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Blood Jun 2023
Topics: Humans; Abetalipoproteinemia
PubMed: 37382999
DOI: 10.1182/blood.2023020260 -
JPGN Reports Nov 2022Cow's milk protein allergy (CMPA) is an abnormal immunologic response to bovine protein that can result in various gastrointestinal and cutaneous manifestations...
Cow's milk protein allergy (CMPA) is an abnormal immunologic response to bovine protein that can result in various gastrointestinal and cutaneous manifestations including diarrhea, failure to thrive, malabsorption, and even protein-losing enteropathy. We describe a case of a 7-month-old breastfed male who presented with severe atopic dermatitis, emesis, oily diarrhea, failure to thrive, electrolyte disturbance, and hemodynamic instability. Following stabilization, additional evaluation revealed concern for abetalipoproteinemia. Ultimately, the patient's symptoms resolved with introduction of an elemental formula and returned with reinitiation of cow's milk protein, confirming the diagnosis of severe CMPA. It is important for the general practitioner to be aware of the various presentations and have a high index of suspicion for CMPA as no symptom or diagnostic test is pathognomonic for diagnosis. Even though it can mimic other causes of malabsorption, a trial with extensively hydrolyzed or elemental formula should be attempted before undertaking invasive testing.
PubMed: 37168480
DOI: 10.1097/PG9.0000000000000246 -
Frontiers in Genetics 2022Dyslipidaemia represents a group of disorders of lipid metabolism, characterized by either an increase or decrease in lipid particles, usually associated with...
Dyslipidaemia represents a group of disorders of lipid metabolism, characterized by either an increase or decrease in lipid particles, usually associated with triglycerides, LDL cholesterol (LDL-C) and/or HDL cholesterol (HDL-C). Most hyperlipidaemias and HDL deficiencies confer an increased cardiovascular risk, while hypolipidaemia, such as abeta or hypobetalipoproteinemia, may present different manifestations ranging from poor weight progression to neurological manifestations. The aim of this study is to present 7 cases with rare dyslipidaemias associated with low LDL or low HDL cholesterol values, referred to our laboratory for the genetic identification of the cause of the dyslipidaemia. Lipid profile was determined for each individual in an automated equipment Integra Cobas (Roche). Molecular analysis was performed by NGS with a target panel of 57 genes involved in lipid metabolism (Sure select QXT, Agilent) and samples were run in a NextSEQ Sequencer (Illumina). Only genes associated to rare forms of low HDL-c or LDL-c were analysed for this work, namely: , , . All rare variants (MAF<5%) found in these genes were confirmed by Sanger sequencing. This study includes 7 index cases (IC), with the following clinical diagnoses: Fish Eye Disease (1), Hypoalphalipoproteinemia (1) and Abetalipoproteinemia (ABL) / Familial Hypobetalipoproteinemia (FHBL) (5). We have identified one IC with a compound heterozygosity in causing Fish Eye Disease and one IC with a variant in in homozygosity causing Tangier disease. We found variants causing homozygous FHBL in 2 IC, one of whom has an undescribed pathogenic variant in homozygosity in (c.12087+1G>A) and the other is a possible compound heterozygous for variants c.2604+1G>A and c.4651C>T/p.(Gln1551*). In two patients only a variant in heterozygosity (c.3365delG/p.(Gly1122Vfs*62) and c.11095A>T/p.(Arg3699*)). In the remaining patient, no variants were identified. NGS proved to be a fundamental key for genetic testing of rare lipid disorders, allowing us to find the genetic cause of disease in 6/7 patients with low HDL-c and LDL-c. Patients with these rare conditions should be identified as early as possible in order to minimize or prevent clinical manifestations. The unsolved case is still under investigation.
PubMed: 37138899
DOI: 10.3389/fgene.2022.1088040 -
Movement Disorders Clinical Practice Mar 2023
PubMed: 36949797
DOI: 10.1002/mdc3.13626 -
Journal of Ayub Medical College,... 2023Klipple-Trenaunay syndrome (KTS) is an extremely rare congenital vascular disorder with poorly defined incidence and prevalence. We report a case of a patient who...
Klipple-Trenaunay syndrome (KTS) is an extremely rare congenital vascular disorder with poorly defined incidence and prevalence. We report a case of a patient who presented after road traffic accident with primary complaints of poor wound healing and persistent bleeding from wound site. Discernible presence of arteriovenous malformation and skin hypertrophy since birth lead to the diagnosis of Klipple-Trenaunay syndrome (KTS). There was an incidental finding of acanthocytosis on peripheral film of blood which remained elevated even after clinical improvement of the patient. This case report highlights a close association of marked acanthocytosis of red blood cells and Klipple-Trenaunay syndrome.
Topics: Humans; Abetalipoproteinemia; Erythrocytes
PubMed: 36849406
DOI: 10.55519/JAMC-01-11307 -
Nutrients Jan 2023Abetalipoproteinemia (FHBL-SD1) and chylomicron retention disease (FHBL-SD3) are rare recessive disorders of lipoprotein metabolism due to mutations in and genes,...
Abetalipoproteinemia (FHBL-SD1) and chylomicron retention disease (FHBL-SD3) are rare recessive disorders of lipoprotein metabolism due to mutations in and genes, respectively, which lead to defective chylomicron formation and secretion. This results in lipid and fat-soluble vitamin malabsorption, which induces severe neuro-ophthalmic complications. Currently, treatment combines a low-fat diet with high-dose vitamin A and E supplementation but still fails in normalizing serum vitamin E levels and providing complete ophthalmic protection. To explore these persistent complications, we developed two knock-out cell models of FHBL-SD1 and FHBL-SD3 using the CRISPR/Cas9 technique in Caco-2/TC7 cells. DNA sequencing, RNA quantification and Western blotting confirmed the introduction of mutations with protein knock-out in four clones associated with i) impaired lipid droplet formation and ii) defective triglyceride (-57.0 ± 2.6% to -83.9 ± 1.6%) and cholesterol (-35.3 ± 4.4% to -60.6 ± 3.5%) secretion. A significant decrease in α-tocopherol secretion was also observed in these clones (-41.5 ± 3.7% to -97.2 ± 2.8%), even with the pharmaceutical forms of vitamin E: tocopherol-acetate and tocofersolan (α-tocopheryl polyethylene glycol succinate 1000). silencing led to a more severe phenotype than silencing, which is consistent with clinical observations. Our cellular models thus provide an efficient tool to experiment with therapeutic strategies and will allow progress in understanding the mechanisms involved in lipid metabolism.
Topics: Humans; alpha-Tocopherol; Apolipoproteins B; Caco-2 Cells; Enterocytes; Hypobetalipoproteinemias; Monomeric GTP-Binding Proteins; Vitamin E
PubMed: 36771214
DOI: 10.3390/nu15030505 -
Journal of Clinical Lipidology 2022The Abetalipoproteinemia and Related Disorders Foundation was established in 2019 to provide guidance and support for the life-long management of inherited... (Review)
Review
The Abetalipoproteinemia and Related Disorders Foundation was established in 2019 to provide guidance and support for the life-long management of inherited hypocholesterolemia disorders. Our mission is "to improve the lives of individuals and families affected by abetalipoproteinemia and related disorders". This review explains the molecular mechanisms behind the monogenic hypobetalipoproteinemia disorders and details their specific pathophysiology, clinical presentation and management throughout the lifespan. In this review, we focus on abetalipoproteinemia, homozygous hypobetalipoproteinemia and chylomicron retention disease; rare genetic conditions that manifest early in life and cause severe complications without appropriate treatment. Absent to low plasma lipid levels, in particular cholesterol and triglyceride, along with malabsorption of fat and fat-soluble vitamins are characteristic features of these diseases. We summarize the genetic basis of these disorders, provide guidance in their diagnosis and suggest treatment regimens including high dose fat-soluble vitamins as therapeutics. A section on preconception counseling and other special considerations pertaining to pregnancy is included. This information may be useful for patients, caregivers, physicians and insurance agencies involved in the management and support of affected individuals.
Topics: Humans; Abetalipoproteinemia; Hypobetalipoproteinemias; Lipid Metabolism Disorders; Homozygote; Vitamins
PubMed: 36243606
DOI: 10.1016/j.jacl.2022.08.009 -
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 -
Journal of Lipid Research Sep 2022The microsomal triglyceride transfer protein (MTP) is essential for the secretion of apolipoprotein B (apoB)48- and apoB100-containing lipoproteins in the intestine and...
The microsomal triglyceride transfer protein (MTP) is essential for the secretion of apolipoprotein B (apoB)48- and apoB100-containing lipoproteins in the intestine and liver, respectively. Loss of function mutations in MTP cause abetalipoproteinemia. Heterologous cells are used to evaluate the function of MTP in apoB secretion to avoid background MTP activity in liver and intestine-derived cells. However, these systems are not suitable to study the role of MTP in the secretion of apoB100-containing lipoproteins, as expression of a large apoB100 peptide using plasmids is difficult. Here, we report a new cell culture model amenable for studying the role of different MTP mutations on apoB100 secretion. The endogenous MTTP gene was ablated in human hepatoma Huh-7 cells using single guide RNA and RNA-guided clustered regularly interspaced short palindromic repeats-associated sequence 9 ribonucleoprotein complexes. We successfully established three different clones that did not express any detectable MTTP mRNA or MTP protein or activity. These cells were defective in secreting apoB-containing lipoproteins and accumulated lipids. Furthermore, we show that transfection of these cells with plasmids expressing human MTTP cDNA resulted in the expression of MTP protein, restoration of triglyceride transfer activity, and secretion of apoB100. Thus, these new cells can be valuable tools for studying structure-function of MTP, roles of different missense mutations in various lipid transfer activities of MTP, and their ability to support apoB100 secretion, compensatory changes associated with loss of MTP, and in the identification of novel proteins that may require MTP for their synthesis and secretion.
Topics: Apolipoprotein B-48; Apolipoproteins B; Carcinoma, Hepatocellular; Carrier Proteins; Cell Line; DNA, Complementary; Humans; Lipoproteins; Liver Neoplasms; RNA, Guide, CRISPR-Cas Systems; RNA, Messenger; Ribonucleoproteins; Triglycerides
PubMed: 35931202
DOI: 10.1016/j.jlr.2022.100257