1 (PMID:18186520, PMID:21546516). "Isolated" SHPK deficiency = SHPK loss without concurrent CTNS loss, and has been reported in only two patients worldwide.

1.2 Key identifiers

Source for the cross-reference set: Orphadata rd-cross-referencing API for ORPHA:440713 (CC-BY-4.0).

1.3 Synonyms

• Isolated SHPK deficiency
• Sedoheptulokinase deficiency (SHPKD)
• Deficiency of sedoheptulokinase / deficiency of heptulokinase
• CARKL deficiency (historic gene name: carbohydrate kinase-like)
• SHK deficiency

1.4 Nature of the evidence base

Individual case reports only — there is no registry, no cohort, and no EHR-derived dataset. A targeted PubMed query (SHPK[TIAB] OR sedoheptulokinase[TIAB] AND deficiency/patient[TIAB]) returns exactly 5 records, of which only one (PMID:25647543) reports isolated human disease. Aggregated resources (Orphanet, OMIM, GARD, MedGen) all trace back to that single 2015 paper. The much larger body of human data comes from cystinosis patients homozygous for the 57-kb deletion, in whom SHPK deficiency is a secondary, co-deleted trait.

2. Etiology

2.1 Causal factors

Genetic, monogenic, autosomal recessive. Two mechanisms produce SHPK deficiency:

(a) Isolated SHPK deficiency — biallelic intragenic loss-of-function variants in SHPK (17p13.2). Both reported patients were homozygous for a nonsense variant, and both came from families with consanguinity:

"Both patients had elevated excretion of erythritol and sedoheptulose, and each had a homozygous nonsense mutation in SHPK." (PMID:25647543)

(b) Contiguous-gene ("non-isolated") SHPK deficiency — homozygous 57-kb deletion at 17p13.2 removing CTNS + SHPK (± TRPV1 5′ exons). This is cystinosis with secondary SHPK deficiency, not this disease entity, and should be curated on the cystinosis entry with a cross-reference:

"Cystinosis patients with the common 57-kb deletion had strongly elevated urinary concentrations of sedoheptulose (28-451 mmol/mol creatinine; controls and other cystinosis patients <9) and erythritol (234-1110 mmol/mol creatinine; controls and other cystinosis patients <148)." (PMID:18186520)

2.2 Genetic risk factors

• Causal variants: NM_013276.4:c.355C>T (p.Arg119Ter) and NM_013276.4:c.211G>T (p.Glu71Ter) — see §4.
• Consanguinity is the dominant risk factor in both reported families (see §9).
• No susceptibility loci, GWAS signals, or modifier genes are known. No GWAS Catalog association exists for SHPK with this phenotype.
• Note the inverse relationship: SHPK has itself been proposed as a modifier of the cystinosis phenotype (NCBI Gene summary for GeneID 23729: "The gene resides in a chromosomal region frequently deleted in cystinosis patients, potentially serving as a disease modifier"). That hypothesis has now been tested and not supported for the HSPC/macrophage axis (§15).

2.3 Environmental risk factors

None identified. No toxin, occupational, infectious, or lifestyle exposure has been associated. Age, sex, and family history other than consanguinity carry no reported effect.

One mechanistically plausible (but unstudied in humans) modifier: dietary sedoheptulose intake, since the accumulating substrate is partly diet-derived:

"Testing plant extracts revealed sedoheptulose presence in carrots and fruits." (PMID:18775706)

2.4 Protective factors

None documented. No protective allele, dietary factor, or lifestyle exposure is described. gnomAD-frequency reasoning (§9.3) suggests the deficiency itself is largely non-deleterious, which makes "protective factor" an ill-posed question here.

2.5 Gene–environment interactions

No demonstrated GxE. A mechanistically predicted interaction, worth curating as a hypothesis rather than a fact: erythritol production in SHPK deficiency depends on a bypass route through ketohexokinase/fructokinase (KHK) and aldolase B (ALDOB) (§6.2). Dietary sedoheptulose load, and in principle KHK/ALDOB genotype (e.g., hereditary fructose intolerance alleles), would therefore modulate the erythritol biomarker. This is an inference from PMID:18775706, not an observed interaction — do not curate it as evidence-backed.

3. Phenotypes

3.1 The two index patients (the entire clinical evidence base)

Verbatim (PMID:25647543):

"The first patient presented with neonatal cholestasis, hypoglycemia, and anemia, while the second patient presented with congenital arthrogryposis multiplex, multiple contractures, and dysmorphisms."

Patient-level demographics are as abstracted by OMIM into ClinVar; for VCV000372203 (p.Glu71Ter) the ClinVar record states the variant was found in "a 2-year-old girl, born of consanguineous Turkish parents." Patient 1's age/ancestry come from the same OMIM abstraction chain and should be re-verified against the paywalled full text before being asserted in a KB entry.

The two presentations share no clinical feature. That absence of a recurrent phenotype is the single most important observation about this disease and is why the authors questioned causality.

3.2 HPO annotation set

Two annotation sources exist and they disagree in scope. Curators must know which they are using.

(a) HPOA / OMIM:617213 — the conservative set (2 terms, frequency 2/2):

This is the defensible core: the only feature present in both patients is the biochemical one.

(b) HPOA / ORPHA:440713 — the expansive set (28 terms):

Curation warning — the "Frequent"/"Obligate" labels here are artifacts. Each term derives from one of the two patients (the arthrogryposis cluster from Patient 2; the cholestasis/anemia cluster from Patient 1). "Obligate" applied to arthrogryposis is literally contradicted by Patient 1, who did not have it. Per the dismech frequency SOP (docs/frequency-evidence-guidelines.md), omit frequency: on these phenotypes rather than importing the Orphanet band. If frequency must be recorded, the honest statement is 1/2 for every clinical feature and 2/2 for the biochemical ones.

Two additional laboratory HPO terms belong on the entry but are absent from both annotation sets:

Note the internal inconsistency: the Orphanet set carries postprandial hyperglycemia (HP:0011998) while the source abstract reports hypoglycemia in Patient 1. Resolve against full text before curating either.

3.3 Phenotype characteristics

• Age of onset: congenital / neonatal in both patients (Orphanet onset category: antenatal and neonatal). The biochemical phenotype is present from birth and lifelong.
• Severity: not gradeable; n=2 with discordant features.
• Progression: unknown. No follow-up beyond ages 2–3 years has been published in the 11 years since.
• Frequency among affected individuals: see the §3.2 warning — effectively unmeasurable.

3.4 Quality of life

No data. No EQ-5D, SF-36, PROMIS, or disease-specific instrument has been applied. Given the likely benign nature of the isolated biochemical defect, the QoL burden in the two index patients is more plausibly attributable to their (unexplained) clinical syndromes than to SHPK loss.

4. Genetic / Molecular Information

4.1 Causal gene

Genomic context is central to this gene's story: SHPK sits immediately adjacent to CTNS, sharing a bidirectional promoter region, inside a segment dense in Alu repeats that mediate the recurrent 57-kb deletion.

"The CTNS promoter region shares 41 nucleotides with the promoter region [of the adjacent CARKL gene], though patient mutations did not affect CARKL activity." (PMID:11505338)

"sequence analysis detected the presence of a novel gene (CARKL) residing within the most common cystinosis-causing deletion." (PMID:10673275, Genome Res 2000;10:165-73 — the gene's discovery paper)

4.2 Pathogenic variants — and their contested classification

Variant 1 — p.Arg119Ter (Patient 1)

The submitter's interpretation is the most consequential text in this whole report for curation purposes:

"The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in SHPK cause disease… This variant is present in population databases (rs144071313, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant… The available evidence is currently insufficient to determine the role of this variant in disease." (Labcorp Genetics, SCV002219788.4)

Population distribution (dbSNP): highest in European and Latin American populations; minimal or absent in East Asian, South Asian, and African populations.

Variant 2 — p.Glu71Ter (Patient 2)

Neither causal variant is classified "Pathogenic" or "Likely pathogenic" in ClinVar. One is a VUS; the other carries only OMIM's "Affects" label — the ClinVar term reserved for variants that alter a measurable trait without established disease causation. Under ACMG/AMP rules, PM2 (absent from controls) actively fails for R119*, and PS3 (functional evidence) is satisfied only for the enzymatic phenotype, not a clinical one. Curating either as PATHOGENIC would misrepresent the primary sources.

4.3 Copy-number variants

ClinVar contains 363 variant records touching SHPK, of which 67 carry a pathogenic classification. Inspection of the top-ranked pathogenic records shows every one is a multi-gene copy-number loss involving CTNS (± TRPV1, ± dozens of 17p13 genes) — i.e., cystinosis deletions and larger 17p13.3–13.2 deletions. Representative records: VCV004851017, VCV004279276, VCV004075905 (all chr17:~3.50–3.56 Mb ×1, genes CTNS, SHPK, TRPV1), and VCV003243030 (NC_000017.10:g.(?_3520391)_(3558524_?)del, conditions: ocular cystinosis / juvenile nephropathic cystinosis).

There is no ClinVar pathogenic CNV restricted to SHPK alone. Isolated SHPK deficiency has never been reported from a CNV.

4.4 Functional consequence

Both variants are loss of function via premature termination, truncating the 478-aa protein at residue 71 or 119 — before the FGGY kinase catalytic core is complete. Both are predicted NMD substrates. Labcorp's assessment: the variant "creates a premature translational stop signal… expected to result in an absent or disrupted protein product," and functional studies in PMID:25647543 confirmed impact on SHPK activity. No gain-of-function or dominant-negative mechanism is described.

For dismech schema purposes: GeneticContext.functional_impact_category: LOSS_OF_FUNCTION, allele_type nonsense, zygosity homozygous, variant_origin germline.

4.5 Modifier genes, epigenetics, chromosomal abnormalities

• Modifier genes: none identified for SHPK deficiency itself.
• Epigenetics: no methylation or chromatin study of SHPK in disease. The shared bidirectional CTNS/CARKL promoter (PMID:11505338) is a cis-regulatory, not epigenetic, finding — and importantly, cystinosis-causing CTNS promoter mutations were shown not to affect CARKL promoter activity.
• Chromosomal abnormalities: the Alu-mediated recurrent 57-kb deletion (see §9.4); larger 17p13.3–13.2 deletions encompassing PAFAH1B1/YWHAE (Miller–Dieker region) also remove SHPK incidentally.
• Transcriptional consequence of the deletion beyond SHPK: the deletion extends into TRPV1, producing measurable downstream dysfunction — relevant when attributing phenotypes in deletion patients:

  "72% reduction in PBMC TRPV1 mRNA levels in cystinosis individuals homozygous for the 57 kb deletion (n=6) compared to unaffected individuals without the deletion (n=6) (p=0.002)." (PMID:21546516) "cystinosis patients homozygous for the 57-kb deletion exhibit a strong reduction of TRPV1 function" — 60% reduction in capsaicin-evoked vasodilation and pain, increased heat detection threshold (PMID:27734949, Sci Rep 2016;6:35395)

5. Environmental Information

• Environmental factors: none. No CTD/TOXNET/EPA association. Not a toxicant-, radiation-, or pollution-related condition.
• Lifestyle factors: none established. The only dietary consideration is the exogenous supply of the accumulating substrate — sedoheptulose is present in carrots and fruits (PMID:18775706). No dietary intervention has been trialled and none is indicated.
• Infectious agents: not applicable.

(Adjacent but distinct: sedoheptulose has been proposed as an anti-inflammatory agent based on the CARKL immunometabolism work — US patent 9,694,026, "Use of sedoheptulose for prevention or treatment of inflammation." This is a therapeutic-development thread about the substrate, not an environmental risk factor for the disease.)

6. Mechanism / Pathophysiology

6.1 The primary enzymatic lesion (upstream)

Sedoheptulokinase catalyses a single, well-defined reaction:

sedoheptulose + ATP → D-sedoheptulose 7-phosphate + ADP + H⁺

The product, sedoheptulose-7-phosphate (CHEBI:15721 ✅), is a core intermediate of the non-oxidative branch of the pentose phosphate pathway (GO:0009052 ✅), feeding transketolase and transaldolase reactions. SHPK thus provides an entry point for free sedoheptulose — dietary or from intracellular hydrolysis — into central carbohydrate metabolism.

"The identification of sedoheptulose kinase demonstrates that free sedoheptulose serves as 'a relevant and accessible carbon source in humans.'" (PMID:23514175, Biochem Soc Trans 2013;41:674-80)

6.2 The causal chain to the biomarker phenotype (the well-established part)

This is the one mechanistic chain in this disease that is fully worked out, and it is the chain a dismech pathophysiology graph should encode:

SHPK biallelic LOF (MOLECULAR)
  → loss of sedoheptulokinase activity (GO:0050277 ↓)  [MOLECULAR]
    → ① reduced hepatic sedoheptulose-7-phosphate  [MOLECULAR/CELLULAR]
    → ② accumulation of free sedoheptulose (CHEBI:16802)  [ORGANISM]
 → renal excretion → increased urinary sedoheptulose (HP:0025157)
 → ③ bypass: fructokinase (KHK) phosphorylates sedoheptulose
      → sedoheptulose 1-phosphate (CHEBI:9082)
      → aldolase B (ALDOB) cleavage
   → dihydroxyacetone phosphate + erythrose
        → reduction of erythrose
             → erythritol (CHEBI:17113) accumulation
                  → increased urinary erythritol (HP:0034613)

Verbatim support for the erythritol arm:

"Sedoheptulose 1-phosphate is shown to be a substrate for aldolase B… the findings suggest that in sedoheptulose-7-kinase-deficient patients, fructokinase phosphorylates sedoheptulose to sedoheptulose 1-phosphate, which aldolase B cleaves, leading to erythrose reduction to erythritol." (PMID:18775706, FEBS Lett 2008;582:3330-4)

Enzymatic confirmation in human cells:

"Enzyme studies performed on fibroblast homogenates derived from patients carrying the 57-kb deletion revealed 80% reduction in their sedoheptulose phosphorylating activity compared to cystinosis patients with other mutations and controls." (PMID:18186520)

And in the mouse knockout: "Analysis of pentose phosphate pathway intermediates in livers demonstrated a reduction in sedoheptulose-7-phosphate and an increase in sedoheptulose and erythritol in the urine" (PMID:34823997).

Where the chain stops. There is no demonstrated causal link from this biochemical chain to any clinical manifestation. Neither sedoheptulose nor erythritol has documented toxicity at the concentrations observed, and the PPP-flux consequences appear compensated in vivo. A dismech pathograph should terminate the causal chain at the laboratory phenotypes and represent the clinical features as unexplained co-occurrence, not downstream consequences.

6.3 The immunometabolic arm (CARKL as a metabolic rheostat)

The richest mechanistic literature on this protein concerns not the inborn error but CARKL's role as a regulator of immune-cell metabolism. This matters for the disease entry because it is the strongest a priori reason to expect a phenotype — and its absence in patients and mice is informative.

Founding observation (PMID:22682222, Haschemi et al., Cell Metab 2012;15:813-26):

"We find that one of these, the carbohydrate kinase-like protein CARKL, is rapidly downregulated in vitro and in vivo upon LPS stimulation in both mice and humans. Interestingly, CARKL catalyzes an orphan reaction in the pentose phosphate pathway, refocusing cellular metabolism to a high-redox state upon physiological or artificial downregulation. We find that CARKL-dependent metabolic reprogramming is required for proper M1- and M2-like macrophage polarization and uncover a rate-limiting requirement for appropriate glucose flux in macrophage polarization."

Downstream and corroborating literature:

Cancer: SHPK is implicated in glioblastoma proliferation —

"SHPK expression in GBM shows a significant correlation with histology, prognosis, and survival. In particular, its increased expression is associated with a worse prognosis. Furthermore, its overexpression in GBM cells confirms an increase in cell proliferation." (PMID:35682658, Int J Mol Sci 2022;23:5978)

⚠️ This paper carries a published Correction (PMID:39941164, Int J Mol Sci 2025;26:1044). Cite the correction alongside the original.

Note the direction of these findings: they concern overexpression or acute downregulation of CARKL as a regulatory event in immune/tumour cells, not constitutional germline deficiency. The clean mouse-knockout phenotype (§15) shows the two do not straightforwardly translate.

6.4 Suggested ontology terms for the mechanism graph

No dismech mechanism module currently fits this disease well. metabolic_intoxication_decompensation does not apply — there is no toxic-metabolite crisis, no catabolic-stress decompensation, and no encephalopathy. Do not force a conforms_to.

7. Anatomical Structures Affected

7.1 Where the enzyme is expressed (the biologically grounded answer)

• Liver, kidney, pancreas — strong expression; placenta, heart — lower (UniProt Q9UHJ6).
• NCBI Gene expression profile: ubiquitous, with notable kidney (RPKM 7.3) and duodenum (RPKM 6.9) across 27 tissues.
• Subcellular: cytoplasm/cytosol. Not mitochondrial, lysosomal, or nuclear.

7.2 Organs implicated in the reported patients (attribution uncertain)

Lateralization: bilateral/symmetric where relevant (contractures, orbits). No asymmetric involvement described.

Important negative: In Shpk^-/- mice there were "no histologic anomalies in kidney and liver" — the two organs with highest SHPK expression (PMID:34823997). This is direct evidence against liver/kidney being target organs of the enzyme defect.

7.3 Cell types

No cell-type-specific pathology has been demonstrated in patients. The mechanistic literature implicates macrophages (M1/M2 polarization), T cells, and microglia as cells where CARKL levels matter functionally — but as regulatory biology, not as sites of disease lesion.

8. Temporal Development

• Onset: congenital. Orphanet records onset as antenatal and neonatal; GARD states symptoms "may appear during pregnancy and as a newborn." Patient 2 had congenital arthrogryposis (prenatal onset, with breech presentation and neonatal asphyxia); Patient 1 presented in the neonatal period with cholestasis.
• Onset pattern: the metabolic derangement is chronic and constitutive from birth. The clinical presentations in the two cases were acute-on-congenital.
• Stages: none defined. No staging system exists.
• Progression rate / course: unknown. Both patients were reported at ages 2–3 years with no published follow-up. There is no natural-history study, no registry, and no longitudinal cohort.
• Duration: the biochemical phenotype is lifelong and non-remitting (it is an enzyme absence).
• Remission: not applicable to the biochemical phenotype. No treatment-induced remission is possible or has been attempted.
• Critical periods: none identified. If the disorder is benign, the concept does not apply; if the neonatal presentations were causally related, the neonatal period would be the window — but that causality is precisely what is unestablished.

9. Inheritance and Population

9.1 Inheritance

Autosomal recessive (HP:0000007, HPOA frequency 2/2; Orphanet; GARD). Both index patients were homozygous for a nonsense variant, both from families with consanguinity. No compound heterozygote has been reported. No X-linked, mitochondrial, or digenic contribution.

• Penetrance: cannot be estimated, and the population-genetic data (§9.3) argue for markedly reduced or zero clinical penetrance. Biochemical penetrance (urinary metabolite elevation) appears complete.
• Expressivity: the two cases are maximally discordant — which is more parsimoniously read as coincidence than as variable expressivity.
• Anticipation: not applicable (no repeat expansion).
• Germline mosaicism: not reported.

9.2 Epidemiology

• Prevalence: not documented. Orphanet assigns no epidemiological class to ORPHA:440713. Only 2 cases have ever been reported (CASES_IN_LITERATURE = 2 is the honest structured value for a dismech Prevalence record; prevalence_class: NOT_YET_DOCUMENTED).
• Incidence: unknown.
• Sex ratio: 1 male : 1 female among reported cases — uninformative at n=2.
• Age distribution: both reported patients ascertained in infancy/early childhood; no adult cases reported (which does not mean none exist — untargeted urine metabolite screening in adults is rare).

9.3 Carrier frequency and the under-ascertainment argument

This calculation is worth recording explicitly in the KB because it is the strongest quantitative argument about the disorder's nature:

• p.Arg119Ter (rs144071313) gnomAD allele frequency ≈ 0.00057 (0.057%; Labcorp cites 0.09% for a subpopulation-inclusive figure).
• Predicted heterozygous carrier frequency for this single allele: ≈1 in 880.
• Predicted homozygote frequency for this single allele alone: p² ≈ 3.2 × 10⁻⁷ ≈ 1 in ~3.1 million — i.e. roughly 2,500 living homozygotes worldwide for R119* alone, before counting any other SHPK LoF allele.
• Observed reported cases: 2.

(This is my arithmetic from the cited gnomAD frequencies, presented as a derived estimate, not a published figure.) The gap of three-plus orders of magnitude is exactly the reasoning Labcorp applied — "an allele count higher than expected for a pathogenic variant" — and it supports either (a) the condition is clinically silent, or (b) it is severely under-ascertained because nobody measures urinary sedoheptulose. Both readings are compatible with the primary paper's own question mark.

⚠️ Not retrieved: gnomAD gene-level constraint metrics for SHPK (pLI, LOEUF, observed/expected pLoF, homozygous pLoF count). The gnomAD browser is a client-rendered application and its GraphQL API requires POST, neither of which was accessible from this session. These should be pulled manually — the LOEUF value and the presence/absence of homozygous pLoF individuals would materially strengthen or weaken the benign-disorder argument.

9.4 Founder effects, geography, and the far more common contiguous-gene form

Isolated form: p.Arg119Ter is enriched in European and Latin American populations and near-absent in East Asian, South Asian, and African populations (dbSNP/ALFA). p.Glu71Ter was found in a Turkish consanguineous family and is absent from TOPMed — consistent with a private or very rare regional allele. Neither constitutes an established founder mutation.

Contiguous-gene form (secondary SHPK deficiency): the 57-kb CTNS/SHPK deletion is a genuine northern European founder allele, thought to have originated in Germany, and: - occurs in ~60% of cystinosis patients in the US and northern Europe (PMID:15365816: "The most prevalent CTNS mutation, a 57-kb deletion, occurs in approximately 60% of patients"); - accounts for 50–70% of pathogenic CTNS alleles in those regions, and is homozygous in ~50% of northern-European cystinosis patients (GeneReviews, Cystinosis); - has not been reported in individuals from the Middle East, Asia, or Africa.

Cystinosis birth prevalence is 1:100,000 to 1:200,000 (1:26,000 in Brittany, France). Combining these figures gives an order-of-magnitude estimate that roughly 1 in 200,000–400,000 births in northern European populations carries biallelic SHPK loss as part of a cystinosis deletion — a population perhaps a thousand-fold larger than the reported isolated cases. (Derived estimate; label as such.) These individuals are, by definition, clinically dominated by cystinosis.

Consanguinity is the operative population factor for the isolated form: both reported families were consanguineous or suspected consanguineous.

10. Diagnostics

10.1 Biochemical (the diagnostic entry point)

Urinary sugar/polyol profiling by GC-MS or LC-MS/MS is the discriminating test. The characteristic pattern:

⚠️ Note these interval values were established in the cystinosis 57-kb-deletion cohort, not the two isolated-deficiency patients (whose exact values are in the paywalled full text of PMID:25647543 and should be extracted before curating a reference_ranges block). No LOINC code exists for urinary sedoheptulose.

Dried blood spot sedoheptulose (LC-MS/MS) — developed for cystinosis screening but directly applicable:

"Sedoheptulose concentrations in the deleted patients were 6 to 23 times above the upper limit for controls. No overlap existed between sedoheptulose levels in patients homozygous for the deletion versus those without it." (PMID:21195649, Mol Genet Metab 2011;102:339-42)

Untargeted metabolomics is an increasingly used unbiased route into non-oxidative PPP disorders:

"Targeted polyol testing and untargeted metabolomic testing methods were both able to identify specific biochemical patterns indicative of TKT and TALDO deficiency… untargeted analysis revealed novel biomarkers including ribonate, ribose, erythronate, and sedoheptulose 7-phosphate." (PMID:32828637, Mol Genet Metab 2020;131:147-154)

Enzyme assay: sedoheptulose-phosphorylating activity in cultured skin fibroblast homogenates — 80% reduction demonstrated in 57-kb-deletion patients vs controls (PMID:18186520). This is a research assay, not a routine clinical service.

10.2 Genetic testing

Critical interpretation caveat: because both known causal variants are ClinVar VUS/"Affects" and SHPK LoF alleles are relatively common in gnomAD, a homozygous SHPK nonsense finding on exome should not be reported as the explanation for a complex neonatal phenotype without biochemical confirmation and, crucially, without continuing the diagnostic search. This is the operational lesson of PMID:25647543.

10.3 Other modalities

• Imaging: no disease-specific findings. Brain MRI abnormalities (myelination, ventriculomegaly, subcortical atrophy) were recorded in one patient; liver imaging for cholestasis in the other. Both are workup of the presenting syndrome, not of SHPK deficiency.
• Biopsy/histopathology: no characteristic finding. Mouse KO liver and kidney are histologically normal.
• Electrophysiology, functional tests: no role.

10.4 Clinical criteria and differential diagnosis

No standardized diagnostic criteria exist. A working definition is: biallelic SHPK LoF + elevated urinary sedoheptulose and erythritol + normal cystine (excluding cystinosis).

Differential diagnosis — causes of elevated urinary sedoheptulose/polyols:

(TALDO/RPI background: Disorders of the Pentose Phosphate Pathway and Polyol Metabolism; RPI deficiency original description in Am J Hum Genet.)

10.5 Screening

• Newborn screening: not performed and not indicated for isolated SHPK deficiency (no treatment, uncertain pathogenicity — fails Wilson–Jungner criteria on both counts).
• However, DBS sedoheptulose is a proposed NBS marker for cystinosis homozygous for the 57-kb deletion, where presymptomatic detection does change management (cysteamine): "The method enables fast pre-symptomatic detection of cystinosis patients homozygous for the 57-kb deletion, facilitating early treatment initiation" (PMID:21195649). Any such programme would incidentally detect isolated SHPK deficiency — an incidental-findings issue worth flagging.
• Carrier screening: not on any expanded carrier screening panel; not recommended.
• Cascade screening: reasonable within a family for genetic-counselling completeness, but the counselling message is one of uncertainty.

11. Outcome / Prognosis

No prognostic data exist. Both index patients were alive at ages 2 and 3 at publication; no follow-up has been published in the subsequent 11 years.

• Survival / life expectancy / mortality: unknown; no deaths attributed to SHPK deficiency. There is no SEER/registry/GBD entry.
• Disease-specific mortality: none reported.
• Morbidity / disability: the disabilities present in the two index patients (arthrogryposis-related motor impairment; neonatal liver disease) are substantial but of unestablished attribution.
• Complications: none attributable to the enzyme defect.
• Recovery potential: the enzyme deficiency is permanent; the biochemical phenotype does not remit.
• Prognostic factors / biomarkers: none. Urinary sedoheptulose and erythritol are diagnostic markers with no demonstrated prognostic value.

The best available prognostic evidence is indirect and reassuring: Shpk^-/- mice show "no obvious phenotypic abnormalities, including the absence of histologic anomalies in kidney and liver" (PMID:34823997), and IMPC phenotyping of the Shpk line reports 0 significant phenotypes across 20 of 24 physiological systems tested.

12. Treatment

There is no specific treatment, and none is currently indicated. No pharmacological, dietary, enzyme-replacement, gene-therapy, or cell-therapy approach targets SHPK deficiency.

Clinical trials: zero. A ClinicalTrials.gov API query for sedoheptulokinase OR SHPK returned 0 studies.

12.1 Management as actually practised

Dietary sedoheptulose restriction (NCIT:C15447 Dietary Intervention) is theoretically capable of lowering the biomarker but has never been trialled, has no rationale in the absence of demonstrated toxicity, and should not be curated as a treatment.

12.2 Pharmacogenomics, advanced therapeutics, surgery

• Pharmacogenomics: no PharmGKB/CPIC entry for SHPK.
• Gene therapy, cell therapy, RNA-based therapy, targeted therapy, immunotherapy: none developed or proposed for this indication.
• Surgery: no role for the metabolic disease.

12.3 The one therapeutically consequential finding — cystinosis gene therapy

The most clinically actionable result in this entire literature concerns whether secondary SHPK deficiency compromises HSPC gene therapy for cystinosis. It does not:

"Transplantation of Shpk-/- HSPCs into Ctns-/- mice resulted in significant reduction in tissue cystine load and restoration of Ctns expression, as well as improved kidney architecture comparable to WT-HSPC recipients. Altogether, these data demonstrate that absence of SHPK does not alter the ability of HSPCs to rescue cystinosis, and then patients homozygous for the 57-kb deletion should benefit from ex vivo gene therapy and can be enrolled in the ongoing clinical trial. However, because of the limits inherent to animal models, outcomes of this patient population will be carefully compared to the other enrolled subjects." (PMID:34823997, Mol Genet Metab 2021;134:309-316)

The concern was specific and well-founded — CARKL "influences macrophage polarization," and the therapy's mechanism of action depends on transplanted HSPCs differentiating into tissue macrophages that transfer cystinosin-bearing lysosomes via tunneling nanotubes.

Relevant registered trials (for the cystinosis cross-reference, not for this disease): - NCT03897361 — Stem Cell Gene Therapy for Cystinosis (CTNS-RD-04; autologous CD34+ HSPC, lentiviral CTNS; Phase 1/2; Completed; UC San Diego) - NCT05146830 — Long-Term Follow-Up of CTNS-RD-04 Recipients (observational, enrolling by invitation) - NCT06910813 — DFT383 in Pediatric Participants With Nephropathic Cystinosis (Phase I/II, recruiting; Novartis)

12.4 Treatment outcomes, adverse events, algorithms

Not applicable — no disease-directed treatment exists, therefore no response rates, no FAERS signal, no algorithm, no combination or genotype-guided strategy.

13. Prevention

• Primary prevention: not applicable to a constitutional genetic disorder. The only lever is reproductive: genetic counselling for consanguineous couples with an affected child. Given that both causal variants are ClinVar VUS/"Affects" and the disorder may be benign, counselling should explicitly frame recurrence risk as risk of the biochemical trait, with clinical consequences unknown. Offering prenatal diagnosis or PGT for a possibly benign biochemical trait raises a real ethical question and should not be presented as routine.
• Secondary prevention: no screening programme; no evidence that presymptomatic detection changes any outcome. Contrast with cystinosis, where DBS sedoheptulose screening would enable early cysteamine (PMID:21195649).
• Tertiary prevention: no complications are known to be preventable, because none are established as disease-related.
• Immunization, behavioural intervention, prophylaxis, public health/environmental intervention: all not applicable.
• Risk stratification: the only actionable stratifier is consanguinity + an affected proband.

14. Other Species / Natural Disease

14.1 Taxonomy and orthologs

The enzyme belongs to the FGGY carbohydrate kinase family, which is deeply conserved across bacteria, plants, and animals — and the substrate sedoheptulose is a Calvin-cycle-adjacent plant metabolite (sedoheptulose-1,7-bisphosphatase), which is why plants are a dietary source.

14.2 Natural disease in other species

None known. An OMIA search for SHPK returns no phene records in any species — there is no naturally occurring animal model, no companion-animal or livestock disease, and no wildlife counterpart. No veterinary relevance.

14.3 Comparative biology and transmission

• Comparative pathology: the mouse knockout replicates the human biochemical phenotype exactly (urinary sedoheptulose ↑, erythritol ↑, hepatic S7P ↓) and shows no clinical or histological phenotype — the strongest available cross-species evidence that the metabolite abnormality is not intrinsically pathogenic.
• Evolutionary conservation: the CARKL-as-metabolic-rheostat function is conserved from echinoderms to mammals — sea cucumber AjCARKL overexpression suppressed G6PD, ROS production, and phagocytosis in coelomocytes and drove M2-like polarization in mouse macrophages (PMID:32283109). This makes the absence of an immune phenotype in human/mouse deficiency more striking, not less.
• Zoonotic potential / cross-species susceptibility: not applicable (non-infectious genetic disease).

15. Model Organisms

15.1 Mouse — Shpk knockout (the key model)

Origin: Goodman et al. 2021 (Cherqui lab, UC San Diego), created specifically to test whether SHPK loss compromises cystinosis HSPC gene therapy (PMID:34823997).

Phenotype recapitulation:

"Shpk-/- mice also recapitulated the urinary excretion of sedoheptulose and erythritol found in cystinosis patients homozygous for the 57-kb deletion." (PMID:34823997)

IMPC broad phenotyping: 20 of 24 physiological systems tested; 0 significant phenotypes; 4 systems not yet evaluated (IMPC Data Release 24.0).

Model limitations: (a) it does not reproduce any human clinical feature — which may reflect genuine benignity rather than model failure; (b) mouse diet differs in sedoheptulose content from human diet, potentially altering substrate load; (c) IMPC coverage is incomplete (4 systems untested), and no aged cohort, immune-challenge, or metabolic-stress paradigm has been reported. A HUMAN_MODEL_MISMATCH discussion is arguably warranted here in the inverse of the usual direction: the model is healthier than the patients, and the open question is whether the patients' illness had anything to do with the gene.

Research applications: PPP flux in vivo; macrophage/HSPC biology in a CARKL-null background; the cystinosis gene-therapy eligibility question (already answered).

15.2 Cellular and in vitro models

No iPSC, organoid, zebrafish, Drosophila, C. elegans, or yeast model of SHPK deficiency has been reported.

15.3 Model databases

MGI (MGI:1921887) · IMPC (mousephenotype.org, Shpk) · MMRRC (043666-UCD) · Alliance of Genome Resources · Cellosaurus (for the GBM lines).

Summary of what could not be retrieved

Stated explicitly so gaps are not mistaken for negatives:

1. OMIM full-text entries (#617213 and *605060) — omim.org returned HTTP 403 to automated fetch. The OMIM clinical-synopsis content is indirectly captured via HPOA (2 terms) and the ClinVar OMIM submissions; the OMIM narrative "Clinical Features"/"Molecular Genetics" prose was not read.
2. gnomAD gene-level constraint for SHPK (pLI, LOEUF, obs/exp pLoF, homozygous pLoF count) — browser is client-rendered; API requires POST. Variant-level frequencies were obtained via ClinVar and dbSNP.
3. Full text of Wamelink et al. 2015 (paywalled, not in PMC) — so the index patients' exact metabolite concentrations, fibroblast enzyme activities, imaging details, and the reasoning behind "extensive functional and clinical workup" were not read directly. This is the single highest-value document to obtain before finalising a KB entry, since it contains the per-patient quantitative data.
4. Human Protein Atlas SHPK page — the fetched URL resolved to a different gene (RIDA); tissue expression here is sourced from UniProt and NCBI Gene instead.

Suggested dismech curation posture

• Curate as a Disease entry with a deliberately thin pathophysiology graph terminating at the two laboratory phenotypes; do not draw causal edges to the clinical features.
• Record a KNOWLEDGE_GAP discussion attached to the disease: "Is isolated SHPK deficiency a disease at all, or a benign biochemical trait? Two discordant cases, LoF alleles at population frequencies exceeding recessive-disease expectation, and a phenotypically normal knockout mouse." With proposed_experiments: systematic urine-metabolite screening of gnomAD-identified SHPK LoF homozygotes; deep phenotyping of the two index families' unresolved syndromes.
• Prefer supports: PARTIAL over SUPPORT for any evidence item linking a clinical phenotype to the genotype.
• Omit frequency: on all clinical phenotypes (see §3.2).
• Cross-reference the cystinosis entry for the contiguous-gene form, and note the TRPV1 co-deletion as a competing explanation for phenotypes in deletion patients.
• No conforms_to module fits; do not force one.

Sources

• First two unrelated cases of isolated sedoheptulokinase deficiency: A benign disorder? — PubMed (PMID:25647543)
• Springer Nature Link — J Inherit Metab Dis 2015, 10.1007/s10545-014-9809-1
• Sedoheptulokinase deficiency due to a 57-kb deletion in cystinosis patients… elucidation of the CARKL gene (PMID:18186520)
• Characterization of mammalian sedoheptulokinase and mechanism of formation of erythritol (PMID:18775706)
• Elevated concentrations of sedoheptulose in bloodspots of patients with cystinosis (PMID:21195649)
• The 57 kb deletion in cystinosis patients extends into TRPV1 (PMID:21546516)
• TRPV1 dysfunction in cystinosis patients harboring the homozygous 57 kb deletion (PMID:27734949)
• The genomic region encompassing CTNS… discovery of a novel gene within the common cystinosis-causing deletion (PMID:10673275)
• The promoter of CTNS… shares sequences with the promoter of an adjacent gene, CARKL (PMID:11505338)
• FISH diagnosis of the common 57-kb deletion in CTNS causing cystinosis (PMID:15365816)
• The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism (PMID:22682222)
• Sedoheptulose kinase regulates cellular carbohydrate metabolism by sedoheptulose 7-phosphate supply (PMID:23514175)
• Metabolic reprograming in macrophage polarization (PMID:25228902)
• Time and Demand are Two Critical Dimensions of Immunometabolism (PMID:25904920)
• Sedoheptulose kinase bridges the pentose phosphate pathway and immune responses in sea cucumber (PMID:32283109)
• Selenium-dependent metabolic reprogramming during inflammation and resolution (PMID:33581115)
• IRAK4 inhibitor mitigates joint inflammation by rebalancing metabolism malfunction in RA (PMID:34732329)
• Deficiency of the sedoheptulose kinase (Shpk) does not alter the ability of hematopoietic stem cells to rescue cystinosis (PMID:34823997)
• Sedoheptulose Kinase SHPK Expression in Glioblastoma (PMID:35682658) and its Correction (PMID:39941164)
• The sedoheptulose kinase CARKL controls T-cell cytokine outputs and migration (PMID:39669692)
• Metabolic reprogramming and signalling networks in microglial activation (PMID:42031319)
• Untargeted metabolomics… non-oxidative branch of the pentose phosphate pathway (PMID:32828637)
• OMIM #617213 — Sedoheptulokinase deficiency (403 to automated retrieval)
• OMIM *605060 — Sedoheptulokinase; SHPK (403 to automated retrieval)
• Orphanet: Isolated sedoheptulokinase deficiency (ORPHA:440713) / Orphadata cross-referencing API
• GARD — Isolated sedoheptulokinase deficiency
• NORD/MONDO — isolated sedoheptulokinase deficiency
• HPO / ontology.jax.org annotations for OMIM:617213 and ORPHA:440713
• NCBI Gene — SHPK (GeneID 23729) · GTR — SHPK
• UniProt Q9UHJ6 — SHPK_HUMAN
• ClinVar VCV000372202 — SHPK c.355C>T (p.Arg119Ter) · ClinVar VCV000372203 — SHPK c.211G>T (p.Glu71Ter)
• dbSNP rs144071313
• MGI:1921887 — mouse Shpk · IMPC — Shpk · MMRRC:043666-UCD
• GeneReviews — Cystinosis
• Disorders of the Pentose Phosphate Pathway and Polyol Metabolism (Springer)
• ClinicalTrials.gov API v2 — NCT03897361, NCT05146830, NCT06910813
• EBI OLS4 (ChEBI, GO term verification)
• OMIA — Online Mendelian Inheritance in Animals (no SHPK phene)