(Bassen Kornzweig syndrome)
- A tale of 2 cousins: An atypical and a typical case of abetalipoproteinemia. [Journal Article]
- JCJ Clin Lipidol 2016 Jul-Aug; 10(4):1030-4
- Abetalipoproteinemia (ABL) is a rare recessive genetic disease caused by mutations of the MTTP gene. This disease is characterised by a defect in the lipidation of APO B and the absence of VLDL and c...
Abetalipoproteinemia (ABL) is a rare recessive genetic disease caused by mutations of the MTTP gene. This disease is characterised by a defect in the lipidation of APO B and the absence of VLDL and chylomicron production. Patients affected by ABL present neurological, hemalogical and gastro-intestinal symptoms due to deficiency in lipophilic vitamins and fat malabsorption. We herein report the case of two cousins, one presenting classical symptoms of abetalipoproteinemia and one presenting a much attenuated phenotype. The proband carried a novel combination of MTTP mutations, the 1867+1G>A and the R540C mutations. This patient never received any vitamin supplements and was relatively free of symptoms despite an undetectable APO B concentration. Her cousin was homozygous for 1867+1G>A MTTP mutation and presented most of the classical symptoms of ABL. In conclusion we report a very unusual kindred where on affected member is strongly symptomatic of ABL whereas the other presents very mostly asymptomatic disease suggesting that ABL can present itself with a very incomplete clinical penetrance.
- Structure-function analyses of microsomal triglyceride transfer protein missense mutations in abetalipoproteinemia and hypobetalipoproteinemia subjects. [Journal Article]
- BBBiochim Biophys Acta 2016; 1861(11):1623-1633
- We describe two new hypolipidemic patients with very low plasma triglyceride and apolipoprotein B (apoB) levels with plasma lipid profiles similar to abetalipoproteinemia (ABL) patients. In these pat...
We describe two new hypolipidemic patients with very low plasma triglyceride and apolipoprotein B (apoB) levels with plasma lipid profiles similar to abetalipoproteinemia (ABL) patients. In these patients, we identified two previously uncharacterized missense mutations in the microsomal triglyceride transfer protein (MTP) gene, R46G and D361Y, and studied their functional effects. We also characterized three missense mutations (H297Q, D384A, and G661A) reported earlier in a familial hypobetalipoproteinemia patient. R46G had no effect on MTP expression or function and supported apoB secretion. H297Q, D384A, and G661A mutants also supported apoB secretion similarly to WT MTP. Contrary to these four missense mutations, D361Y was unable to support apoB secretion. Functional analysis revealed that this mutant was unable to bind protein disulfide isomerase (PDI) or transfer lipids. The negative charge at residue 361 was critical for MTP function as D361E was able to support apoB secretion and transfer lipids. D361Y most likely disrupts the tightly packed middle α-helical region of MTP, mitigates PDI binding, abolishes lipid transfer activity, and causes ABL. On the other hand, the hypolipidemia in the other two patients was not due to MTP dysfunction. Thus, in this study of five missense mutations spread throughout MTP's three structural domains found in three hypolipidemic patients, we found that four of the mutations did not affect MTP function. Thus, novel mutations that cause severe hypolipidemia probably exist in other genes in these patients, and their recognition may identify novel proteins involved in the synthesis and/or catabolism of plasma lipoproteins.
- Identification of novel APOB mutations by targeted next-generation sequencing for the molecular diagnosis of familial hypobetalipoproteinemia. [Journal Article]
- AAtherosclerosis 2016; 250:52-6
- CONCLUSIONS: Our study further demonstrates that NGS is a reliable and practical approach for the molecular screening of FHBL-causative genes that may provide a mean for deciphering the genetic basis in FHBL.
- Microsomal triglyceride transfer protein gene mutations in Turkish children: A novel mutation and clinical follow up. [Journal Article]
- IJIndian J Gastroenterol 2016; 35(3):236-41
- Abetalipoproteinemia (ABL; OMIM 200100) is a rare autosomal recessive disease that affects the absorption of dietary fats and fat soluble vitamins. Here, we describe the clinical and genetic characte...
Abetalipoproteinemia (ABL; OMIM 200100) is a rare autosomal recessive disease that affects the absorption of dietary fats and fat soluble vitamins. Here, we describe the clinical and genetic characteristics of three patients with ABL. Two patients (patients 1 and 2) who were carriers of the c.398-399delAA mutation (previously known mutation) had developmental delay and hepatic steatosis developed at the age of five in patient 1. Patient 3 was the carrier of a novel mutation (g.10886-10902delAAGgtaagtttgtgttg in intron 3 and c.506A>T exon 5) in microsomal triglyceride transfer protein (MTP) gene and had hepatic steatosis.
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- Standard lipid analysis includes measuring serum or plasma total cholesterol, triglycerides, and high density lipoprotein cholesterol (HDL-C) after an overnight fast. Low density lipoprotein choleste...
Standard lipid analysis includes measuring serum or plasma total cholesterol, triglycerides, and high density lipoprotein cholesterol (HDL-C) after an overnight fast. Low density lipoprotein cholesterol (LDL-C) is then calculated. Our own prospective studies from the Framingham Offspring Study indicates that LDL-C, small dense LDL-C (sdLDL-C), lipoprotein(a) or Lp(a), and HDL particle measurements add significant information about cardiovascular disease (CVD) risk to the standard lipid profile. Common familial lipid disorders associated with premature CVD include Lp(a) excess, combined hyperlipidemia, and dyslipidemia. Plasma fatty acid analysis is important in order to assess adequacy of omega-3 fatty acid intake, and whether there are excess levels of saturated and trans fatty acids for dietary recommendations. Plasma sterol analysis can be helpful for the diagnosis of causes of elevated very low density lipoprotein (VLDL-C > 50 mg/dL) and/or LDL-C (> 160 mg/dL) which includes familial combined hyperlipidemia (elevated lathosterol), familial hypercholesterolemia (normal sterols), dysbetalipoproteinemia (moderate increases in β-sitosterol), phytosterolemia (very high β-sitosterol), and cerebrotendinous xanthomatosis (very high cholestanol). The measurement of apolipoprotein (apo) A-I in HDL particles by gel electrophoresis is important in assessing CVD risk, HDL functionality, and for the diagnosis of marked HDL deficiency states (HDL-C < 20 mg/dL due to apoA-I deficiency and variants, Tangier disease and lecithin:cholesteryl acyltransferase (LCAT) deficiency, as well as hepatic lipase and cholesteryl ester transfer protein deficiency. The measurement of apoB is important for the diagnosis of abetalipoproteinemia and hypobetalipoproteinemia. The definitive diagnosis of the above mentioned disorders along with causes of markedly elevated triglycerides (> 1,000 mg/dL) requires next generation DNA sequencing of the appropriate and relevant genes for these disorders in order to provide a definitive molecular diagnosis often necessary to formulate optimal therapy strategies. For complete coverage of this and all related areas of Endocrinology, please visit our FREE web-textbok, www.endotext.org.
- Chylomicrons: Advances in biology, pathology, laboratory testing, and therapeutics. [Review]
- CCClin Chim Acta 2016 Apr 1; 455:134-48
- The adequate absorption of lipids is essential for all mammalian species due to their inability to synthesize some essential fatty acids and fat-soluble vitamins. Chylomicrons (CMs) are large, trigly...
The adequate absorption of lipids is essential for all mammalian species due to their inability to synthesize some essential fatty acids and fat-soluble vitamins. Chylomicrons (CMs) are large, triglyceride-rich lipoproteins that are produced in intestinal enterocytes in response to fat ingestion, which function to transport the ingested lipids to different tissues. In addition to the contribution of CMs to postprandial lipemia, their remnants, the degradation products following lipolysis by lipoprotein lipase, are linked to cardiovascular disease. In this review, we will focus on the structure-function and metabolism of CMs. Second, we will analyze the impact of gene defects reported to affect CM metabolism and, also, the role of CMs in other pathologies, such as atherothrombotic cardiovascular disease and diabetes mellitus. Third, we will provide an overview of the laboratory tests currently used to study CM disorders, and, finally, we will highlight current treatments in diseases affecting CMs.
- HYPERGLYCAEMIC HEMIBALLISMUS: IMPLICATIONS FROM CONNECTIVITY ANALYSIS FOR COGNITIVE IMPAIRMENTS. [Case Reports]
- ISIdeggyogy Sz 2015 Nov 30; 68(11-12):417-21
- Hyperglycaemia induced movement disorders, such as hemiballism are rare disorders. The syndrome is characterised by the triad of hemiballism, contralateral T1-hyperintense striatal lesion and non-ket...
Hyperglycaemia induced movement disorders, such as hemiballism are rare disorders. The syndrome is characterised by the triad of hemiballism, contralateral T1-hyperintense striatal lesion and non-ketotic hyperglycaemia. Here we report a patient with untreated diabetes presenting with acute onset of hemiballism. MRI revealed T1 hyperintensity of the head of the caudate nucleus and the anterior putamen. The patient also had acantocytosis. Based on the detailed examination of the neuroradiological results and earlier findings we will discuss the pathomechanism. Based on previous findings microhemorrhages, extensive mineralisation, gemistocytic astrocytosis might play a role in the development of the imaging signs. The connectivity pattern of the striatal lesion showed extensive connections to the frontal cortex. In coexistence with that the most severe impairment was found on the phonemic verbal fluency task measuring frontal executive functions.
- The role of enterocyte defects in the pathogenesis of congenital diarrheal disorders. [Review]
- DMDis Model Mech 2016; 9(1):1-12
- Congenital diarrheal disorders are rare, often fatal, diseases that are difficult to diagnose (often requiring biopsies) and that manifest in the first few weeks of life as chronic diarrhea and the m...
Congenital diarrheal disorders are rare, often fatal, diseases that are difficult to diagnose (often requiring biopsies) and that manifest in the first few weeks of life as chronic diarrhea and the malabsorption of nutrients. The etiology of congenital diarrheal disorders is diverse, but several are associated with defects in the predominant intestinal epithelial cell type, enterocytes. These particular congenital diarrheal disorders (CDD(ENT)) include microvillus inclusion disease and congenital tufting enteropathy, and can feature in other diseases, such as hemophagocytic lymphohistiocytosis type 5 and trichohepatoenteric syndrome. Treatment options for most of these disorders are limited and an improved understanding of their molecular bases could help to drive the development of better therapies. Recently, mutations in genes that are involved in normal intestinal epithelial physiology have been associated with different CDD(ENT). Here, we review recent progress in understanding the cellular mechanisms of CDD(ENT). We highlight the potential of animal models and patient-specific stem-cell-based organoid cultures, as well as patient registries, to integrate basic and clinical research, with the aim of clarifying the pathogenesis of CDD(ENT) and expediting the discovery of novel therapeutic strategies.
- Hypolipidemia in a Special Operations Candidate: Case Report and Review of the Literature. [Case Reports]
- JSJ Spec Oper Med 2015; 15(4):1-5
- CONCLUSIONS: Individuals with presumed or proven heterozygous FHBL seeking clearance for Special Operations duty should be given precautions, undergo careful questioning for history of disease-specific complications, and should have a baseline evaluation. If negative, it seems reasonable to clear the patient for Special Operations and diving.
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- Homozygous familial hypobetalipoproteinemia: A Turkish case carrying a missense mutation in apolipoprotein B. [Case Reports]
- CCClin Chim Acta 2016 Jan 15; 452:185-90
- The autosomal co-dominant disorder familial hypobetalipoproteinemia (FHBL) may be due to mutations in the APOB gene encoding apolipoprotein B (apoB), the main constituent peptide of chylomicrons, ver...
The autosomal co-dominant disorder familial hypobetalipoproteinemia (FHBL) may be due to mutations in the APOB gene encoding apolipoprotein B (apoB), the main constituent peptide of chylomicrons, very low and low density lipoproteins. We describe an 11month-old child with failure to thrive, intestinal lipid malabsorption, hepatic steatosis and severe hypobetalipoproteinemia, suggesting the diagnosis of homozygous FHBL, abetalipoproteinemia (ABL) or chylomicron retention disease (CMRD). The analysis of candidate genes showed that patient was homozygous for a variant (c.1594 C>T) in the APOB gene causing arginine to tryptophan conversion at position 505 of mature apoB (Arg505Trp). No mutations were found in a panel of other potential candidate genes for hypobetalipoproteinemia. In vitro studies showed a reduced secretion of mutant apoB-48 with respect to the wild-type apoB-48 in transfected McA-RH7777 cells. The Arg505Trp substitution is located in the βα1 domain of apoB involved in the lipidation of apoB mediated by microsomal triglyceride transfer protein (MTP), the first step in VLDL and chylomicron formation. The patient's condition improved in response to a low fat diet supplemented with fat-soluble vitamins. Homozygosity for a rare missense mutation in the βα1 domain of apoB may be the cause of both severe hypobetalipoproteinemia and intestinal lipid malabsorption.