Materiały źródłowe

• #1 Inherited metabolic disorders – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/inherited-metabolic-disorders/symptoms-causes/syc-20352590

  Inherited metabolic disorders are medical conditions caused by changes in specific genes that affect metabolism. Different gene changes cause different types of inherited metabolic disorders. These gene changes are most commonly passed down from both parents. But sometimes the gene change comes only from one parent, most often from the mother. These disorders also are called inborn errors of metabolism. […] When these processes don’t work properly, a metabolic disorder occurs. It may be due to an enzyme that’s too low or missing or to another problem. Inherited metabolic disorders fall into different groups. They’re grouped by the substance affected and whether it builds up too much because it can’t be broken down or it’s too low or missing. […] Inherited metabolic disorders are caused by changes in specific genes that affect metabolism. Different gene changes cause different types of inherited metabolic disorders. These gene changes are most commonly passed down from both parents. But sometimes the gene change comes only from one parent, most often from the mother. There are hundreds of inherited metabolic disorders caused by different genes.

• #1 Inherited Metabolic Disorders: Overview and Resources

  https://metab.ern-net.eu/inherited-metabolic-disorders/

  Inherited Metabolic Disorders (IMDs), in particular, represent a group of more than 1400 rare genetic pathologies, classified in 130 different biochemical groups, that impact both children and adults and are quite heterogeneous. […] Metabolic disorders are generally chronic and progressive and can involve multiple organs, thus early diagnosis and treatment are crucial to avoid further complications. […] IMDs are a complex class of conditions that can affect the metabolism of carbohydrates, amino acids, lipids, steroids but also nucleic acids, mitochondria and neurotransmitters. […] Disorders of intermediary metabolism involve pathways that mediate the breakdown of low-molecular weight nutrient compounds (such as proteins, carbohydrates, and lipids) or convert them into substrates for the biosynthesis of complex molecules.

• #1 Inherited Metabolic Disorders: Types, Signs, Causes & Treatment

  https://www.webmd.com/a-to-z-guides/inherited-metabolic-disorder-types-and-treatments

  The original cause of most genetic metabolic disorders is a gene mutation that occurred many generations ago. The gene mutation is passed along through the generations, ensuring its preservation. […] Each inherited metabolic disorder is very rare in the general population. But considered together, inherited metabolic disorders may affect about 1 in 1,000 to 2,500 newborns. […] Limited treatments are available for inherited metabolic disorders. The essential genetic defect causing the condition cant be corrected with the technology we have right now. Instead, treatments try to work around the problem with metabolism. […] There are new and promising therapies coming out in the realm of gene therapy, enzyme replacement therapy, and prenatal therapies in fetuses with a known diagnosis, Tise says.

• #1 Inborn Errors of Metabolism: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/804757-overview

  Inborn errors of metabolism describes a class of over 1000 inherited disorders caused by mutations in genes coding for proteins that function in metabolism. Most of the disorders are inherited as autosomal recessive, but some are autosomal dominant or X-linked. […] The presentation of specific IEMs as a spectrum of disease phenotypes in which a clear correlation between the severity of mutation at the affected locus and the phenotype (genotype-phenotype correlation) is often lacking and impacts the ability to predict disease course. […] Additional genes and environmental, epigenetic, and microbiome factors are also potential modifying etiologic factors in individual IEMs.

• #1 Inborn Errors of Metabolism: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/804757-overview

  Inborn errors of metabolism (IEMs) are a large group of rare genetic diseases most commonly resulting from a defect in an enzyme or transport protein that causes a block in a metabolic pathway. Effects are due to toxic accumulations of substrates before the block, intermediates from alternative metabolic pathways, defects in energy production and use caused by a deficiency of products beyond the block, abnormal molecule transport, or a combination of these metabolic deviations. […] Single-gene defects result in abnormalities in the synthesis or catabolism of proteins, carbohydrates, fats, or complex molecules. As previously stated, most are due to a defect in an enzyme or transport protein, which results in a block in a metabolic pathway. Effects are due to toxic accumulations of substrates before the block, intermediates from alternative metabolic pathways, defects in energy production and use caused by a deficiency of products beyond the block, or a combination of these metabolic deviations.

• #1 Pathophysiology of Inherited Metabolic Disorders: Enzymatic Defects and their Impact on Cellular Metabolism

  https://www.jmolpat.com/jmolpat-articles/pathophysiology-of-inherited-metabolic-disorders-enzymatic-defects-and-their-impact-on-cellular-metabolism-109039.html

  Inherited metabolic disorders are a group of genetic conditions that result from defects in specific enzymes or transport proteins, disrupting normal metabolic processes. […] These disorders are often due to single-gene mutations that lead to the accumulation or deficiency of substrates, intermediates, or products in metabolic pathways. […] The resultant biochemical imbalances can affect various tissues and organs, leading to a wide range of clinical manifestations. […] Inherited metabolic disorders typically involve mutations in genes encoding enzymes responsible for the metabolism of carbohydrates, proteins, fats, or other essential biomolecules. […] When a particular enzyme is deficient or non-functional, the metabolic pathway it controls is disrupted. […] This can result in the accumulation of toxic substances or a deficiency in essential products, both of which can have detrimental effects on cellular function and overall health.

• #1 Pathophysiology of Inherited Metabolic Disorders: Enzymatic Defects and their Impact on Cellular Metabolism

  https://www.jmolpat.com/jmolpat-articles/pathophysiology-of-inherited-metabolic-disorders-enzymatic-defects-and-their-impact-on-cellular-metabolism-109039.html

  One of the primary ways these disorders happen through the accumulation of toxic metabolites. […] For instance, in Phenylketonuria (PKU), a deficiency in the enzyme phenylalanine hydroxylase leads to the buildup of phenylalanine. […] High levels of phenylalanine can be neurotoxic, leading to intellectual disability, seizures, and behavioral problems if not managed through dietary restrictions. […] Similarly, in Maple Syrup Urine Disease (MSUD), defects in the enzymes responsible for breaking down branched-chain amino acids cause these amino acids and their toxic by-products to accumulate, resulting in severe neurological damage and potentially life-threatening metabolic crises. […] Inherited metabolic disorders can also cause disease through the deficiency of vital compounds. […] For example, in glycogen storage diseases, mutations in enzymes involved in glycogen metabolism result in inadequate glucose production during fasting states.

• #1 Overview of Hereditary Metabolic Disorders – Children’s Health Issues – Merck Manual Consumer Version

  https://www.merckmanuals.com/home/children-s-health-issues/hereditary-metabolic-disorders/overview-of-hereditary-metabolic-disorders

  Hereditary metabolic disorders develop when children inherit defective genes that control metabolism. […] If a genetic abnormality affects the function of an enzyme or causes it to be deficient or missing altogether, various metabolic disorders can occur. […] These disorders usually result from one or both of the following: Inability to break down a substance that should be broken down, allowing a toxic intermediate substance to build up; Inability to produce some essential substance. […] Metabolic disorders are classified by the particular building block that is affected.

• #1 Inherited Metabolic Disorders: Overview and Resources

  https://metab.ern-net.eu/inherited-metabolic-disorders/

  Mitochondrial disorders were first genetically characterized by identifying deletions and point mutations within mitochondrial DNA (mtDNA). […] The products of amino acid, carbohydrate, and lipid breakdown are transported into the mitochondria where they serve as substrates for adenosine triphosphate (ATP) synthesis by the process of oxidative phosphorylation. […] These disorders are generally due to deficiency of several enzymes or molecule transporters, leading to the accumulation of toxic intermediates which can disrupt the normal functions of cells. […] Disorders of lipid metabolism and transport encompass a wide range of conditions that affect the metabolism of various lipid types (fatty acids, sphingolipids, sterol lipids) and of lipoproteins, from the first stages of biosynthesis to their transport within the body.

• #1 Inherited metabolic disorders – WikiLectures

  https://www.wikilectures.eu/w/Inherited_metabolic_disorders

  The affected protein is usually an enzyme of some metabolic pathway, which then binds to its product, which may be missing, and does not drain the substrate, which may accumulate, or metabolize to by-product. From this, the involvement of different organs derives to different degrees. […] Diseases of small molecules are caused by the accumulation of small toxic molecules (ammonia, organic acids) or lack of desirable metabolites (ketone bodies, glucose), which are caused by catabolism of food-borne substances (protein amino acids, carbohydrates, fatty acids). […] Diseases of large molecules are caused by a defect in the metabolism (disorder of production, transport of substances, but also in their degradation) of endogenously formed macromolecules (glycosaminoglycans, glycolipids, glycoproteins and others).

• #1 Inherited Metabolic Disorders: From Bench to Bedside

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10813142/

  Inherited metabolic disorders (IMDs), commonly referred to as inborn errors of metabolism, represent a spectrum of disorders with a defined (or presumed) primary genetic cause which disrupts the normal metabolism of essential molecules in the body. […] Although these are relatively rare conditions, they represent a diverse array of disorders which encompass a significant amount of morbidity and mortality worldwide. […] Specific mutations in genes related to lysosomal proteins or non-lysosomal proteins crucial for lysosomal function can result in these diseases. Certain mutations lead to the accumulation of molecules such as sphingolipids, glycoproteins, and mucopolysaccharides within the lysosomes, leading to cellular damage. Consequently, a cascade of effects is generated, impacting cellular function through signaling abnormalities, defects in calcium homeostasis, oxidative stress, and inflammation. However, the mechanisms behind the pathogenesis of LSD is not yet fully understood.

• #1 Inherited metabolic disorders associated with hypoglycaemia in adulthood: a narrative review – Dawson – Journal of Laboratory and Precision Medicine

  https://jlpm.amegroups.org/article/view/6373/html

  IMD causes of fasting hypoglycaemia are sub-divided into those associated with ketone production and those in which ketones are absent. In the fasting state, up to 80% of the total energy requirement is normally met by ketones generated from the metabolism of FFA. Thus, the absence of ketones in a fasted individual is a key diagnostic clue pointing towards a fatty acid oxidation disorder or glycogen storage disorder type I (GSD I). […] Conversely, ketotic hypoglycaemia has a wide potential differential diagnosis including non-IMD causes which must be excluded first. IMD causes are other GSDs and fructose 1,6 bisphosphatase deficiency, a disorder of gluconeogenesis. […] Recurrent clinically significant hypoglycaemia is a feature of disorders of gluconeogenesis caused by enzyme defects immediately upstream of glucose in the gluconeogenesis pathway. These are GSD I (discussed above) and fructose-1,6-bisphosphatase deficiency.

• #1 Advances in the Pathogenesis of Metabolic Liver Disease-Related Hepato | JHC

  https://www.dovepress.com/advances-in-the-pathogenesis-of-metabolic-liver-disease-related-hepato-peer-reviewed-fulltext-article-JHC

  Inherited metabolic liver diseases primarily encompass hereditary hemochromatosis (HH), Alpha 1 antitrypsin (AAT) deficiency, and hereditary tyrosinemia type 1(HT1). These genetic disorders give rise to complications, including emphysema, chronic liver disease, and HCC. Here, we focus on the pathogenesis of inherited metabolic liver diseases-related HCC, but relevant studies still need to be completed. […] HH is an inherited metabolic liver disease common in whites that manifests as increased intestinal iron absorption, resulting in progressive iron accumulation in organs like the liver, heart, and pancreas. This condition is accompanied by reduced secretion of the iron-regulating hormone ferromodulin. The most common genetic variant is linked to the HFE (high-frequency iron) gene on chromosome 6, primarily the C282Y mutation, identified as a molecular risk factor for HCC in its pure state. HH gives rise to complications including cirrhosis, HCC, congestive heart failure, diabetes mellitus, and arthropathy, with HCC being a long-term complication of HH that leads to increased mortality. An earlier cohort study revealed a 20-fold higher risk of liver cancer development in individuals with hereditary hemochromatosis compared to the general population. There are fewer studies on the pathogenesis of HH progressing to HCC. Iron overload, recognized as a crucial factor. The liver as the main iron metabolizing organ, the large accumulation of iron in the liver leads to ROS production and lipid peroxidation, causing DNA damage and mutations in the oncogene p53. Another study linking iron overload with HCC-specific epigenetic defects reported increased and more extensive aberrant hypermethylation in HH patients compared to non-HH individuals, not associated with cirrhosis. Furthermore, hypermethylation of SOCS-1 in affected genes correlated with heightened activity of the JAK/STAT pathway in tumor cells. Conversely, inactivation of pro-apoptotic genes, RASSF1A and GSP 1, may induce hepatocyte over-proliferation under iron-overload-induced genotoxic stress, increasing the likelihood of mutations leading to HCC. Capua et al observed that patients with HFE-HCC exhibited a more aggressive disease course and increased co-expression of cancer stem cell markers EpCAM (epithelial cell adhesion molecule) and EpCAM/SALL4 (salt-like transcription factor 4). In conclusion, iron overload, a characteristic pathologic feature of HH, can be an independent carcinogenic factor in HCC.

• #1

  https://consensus.app/questions/what-causes-consequences-metabolic-disorders/

  Oxidative stress and chronic inflammation contribute to the development of metabolic disorders like obesity, diabetes, and cardiovascular diseases, with strategies for prevention and therapy being crucial. […] Metabolic syndrome, a clustering of risk factors, is primarily caused by central obesity and is linked to insulin resistance, requiring preventive measures and therapeutic strategies in children and adolescents. […] Intracellular stress and inflammation contribute to metabolic disorders like obesity, type 2 diabetes, and non-alcoholic fatty liver disease, with potential therapies targeting stress response pathways. […] Mitochondrial alterations are common to metabolic disorders like Alzheimer’s, obesity, and type 2 diabetes, suggesting impaired coordination between cellular needs and mitochondrial responses. […] Endocrine disrupting chemicals (EDCs) may contribute to the rapid increase in metabolic diseases like obesity, type 2 diabetes, and non-alcoholic fatty liver disease, potentially leading to metabolic syndrome.

• #1 The Reciprocal Interplay between Infections and Inherited Metabolic Disorders

  https://www.mdpi.com/2076-2607/11/10/2545

  Therefore, infective agents may affect cellular metabolic pathways, by mediation or not of an altered immune system. […] The data reviewed here strongly suggest that the role of infections in many types of IMDs deserves greater attention for a better management of these disorders and a more focused therapeutic approach. […] The reason behind this close relationship can be, first of all, attributed to the fact that infections represent a stimulus to the functioning of the immune system, which is a large user of energy, whose production and recycling is essential for its correct functioning. […] Recent studies have shown that mitochondria play a crucial role in the regulation and proper functioning of the immune response to pathogenic noxae participating in both innate and adaptive immunoresponses.

• #1 Advances in the Pathogenesis of Metabolic Liver Disease-Related Hepato | JHC

  https://www.dovepress.com/advances-in-the-pathogenesis-of-metabolic-liver-disease-related-hepato-peer-reviewed-fulltext-article-JHC

  AAT deficiency, one of the most prevalent inherited liver diseases, arises from mutations in the SERPINA1 gene, causing misfolding of the ATZ protein and subsequent polymerization within the endoplasmic reticulum of hepatocytes, initiating liver injury. The most common defective type is the Protease Inhibitor (Pi) type Z, and evidence suggests that individuals heterozygous for PiZ are at an elevated risk of developing chronic hepatitis, cirrhosis, and HCC in late childhood. Reports indicate that HCC occurs in 31-67% of cirrhotic AAT-deficient adults. The accumulation of ATZ in the endoplasmic reticulum induces mitochondrial dysfunction, and significant mitochondrial autophagy and damage were observed in the livers of AAT-deficient PiZ mice, accompanied by the presence of markedly activated caspase-3, potentially linked to HCC development. Beyond mitochondrial dysfunction and autophagy, the aggregation of ATZ activates endoplasmic reticulum stress signaling pathways, particularly NF-B activation, ER caspases, and BAP31. NF-B activation is particularly significant for liver injury, as ATZ accumulation can mediate hepatic inflammation via NF-B, including neutrophil infiltration and NF-B-targeted interleukin-8. NF-B activation is closely associated with inflammation-induced carcinogenesis and may play a role in the pathogenesis of AAT deficiency-associated HCC. BAP31, involved in protein polymerization in the endoplasmic reticulum, may contribute to mitochondrial dysfunction and the activation of mitochondrial caspase. In addition, the aggregation of ATZ results in the absence of UPR signaling, potentially allowing the survival of abnormal cells and contributing to the pathogenesis of HCC. Finally, Perlmutter et al found that ATZ accumulation in PiZ mice leads to the proliferation of globule-devoid hepatocytes, heightening the likelihood of HCC development, as adenomas and subsequent carcinomas arise in glomerular livers.

• #1 Advances in the Pathogenesis of Metabolic Liver Disease-Related Hepato | JHC

  https://www.dovepress.com/advances-in-the-pathogenesis-of-metabolic-liver-disease-related-hepato-peer-reviewed-fulltext-article-JHC

  HT1 is a rare and severe autosomal recessive hereditary liver disease primarily resulting from the accumulation of toxic metabolites due to the deficiency of fumarylacetoacetate hydrolase (FAH), a key enzyme in tyrosine catabolism, and is strongly associated with an elevated risk of cancer (HCC). Angileri et al utilizing the fah/ mouse model observed elevated expression of miRNA-98 and miRNA-200b in HT1 mice, and these miRNAs were demonstrated to be associated with the progression of HT1. An investigation targeting the AKT signaling pathway found that the accumulation of the HT1 metabolite fumaric acid ethyl ester (FAA) in fah/ mice induced chronic stress in the liver, stabilizing the activation of the AKT survival signaling pathway and inhibiting intrinsic apoptosis, thereby facilitating the development of HCC. Moreover, Willenbring et al reported severe hepatocellular DNA damage and additional deletions of p21 in FAH-deficient mice, where the proliferation of hepatocytes with DNA damage leads to rapid cancer formation. The deletion of p21 expression is indicative of the transition from hepatocellular dysplasia to HCC. Lastly, heat shock proteins (HSPs) also play a pivotal role in the transition from HT1 to HCC. They are overexpressed in FAH-deficient mice, and in conjunction with BCL-2, HSPs promote resistance to apoptosis in tumorigenesis, thereby accelerating HCC.

• #1 Inherited Metabolic Disorders: Overview and Resources

  https://metab.ern-net.eu/inherited-metabolic-disorders/

  Disorders affecting heterocyclic compounds, particularly those involved in nucleotide and tetrapyrrole metabolism, can lead to severe metabolic imbalances, causing neurological symptoms, immune deficiencies, hematological abnormalities and skin conditions. […] The proper functioning of complex macromolecules and organelles depends on the balance between biological processes, including synthesis, modification, and degradation. […] Disorders of cofactors and mineral metabolism encompass a wide range of conditions that affect the body’s ability to produce, absorb, or utilize essential vitamins, minerals, and cofactors. […] Metabolic cell signaling disorders encompass a wide range of conditions that disrupt the complex communication networks within cells.

• #1

  https://xiahepublishing.com/1555-3884/GE-2023-00202

  New areas of science that have developed rapidly over the last decade (e.g., epigenetics and transgenerational inheritance) point to another fundamental reason for the development of MetS, linking the internal and external aspects of pathogenesis and allowing us to look at deeper connections when studying this disease. […] At the same time, transient changes in the genome (e.g., methylation and acetylation), which can be inherited among generations and stabilized due to environmental factors, may play a key role in MetS. […] Furthermore, transgenerational effects may be mechanistically mediated by small RNAs, DNA methylation, histone modification, and cellular reprogramming in the hypothalamus. […] The important role of transgenerational inheritance in the development of MetS has been confirmed by studies showing a high risk of developing MetS components in the offspring against a background of the same pathologies in the parents.

• #1 A mechanism for inherited metabolic disorders | Lab Animal

  https://www.nature.com/articles/laban.987

  From worms to mammals, environmental influences on one generation can be passed on to another through 'epigenetics’, a set of mechanisms controlling gene expression without a change to the underlying DNA sequence. […] The researchers used mice fed a high-fat diet to explore how diet-induced changes in the father are passed on to his offspring. […] The resulting offspring of mice that had been fed a high-fat diet displayed glucose intolerance and insulin sensitivity, two symptoms associated with diabetes. […] Previous data suggest that the RNA profiles of sperm are altered in response to changes in diet, indicating that an RNA molecule might transmit these phenotypes. […] Strikingly, injection of only tsRNAs from mice fed the high-fat diet recapitulated the phenotype of glucose intolerance in resulting progeny, whereas injection of other types of small non-coding RNAs, such as microRNAs, did not.

• #1 Extending inherited metabolic disorder diagnostics with biomarker interaction visualizations | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-023-02683-9

  Inherited Metabolic Disorders (IMDs) are rare diseases where one impaired protein leads to a cascade of changes in the adjacent chemical conversions. […] The goal of this study was to provide a proof-of-concept framework for integrating knowledge of metabolic interactions with real-life patient data before scaling up this approach. […] The presented framework shows how metabolic interaction knowledge can be integrated with clinical data in one visualization, which can be relevant for future analysis of difficult patient cases and untargeted metabolomics data. […] Our framework was tested on two groups of IMDs with a well-understood molecular mechanism (pyrimidine metabolism and the urea cycle) known for biomarker overlap for several IMDs due to their common metabolite carbamoyl phosphate.

• #1 Program for Inherited Metabolic Diseases | Mount Sinai – New York

  https://www.mountsinai.org/care/genetics/services/inherited-metabolic-diseases

  Disorders that are treated in the PIMD at Mount Sinai include: Argininemia, Argininosuccinic Acid Lyase deficiency, Beta ketothiolase deficiency, Biotinidase deficiency, Carnitine cycle disorders, Carbamylphosphate synthetase deficiency (CPS-1), Carnitine palmitoyl transferase 1 deficiency (CPT-1), Carnitine palmitoyl transferase 2 deficiency (CPT2), Carnitine translocase deficiency, Citrullinemia, Cobalamin disorders (cbl a, b, c, etc.), Congenital Disorders of Glycosylation (CDG), Developmental delay, 2,4 Dienyl CoA reductase deficiency, Failure to thrive, Fatty Acid Oxidation defects, Fucosidosis, Galactosemia, Glutaric acidemia types 1 and 2, Glutathione synthetase deficiency, Glycogen storage diseases, GPI-anchor disorders, Holocarboxylase synthetase deficiency, Homocystinuria, Hyperammonemia, homocitrullinemia, hyperornithinemia syndrome (HHH), Hypermethioninemia, Hyperprolinemia, Hypoglycemia, Isovaleric acidemia, Krabbe disease, Long chain hydroxyl acyl CoA dehydrogenase deficiency (LCHAD), Lysosomal Storage Diseases, Maple syrup urine disease, Malonic aciduria, Medium chain acyl CoA dehydrogenase deficiency (MCAD), Metabolic acidosis, 3-Methylcrotonyl CoA carboxylase deficiency, Methylene tetrahydrofolate reductase deficiency (MTHFR), Methylmalonic acidemia, Mitochondrial diseases, Mucopolysaccharidoses, Multiple Acyl CoA dehydrogenase deficiency, Niemann-Pick disease types A, B, and C, Organic acidemias, Ornithine carbamylase deficiency, Phenylketonuria, Pompe disease, Propionic acidemia, Seizure disorders, Short chain acyl CoA dehydrogenase deficiency (SCAD), Tay Sachs Disease, Tetrahydrobiopterin deficiencies, Trifunctional protein deficiency, Trimethylaminuria, Tyrosinemia, Urea cycle defects, Very long chain acyl CoA dehydrogenase deficiency (VLCAD).

• #1 Pathophysiology of Inherited Metabolic Disorders: Enzymatic Defects and their Impact on Cellular Metabolism

  https://www.jmolpat.com/jmolpat-articles/pathophysiology-of-inherited-metabolic-disorders-enzymatic-defects-and-their-impact-on-cellular-metabolism-109039.html

  This can lead to hypoglycemia, muscle weakness, and organ dysfunction. […] In other cases, such as in certain types of mucopolysaccharidoses, the inability to degrade glycosaminoglycans leads to their accumulation within lysosomes, causing cellular and tissue damage that appears as delays in development, organomegaly, and skeletal abnormalities. […] The clinical presentation of inherited metabolic disorders is often complex and can vary widely, even among individuals with the same genetic mutation. […] Newborns may appear normal at birth, but symptoms often develop as metabolic demands increase with feeding or illness. […] In some cases, symptoms may be worsening by fasting, stress, or other environmental factors that exacerbate the underlying metabolic defect. […] Early signs can include poor feeding, vomiting, lethargy, and failure to thrive.

• #1 Inherited Metabolic Disorders: From Bench to Bedside

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10813142/

  Lysosomal dysfunction, a well-established mechanism of PD pathogenesis, serves as a backdrop for interpreting the biological links between AFD and PD. […] This accumulation leads to the impairment of alpha-synuclein traffic, resulting in disruptions in the autophagy-lysosome system (ALS) and subsequent axonal degeneration. […] These disruptions mirror features observed in the brains of -galactosidase A (-Gal A)-deficient mice, suggesting that insufficient -Gal A activity in AFD may contribute to neurodegenerative processes akin to those seen in PD, namely the presence of aggregates of alpha-synuclein. […] The convergence of clinical evidence, lysosomal dysfunction mechanisms, and experimental findings, including bradykinetic phenotypes in individuals with causal GLA mutations, underscores a compelling association between AFD and PD.

• #1 SciELO Brazil – Clinical Manifestation in Females with X-linked Metabolic Disorders: Genetic and Pathophysiological Considerations Clinical Manifestation in Females with X-linked Metabolic Disorders: Genetic and Pathophysiological Considerations

  https://www.scielo.br/j/jiems/a/CmL7nkgjBcjZbppYjL9nScF/

  This explains why females with a severe mutation E1 mutation and an unfavourable (skewed) X chromosome inactivation profile, in which predominantly the normal allele is inactivated, have substantial neurological symptoms, but only slightly elevated or even normal lactate levels. […] Furthermore, the gene product may function differently in different organs: In carriers of Danon disease the X-inactivation pattern contributes to the degree of clinical manifestation, because the gene product LAMP-2 is a membrane bound, not soluble protein, which means it is autonomous and cannot be compensated by normal cells. […] Although the lysosomal enzymes that are deficient in Hunter syndrome and Fabry disease, namely iduronate-2-sulfatase and -galactosidase respectively, are soluble proteins, carriers of Hunter syndrome are asymptomatic, whereas heterozygotes of Fabry disease have symptoms to variable degree.

• #1 SciELO Brazil – Clinical Manifestation in Females with X-linked Metabolic Disorders: Genetic and Pathophysiological Considerations Clinical Manifestation in Females with X-linked Metabolic Disorders: Genetic and Pathophysiological Considerations

  https://www.scielo.br/j/jiems/a/CmL7nkgjBcjZbppYjL9nScF/

  This discrepancy can be explained by the fact that iduronate-2-sulfatase and -galactosidase differ in their biological properties: In Hunter syndrome an exchange of iduronate-2-sulfatase between unaffected and affected cells can take place, enabling complementation of enzyme activity in females with a skewed X-inactivation favouring the mutant cells. […] In Fabry disease, however, the unaffected cells do not secrete the mannose-6-phosphorylated, but the mature form of -galactosidase, which cannot complement the activity in cells lacking expression of the enzyme: Carriers of Fabry disease show clinical manifestation, because the gene product (-galactosidase) is operationally cell autonomous (although it is a soluble protein) as it cannot be readily complemented in the presence of wild type cells. […] In summary, it can be concluded that it is not possible to assign an X-linked metabolic disorder clearly to a dominant or recessive type.

• #1

  https://www.archivesofmedicalscience.com/Hepatic-glycogen-storage-diseases-pathogenesis-clinical-symptoms-and-therapeutic,81093,0,2.html

  Glycogen storage diseases (GSDs) are genetically determined metabolic diseases that cause disorders of glycogen metabolism in the body. Due to the enzymatic defect at some stage of glycogenolysis/glycogenesis, excess glycogen or its pathologic forms are stored in the body tissues. […] Glycogen storage disease (GSD) is caused by a genetically determined metabolic block involving enzymes that regulate synthesis (glycogenesis) or glycogen breakdown (glycogenolysis). The nature of the individual types of glycogenosis is related to the impaired accumulation of abnormal molecules of this branched polysaccharide. […] The typical, biochemical characteristics of this type of GSD are postprandial hyperglycemia (blood glucose cannot be stored in the liver and therefore it is kept high in the blood) with subsequent hypoglycemia (no hepatic glycogen storage from which the body could boost the reserves in case of a drop in the blood glucose).

• #1 169 Inherited Metabolic Disorders and the Skin | Plastic Surgery Key

  https://plasticsurgerykey.com/169-inherited-metabolic-disorders-and-the-skin/

  Phenylketonuria is a genetically determined disease with an autosomal recessive inheritance. […] Oculocutaneous tyrosinaemia or RichnerHanhart syndrome is one of the known inborn errors of tyrosine catabolism, and is due to a defect of hepatic cytosol aminotransferase. This results in increased plasma tyrosine levels as well as in abnormal urinary tyrosine metabolites. […] Cystathionine -synthase deficiency is a disorder of trans-sulphuration resulting in elevated plasma levels of homocyst(e)ine and methionine and a decreased level of cysteine. […] As a result of homogentisic acid oxidase enzyme deficiency, homogentisic acid accumulates and is excreted in the urine. Homogentisic acid is an intermediary product in the metabolism of the aromatic amino acids phenylalanine and tyrosine. […] The essential amino acids, isoleucine, valine, methionine and threonine, are metabolized into propionyl CoA. Propionyl CoA is converted into methylmalonyl CoA by the enzyme propionyl CoA carboxylase. Deficiency of this enzyme causes propionic acidaemia.

• #1 SciELO Brazil – Clinical Manifestation in Females with X-linked Metabolic Disorders: Genetic and Pathophysiological Considerations Clinical Manifestation in Females with X-linked Metabolic Disorders: Genetic and Pathophysiological Considerations

  https://www.scielo.br/j/jiems/a/CmL7nkgjBcjZbppYjL9nScF/

  In X-linked disorders an important, but not only, factor for disease expression in heterozygous patients is the degree of X-inactivation skewing. […] The purpose of this mechanism, also called Lyonization, is to prevent female cells from expressing twice the amount of X-linked gene products compared with male cells. […] Skewed X-inactivation, that means the preferential expression (ratio more than 0.5) of either the paternal or the maternal chromosome, is not uncommon in the general female population. […] This phenomenon, which prevents carriers from becoming symptomatic, has been observed for example in incontinentia pigmenti. […] However, selection against cells containing the wild type allele on the active X-chromosome has also been reported, such as in cultured fibroblasts and blood cells from females heterozygous for X-linked adrenoleucodystrophy.

• #1 SciELO Brazil – Clinical Manifestation in Females with X-linked Metabolic Disorders: Genetic and Pathophysiological Considerations Clinical Manifestation in Females with X-linked Metabolic Disorders: Genetic and Pathophysiological Considerations

  https://www.scielo.br/j/jiems/a/CmL7nkgjBcjZbppYjL9nScF/

  In order to explain this variable clinical manifestation, Dobyns et al. analysed in a pioneering article the pattern of inheritance and phenotypic expression of 32 X-linked diseases. […] This study revealed several factors that can explain the variable clinical expression: These factors include the degree of skewed X-inactivation, the type and severity of the underlying mutation and whether the gene product is cell autonomous or non-autonomous. […] This review aims to discuss these considerations in several X-linked metabolic disorders including defects of energy metabolism, defects of cholesterol biosynthesis, disturbance of phosphate metabolism and lysosomal storage disorders. […] In some diseases, the gene product has several functions; one function can be autonomous, and the other part non-autonomous.

• #1 Inherited metabolic disorders involving the eye: a clinico-biochemical perspective | Eye

  https://www.nature.com/articles/eye2009229

  The diagnosis of inborn errors of metabolism is challenging for most physicians. […] Although there is an extensive understanding of many inborn errors of metabolism at the biochemical, molecular, and metabolic levels, little is known about their pathogenesis. In particular, how systemic metabolic disease contributes to ocular defects remains to be elucidated in IMDs. The occurrence of eye abnormalities could be due to direct toxic mechanisms of abnormal metabolic products or accumulation of normal metabolites by errors of synthetic pathways or by deficient energy metabolism. […] Although there is an extensive understanding of many inborn errors of metabolism at the metabolic, biochemical, and molecular levels, their exact pathogenesis remains to be established. The mechanisms by which systemic metabolic disease contributes to ocular defects remains to be elucidated. The various mechanisms involved could be due to direct toxic mechanisms of abnormal metabolic products, accumulation of normal metabolites by errors of synthetic pathways, or by deficient energy metabolism.

• #1 Inherited metabolic disorders involving the eye: a clinico-biochemical perspective | Eye

  https://www.nature.com/articles/eye2009229

  The latest discoveries in the human genome project and advances in medical technology have resulted in significant alterations in the diagnosis, classification, and treatment of IMDs. […] The various mechanisms involved could be due to direct toxic mechanisms of abnormal metabolic products, accumulation of normal metabolites by errors of synthetic pathways, or by deficient energy metabolism. […] Although the basic pathophysiology of the disease is not exactly known, the occurrence of RP in IMDs suggests that it might be induced by abnormal metabolic products, errors of synthetic pathways, or deficient energy metabolism.

• #1 Extending inherited metabolic disorder diagnostics with biomarker interaction visualizations | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-023-02683-9

  The developed framework enables the visualization of clinical biomarker profiles with biological pathway knowledge, by connecting individual markers to changes on the process level. This approach shows which metabolic reactions are disturbed, which proteins are related to these reactions, and potentially which specific protein is impaired, aiding diagnosis. […] The framework could aid in the diagnostic process of other (novel) IMDs and is adaptable to analyze different types of IMDs and functional assays in the future, as well as integrating other types of (omics) data analysis, e.g. transcriptomics, metabolomics, and fluxomics. […] The issues highlighted in the discussion section should be overcome in the future to allow our developed framework to be easily used for other IMDs, by adding persistent identifiers to (clinical) biomarker data, allowing automatable data downloads from relevant databases, and creating computer-readable pathway models from pathway figures.

• #1 Inborn Errors of Metabolism (IEM) – Inherited Metabolic Disorders

  https://my.clevelandclinic.org/health/diseases/17962-inherited-metabolic-disorders

  Inborn errors of metabolism can be harmful to your body if you’re unable to process certain food products in your metabolism. This could cause toxic substances to build up in your blood and cause: seizures, organ failure, brain damage. […] There isn’t a cure for inborn errors of metabolism (IEM). Your outlook varies based on the severity of your symptoms. Some cases of IEM can be very dangerous if you have high levels of toxic material in your body that your body can’t get rid of on its own. Most people diagnosed with the condition have a normal lifespan with early detection and treatment, along with lifelong lifestyle changes.

• #1 Inherited Metabolic Disorders | Memorial Sloan Kettering Cancer Center

  https://www.mskcc.org/pediatrics/cancer-care/types/pediatric-blood-disorders/about-pediatric-blood-disorders/inherited-metabolic-disorders

  Inborn errors of metabolism are a diverse group of disorders caused by an inherited deficiency or defect in a single enzyme or protein. Your body needs these vital enzymes and proteins. When there are not enough of them, the body cannot break down certain large molecules correctly. As a result, a harmful amount of these large molecules, or storage materials, builds up and damages organs and body systems. […] People with inborn errors of metabolism often develop nerve deterioration. These disorders may also impair the heart, vision, hearing, bone growth, lungs, and muscles. […] The only effective treatment for cALD is a stem cell transplant before the disease becomes too advanced. Early diagnosis and monitoring are therefore very important. […] Treatment is possible for juvenile and adult MLD. A stem cell transplant is the only known cure and should be done before the disease becomes too advanced. Early diagnosis and monitoring are therefore very important.

• #1 Pathophysiology of Inherited Metabolic Disorders: Enzymatic Defects and their Impact on Cellular Metabolism

  https://www.jmolpat.com/jmolpat-articles/pathophysiology-of-inherited-metabolic-disorders-enzymatic-defects-and-their-impact-on-cellular-metabolism-109039.html

  As the disorder progresses, more specific symptoms related to the affected metabolic pathway become apparent, such as developmental delays, neurological impairments, hepatomegaly, cardiomyopathy, or renal dysfunction. […] Diagnosis of inherited metabolic disorders typically involves a combination of clinical evaluation, biochemical testing, and genetic analysis. […] Biochemical tests can detect abnormal levels of metabolites in blood, urine, or other body fluids, providing clues to the specific metabolic pathway affected. […] Enzyme assays can directly measure the activity of possible insufficiency of enzymes. […] Genetic testing can identify mutations in the genes encoding these enzymes, confirming the diagnosis and allowing for carrier testing and prenatal diagnosis in affected families.

• #2 Inborn Errors of Metabolism: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/804757-overview

  Inborn errors of metabolism (IEMs) are a large group of rare genetic diseases most commonly resulting from a defect in an enzyme or transport protein that causes a block in a metabolic pathway. Effects are due to toxic accumulations of substrates before the block, intermediates from alternative metabolic pathways, defects in energy production and use caused by a deficiency of products beyond the block, abnormal molecule transport, or a combination of these metabolic deviations. […] Single-gene defects result in abnormalities in the synthesis or catabolism of proteins, carbohydrates, fats, or complex molecules. As previously stated, most are due to a defect in an enzyme or transport protein, which results in a block in a metabolic pathway. Effects are due to toxic accumulations of substrates before the block, intermediates from alternative metabolic pathways, defects in energy production and use caused by a deficiency of products beyond the block, or a combination of these metabolic deviations.

• #2 Metabolic Disorders: Symptoms & Causes | NewYork-Presbyterian

  https://www.nyp.org/digestive/weight-loss-and-metabolic-disorders/metabolic-disorders

  Inherited metabolic disorders may affect about one in 1,000 to 2,500 newborns. […] Genetic mutations cause hundreds of genetic metabolic disorders passed down from generation to generation. […] Common causes of metabolic disorders are: Genetics: Metabolic disorders are caused by genetic defects commonly inherited from both parents. Gaucher’s disease and phenylketonuria (PKU) are examples of inherited metabolic disorders. […] It’s important to be aware of the various risk factors associated with this condition. Individuals with a higher risk for inherited metabolic disorders are primarily those who have a family history of the condition.

• #2 Inherited metabolic disorders – WikiLectures

  https://www.wikilectures.eu/w/Inherited_metabolic_disorders

  Inherited metabolic disorders (IMDs) form a diverse group of 700-800 diseases that are caused by enzyme deficiency, transport protein dysfunction or a disorder of another protein associated with a metabolic pathway. They are characterized by autosomal recessive, gonosomal recessive and dominant, but also mitochondrial inheritance. Insufficient production of the enzyme or the required protein occurs as a result of mutations in nuclear or mitochondrial DNA. […] The most common cause of inherited metabolic disorders are nuclear DNA mutations in germ cells (and thus in somatic cells) with typical monogenic Mendelian inheritance usually autosomal recessive, gonosomal recessive and dominant. A less common cause of IMD is mitochondrial DNA mutations, which are transmitted by the maternal type of inheritance.

• #2 Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features – UpToDate

  https://www.uptodate.com/contents/inborn-errors-of-metabolism-epidemiology-pathogenesis-and-clinical-features

  Congenital metabolic disorders result from the absence or abnormality of an enzyme or its cofactor, leading to either accumulation or deficiency of a specific metabolite. […] The epidemiology, pathogenesis, and most common chronic clinical and laboratory manifestations of IEM are discussed below. […] Delay in diagnosis may result in acute metabolic decompensation, progressive neurologic injury, or death.

• #2 Overview of Hereditary Metabolic Disorders – Children’s Health Issues – Merck Manual Consumer Version

  https://www.merckmanuals.com/home/children-s-health-issues/hereditary-metabolic-disorders/overview-of-hereditary-metabolic-disorders

  Hereditary metabolic disorders develop when children inherit defective genes that control metabolism. […] If a genetic abnormality affects the function of an enzyme or causes it to be deficient or missing altogether, various metabolic disorders can occur. […] These disorders usually result from one or both of the following: Inability to break down a substance that should be broken down, allowing a toxic intermediate substance to build up; Inability to produce some essential substance. […] Metabolic disorders are classified by the particular building block that is affected.

• #2 Pathophysiology of Inherited Metabolic Disorders: Enzymatic Defects and their Impact on Cellular Metabolism

  https://www.jmolpat.com/jmolpat-articles/pathophysiology-of-inherited-metabolic-disorders-enzymatic-defects-and-their-impact-on-cellular-metabolism-109039.html

  One of the primary ways these disorders happen through the accumulation of toxic metabolites. […] For instance, in Phenylketonuria (PKU), a deficiency in the enzyme phenylalanine hydroxylase leads to the buildup of phenylalanine. […] High levels of phenylalanine can be neurotoxic, leading to intellectual disability, seizures, and behavioral problems if not managed through dietary restrictions. […] Similarly, in Maple Syrup Urine Disease (MSUD), defects in the enzymes responsible for breaking down branched-chain amino acids cause these amino acids and their toxic by-products to accumulate, resulting in severe neurological damage and potentially life-threatening metabolic crises. […] Inherited metabolic disorders can also cause disease through the deficiency of vital compounds. […] For example, in glycogen storage diseases, mutations in enzymes involved in glycogen metabolism result in inadequate glucose production during fasting states.

• #2 Inherited Metabolic Disorders: Overview and Resources

  https://metab.ern-net.eu/inherited-metabolic-disorders/

  Mitochondrial disorders were first genetically characterized by identifying deletions and point mutations within mitochondrial DNA (mtDNA). […] The products of amino acid, carbohydrate, and lipid breakdown are transported into the mitochondria where they serve as substrates for adenosine triphosphate (ATP) synthesis by the process of oxidative phosphorylation. […] These disorders are generally due to deficiency of several enzymes or molecule transporters, leading to the accumulation of toxic intermediates which can disrupt the normal functions of cells. […] Disorders of lipid metabolism and transport encompass a wide range of conditions that affect the metabolism of various lipid types (fatty acids, sphingolipids, sterol lipids) and of lipoproteins, from the first stages of biosynthesis to their transport within the body.

• #2 Inherited Metabolic Disorders: From Bench to Bedside

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10813142/

  Inherited metabolic disorders (IMDs), commonly referred to as inborn errors of metabolism, represent a spectrum of disorders with a defined (or presumed) primary genetic cause which disrupts the normal metabolism of essential molecules in the body. […] Although these are relatively rare conditions, they represent a diverse array of disorders which encompass a significant amount of morbidity and mortality worldwide. […] Specific mutations in genes related to lysosomal proteins or non-lysosomal proteins crucial for lysosomal function can result in these diseases. Certain mutations lead to the accumulation of molecules such as sphingolipids, glycoproteins, and mucopolysaccharides within the lysosomes, leading to cellular damage. Consequently, a cascade of effects is generated, impacting cellular function through signaling abnormalities, defects in calcium homeostasis, oxidative stress, and inflammation. However, the mechanisms behind the pathogenesis of LSD is not yet fully understood.

• #2 Advances in the Pathogenesis of Metabolic Liver Disease-Related Hepato | JHC

  https://www.dovepress.com/advances-in-the-pathogenesis-of-metabolic-liver-disease-related-hepato-peer-reviewed-fulltext-article-JHC

  Inherited metabolic liver diseases primarily encompass hereditary hemochromatosis (HH), Alpha 1 antitrypsin (AAT) deficiency, and hereditary tyrosinemia type 1(HT1). These genetic disorders give rise to complications, including emphysema, chronic liver disease, and HCC. Here, we focus on the pathogenesis of inherited metabolic liver diseases-related HCC, but relevant studies still need to be completed. […] HH is an inherited metabolic liver disease common in whites that manifests as increased intestinal iron absorption, resulting in progressive iron accumulation in organs like the liver, heart, and pancreas. This condition is accompanied by reduced secretion of the iron-regulating hormone ferromodulin. The most common genetic variant is linked to the HFE (high-frequency iron) gene on chromosome 6, primarily the C282Y mutation, identified as a molecular risk factor for HCC in its pure state. HH gives rise to complications including cirrhosis, HCC, congestive heart failure, diabetes mellitus, and arthropathy, with HCC being a long-term complication of HH that leads to increased mortality. An earlier cohort study revealed a 20-fold higher risk of liver cancer development in individuals with hereditary hemochromatosis compared to the general population. There are fewer studies on the pathogenesis of HH progressing to HCC. Iron overload, recognized as a crucial factor. The liver as the main iron metabolizing organ, the large accumulation of iron in the liver leads to ROS production and lipid peroxidation, causing DNA damage and mutations in the oncogene p53. Another study linking iron overload with HCC-specific epigenetic defects reported increased and more extensive aberrant hypermethylation in HH patients compared to non-HH individuals, not associated with cirrhosis. Furthermore, hypermethylation of SOCS-1 in affected genes correlated with heightened activity of the JAK/STAT pathway in tumor cells. Conversely, inactivation of pro-apoptotic genes, RASSF1A and GSP 1, may induce hepatocyte over-proliferation under iron-overload-induced genotoxic stress, increasing the likelihood of mutations leading to HCC. Capua et al observed that patients with HFE-HCC exhibited a more aggressive disease course and increased co-expression of cancer stem cell markers EpCAM (epithelial cell adhesion molecule) and EpCAM/SALL4 (salt-like transcription factor 4). In conclusion, iron overload, a characteristic pathologic feature of HH, can be an independent carcinogenic factor in HCC.

• #2 Advances in the Pathogenesis of Metabolic Liver Disease-Related Hepato | JHC

  https://www.dovepress.com/advances-in-the-pathogenesis-of-metabolic-liver-disease-related-hepato-peer-reviewed-fulltext-article-JHC

  AAT deficiency, one of the most prevalent inherited liver diseases, arises from mutations in the SERPINA1 gene, causing misfolding of the ATZ protein and subsequent polymerization within the endoplasmic reticulum of hepatocytes, initiating liver injury. The most common defective type is the Protease Inhibitor (Pi) type Z, and evidence suggests that individuals heterozygous for PiZ are at an elevated risk of developing chronic hepatitis, cirrhosis, and HCC in late childhood. Reports indicate that HCC occurs in 31-67% of cirrhotic AAT-deficient adults. The accumulation of ATZ in the endoplasmic reticulum induces mitochondrial dysfunction, and significant mitochondrial autophagy and damage were observed in the livers of AAT-deficient PiZ mice, accompanied by the presence of markedly activated caspase-3, potentially linked to HCC development. Beyond mitochondrial dysfunction and autophagy, the aggregation of ATZ activates endoplasmic reticulum stress signaling pathways, particularly NF-B activation, ER caspases, and BAP31. NF-B activation is particularly significant for liver injury, as ATZ accumulation can mediate hepatic inflammation via NF-B, including neutrophil infiltration and NF-B-targeted interleukin-8. NF-B activation is closely associated with inflammation-induced carcinogenesis and may play a role in the pathogenesis of AAT deficiency-associated HCC. BAP31, involved in protein polymerization in the endoplasmic reticulum, may contribute to mitochondrial dysfunction and the activation of mitochondrial caspase. In addition, the aggregation of ATZ results in the absence of UPR signaling, potentially allowing the survival of abnormal cells and contributing to the pathogenesis of HCC. Finally, Perlmutter et al found that ATZ accumulation in PiZ mice leads to the proliferation of globule-devoid hepatocytes, heightening the likelihood of HCC development, as adenomas and subsequent carcinomas arise in glomerular livers.

• #2

  https://xiahepublishing.com/1555-3884/GE-2023-00202

  New areas of science that have developed rapidly over the last decade (e.g., epigenetics and transgenerational inheritance) point to another fundamental reason for the development of MetS, linking the internal and external aspects of pathogenesis and allowing us to look at deeper connections when studying this disease. […] At the same time, transient changes in the genome (e.g., methylation and acetylation), which can be inherited among generations and stabilized due to environmental factors, may play a key role in MetS. […] Furthermore, transgenerational effects may be mechanistically mediated by small RNAs, DNA methylation, histone modification, and cellular reprogramming in the hypothalamus. […] The important role of transgenerational inheritance in the development of MetS has been confirmed by studies showing a high risk of developing MetS components in the offspring against a background of the same pathologies in the parents.

• #2 A mechanism for inherited metabolic disorders | Lab Animal

  https://www.nature.com/articles/laban.987

  From worms to mammals, environmental influences on one generation can be passed on to another through 'epigenetics’, a set of mechanisms controlling gene expression without a change to the underlying DNA sequence. […] The researchers used mice fed a high-fat diet to explore how diet-induced changes in the father are passed on to his offspring. […] The resulting offspring of mice that had been fed a high-fat diet displayed glucose intolerance and insulin sensitivity, two symptoms associated with diabetes. […] Previous data suggest that the RNA profiles of sperm are altered in response to changes in diet, indicating that an RNA molecule might transmit these phenotypes. […] Strikingly, injection of only tsRNAs from mice fed the high-fat diet recapitulated the phenotype of glucose intolerance in resulting progeny, whereas injection of other types of small non-coding RNAs, such as microRNAs, did not.

• #2 Inherited Metabolic Disorders: From Bench to Bedside

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10813142/

  Lysosomal dysfunction, a well-established mechanism of PD pathogenesis, serves as a backdrop for interpreting the biological links between AFD and PD. […] This accumulation leads to the impairment of alpha-synuclein traffic, resulting in disruptions in the autophagy-lysosome system (ALS) and subsequent axonal degeneration. […] These disruptions mirror features observed in the brains of -galactosidase A (-Gal A)-deficient mice, suggesting that insufficient -Gal A activity in AFD may contribute to neurodegenerative processes akin to those seen in PD, namely the presence of aggregates of alpha-synuclein. […] The convergence of clinical evidence, lysosomal dysfunction mechanisms, and experimental findings, including bradykinetic phenotypes in individuals with causal GLA mutations, underscores a compelling association between AFD and PD.

• #2 Inherited metabolic disorders associated with hypoglycaemia in adulthood: a narrative review – Dawson – Journal of Laboratory and Precision Medicine

  https://jlpm.amegroups.org/article/view/6373/html

  IMD causes of fasting hypoglycaemia are sub-divided into those associated with ketone production and those in which ketones are absent. In the fasting state, up to 80% of the total energy requirement is normally met by ketones generated from the metabolism of FFA. Thus, the absence of ketones in a fasted individual is a key diagnostic clue pointing towards a fatty acid oxidation disorder or glycogen storage disorder type I (GSD I). […] Conversely, ketotic hypoglycaemia has a wide potential differential diagnosis including non-IMD causes which must be excluded first. IMD causes are other GSDs and fructose 1,6 bisphosphatase deficiency, a disorder of gluconeogenesis. […] Recurrent clinically significant hypoglycaemia is a feature of disorders of gluconeogenesis caused by enzyme defects immediately upstream of glucose in the gluconeogenesis pathway. These are GSD I (discussed above) and fructose-1,6-bisphosphatase deficiency.

• #2

  https://www.archivesofmedicalscience.com/Hepatic-glycogen-storage-diseases-pathogenesis-clinical-symptoms-and-therapeutic,81093,0,2.html

  Glycogen storage diseases (GSDs) are genetically determined metabolic diseases that cause disorders of glycogen metabolism in the body. Due to the enzymatic defect at some stage of glycogenolysis/glycogenesis, excess glycogen or its pathologic forms are stored in the body tissues. […] Glycogen storage disease (GSD) is caused by a genetically determined metabolic block involving enzymes that regulate synthesis (glycogenesis) or glycogen breakdown (glycogenolysis). The nature of the individual types of glycogenosis is related to the impaired accumulation of abnormal molecules of this branched polysaccharide. […] The typical, biochemical characteristics of this type of GSD are postprandial hyperglycemia (blood glucose cannot be stored in the liver and therefore it is kept high in the blood) with subsequent hypoglycemia (no hepatic glycogen storage from which the body could boost the reserves in case of a drop in the blood glucose).

• #2 SciELO Brazil – Clinical Manifestation in Females with X-linked Metabolic Disorders: Genetic and Pathophysiological Considerations Clinical Manifestation in Females with X-linked Metabolic Disorders: Genetic and Pathophysiological Considerations

  https://www.scielo.br/j/jiems/a/CmL7nkgjBcjZbppYjL9nScF/

  In X-linked disorders an important, but not only, factor for disease expression in heterozygous patients is the degree of X-inactivation skewing. […] The purpose of this mechanism, also called Lyonization, is to prevent female cells from expressing twice the amount of X-linked gene products compared with male cells. […] Skewed X-inactivation, that means the preferential expression (ratio more than 0.5) of either the paternal or the maternal chromosome, is not uncommon in the general female population. […] This phenomenon, which prevents carriers from becoming symptomatic, has been observed for example in incontinentia pigmenti. […] However, selection against cells containing the wild type allele on the active X-chromosome has also been reported, such as in cultured fibroblasts and blood cells from females heterozygous for X-linked adrenoleucodystrophy.

• #2 Inherited metabolic disorders involving the eye: a clinico-biochemical perspective | Eye

  https://www.nature.com/articles/eye2009229

  The diagnosis of inborn errors of metabolism is challenging for most physicians. […] Although there is an extensive understanding of many inborn errors of metabolism at the biochemical, molecular, and metabolic levels, little is known about their pathogenesis. In particular, how systemic metabolic disease contributes to ocular defects remains to be elucidated in IMDs. The occurrence of eye abnormalities could be due to direct toxic mechanisms of abnormal metabolic products or accumulation of normal metabolites by errors of synthetic pathways or by deficient energy metabolism. […] Although there is an extensive understanding of many inborn errors of metabolism at the metabolic, biochemical, and molecular levels, their exact pathogenesis remains to be established. The mechanisms by which systemic metabolic disease contributes to ocular defects remains to be elucidated. The various mechanisms involved could be due to direct toxic mechanisms of abnormal metabolic products, accumulation of normal metabolites by errors of synthetic pathways, or by deficient energy metabolism.

• #2 Pathophysiology of Inherited Metabolic Disorders: Enzymatic Defects and their Impact on Cellular Metabolism

  https://www.jmolpat.com/jmolpat-articles/pathophysiology-of-inherited-metabolic-disorders-enzymatic-defects-and-their-impact-on-cellular-metabolism-109039.html

  This can lead to hypoglycemia, muscle weakness, and organ dysfunction. […] In other cases, such as in certain types of mucopolysaccharidoses, the inability to degrade glycosaminoglycans leads to their accumulation within lysosomes, causing cellular and tissue damage that appears as delays in development, organomegaly, and skeletal abnormalities. […] The clinical presentation of inherited metabolic disorders is often complex and can vary widely, even among individuals with the same genetic mutation. […] Newborns may appear normal at birth, but symptoms often develop as metabolic demands increase with feeding or illness. […] In some cases, symptoms may be worsening by fasting, stress, or other environmental factors that exacerbate the underlying metabolic defect. […] Early signs can include poor feeding, vomiting, lethargy, and failure to thrive.

• #2

  https://consensus.app/questions/what-causes-consequences-metabolic-disorders/

  Oxidative stress and chronic inflammation contribute to the development of metabolic disorders like obesity, diabetes, and cardiovascular diseases, with strategies for prevention and therapy being crucial. […] Metabolic syndrome, a clustering of risk factors, is primarily caused by central obesity and is linked to insulin resistance, requiring preventive measures and therapeutic strategies in children and adolescents. […] Intracellular stress and inflammation contribute to metabolic disorders like obesity, type 2 diabetes, and non-alcoholic fatty liver disease, with potential therapies targeting stress response pathways. […] Mitochondrial alterations are common to metabolic disorders like Alzheimer’s, obesity, and type 2 diabetes, suggesting impaired coordination between cellular needs and mitochondrial responses. […] Endocrine disrupting chemicals (EDCs) may contribute to the rapid increase in metabolic diseases like obesity, type 2 diabetes, and non-alcoholic fatty liver disease, potentially leading to metabolic syndrome.

• #2 Treatable inherited metabolic disorders causing intellectual disability: 2021 review and digital app | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-021-01727-2

  The past decade has seen revolutionary changes in the diagnosis and discovery of inherited metabolic disorders (IMDs), as well as development of new treatments. […] The ideal outcome of therapy for a treatable ID is the improvement of IQ and related developmental scores. […] The different types of treatment as defined in Table 1A are shown per disorder in Table 3. Nutritional therapy was the most frequently used treatment strategy (32%), followed by pharmacological therapy 22%, vitamin and trace element substitution 22%, solid organ transplantation 8%, hematopoietic stem cell transplant 4%, enzyme replacement therapy 3%, gene-based therapy 2% and other therapy 7% (multiple treatments per disease entity were possible). […] Treatment prevented, halted, or slowed clinical deterioration in 62%, improved neurological manifestations (incl. neuro-imaging) in 47%, systemic manifestations in 44% and psychomotor/cognitive development/IQ in 37%; it prevented acute metabolic decompensation in 30%, improved seizure/epilepsy control in 22% and improved behavioural/psychiatric disturbance(s) in 21%.

• #3 Advances in the Pathogenesis of Metabolic Liver Disease-Related Hepato | JHC

  https://www.dovepress.com/advances-in-the-pathogenesis-of-metabolic-liver-disease-related-hepato-peer-reviewed-fulltext-article-JHC

  AAT deficiency, one of the most prevalent inherited liver diseases, arises from mutations in the SERPINA1 gene, causing misfolding of the ATZ protein and subsequent polymerization within the endoplasmic reticulum of hepatocytes, initiating liver injury. The most common defective type is the Protease Inhibitor (Pi) type Z, and evidence suggests that individuals heterozygous for PiZ are at an elevated risk of developing chronic hepatitis, cirrhosis, and HCC in late childhood. Reports indicate that HCC occurs in 31-67% of cirrhotic AAT-deficient adults. The accumulation of ATZ in the endoplasmic reticulum induces mitochondrial dysfunction, and significant mitochondrial autophagy and damage were observed in the livers of AAT-deficient PiZ mice, accompanied by the presence of markedly activated caspase-3, potentially linked to HCC development. Beyond mitochondrial dysfunction and autophagy, the aggregation of ATZ activates endoplasmic reticulum stress signaling pathways, particularly NF-B activation, ER caspases, and BAP31. NF-B activation is particularly significant for liver injury, as ATZ accumulation can mediate hepatic inflammation via NF-B, including neutrophil infiltration and NF-B-targeted interleukin-8. NF-B activation is closely associated with inflammation-induced carcinogenesis and may play a role in the pathogenesis of AAT deficiency-associated HCC. BAP31, involved in protein polymerization in the endoplasmic reticulum, may contribute to mitochondrial dysfunction and the activation of mitochondrial caspase. In addition, the aggregation of ATZ results in the absence of UPR signaling, potentially allowing the survival of abnormal cells and contributing to the pathogenesis of HCC. Finally, Perlmutter et al found that ATZ accumulation in PiZ mice leads to the proliferation of globule-devoid hepatocytes, heightening the likelihood of HCC development, as adenomas and subsequent carcinomas arise in glomerular livers.

• #3

  https://xiahepublishing.com/1555-3884/GE-2023-00202

  New areas of science that have developed rapidly over the last decade (e.g., epigenetics and transgenerational inheritance) point to another fundamental reason for the development of MetS, linking the internal and external aspects of pathogenesis and allowing us to look at deeper connections when studying this disease. […] At the same time, transient changes in the genome (e.g., methylation and acetylation), which can be inherited among generations and stabilized due to environmental factors, may play a key role in MetS. […] Furthermore, transgenerational effects may be mechanistically mediated by small RNAs, DNA methylation, histone modification, and cellular reprogramming in the hypothalamus. […] The important role of transgenerational inheritance in the development of MetS has been confirmed by studies showing a high risk of developing MetS components in the offspring against a background of the same pathologies in the parents.

• #3

  https://www.archivesofmedicalscience.com/Hepatic-glycogen-storage-diseases-pathogenesis-clinical-symptoms-and-therapeutic,81093,0,2.html

  Glycogen storage diseases (GSDs) are genetically determined metabolic diseases that cause disorders of glycogen metabolism in the body. Due to the enzymatic defect at some stage of glycogenolysis/glycogenesis, excess glycogen or its pathologic forms are stored in the body tissues. […] Glycogen storage disease (GSD) is caused by a genetically determined metabolic block involving enzymes that regulate synthesis (glycogenesis) or glycogen breakdown (glycogenolysis). The nature of the individual types of glycogenosis is related to the impaired accumulation of abnormal molecules of this branched polysaccharide. […] The typical, biochemical characteristics of this type of GSD are postprandial hyperglycemia (blood glucose cannot be stored in the liver and therefore it is kept high in the blood) with subsequent hypoglycemia (no hepatic glycogen storage from which the body could boost the reserves in case of a drop in the blood glucose).

• #3 Inherited metabolic disorders involving the eye: a clinico-biochemical perspective | Eye

  https://www.nature.com/articles/eye2009229

  The diagnosis of inborn errors of metabolism is challenging for most physicians. […] Although there is an extensive understanding of many inborn errors of metabolism at the biochemical, molecular, and metabolic levels, little is known about their pathogenesis. In particular, how systemic metabolic disease contributes to ocular defects remains to be elucidated in IMDs. The occurrence of eye abnormalities could be due to direct toxic mechanisms of abnormal metabolic products or accumulation of normal metabolites by errors of synthetic pathways or by deficient energy metabolism. […] Although there is an extensive understanding of many inborn errors of metabolism at the metabolic, biochemical, and molecular levels, their exact pathogenesis remains to be established. The mechanisms by which systemic metabolic disease contributes to ocular defects remains to be elucidated. The various mechanisms involved could be due to direct toxic mechanisms of abnormal metabolic products, accumulation of normal metabolites by errors of synthetic pathways, or by deficient energy metabolism.

• #3 Pathophysiology of Inherited Metabolic Disorders: Enzymatic Defects and their Impact on Cellular Metabolism

  https://www.jmolpat.com/jmolpat-articles/pathophysiology-of-inherited-metabolic-disorders-enzymatic-defects-and-their-impact-on-cellular-metabolism-109039.html

  This can lead to hypoglycemia, muscle weakness, and organ dysfunction. […] In other cases, such as in certain types of mucopolysaccharidoses, the inability to degrade glycosaminoglycans leads to their accumulation within lysosomes, causing cellular and tissue damage that appears as delays in development, organomegaly, and skeletal abnormalities. […] The clinical presentation of inherited metabolic disorders is often complex and can vary widely, even among individuals with the same genetic mutation. […] Newborns may appear normal at birth, but symptoms often develop as metabolic demands increase with feeding or illness. […] In some cases, symptoms may be worsening by fasting, stress, or other environmental factors that exacerbate the underlying metabolic defect. […] Early signs can include poor feeding, vomiting, lethargy, and failure to thrive.

• #4

  https://www.archivesofmedicalscience.com/Hepatic-glycogen-storage-diseases-pathogenesis-clinical-symptoms-and-therapeutic,81093,0,2.html

  Glycogen storage diseases (GSDs) are genetically determined metabolic diseases that cause disorders of glycogen metabolism in the body. Due to the enzymatic defect at some stage of glycogenolysis/glycogenesis, excess glycogen or its pathologic forms are stored in the body tissues. […] Glycogen storage disease (GSD) is caused by a genetically determined metabolic block involving enzymes that regulate synthesis (glycogenesis) or glycogen breakdown (glycogenolysis). The nature of the individual types of glycogenosis is related to the impaired accumulation of abnormal molecules of this branched polysaccharide. […] The typical, biochemical characteristics of this type of GSD are postprandial hyperglycemia (blood glucose cannot be stored in the liver and therefore it is kept high in the blood) with subsequent hypoglycemia (no hepatic glycogen storage from which the body could boost the reserves in case of a drop in the blood glucose).

• #4 Pathophysiology of Inherited Metabolic Disorders: Enzymatic Defects and their Impact on Cellular Metabolism

  https://www.jmolpat.com/jmolpat-articles/pathophysiology-of-inherited-metabolic-disorders-enzymatic-defects-and-their-impact-on-cellular-metabolism-109039.html

  This can lead to hypoglycemia, muscle weakness, and organ dysfunction. […] In other cases, such as in certain types of mucopolysaccharidoses, the inability to degrade glycosaminoglycans leads to their accumulation within lysosomes, causing cellular and tissue damage that appears as delays in development, organomegaly, and skeletal abnormalities. […] The clinical presentation of inherited metabolic disorders is often complex and can vary widely, even among individuals with the same genetic mutation. […] Newborns may appear normal at birth, but symptoms often develop as metabolic demands increase with feeding or illness. […] In some cases, symptoms may be worsening by fasting, stress, or other environmental factors that exacerbate the underlying metabolic defect. […] Early signs can include poor feeding, vomiting, lethargy, and failure to thrive.

Zobacz więcej