Search Results (519)

Background and Clinical Significance: Tarui disease, or glycogen storage disease type VII, is a rare autosomal recessive metabolic myopathy caused by muscle phosphofructokinase deficiency. Its manifestations include exercise intolerance, exertional myalgia, muscle cramps, myoglobinuria, rhabdomyolysis, hyperuricemia, and compensated hemolysis. The hematologic phenotype may obscure the underlying metabolic disorder and raise concern for a clonal myeloid neoplasm. Case Presentation: A 23-year-old man was referred for persistent mild thrombocytopenia following evaluation for jaundice and hepatosplenomegaly. He had undergone cholecystectomy at 18 years of age and reported exercise-induced myalgia, muscle cramps, and episodes of dark urine. Laboratory investigations demonstrated mild monocytosis, reticulocytosis, thrombocytopenia, hyperuricemia, elevated lactate dehydrogenase, and predominantly unconjugated hyperbilirubinemia, with a negative direct antiglobulin test. Selected inherited hemolytic disorders, hemoglobinopathies, and paroxysmal nocturnal hemoglobinuria were excluded. Bone marrow examination showed marked erythroid hyperplasia and mild megakaryocytic dysplasia. Testing for JAK2, CALR, and MPL mutations and an extended myeloid next-generation sequencing panel identified no pathogenic variants, and monocytosis resolved during follow-up. Whole-exome sequencing identified a homozygous PFKM missense variant, NM_001354735.1:c.1087A>T, p.(Ile363Phe), classified as a variant of uncertain significance. The patient subsequently developed severe rhabdomyolysis, with a creatine kinase level of 225,000 U/L and recovered after intensive intravenous hydration without renal impairment. Conclusions: Tarui disease should be considered in young patients with compensated hemolysis, hyperuricemia, exertional muscle symptoms, dark urine, or rhabdomyolysis, even when hematologic abnormalities suggest a myeloid disorder. The highly concordant phenotype and homozygous PFKM variant support a clinically probable diagnosis, although pathogenicity remains unconfirmed. Functional and segregation evidence may strengthen causal interpretation and support future variant reclassification. Full article

Ehlers–Danlos syndrome (EDS) comprises a heterogeneous group of inherited connective tissue disorders. The 2017 International Classification of EDS delineates 13 subtypes, which are caused by pathogenic variants in 19 distinct genes encoding various collagen types or proteins involved in collagen metabolism. EDS is characterized by considerable clinical variability, both across EDS subtypes and in terms of phenotypic polymorphism and disease severity within individual subtypes. The present study describes a clinical case of classical-type Ehlers–Danlos syndrome segregating across three generations, illustrating the clinical variability observed within a single family carrying a single rare pathogenic variant, NM_000093.5(COL5A1):c.4050dup (p.Gly1351fs). Furthermore, this report clarifies and expands the phenotypic spectrum associated with this specific variant. Full article

Newborn screening (NBS) is a critical component of the three-tiered prevention strategy for birth defects, reducing congenital disorder burden and improving long-term child health outcomes. Over the past 45 years, NBS in China has evolved into a nationwide quality-controlled network driven by policy support and technological advances. Currently, phenylketonuria and congenital hypothyroidism are included in universal NBS across the country, and several provinces have expanded to encompass congenital adrenal hyperplasia, glucose-6-phosphate dehydrogenase deficiency, and additional inherited metabolic disorders identified through tandem mass spectrometry. The application of next-generation sequencing and other technologies has further enhanced detection capacity and expanded detectable disease spectra. Meanwhile, the National Quality Management System for NBS (QMS-NBS) has realized the visualization and standardization of screening quality and performance. Despite these advances, challenges remain, including regional disparities, inadequate follow-up, and long-term management. This review summarizes the historical evolution and policy framework of NBS in China, outlines the development of screening institutions, the spectrum and incidence of screened disorders, advances in detection technologies, and the establishment of QMS-NBS. It also highlights future priorities: expanding screened conditions, strengthening follow-up and long-term care, promoting regional equity, and advancing novel technologies to improve child health and foster precision public health. Full article

Background: Inherited metabolic disorders (IMDs) are a heterogeneous group of genetic diseases, some of which require lifelong disease-specific dietary management. Children with phenylketonuria (PKU), organic acidemias (OAs), and glycogen storage diseases (GSDs) are particularly susceptible to nutritional imbalances and metabolic disturbances that may adversely affect bone metabolism and skeletal health. However, data regarding bone turnover markers and bone health in these pediatric IMD populations remain limited. Objective: This study aimed to evaluate bone metabolism by assessing biochemical parameters, bone turnover markers, and bone mineral density in children with PKU, OA, and GSD receiving long-term dietary treatment. Methods: This cross-sectional study included 95 children, comprising 25 patients with PKU, 20 patients with organic acidemias, 20 patients with glycogen storage diseases, and 30 healthy age-matched controls. Demographic characteristics, anthropometric measurements, and dietary intake were recorded. Biochemical evaluation included serum calcium, phosphorus, alkaline phosphatase (ALP), parathyroid hormone (PTH), and 25-hydroxyvitamin D levels. Bone turnover was assessed using C-terminal telopeptide of type I collagen (CTX), procollagen type I N-terminal propeptide (P1NP), and osteocalcin (OC) levels. Bone mineral density was evaluated by dual-energy X-ray absorptiometry (DXA). Results: Age and sex distributions were similar among the groups. Height was lower in OA than in controls and PKU, and in GSD than in PKU; weight and BMI were lower in both OA and GSD than in controls and PKU (p < 0.05). Significant differences were observed in dietary energy and macronutrient intake according to disease-specific nutritional regimens. Serum calcium, phosphorus, and 25-hydroxyvitamin D levels were significantly lower in all IMD groups compared with healthy controls (p < 0.001). ALP and PTH levels were significantly higher in PKU, OA, and GSD patients than in controls (p < 0.001). Among bone turnover markers, P1NP and osteocalcin levels significantly differed among groups, with the highest values observed in PKU patients (p = 0.006 and p = 0.028, respectively). CTX levels did not significantly differ among the groups (p = 0.183). DXA Z-scores were significantly lower in all IMD groups than in controls, with the lowest mean Z-scores observed in GSD patients. Conclusions: Children with PKU, OA, and GSD receiving long-term dietary treatment exhibited significant alterations in bone metabolism, characterized by lower vitamin D, calcium, and phosphorus levels, higher ALP and PTH concentrations, differences in bone formation markers, and lower DXA Z-scores compared with controls. Significant differences were observed in the bone formation markers P1NP and osteocalcin, whereas CTX levels remained comparable among the study groups. These findings underscore the importance of regular assessment of bone health and optimization of nutritional management in children under dietary treatment, while acknowledging that disease-specific mechanisms of skeletal involvement may differ among these conditions. Full article

Nicotinamide adenine dinucleotide (NAD⁺) is a fundamental metabolic cofactor and signaling molecule that supports redox reactions, DNA repair, chromatin regulation, stress adaptation, inflammation, and neuronal maintenance. Age-associated NAD⁺ decline has been implicated in brain aging and neurodegenerative disorders, but the causal node and limiting compartment differ across tissues and disease states. Nicotinamide mononucleotide adenylyltransferase 1 (NMNAT-1) catalyzes the final step in NAD⁺ biosynthesis and represents the major nuclear isoform of the mammalian NMNAT family. Direct human genetic evidence establishes NMNAT-1 as a causal gene in inherited retinal degeneration, whereas evidence linking endogenous NMNAT-1 to broader brain aging or sporadic neurodegeneration is mainly convergent preclinical, preliminary, or indirect. Beyond NAD⁺ synthesis, biochemical and Drosophila studies suggest possible chaperone-like and proteostasis-supporting functions, but a separable NAD⁺-independent function of endogenous mammalian NMNAT-1 has not yet been established in vivo. Here, we review the molecular structure, localization, and regulation of NMNAT-1, emphasizing calibrated distinctions among catalytic nuclear NAD⁺ supply, engineered axonal protection, pathway-adjacent NAD⁺ interventions, and putative non-catalytic protection. We further discuss how NMNAT-1 dysfunction may contribute to aging-associated genomic instability, neuroinflammation, synaptic impairment, retinal degeneration, selected neurodegenerative models, and glioma biology. Finally, we evaluate therapeutic strategies targeting NMNAT-1 and NAD⁺ pathways, noting that no human trial has yet established efficacy for an NMNAT-1-directed neurological therapy. A compartment-aware and evidence-stratified view is therefore essential for translating NMNAT-1 biology into interventions for age-related neural disease. Full article

Metabolic diseases have diverse etiologies, prolonged courses, and multiorgan involvement, making selection of animal models matched to the research objective and disease stage essential. Zebrafish develop rapidly, are genetically tractable, and support in vivo imaging and high-throughput screening, enabling studies of obesity and dyslipidemia, diabetes and its complications, fatty liver disease, atherosclerosis, and inherited metabolic diseases. However, zebrafish models differ in developmental stage, induction conditions, phenotypic evidence, and fidelity to human disease, and a single abnormal phenotype rarely supports a complete disease designation or mechanistic conclusion. This review compares dietary, chemical, genetic, and combined models in terms of modeling characteristics, representative phenotypes, applications, and limitations. It summarizes morphological, biochemical, and functional assays, in vivo imaging, omics, and automated quantification for phenotypic validation; discusses metabolic imbalance, mitochondrial dysfunction and oxidative stress, inflammation and immunometabolism, and interorgan crosstalk; and evaluates drug-screening applications and translational limitations. We propose a model-selection framework based on research objective and disease stage, developmental stage, modeling strategy, and core-phenotype validation. Minimum validation criteria define appropriate disease terminology and inference. A larval rapid-screening-to-adult-systemic-validation strategy, multilevel outcome assessment, and cross-model validation may improve the reliability and translational value of zebrafish research on metabolic diseases. Full article

Mitochondrial mechanisms are increasingly implicated in complex neurological conditions, including Autism Spectrum Disorder (ASD). Propionic acid (PPA) is widely used to study mitochondrial dysfunction in preclinical models of ASD. However, the molecular mechanisms that drive PPA-induced neurotoxicity are unresolved. Here, we examined mitochondrial remodeling under PPA-induced stress in neuroblastoma SH-SY5Y cells. PPA systemically altered the transcriptional regulation of mitochondrial dynamics and disrupted canonical proteins involved in mitochondrial fusion (L-OPA1, MFN2), fission (DRP1) and quality control (LC3-II). Confocal microscopy revealed an upregulation of both fission and fusion events and impairments to mitochondrial integrity, connectivity and turnover. Live-cell respirometry demonstrated consequent deficits in both oxidative and glycolytic energy production, while respiratory chain electron flow assays illustrated a shift in TCA cycle flux driven by a remodeling of mitochondrial substrate utilization. This work describes a molecular signature of metabolic stress in the SH-SY5Y system, providing novel insights into the mechanisms and manifestations of PPA-induced neurotoxicity. Full article

Cerebral venous sinus thrombosis (CVST) is an uncommon cerebrovascular disorder with heterogeneous manifestations and may occasionally precede the diagnosis of an underlying malignancy. We report the case of a 24-year-old man who presented with recurrent fever, headache, pharyngodynia, and systemic inflammation initially attributed to a sinonasal or odontogenic infectious process. He subsequently developed binocular horizontal diplopia, left abducens nerve palsy, papilledema, severe headache, and nausea. Neuroimaging demonstrated extensive CVST involving the left internal jugular vein, bilateral transverse sinuses, and superior sagittal sinus, without ischemic, hemorrhagic, or tumoral brain parenchymal lesions. Thrombophilia testing identified heterozygous prothrombin G20210A as the only established inherited thrombophilic factor. Despite initial neurological stabilization, the patient developed a rapidly recurrent frontal calvarial, epicranial, and cranio-dural lesion extending toward the superior sagittal sinus, without brain parenchymal involvement or imaging evidence of leptomeningeal disease. Initial morphological assessment suggested Langerhans cell histiocytosis. However, comprehensive histopathological and immunohistochemical reassessment demonstrated diffuse strong CD30 expression, nuclear and cytoplasmic ALK positivity, CD43 expression, and focal epithelial membrane antigen and granzyme B positivity, while CD1a and S100 were negative. These findings established the diagnosis of systemic ALK-positive anaplastic large cell lymphoma with secondary extra-axial cranio-dural involvement. Systemic staging demonstrated disseminated nodal disease and a noncontiguous cranio-dural extranodal lesion, consistent with stage IV disease. Treatment with anticoagulation and six cycles of brentuximab vedotin combined with cyclophosphamide, doxorubicin, and prednisone resulted in a favorable neurological and oncological outcome, with no metabolically active or residual enhancing disease on follow-up imaging. This case emphasizes the importance of continued etiological investigation in young patients with extensive CVST and an atypical clinical course, even when plausible infectious and inherited thrombotic risk factors coexist. Full article

Both genetics and the environment affect the phenotypes of polycystic kidney diseases (PKD), such as autosomal dominant (AD) PKD, autosomal recessive (AR) PKD and nephronophthisis (NPH). Variable phenotypes, pleiotropy, divergent severity and progression, even in family members who inherited the same disease-causing mutation(s), signal the involvement of networked genes and modifiers. Several PKD-linked genes function in development and renal tubule morphogenesis. Cystic renal tissues feature metabolic remodeling, functional reprogramming and dysregulation of several shared factors and pathways. ADPKD, ARPKD and NPH partially phenocopy each other. Understanding the developmental arc of cystic kidney disease and its complex phenotypes would improve diagnostics and help develop effective personalized treatments. However, this is challenging to study in vertebrate systems due to genetic redundancy, functional overlap, and a dearth of genetic tools. Underused in this context, Drosophila melanogaster offers high genomic and pathway conservation, a wealth of genetic tools, and rapid generation times, making it a reliable and sustainable model for mechanistic, genome-wide, and precision medicine studies. Here, we surveyed ADPKD, ARPKD, and NPH, compared renal and extrarenal phenotypes, and examined the network of shared and unique contributors, their healthy and diseased functions and conservation from the perspective of mechanistic whole-animal modeling. Full article

Background/Objectives: Hereditary fructose intolerance (HFI) is a rare autosomal recessive metabolic disorder caused by variants in the ALDOB gene, resulting in aldolase B deficiency. Symptoms occur after the ingestion of fructose, sucrose, or sorbitol, leading to metabolic toxicity. Management is exclusively dietary, but clinical practice remains highly variable. This survey aimed to investigate current Italian dietary management practices for patients with HFI. Methods: A cross-sectional centre-level survey was conducted using a 29-item questionnaire distributed to metabolic dietitians within the Italian Society for the Study of Inherited Metabolic Diseases network between April and May 2026. Results: Data from 27 dietitians across 15 Italian inherited metabolic disease centres were analysed. Over half of the centres (53.3%) provided care for both paediatric and adult patients, and all centres (100%) supplied structured educational materials for the fructose-, sucrose-, and sorbitol-restricted diet. Marked heterogeneity was observed in dietary practices, particularly in the classification of sugars and sweeteners, recommendations for cereal-based products, and fibre supplementation strategies. Cereal-based dietary guidance was provided by 10/15 centres (66.7%), ranging from no specific recommendations (5/15, 33.3%) to a preference for refined grains (7/15, 46.7%) or fibre-based restrictions (2/15, 13.3%). With regard to sugars and sweeteners, consensus was observed only for maltitol and sorbitol, which were classified as prohibited by all centres (15/15, 100%). Mannitol and isomalt were prohibited in 14/15 centres (93.3%). All other compounds showed variable recommendations across centres, including xylitol (prohibited 46.7%, permitted 40.0%), erythritol (permitted 60.0%), and sucralose (prohibited 33.3%, permitted 20.0%, restricted 20.0%, unspecified 26.7%). Vitamin C (100%) and folic acid (86.6%) were the most commonly prescribed supplements. One-third (33%) of the centres required the use of fibre supplements or osmotic laxatives to manage chronic constipation, with wide variability in the specific type of fibre recommended. Conclusions: These findings highlight substantial heterogeneity in dietary management of HFI across specialised Italian centres and support the development of evidence-based, standardised nutritional guidelines to improve the consistency of care, nutritional adequacy, and patient outcomes. Full article

Background: Heart failure (HF) represents the final common pathway of diverse cardiovascular disorders, including coronary artery disease, primary myocardial pathology, and abnormalities of cardiac conduction. These conditions arise from an interplay of genetic, environmental, and psychosocial influences, making it essential to understand these determinants to improve risk prediction and prevention. Multiple biological pathways of inflammation, fibrosis, coagulation, oxidative stress, lipid dysregulation, endothelial dysfunction, and metabolic disturbances are shaped by inherited susceptibility and modifiable exposures. Together, these mechanisms drive HF development and progression, though their relative contributions vary across populations. Methods: PubMed and Google Scholar were searched for clinical, biomedical, and interdisciplinary studies published between 1 January 2000, and 31 December 2025. Keywords included “Asian,” “adult,” “India,” “heart failure,” “risk assessment,” “prognosis,” and “predictive value.” Studies were included if they focused on South Asian Indian adults, with priority given to original research, systematic reviews, and meta-analyses. Pediatric studies and those centered on other ethnic groups were excluded. Results: Among South Asian Indians, cardiovascular disease burden remains disproportionately high compared with Western populations. Unique genetic architecture, environmental exposures, and sociocultural factors appear to contribute to earlier onset and more aggressive disease. Identifying population-specific genetic variants, clarifying psychosocial influences, and addressing environmental risks may help reduce these disparities. Conclusions: This qualitative review highlights key gaps in current knowledge. A deeper understanding of these determinants could refine HF risk stratification, guide targeted prevention strategies, and reduce the growing cardiovascular burden in South Asian Indians. There is an urgent need for South Asian specific HF risk prediction models. Full article

Intracellular retinoid-binding proteins, including cellular retinol-binding proteins (CRBPs) and cellular retinoic acid-binding proteins (CRABPs), belong to the intracellular lipid-binding protein (iLBP) family, whereas cellular retinaldehyde-binding protein (CRALBP) is a structurally distinct retinoid-binding protein belonging to the CRAL-TRIO protein family and functions as an active regulator of retinoid trafficking, metabolism, and signaling. Although these proteins are directly implicated in inherited retinal dystrophies, retinoid-dependent cancers, and neurodegenerative diseases, they have received comparatively little attention as pharmacological targets relative to the extracellular carrier Retinol-Binding Protein 4 (RBP4). High-resolution structural studies, including atomic-resolution X-ray co-crystal structures of protein–ligand complexes, have defined the binding pocket architecture of each protein and established a basis for structure-guided drug discovery. This review critically evaluates the druggability of CRBP, CRALBP, and CRABP by integrating structural, biochemical, and pharmacological evidence. We discuss known small-molecule modulators, including the first-in-class CRBP1 inhibitor abn-CBD and next-generation non-retinoid scaffolds, alongside gene therapy strategies targeting CRALBP deficiency. We further address the selectivity challenges inherent to the conserved iLBP fold and identify future directions for the development of isoform-selective therapeutics for retinal degeneration, oncology, and neurodegeneration. Full article

Cardiovascular disease is a leading cause of morbidity and premature mortality in many inherited syndromic and metabolic disorders. However, its cardiac manifestations are often recognized late and are rarely described collectively within a single cohort. We reviewed eight years of outsourced next-generation sequencing (NGS) requested through the pediatric genetics service of a single tertiary center in Taiwan and identified 22 patients with molecularly confirmed genetic disorders and documented cardiovascular involvement. For each patient, the causative genotype—including lysosomal storage diseases, RASopathies, CHARGE syndrome, connective-tissue disorders, primary cardiomyopathies and channelopathies, neuromuscular disorders, contiguous-gene syndromes, and other metabolic and syndromic conditions—was mapped to a structured echocardiographic phenotype. Septal defects or shunts and valvular regurgitation were the most common findings (10/22 and 9/22, respectively), followed by septal hypertrophy, valvular stenosis, and great-vessel or aortic abnormalities. Two children had left ventricular systolic dysfunction, and one died following an out-of-hospital cardiac arrest. Several cardiac lesions clustered by disease category, most notably valvular thickening in mucopolysaccharidoses and elastin arteriopathy in Williams–Beuren syndrome. These genotype-to-cardiac phenotype patterns support the need for gene-informed, systematic cardiac surveillance rather than symptom-driven referral in children with these disorders. Full article

Objectives: Coronary artery disease (CAD) remains a leading cause of morbidity and mortality worldwide, yet population-specific evidence regarding the contribution of MIA3 genetic variation in Middle Eastern populations remains limited. This study investigated the association of the MIA3 rs17465637 polymorphism with CAD susceptibility and its relationship with lipid-related phenotypes in a Saudi population. Methods: A case–control study was conducted between June 2020 and August 2022, including 200 patients with angiographically confirmed CAD and 200 age- and sex-matched healthy Saudi controls. Genotyping of rs17465637 was performed using a TaqMan real-time polymerase chain reaction assay. Genotype distributions were evaluated using chi-square analysis under multiple inheritance models. Multivariable logistic regression was subsequently performed to estimate adjusted odds ratios after controlling age, BMI, smoking, physical inactivity, systolic BP, diastolic BP, blood glucose, triglycerides, total cholesterol, LDL-C, and HDL-C. Associations between rs17465637 genotypes and serum lipid parameters were also examined. Results: Genotype frequencies of rs17465637 differed modestly between cases and controls; however, unadjusted comparisons under codominant, dominant, recessive, and allelic inheritance models did not reach statistical significance, and none remained significant after Bonferroni correction. In contrast, multivariable logistic regression demonstrated an independent association between the rs17465637 C allele and CAD after adjustment for conventional cardiovascular risk factors. In genotype–phenotype analyses, carriers of the C allele exhibited higher association with low-density lipoprotein cholesterol concentrations and less favorable lipid profiles than AA homozygotes, supporting a relationship between the variant and lipid metabolism. These findings are consistent with a potential contribution of rs17465637 to CAD susceptibility through lipid-related pathways. Conclusions: Although unadjusted genotype comparisons were not statistically significant after correction for multiple testing, multivariable analysis provides evidence supporting an independent association between the MIA3 rs17465637 variant and CAD susceptibility in this Saudi cohort. The observed associations with adverse lipid profiles further provide evidence linking this specific locus to the molecular mechanisms underlying cardiovascular disease. Replication in larger, multi-center studies incorporating genome-wide ancestry-informative markers and functional investigations is warranted to further minimize the possibility of residual population stratification, confirming these findings and clarifying the biological mechanisms underlying this association. Full article

Hypophosphatasia (HPP) is a rare inherited disorder caused by deficient tissue-nonspecific alkaline phosphatase (TNSALP) activity and classically characterized by impaired mineralization processes, although growing evidence suggests broader systemic involvement beyond bone. This cross-sectional study aimed to characterize circulating levels of osteoglycin and sclerostin in patients with HPP and to explore their relationships with TNSALP activity and systemic clinical–biochemical profiles. This cross-sectional study included 25 genetically confirmed HPP patients and 25 age- and sex-matched controls without cardiovascular disease. Circulating osteoglycin and sclerostin were measured by ELISA, and clinical, metabolic, renal, inflammatory, cardiovascular, and bone-related variables were assessed. HPP patients showed lower osteoglycin and higher sclerostin levels compared with controls. Osteoglycin was mainly associated with ALP activity and mineral-related variables, while sclerostin showed broader associations involving glycemic, inflammatory, renal, and cardiovascular domains. In multivariable analyses, osteoglycin was linked to ALP, renal and inflammatory markers, whereas sclerostin was associated with glycemic, mineral, inflammation, and circulatory markers. Overall, osteoglycin variability appeared mainly driven by mineral-related factors, while sclerostin was more influenced by metabolic and inflammatory domains. In conclusion, HPP is associated with an imbalance in circulating bone-derived proteins, characterized by reduced osteoglycin and increased sclerostin, suggesting systemic alterations in bone-related signaling beyond impaired mineralization. Full article