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Bassen Kornzweig syndrome [keywords]
- Novel missense MTTP gene mutations causing abetalipoproteinemia. [JOURNAL ARTICLE]
- Biochim Biophys Acta 2014 Aug 6.
The microsomal triglyceride transfer protein (MTTP) plays a critical role in the formation of hepatic very low density lipoprotein. Abetalipoproteinemia (ABL) is a rare, naturally occurring extreme form of MTTP inhibition, which is characterized by the virtual absence of apolipoprotein (apo) B-containing lipoproteins in blood. The goal of this study was to examine the effect that four novel MTTP missense mutations had on protein interactions, expression and lipid-transfer activity, and to determine which mutations were responsible for the ABL phenotype observed in two patients.In two patients with ABL, we identified in MTTP a novel frameshift mutation (p.K35Ffs*37), and four novel missense mutations, namely, G264R, Y528H, R540C, and N649S. When transiently expressed in COS-7 cells, all missense MTTP mutations interacted with apoB17, apoB48, and protein disulfide isomerase. Mutations Y528H and R540C, however, displayed negligible levels of MTTP activity and N649S displayed a partial reduction relative to the wild-type MTTP. In contrast, G264R retained full lipid-transfer activity.These studies indicate that missense mutations Y528H, R540C, and N649S appear to cause ABL by reducing MTTP activity rather than by reducing binding of MTTP with protein disulfide isomerase or apoB. The region of MTTP containing amino acids 528 and 540 constitutes a critical domain for its lipid-transfer activity.
- Intractable Diarrhea of Infancy: Ten Years of Experience. [JOURNAL ARTICLE]
- J Pediatr Gastroenterol Nutr 2014 Jul 2.
'Intractable diarrhea of infancy' (IDI), a group of prolonged diarrheal disorders, has difficulties in diagnose and management. As a referral centre in Turkey, we documented general features of patients and the causes of IDI.This retrospective study included 60 hospitalized IDI patients aged 0-24 months old in the period of January 2000-December 2010. Detailed history, laboratory and endoscopic findings, diagnoses and clinical courses were reviewed. Descriptive analyses were used for statistical evaluation.Male/female ratio was 1.4. The median age of diarrhea onset was 12 days. Seventy and eleven percent of patients were severe and moderate malnourished, respectively. Carbohydrate malabsorption (CM) and food allergies (n = 11, 18% for both) were the most frequent causes. Sixteen of the patients (27%) didn't have a specific diagnose. The other diagnosis were infections (n = 5), immune mediated disorders (IMD) (n = 6), congenital enterocyte defects (CED) (n = 3, 5%), short bowel syndrome (n = 2), cystic fibrosis (n = 2), intestinal pseudoobstruction (n = 1), congenital disorder of glycosylation (n = 1), abetalipoproteinemia (n = 1) and proprotein convertase (PC)1 deficiency (n = 1). Stool calprotectin level was high in 10 out of 19 patients with Crohn's disease (n = 3, mean:1116±851 mg/L), food allergy (n = 4, mean: 516 ± 288 mg/L) and undefined etiology (n = 3, mean: 616 ± 780 mg/L). The mean duration of hospitalization was 76 days. CONCLUSıON:: IDI is a heterogenous group of diarrheal disorders. The most frequent causes were CM and food allergies in our study. As high levels of calprotectin supports inflammation, calprotectin levels may help to discriminate CED and inflammatory causes of IDI.
- Hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia due to homozygous MTTP and APOB mutations. [JOURNAL ARTICLE]
- J Hepatol 2014 May 16.
Non-alcoholic steatohepatitis leading to fibrosis occurs in patients with abetalipoproteinemia (ABL) and homozygous or compound heterozygous familial hypobetalipoproteinemia (Ho-FHBL). We wanted to establish if liver alterations were more frequent in one of both diseases and were influenced by comorbidities.We report genetic, clinical, histological and biological characteristics of new cases of ABL (n=7) and Ho-FHBL (n=7), and compare them with all published ABL (51) and Ho-FHBL (22) probands.ABL patients, diagnosed during infancy, presented mainly with diarrhea, neurological and ophthalmological impairments and remained lean, whereas Ho-FHBL were diagnosed later, with milder symptoms often becoming overweight in adulthood. Despite subtle differences in lipid phenotype, liver steatosis was observed in both groups with a high prevalence of severe fibrosis (5/27 for Ho-FHBL vs 4/58 for ABL (ns)). Serum triglycerides concentration was higher in Ho-FHBL whereas total and HDL-cholesterol were similar in both groups. In Ho-FHBL liver alterations were found to be independent from the apoB truncation size and apoB concentrations.Our findings provide evidence for major liver abnormalities in both diseases. While ABL and Ho-FHBL patients have subtle differences in lipid phenotype, carriers of APOB mutations are more frequently obese. These results raise the question of a complex causal link between apoB metabolism and obesity. They suggest that the genetic defect in VLDL assembly is critical for the occurrence of liver steatosis leading to fibrosis and shows that obesity and insulin resistance might contribute by increasing lipogenesis.
- Zebrafish yolk lipid processing: a tractable tool for the study of vertebrate lipid transport and metabolism. [Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't]
- Dis Model Mech 2014 Jul; 7(7):915-27.
Dyslipidemias are a major cause of morbidity and mortality in the world, particularly in developed nations. Investigating lipid and lipoprotein metabolism in experimentally tractable animal models is a crucial step towards understanding and treating human dyslipidemias. The zebrafish, a well-established embryological model, is emerging as a notable system for studies of lipid metabolism. Here, we describe the value of the lecithotrophic, or yolk-metabolizing, stages of the zebrafish as a model for studying lipid metabolism and lipoprotein transport. We demonstrate methods to assay yolk lipid metabolism in embryonic and larval zebrafish. Injection of labeled fatty acids into the zebrafish yolk promotes efficient uptake into the circulation and rapid metabolism. Using a genetic model for abetalipoproteinemia, we show that the uptake of labeled fatty acids into the circulation is dependent on lipoprotein production. Furthermore, we examine the metabolic fate of exogenously delivered fatty acids by assaying their incorporation into complex lipids. Moreover, we demonstrate that this technique is amenable to genetic and pharmacologic studies.
- Update on primary hypobetalipoproteinemia. [Journal Article]
- Curr Atheroscler Rep 2014 Jul; 16(7):423.
"Primary hypobetalipoproteinemia" refers to an eclectic group of inherited lipoprotein disorders characterized by low concentrations of or absence of low-density lipoprotein cholesterol and apolipoprotein B in plasma. Abetalipoproteinemia and homozygous familial hypobetalipoproteinemia, although caused by mutations in different genes, are clinically indistinguishable. A framework for the clinical follow-up and management of these two disorders has been proposed recently, focusing on monitoring of growth in children and preventing complications by providing specialized dietary advice and fat-soluble vitamin therapeutic regimens. Other recent publications on familial combined hypolipidemia suggest that although a reduction of angiopoietin-like 3 activity may improve insulin sensitivity, complete deficiency also reduces serum cholesterol efflux capacity and increases the risk of early vascular atherosclerotic changes, despite low low-density lipoprotein cholesterol levels. Specialist laboratories offer exon-by-exon sequence analysis for the molecular diagnosis of primary hypobetalipoproteinemia. In the future, massively parallel sequencing of panels of genes involved in dyslipidemia may play a greater role in the diagnosis of these conditions.
- Clinical, hematological, and imaging observations in a 25-year-old woman with abetalipoproteinemia. [Journal Article]
- Ann Indian Acad Neurol 2014 Jan; 17(1):113-6.
Abetalipoproteinemia is an uncommon cause of ataxia and retinitis pigmentosa (RP). Most of the neurological and ocular manifestations occur secondary to deficiency syndromes that is consequent to fat malabsorption from the small intestine. In this report, we have described the phenotype of a young adult female who manifested with recurrent diarrheal illness in her first decade, followed by anemia, RP, and neurological involvement with progressive deafness, cerebellar and sensory ataxia, and subclinical neuropathy in her second decade of life. While RP and sensory ataxia due to vitamin E deficiency are well-recognized features of abetalipoproteinemia, deafness is rarely described. In addition, we have highlighted the abnormal posterior column signal changes in the cervical cord in this patient. Early recognition avoids unnecessary investigations and has a potential to retard the disease progression by replacing some of the deficient vitamins.
- Hypobetalipoproteinemia and abetalipoproteinemia. [JOURNAL ARTICLE]
- Curr Opin Lipidol 2014 Apr 21.
Several mutations in the apoB, proprotein convertase subtilisin/kexin type 9 (PCSK9), and MTP genes result in low or absent levels of apoB and LDL-cholesterol in plasma, which cause familial hypobetalipoproteinemia and abetalipoproteinemia. Mutations in the ANGPTL3 gene cause familial combined hypolipidemia. Clinical manifestations range from none to severe, debilitating, and life-threatening disorders. This review summarizes recent genetic, metabolic, and clinical findings and presents an update on management strategies.Cases of cirrhosis and hepatocellular carcinoma have now been identified in heterozygous familial hypobetalipoproteinemia probably because of decreased triglyceride transport capacity from the liver. ANGPTL3 mutations cause low levels of LDL-cholesterol and low HDL-cholesterol in compound heterozygotes and homozygous individuals, decrease reverse cholesterol transport, and lower glucose levels. The effect on atherosclerosis is unknown; however, severe fatty liver has been identified. Loss-of-function mutations in PCSK9 cause familial hypobetalipoproteinemia, which appears to lower risk for coronary artery disease and has no adverse sequelae. Phase III clinical trials are now underway examining the effect of PCSK9 inhibitors on cardiovascular events in combination with statin drugs.Mutations causing low LDL-cholesterol and apoB have provided insight into lipid metabolism, disease associations, and the basis for drug development to lower LDL-cholesterol in disorders causing high levels of cholesterol. Early diagnosis and treatment are necessary to prevent adverse sequelae from familial hypobetalipoproteinemia and abetalipoproteinemia.
- Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management. [JOURNAL ARTICLE]
- J Inherit Metab Dis 2013 Nov 28.
Abetalipoproteinemia (ABL; OMIM 200100) and homozygous hypobetalipoproteinemia (HHBL; OMIM 107730) are rare diseases characterized by hypocholesterolemia and malabsorption of lipid-soluble vitamins leading to retinal degeneration, neuropathy and coagulopathy. Hepatic steatosis is also common. The root cause of both disorders is improper packaging and secretion of apolipoprotein (apo) B-containing lipoprotein particles due to mutations either in both alleles of the MTP (alias MTTP) gene encoding microsomal triglyceride transfer protein (MTP) or both alleles of the APOB gene itself in the case of ABL and HHBL, respectively. Clinical diagnosis is based on signs and symptoms, acanthocytosis on blood smear, and virtually absent apo B-containing lipoproteins, including chylomicrons, very low density lipoprotein and low density lipoprotein. Obligate heterozygote parents of ABL patients usually have normal lipids consistent with autosomal recessive inheritance, while heterozygous parents of HHBL patients typically have half normal levels of apo B-containing lipoproteins consistent with autosomal co-dominant inheritance. Definitive diagnosis involves sequencing the MTP and APOB genes, for which >30 and >60 mutations have been described for ABL and HHBL, respectively. Follow-up includes monitoring for ophthalmologic, neurologic, hematologic, and hepatic complications, as well as compliance with treatment. Investigations include lipid profile, serum transaminases, markers for lipid-soluble vitamins, and periodic instrumental assessment of ocular and neurological function. Mainstays of treatment include adherence to a low-fat diet, and supplementation with essential fatty acids and high oral doses of fat soluble vitamins. Prognosis is variable, but early diagnosis and strict adherence to treatment can recover normal neurological function and halt disease progression.
- Knee pain: an unanticipated finding related to a rare genetic disorder--abetalipoproteinemia. [Journal Article]
- J Am Assoc Nurse Pract 2013 Jun; 25(6):297-301.
The purpose of this case study is to raise awareness about an uncommon cause of knee pain.Review of literature was done using PubMed, CINAHL, and Medline. There was no limitation placed on the publication year. Only articles written in English were included.Knee pain is a common diagnosis that many healthcare providers see on a daily basis in their practice. Musculoskeletal injury or trauma is most commonly identified as the cause of this symptom. However, there are rare instances in which an unexpected finding in a client's history and physical exam lead us to an unexpected cause, such as abetalipoproteinemia. Abetalipoproteinemia is a rare autosomal recessive disorder in which an affected individual does not absorb lipids or the lipid-soluble vitamins A, D, E, and K. Multiple body systems are impacted by this fat malabsorption and resultant vitamin deficiencies. Without corrective supplementation, clinical manifestations which are directly related to the vitamin deficiencies will appear as presented in this case study-knee pain.This case study emphasizes the need for nurse practitioners to seek out opportunities to further our knowledge which will enhance our clinical expertise as well as the quality of the health care we provide to our clients.
- Clinical features and molecular genetics of two Tunisian families with abetalipoproteinemia. [Journal Article]
- J Clin Neurosci 2014 Feb; 21(2):311-5.
Abetalipoproteinemia (ABL) is a rare monogenic disease characterized by very low plasma levels of cholesterol and triglyceride and almost complete absence of apolipoprotein B (apoB)-containing lipoproteins. Typically, patients present with failure to thrive, acanthocytosis, pigmented retinopathy and neurological features. It has been shown that ABL results from mutations in the gene encoding the microsomal triglyceride transfer protein (MTTP). Sanger sequencing of MTTP was performed for two unrelated consanguineous Tunisian families with two affected individuals each, presenting a more severe ABL phenotype than previously reported in the literature. The patients were found to be homozygous for two novel mutations. In the first family, a nonsense mutation, c.2313T>A, leading to a truncated protein (p.Y771X) was identified. In the second family, a splice mutation, IVS 9+2T>G, was found. These mutations are believed to abolish the assembly and secretion of apoB-containing lipoproteins.