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Advances in Experimental Medicine and... 2020Rare diseases are gathering increasing attention in last few years, not only for its effects on innovation scientific research, but also for its propounding influence on... (Review)
Review
Rare diseases are gathering increasing attention in last few years, not only for its effects on innovation scientific research, but also for its propounding influence on common diseases. One of the most famous milestones made by Michael Brown and Joseph Goldstein in metabolism field is the discovery of the defective gene in familial hypercholesterolemia, a rare human genetic disease manifested with extreme high level of serum cholesterol (Goldstein JL, Brown MS, Proc Natl Acad Sci USA 70:2804-2808, 1973; Brown MS, Dana SE, Goldstein JL, J Biol Chem 249:789-796, 1974). Follow-up work including decoding the gene function, mapping-related pathways, and screening therapeutic targets are all based on the primary finding (Goldstein JL, Brown MS Arterioscler Thromb Vasc Biol 29:431-438, 2009). A series of succession win the two brilliant scientists the 1985 Nobel Prize, and bring about statins widely used for lipid management and decreasing cardiovascular disease risks. Translating the clinical extreme phenotypes into laboratory bench work has turned out to be the first important step in the paradigm conducting translational and precise medical research. Here we review the main categories of rare disorders related with lipoprotein metabolism, aiming to strengthen the notion that human rare inheritable genetic diseases would be the window to know ourselves better, to treat someone more efficiently, and to lead a healthy life longer. Few rare diseases related with lipoprotein metabolism were clustered into six sections based on changes in lipid profile, namely, hyper- or hypocholesterolemia, hypo- or hyperalphalipoproteinemia, abetalipoproteinemia, hypobetalipoproteinemia, and sphingolipid metabolism diseases. Each section consists of a brief introduction, followed by a summary of well-known disease-causing genes in one table, and supplemented with one or two diseases as example for detailed description. Here we aimed to raise more attention on rare lipoprotein metabolism diseases, calling for more work from basic research and clinical trials.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipid Metabolism; Lipid Metabolism, Inborn Errors; Lipoproteins; Rare Diseases
PubMed: 32705600
DOI: 10.1007/978-981-15-6082-8_11 -
Neurologia Mar 2020
Topics: Abetalipoproteinemia; Adult; Chorea; Creatine Kinase; Humans; Male; Mutation; Vesicular Transport Proteins
PubMed: 29752031
DOI: 10.1016/j.nrl.2018.03.012 -
Cells Sep 2023A number of hereditary ataxias are caused by inborn errors of metabolism (IEM), most of which are highly heterogeneous in their clinical presentation. Prompt diagnosis... (Review)
Review
A number of hereditary ataxias are caused by inborn errors of metabolism (IEM), most of which are highly heterogeneous in their clinical presentation. Prompt diagnosis is important because disease-specific therapies may be available. In this review, we offer a comprehensive overview of metabolic ataxias summarized by disease, highlighting novel clinical trials and emerging therapies with a particular emphasis on first-in-human gene therapies. We present disease-specific treatments if they exist and review the current evidence for symptomatic treatments of these highly heterogeneous diseases (where cerebellar ataxia is part of their phenotype) that aim to improve the disease burden and enhance quality of life. In general, a multimodal and holistic approach to the treatment of cerebellar ataxia, irrespective of etiology, is necessary to offer the best medical care. Physical therapy and speech and occupational therapy are obligatory. Genetic counseling is essential for making informed decisions about family planning.
PubMed: 37759536
DOI: 10.3390/cells12182314 -
Best Practice & Research. Clinical... 2022Congenital diarrhea may result from 2 main different mechanisms: 1) osmotic diarrhea is caused by the non-digestion-absorption of nutrients leading to the non-absorbed... (Review)
Review
Congenital diarrhea may result from 2 main different mechanisms: 1) osmotic diarrhea is caused by the non-digestion-absorption of nutrients leading to the non-absorbed nutrients going into the lumen, increasing the osmotic force and driving fluids; 2) secretory diarrhea induced by the inhibition of intestinal absorption of electrolytes, increasing electrolyte and water flux towards the intestinal lumen. The malabsorption of macronutrients (carbohydrates, proteins and lipids) induces energy deficiency with symptoms depending on the macronutrient: carbohydrates with watery acidic diarrhea; protein with rapid malnutrition, edema, and hypoalbuminemia; and lipids with malnutrition, steatorrhea and hypocholesterolemia. Ionic malabsorption (Cl and Na) is responsible for severe and rapid dehydration sometimes with prenatal abnormalities (polyhydramnios and bowel dilatation).
Topics: Digestion; Female; Humans; Intestines; Ions; Lipids; Pregnancy; Sugars
PubMed: 35331397
DOI: 10.1016/j.bpg.2022.101785 -
Gastroenterology May 2021
Topics: Abetalipoproteinemia; Apolipoprotein B-100; Female; Humans; Hyperlipidemia, Familial Combined; Hypobetalipoproteinemia, Familial, Apolipoprotein B; Hypobetalipoproteinemias; Malabsorption Syndromes; Pregnancy; Pregnancy Complications
PubMed: 33275938
DOI: 10.1053/j.gastro.2020.11.040 -
British Journal of Haematology Apr 2022
Topics: Abetalipoproteinemia; Carbazoles; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors
PubMed: 35128635
DOI: 10.1111/bjh.18020 -
JHEP Reports : Innovation in Hepatology Aug 2023Non-alcoholic fatty liver disease (NAFLD) is a complex trait with an estimated prevalence of 25% globally. We aimed to identify the genetic variant underlying a...
BACKGROUND & AIMS
Non-alcoholic fatty liver disease (NAFLD) is a complex trait with an estimated prevalence of 25% globally. We aimed to identify the genetic variant underlying a four-generation family with progressive NAFLD leading to cirrhosis, decompensation, and development of hepatocellular carcinoma in the absence of common risk factors such as obesity and type 2 diabetes.
METHODS
Exome sequencing and genome comparisons were used to identify the likely causal variant. We extensively characterised the clinical phenotype and post-prandial metabolic responses of family members with the identified novel variant in comparison with healthy non-carriers and wild-type patients with NAFLD. Variant-expressing hepatocyte-like cells (HLCs) were derived from human-induced pluripotent stem cells generated from homozygous donor skin fibroblasts and restored to wild-type using CRISPR-Cas9. The phenotype was assessed using imaging, targeted RNA analysis, and molecular expression arrays.
RESULTS
We identified a rare causal variant c.1691T>C p.I564T (rs745447480) in , encoding microsomal triglyceride transfer protein (MTP), associated with progressive NAFLD, unrelated to metabolic syndrome and without characteristic features of abetalipoproteinaemia. HLCs derived from a homozygote donor had significantly lower MTP activity and lower lipoprotein ApoB secretion than wild-type cells, while having similar levels of mRNA and protein. Cytoplasmic triglyceride accumulation in HLCs triggered endoplasmic reticulum stress, secretion of pro-inflammatory mediators, and production of reactive oxygen species.
CONCLUSIONS
We have identified and characterised a rare causal variant in , and homozygosity for pI564T is associated with progressive NAFLD without any other manifestations of abetalipoproteinaemia. Our findings provide insights into mechanisms driving progressive NAFLD.
IMPACT AND IMPLICATIONS
A rare genetic variant in the gene has been identified as responsible for the development of severe non-alcoholic fatty liver disease in a four-generation family with no typical disease risk factors. A cell line culture created harbouring this variant gene was characterised to understand how this genetic variation leads to a defect in liver cells, which results in accumulation of fat and processes that promote disease. This is now a useful model for studying the disease pathways and to discover new ways to treat common types of fatty liver disease.
PubMed: 37484212
DOI: 10.1016/j.jhepr.2023.100764 -
Journal of Movement Disorders Sep 2022Treatable ataxias are a group of ataxic disorders with specific treatments. These disorders include genetic and metabolic disorders, immune-mediated ataxic disorders,...
Treatable ataxias are a group of ataxic disorders with specific treatments. These disorders include genetic and metabolic disorders, immune-mediated ataxic disorders, and ataxic disorders associated with infectious and parainfectious etiology, vascular causes, toxins and chemicals, and endocrinopathies. This review provides a comprehensive overview of different treatable ataxias. The major metabolic and genetic treatable ataxic disorders include ataxia with vitamin E deficiency, abetalipoproteinemia, cerebrotendinous xanthomatosis, Niemann-Pick disease type C, autosomal recessive cerebellar ataxia due to coenzyme Q10 deficiency, glucose transporter type 1 deficiency, and episodic ataxia type 2. The treatment of these disorders includes the replacement of deficient cofactors and vitamins, dietary modifications, and other specific treatments. Treatable ataxias with immune-mediated etiologies include gluten ataxia, anti-glutamic acid decarboxylase antibody-associated ataxia, steroid-responsive encephalopathy associated with autoimmune thyroiditis, Miller-Fisher syndrome, multiple sclerosis, and paraneoplastic cerebellar degeneration. Although dietary modification with a gluten-free diet is adequate in gluten ataxia, other autoimmune ataxias are managed by short-course steroids, plasma exchange, or immunomodulation. For autoimmune ataxias secondary to malignancy, treatment of tumor can reduce ataxic symptoms. Chronic alcohol consumption, antiepileptics, anticancer drugs, exposure to insecticides, heavy metals, and recreational drugs are potentially avoidable and treatable causes of ataxia. Infective and parainfectious causes of cerebellar ataxias include acute cerebellitis, postinfectious ataxia, Whipple's disease, meningoencephalitis, and progressive multifocal leukoencephalopathy. These disorders are treated with steroids and antibiotics. Recognizing treatable disorders is of paramount importance when dealing with ataxias given that early treatment can prevent permanent neurological sequelae.
PubMed: 36065614
DOI: 10.14802/jmd.22069 -
Advances in Experimental Medicine and... 2020Microsomal triglyceride transfer protein (MTP) was first identified as an endoplasmic reticulum (ER) resident protein that helps in the transfer of neutral lipids to... (Review)
Review
Microsomal triglyceride transfer protein (MTP) was first identified as an endoplasmic reticulum (ER) resident protein that helps in the transfer of neutral lipids to nascent apolipoprotein B (apoB). Its critical role in the assembly and secretion of apoB-containing lipoproteins was identified in abetalipoproteinemia patients who have mutations in MTP and completely lack apoB-containing lipoproteins in the circulation. It has been established now that MTP not only is involved in the transfer of neutral lipids but also plays a role in cholesterol ester and cluster of differentiation 1d (CD1d) biosynthesis. Besides neutral lipids, MTP may also help in the transfer of sphingolipids such as ceramides and sphingomyelin to the apoB-containing lipoproteins. MTP is a multifunctional protein, and its deregulation during pathophysiological conditions gives rise to different metabolic conditions. This book chapter discusses the physiological role and regulation of MTP to maintain the homeostasis of lipids and lipoproteins. It also reviews the regulation of MTP during certain pathophysiological conditions and provides a brief overview of therapeutic interventions that can be possibly used to target its activity or expression to alleviate some of these metabolic diseases.
Topics: Abetalipoproteinemia; Apolipoproteins B; Carrier Proteins; Humans; Lipid Metabolism; Metabolic Diseases
PubMed: 32705593
DOI: 10.1007/978-981-15-6082-8_4