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PubMed1981

Normotriglyceridemic abetalipoproteinemia. absence of the B-100 apolipoprotein.

In the two genetic forms of abetalipoproteinemia described previously, recessive abetalipoproteinemia and homozygous hypobetalipoproteinemia, all lipoproteins that normally contain apolipoprotein B are absent from plasma. We describe here a new disorder in which normal low density and very low density lipoproteins are absent, but in which triglycerides are absorbed from the intestine and chylomicrons are present in plasma. The underlying molecular defect appears to be selective deletion of the hepatogenous B-100 apolipoprotein. The B-48 apolipoprotein found in chylomicrons is spared. These findings suggest that the two species of apolipoprotein B are under separate genetic control and that low density lipoproteins are not normally derived from chylomicrons.

Apolipoproteins↗

PubMed1980

Abetalipoproteinemia. Report of two cases and review of therapy.

The clinical presentation and course of abetalipoproteinemia in two male patients, a child and an adult, are described. Apoprotein B was absent in both cases and each patient had > 50% acanthocytes present on peripheral blood smear. Family studies revealed normal lipid profiles in the parents of both patients, which is consistent with the usual autosomal recessive inheritance of this disorder. In addition to a low-fat diet, both patients have been maintained on high doses of vitamins A and E. In the adult patient, detailed evaluations over a five-year period have failed to show any progression of neurological disease while maintained on high-dose vitamins. The role of supplemental vitamins A and E in the therapy of abetalipoprotenemia is discussed.

Abetalipoproteinemia↗

PubMed1984

Abetalipoproteinemia and metastatic spinal cord glioblastoma.

Abetalipoproteinemia (ABL [Bassen-Kornzweig syndrome]) is characterized by marked hypolipidemia with absence of low-density lipoproteins, fat-soluble vitamin deficiency, spinocerebellar ataxia, and retinitis pigmentosa. Our patient had ABL, severe neurologic disease, and spinal cord malignancy, as well as disseminated CNS and extraneural metastases. It is possible that patients with this disorder and long-standing fat-soluble vitamin deficiency may have increased risk for CNS malignancy.

Abetalipoproteinemia↗

PubMed1993

Abetalipoproteinemia. New insights into lipoprotein assembly and vitamin E metabolism from a rare genetic disease.

Abetalipoproteinemia is a rare genetic disease that has provided important new insights into the physiology of lipoprotein assembly and vitamin E metabolism. Forty-two years after its initial description, a molecular etiology of ABL has been reported to be a deficiency of a microsomal transfer protein, thus suggesting that this protein plays a key role in lipoprotein particle assembly and secretion both in the intestine and in the liver. Furthermore, studies in patients with ABL have established the critical role of hepatic secretion of VLDL in the delivery of vitamin E to peripheral tissues and the essential role of vitamin E in the maintenance of normal physiological function of multiple tissues. The systematic investigation of this rare genetic disease has provided insights that have substantially enhanced our understanding of human physiology.

Abetalipoproteinemia↗

PubMed2000

Microsomal triglyceride transfer protein (MTP) gene mutations in Canadian subjects with abetalipoproteinemia.

Abetalipoproteinemia (ABL) is an extremely rare autosomal recessive disorder, which is characterized by defective assembly and secretion of plasma apolipoprotein (apo) B-containing lipoproteins. ABL results from mutations in the gene encoding the microsomal triglyceride transfer protein (MTP). We sequenced the MTP gene in six Canadian subjects with ABL, of whom four were found to be simple homozygotes and two were found to be compound heterozygotes for MTP gene mutations. Of the 8 MTP gene mutations identified, 6 had not been previously reported, including two new nonsense mutations (K448X and K842X), two new missense mutations (S590I and G746E), one new frameshift mutation (1820del1) and one new splice donor site mutation (G1770A). Despite appropriate treatment with high doses of fat-soluble vitamins in all subjects, there was a wide variation in the progression and severity of the clinical phenotypes. For example, the presence of severe retinopathy and neuropathy did not correlate with the type and position of the mutation, but rather with the age at diagnosis and onset of treatment with fat-soluble vitamins. These findings suggest that genetic and non-genetic factors can modulate the clinical impact of mutant MTP in ABL patients.

Abetalipoproteinemia↗

PubMed1988

In vivo evidence for cholesterol ester and triglyceride exchange between high density lipoprotein and infused triglyceride rich particles in abetalipoproteinemia.

Abetalipoproteinemia is characterized by the absence of chylomicrons, very low density and low density lipoproteins from the plasma. To study neutral lipid exchange between lipoproteins in vivo a chylomicron model, Intralipid R, was infused in an abetalipoproteinemic patient. During a three hour infusion of 250 mg/kg/hr after a priming dose of 100 mg/kg triglyceride, 8% of the triglyceride mass of Intralipid was replaced by cholesterolester, while 8% of the cholesterylester mass was replaced by triglyceride in high density lipoproteins. Thus, the exchange of cholesterylester and triglyceride between high density lipoprotein and triglyceride rich particles in vivo was directly demonstrated in the absence of apolipoprotein B.

Abetalipoproteinemia↗

PubMed1993

Histochemical and ultrastructural pathology of skeletal muscle in a patient with abetalipoproteinemia.

Pathological examination was carried out of the skeletal muscle of an 8-year-old boy with abetalipoproteinemia. The patient complained of diarrhea, and showed a deficiency of betalipoprotein, decreased fat-soluble vitamins, acanthocytosis and a mild increase in serum creatine kinase. The prominent histochemical finding was punctate deposits of acid phosphatase activity in most fibers. Ultrastructural lesions revealed a number of giant lysosomes. Although these pathological findings seemed to be related to vitamin E deficiency, other pathological findings such as concentric laminated bodies or filamentous bodies were also observed. The clinical course and the changes in the pathological findings in our patient after long-term vitamin E therapy need to be observed.

Abetalipoproteinemia↗

PubMed1977

Abetalipoproteinemia (Bassen-Kornzweig syndrome). Muscle involvement.

A 26-year old male suffered from Abeta-lipoproteinemia (Bassen-Kornzweig disease). In addition to C.N.S. lesions, he had myopathy. A muscle biopsy revealed accumulation of ceroid pigment in the striated muscle. A few muscle fibers showed severe degeneration of the myofibrils. Fibroblasts and macrophages in the interstitial tissue contained abundant ceroid. The relation between ceroid accumulation, abetalipoproteinemia and vitamin E-deficiency is discussed.

Abetalipoproteinemia↗

PubMed1984

Alterations in erythrocyte membrane lipids in abetalipoproteinemia: phospholipid and fatty acyl composition.

Scanning electron microscopic observation revealed that there were wide variations including typical acanthocytes in morphology of erythrocytes from a patient with abetalipoproteinemia. The erythrocyte membrane phospholipids and cholesterol contents from a patient was higher by 25% compared to an age-matched control subject. Analysis of phospholipid composition of red blood cells showed an increase of sphingomyelin (25.1----30.1%) with a concomitant decrease of lecithin (27.5----21.0%). Thus, the sphingomyelin/lecithin ratio was increased dramatically (0.91----1.43). As for fatty acyl chain composition of main phospholipids, an increased percentage of palmitic acid and docosahexaenoic acid and a decreased proportion of arachidonic acid and lignoceric acid were observed for sphingomyelin. There was an increment of palmitic acid which was accompanied with a decrease of linoleic acid in lecithin. On the other hand, no significant difference was shown in the fatty acid composition of phosphatidylethanolamine and phosphatidylserine plus phosphatidylinositol between a patient and control.

Abetalipoproteinemia↗

PubMed1985

Somatosensory evoked potentials in abetalipoproteinemia.

Visual, brain-stem auditory, and somatosensory evoked potentials (SEPs) were obtained on a patient with known abetalipoproteinemia. Only the SEP was abnormal, and it correlated with the reported neuropathology of this disease. Serial SEP studies remained stable, as had the clinical condition of this patient on vitamin E therapy. The SEP may supplement clinical examination in follow-up of patients under treatment.

Abetalipoproteinemia↗

PubMed1989

Hepatic peroxisomal abnormalities in abetalipoproteinemia.

Spinocerebellar degeneration in a 17-yr-old boy with abetalipoproteinemia was associated with vitamin E deficiency and hepatic steatosis. In liver biopsy samples before and after 15 mo of vitamin E treatment, hepatocellular peroxisomes were morphologically abnormal; pleomorphic, with a broadened range of sizes; often larger than normal; and with marginal bars in some. In the first sample, peroxisomes exhibited matrical heterogeneity and dense nucleoids. Peroxisomes in the second biopsy sample lacked nucleoids and contained more homogeneous matrices. The mean peroxisomal diameter increased from 0.77 +/- 0.33 to 0.86 +/- 0.32 microM (normal, 0.62 +/- 0.14). These observations raise the possibility that peroxisomes may be involved in the metabolism of apolipoprotein B or may be affected by the disturbances of hepatocellular lipid metabolism caused by this disease.

Abetalipoproteinemia↗

PubMed1985

Platelet function in a case with abetalipoproteinemia.

Platelet aggregation, [14C]serotonin release and platelet malondialdehyde production were determined in a patient with abetalipoproteinemia (ABL) and found to be normal. The patient demonstrated complete absence of apolipoprotein (apo) B and decreased apo A-I concentration in plasma. The high density lipoprotein (HDL) composition of plasma was abnormal, with an increased cholesterol/protein ratio, increased apo E levels and reduced apo C concentration. The patient's platelets, like platelets derived from a normolipidemic control, possessed receptors capable of binding lipoproteins. On incubating washed platelets derived from a control subject with HDL obtained from the ABL patient, an enhancement in platelet function was observed. A similar concentration of HDL derived from the control had the opposite effect, a depression of platelet function. Lipoprotein-deficient plasma (LPDP) derived from the patient, on the other hand, decreased platelet aggregation and [14C]serotonin release in comparison to the LPDP obtained from the control. The normal platelet function observed in the patient appears to be the result of the platelet-enhancing effect of an abnormal HDL, thus compensating for the absence of low and very low density lipoproteins from the patient's plasma which, when present, stimulate platelet function.

Abetalipoproteinemia↗

PubMed1987

The influence of plasma lipoproteins from patients with abetalipoproteinemia on cellular cholesterol esterification.

In normal humans low density lipoproteins (LDL) constitute the major lipoprotein responsible for the delivery of cholesterol to cells and their uptake results in a decrease in cholesterol biosynthesis and an increase in cholesterol esterification. In the present study, we have examined whether plasma lipoproteins from patients with abetalipoproteinemia (ABL), who lack LDL in their plasma, can stimulate intracellular cholesterol esterification and, quantitatively, how this compares with normal LDL. Fibroblasts from normal and abetalipoproteinemic patients had similar cholesterol esterification rates when LDL was present in the medium. Esterification rates using ABL HDL2 were significantly higher than that of normal HDL2 in both normal and ABL fibroblasts. However, maximal rates of cellular cholesterol delivery are considerably greater for normal LDL than for the HDL2 particles in ABL plasma. Our results indicate that lipoprotein particles present in the HDL2 fraction of plasma from patients with ABL are able to provide sufficient cholesterol to cells so that cholesterol esterification is stimulated.

Abetalipoproteinemia↗

PubMed1994

Discrimination between RRR- and all-racemic-alpha-tocopherols labeled with deuterium by patients with abetalipoproteinemia.

The ability to discriminate between stereoisomers of alpha-tocopherol was studied in five patients with abetalipoproteinemia (ABL) because an impairment in secretion of apolipoprotein B-containing lipoproteins might impede the normally enhanced plasma transport of RRR-alpha-tocopherol. An oral dose containing 3.7 g of each 2R, 4'R,8'R-alpha-[5-C2H3]tocopheryl acetate (d3RRR-alpha-tocopheryl acetate) and 2RS,4'RS,8'RS-alpha-[5,7-(C2H3)2]tocopheryl acetate (d6 all rac-alpha-tocopheryl acetate) was administered, then the labeled and unlabeled alpha-tocopherol contents of plasma and red blood cells from multiple blood samples obtained at selected times up to 72 h following the dose were quantitated. ABL plasma contained about 1%-10% of the d3-RRR-alpha-tocopherol concentrations of normal subjects given only 150 mg of each isotope. Three of the patients discriminated between forms of alpha-tocopherol with ratios of RRR-/allrac-alpha-tocopherol > or = 1.8, similar to normals. These data suggest that the hepatic tocopherol binding protein is present and functional in ABL patients. Although two of the patients did not discriminate between stereoisomers of alpha-tocopherol, it is likely that this resulted from nearly a complete block in very low density lipoprotein (VLDL) secretion. Thus, the ability of ABL patients to absorb and transport orally administered vitamin E is markedly impaired and variable among patients.

Abetalipoproteinemia↗

PubMed1995

Lipoproteins containing apolipoprotein B isolated from patients with abetalipoproteinemia and homozygous hypobetalipoproteinemia: identification and characterization.

Abetalipoproteinemia (ABL) and homozygous hypobetalipoproteinemia (HBL) are inherited disorders which are classically characterized by progressive retinal and spinocerebellar disease, fat-soluble vitamin deficiency, and absence of apolipoprotein (apo) B from the plasma. Using immunoaffinity chromatography with an anti-apo B antiserum, we isolated apo B-containing lipoprotein (LpB) particles from the plasma of 4 ABL and 2 HBL patients. The LpB particles were characterized and compared with low density lipoprotein (LDL) and LpB isolated from normal plasma. The ABL/HBL LpB particles were similar in size and charge to normal LpB particles but were relatively enriched in several other apolipoproteins. They contained alpha-tocopherol in a ratio to cholesterol that was proportionately much higher than the very low ratio of alpha-tocopherol to cholesterol in plasma. They bound saturably to fibroblasts and were internalized and degraded similarly to LDL. Hence, the molecular defects in ABL and HBL permit the secretion of a very small number of apo B-containing lipoproteins which may be important for transport of alpha-tocopherol to peripheral tissues.

Abetalipoproteinemia↗

PubMed2004

The c.419-420insA in the MTP gene is associated with abetalipoproteinemia among French-Canadians.

Abetalipoproteinemia (ABL) is a rare autosomal recessive disease characterised by the absence of apolipoprotein B (apoB) containing lipoproteins and, in consequence, very low triglyceride and cholesterol levels. Microsomal triglyceride transfer protein (MTP) has been associated with ABL. A search for sequence variants in the large subunit of MTP in a kindred of 10 individuals from Saguenay-Lac-St Jean area with a propositus exhibiting ABL as well as in four independent patients from the greater Quebec city area and exhibiting very low apoB and LDL-cholesterol levels identified 12 variations. Only one sequence variation, the c.419-420insA, was observed, in the homozygous form, in the abetalipoproteinemic patient. The -493G/-400A/-164T/282G/383T/419-420insA/453T/891C/969T/1151A/2884G haplotype carries the insertion and was found in all members of the family studied. In conclusion, the present study showed that the c.419-420insA alone, in the homozygous form, is a cause of classical recessive inherited ABL in the French-Canadian population.

Abetalipoproteinemia↗

PubMed1992

Genetic analysis of a Japanese family with normotriglyceridemic abetalipoproteinemia indicates a lack of linkage to the apolipoprotein B gene.

Normotriglyceridemic abetalipoproteinemia is a rare familial disorder characterized by an isolated deficiency of apoB-100. We have previously reported a patient with this disease, who had normal apoB-48 but no apoB-100. To elucidate the genetic abnormalities in this family, we studied the linkage of apoB gene using three genetic markers. The proband and her affected brother showed completely different apoB gene alleles, suggesting that the apoB gene itself is not related to this disorder in this family. By contrast, an American case had a point substitution in the apoB gene generating an in-frame stop codon. These results indicate that this disorder can be caused by defect(s) of either an apoB gene or other genes.

Abetalipoproteinemia↗

PubMed1984

Ocular abnormalities in abetalipoproteinemia. A clinicopathologic correlation.

The present paper documents the clinical characteristics and ocular pathology in a patient with abetalipoproteinemia. Noteworthy were: the predominant involvement of the posterior fundus characterized by a loss of photoreceptors; loss or attenuation of the pigment epithelium (producing a sharply demarcated white appearance on ophthalmoscopy); preservation of the submacular pigment epithelium with an excessive accumulation of lipofuscin (including bizarre laminar profiles by electron microscopy); invasion of the retina by macrophage-like pigmented cells. The retina and pigment epithelium in the periphery were morphologically normal. The patient died of a presumably unrelated brain tumor which was believed to have accounted for the terminal blindness and loss of ganglion cells in the retina.

Abetalipoproteinemia↗