Alternative titles; symbols
SNOMEDCT: 190787008; ICD10CM: E78.6; ORPHA: 14; DO: 1386;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 4q23 | Abetalipoproteinemia | 200100 | Autosomal recessive | 3 | MTTP | 157147 |
A number sign (#) is used with this entry because abetalipoproteinemia is caused by homozygous or compound heterozygous mutation in the MTP gene (MTTP; 157147) on chromosome 4q23.
See familial hypobetalipoproteinemia (FHBL; 615558) for a similar disorder caused by mutation in the APOB gene (107730).
Abetalipoproteinemia and familial hypobetalipoproteinemia (FBHL; 615558) 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 B-containing particles. Obligate heterozygous parents of ABL patients usually have normal lipids consistent with autosomal recessive inheritance, whereas obligate heterozygous parents of FBHL patients typically have half normal levels of apoB-containing lipoproteins consistent with autosomal codominant inheritance (summary by Lee and Hegele, 2014).
Features are celiac syndrome, pigmentary degeneration of the retina, progressive ataxic neuropathy, and a peculiar 'burr-cell' malformation of the red cells called acanthocytosis. Intestinal absorption of lipids is defective, serum cholesterol very low, and serum beta lipoprotein absent. Almost all of the earlier reported patients were Jewish. For example, the first case was that of an 18-year-old Jewish girl referred to the Consultation Service at the Mt. Sinai Hospital in New York City for diagnostic studies (Bassen and Kornzweig, 1950). The picture was that of Friedreich ataxia and retinitis pigmentosa with red cells of bizarre shapes. The girl had also had protracted steatorrhea from childhood, and a 9-year-old brother had red cells of the same type and early retinal pigmentary changes. For the peculiar red cells, Singer et al. (1952) conferred the designation 'acanthrocytes,' later changed to 'acanthocytes' by Druez (1959).
Autopsy (Sobrevilla et al., 1964) and biopsy of peripheral nerves showed extensive central and peripheral demyelination.
Many of the manifestations of this disorder are the consequence of vitamin E deficiency, and treatment with vitamin E is recommended (Muller et al., 1977; Azizi et al., 1978; Muller and Lloyd, 1982).
Spinocerebellar degeneration occurs with various forms of chronic intestinal malabsorption, including that of cholestatic liver disease and of Crohn disease (Harding et al., 1982). Despite the absence of low density lipoproteins and chylomicron fragments from the plasma of patients with abetalipoproteinemia, the rates of cholesterol synthesis and the number of LDL receptors expressed on freshly isolated cells are not markedly increased.
Glickman et al. (1979) had found absence of apoB immunoreactivity in the enterocytes of 2 abetalipoproteinemia patients and had postulated a genetic defect in the synthesis of apoB. The results of Dullaart et al. (1986) suggest a defect in secretion of apoB or a failure of appropriate secretion with lipids in both liver and intestine.
Pathologic implications of apolipoprotein B were discussed by Brunzell et al. (1983) and by Sniderman et al. (1980).
Lackner et al. (1986) found a massive increase of apoB-100 mRNA in ABL hepatocytes, and the synthesis of apoB, or an apoB-like protein, which is not secreted by the cells. The first result suggested that the apoB-100 gene is considerably up-regulated in this disorder. An abnormally low plasma LDL concentration may be the stimulus. ABL must not be due to a promoter or enhancer defect, because in that case an abnormally low mRNA level would be expected. Neither Southern nor Northern blots revealed any insertions or deletions within the gene, nor did they provide any evidence for a splicing defect. Blackhart et al. (1986) found no abnormality of the APOB gene on Southern blot analysis, but found increased amounts of mRNA and apoB protein in hepatocytes. Blackhart et al. (1986) and Ross et al. (1988) proposed that the molecular defect in abetalipoproteinemia involves defective cellular secretion of the protein. The mutation could be either in the APOB gene itself or in some other product necessary for apoB secretion.
Liver disease is an unusual feature of abetalipoproteinemia. In some patients steatosis of the liver has been found, and in a few patients liver cirrhosis has been observed. In these cases, medium chain triglyceride (MCT) complementation has been implicated as a cause of liver disease (Illingworth et al., 1980; Partin et al., 1974). Braegger et al. (1998) described a 16-year-old girl with abetalipoproteinemia who underwent liver transplantation for hepatic cirrhosis. After this procedure, her serum lipoprotein profile was corrected; however, fat malabsorption and steatorrhea persisted because the primary defect, a mutant MTP, remained expressed in the intestine.
Lee and Hegele (2014) stated that the incidences of both ABL and familial hyopbetalipoproteinemia are reported as less than 1 in 1 million.
Talmud et al. (1988) presented evidence that the defect in abetalipoproteinemia (at least in the 2 families studied) did not involve the APOB gene: in each of these 2 families, 2 affected children inherited different APOB RFLP alleles from at least 1 parent, whereas the sibs would be anticipated to share common alleles if this disorder were due to an APOB mutation. In one of these families, Shoulders et al. (1993) identified a homozygous splicing mutation in the gene encoding the 97-kD subunit of microsomal triglyceride transfer protein (157147.0003).
Microsomal triglyceride transfer protein, which catalyzes the transport of triglyceride, cholesteryl ester, and phospholipid from phospholipid surfaces, is a heterodimer composed of the multifunctional protein, protein disulfide isomerase (176790), and a unique large subunit with an apparent molecular mass of 88 kD (MTP; 157147). MTP is isolated as a soluble protein from the lumen of the microsomal fraction of liver and intestine. Wetterau et al. (1992) demonstrated that MTP activity and the large subunit of MTP were present in intestinal biopsy samples from 8 control persons but were absent in 4 abetalipoproteinemic subjects. They suggested that the findings proved that MTP is the site of the defect in abetalipoproteinemia and that MTP is required for lipoprotein assembly. MTP was normal in chylomicron retention disease (Anderson disease; 246700), a disorder with some of the same features as abetalipoproteinemia. Sharp et al. (1993) demonstrated point mutations in the large MTP subunit in 2 ABL patients (157147.0001-157147.0002).
In a patient with abetalipoproteinemia studied by Wetterau et al. (1992), Rehberg et al. (1996) identified compound heterozygous mutations in the MTTP gene (157147.0005-157145.0006).
In a Japanese patient with abetalipoproteinemia, Ohashi et al. (2000) identified a homozygous missense mutation in the MTP gene (157147.0007). The parents were consanguineous.
In a 58-year-old man with abetalipoproteinemia, Al-Shali et al. (2003) identified a homozygous missense mutation in the MTP gene (157147.0008).
Benayoun et al. (2007) investigated the genetic basis for abetalipoproteinemia in a cohort of Israeli families. In Ashkenazi Jewish patients, Benayoun et al. (2007) identified a conserved haplotype and a common MTP mutation, gly865 to ter (157147.0010), with a carrier frequency of 1:131 in this population. They also reported the first case of abetalipoproteinemia and additional abnormalities in a Muslim Arab patient, due to a homozygous contiguous gene deletion of approximately 481 kb, including MTP and 8 other genes.
Raabe et al. (1998) used gene targeting to knock out the mouse MTP gene (Mttp). In heterozygous knockout mice, the MTP mRNA, protein, and activity levels were reduced by 50% in both liver and intestine. Compared with homozygous normal control mice, chow-fed heterozygous mice had reduced plasma levels of low density lipoprotein cholesterol and had a 28% reduction in plasma apoB-100 levels. On a high-fat diet, the heterozygous mice exhibited a marked reduction in total plasma cholesterol levels, compared with those in homozygous normal mice. Both the liver of adult heterozygous mice and the visceral endoderm of the yolk sacs from heterozygous embryos manifested an accumulation of cytosolic fat. All homozygous knockout embryos died during embryonic development. In the visceral endoderm of homozygous defective yolk sacs, lipoprotein synthesis was virtually absent, and there was a marked accumulation of cytosolic fat droplets. Thus, half-normal MTP levels did not support normal levels of lipoprotein synthesis and secretion, and a complete deficiency of MTP caused lethal developmental abnormalities, perhaps because of an impaired capacity of the yolk sac to export lipids to the developing embryo.
Using haplotype analysis in a study of 8 families with abetalipoproteinemia, Huang et al. (1990) found clear evidence excluding the APOB gene as the site of the mutation in 4 of the families. In the other 4 families, inheritance of the disease was compatible with cosegregation with the APOB alleles but the lod score did not reach statistical significance (0.97 at theta = 0.0).
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