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HYPOBETALIPOPROTEINEMIA, FAMILIAL, 1; FHBL1

HYPOBETALIPOPROTEINEMIA, FAMILIAL, 1; FHBL1

Alternative titles; symbolsHYPOBETALIPOPROTEINEMIA, FAMILIAL; FHBLACANTHOCYTOSIS WITH HYPOBETALIPOPROTEINEMIAHYPOBETALIPOPROTEINEMIA, NORMOTRIGLYCERIDEMICOther e...

Alternative titles; symbols

  • HYPOBETALIPOPROTEINEMIA, FAMILIAL; FHBL
  • ACANTHOCYTOSIS WITH HYPOBETALIPOPROTEINEMIA
  • HYPOBETALIPOPROTEINEMIA, NORMOTRIGLYCERIDEMIC

Other entities represented in this entry:

  • LOW DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS 4, INCLUDED; LDLCQ4, INCLUDED

Hypobetalipoproteinemia (FHBL) and abetalipoproteinemia (ABL; 200100) 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 FHBL patients typically have half normal levels of apoB-containing lipoproteins consistent with autosomal codominant inheritance, whereas obligate heterozygous parents of ABL patients usually have normal lipids consistent with autosomal recessive inheritance (summary by Lee and Hegele, 2014).

Genetic Heterogeneity of Familial Hypobetalipoproteinemia

Familial hypobetalipoproteinemia-2 (FHBL2; 605019) is caused by mutation in the ANGPTL3 gene (604774) on chromosome 1p31.

▼ Clinical Features

Brown et al. (1974) noted that the consistent laboratory findings of reduced serum cholesterol and beta-lipoprotein define hypobetalipoproteinemia as a distinct syndrome. They found 4 reported kindreds and added a fifth. Only 2 of the patients in the reported families had symptoms. Mars et al. (1969) observed a family in which 1 of the 14 hypobetalipoproteinemic persons (in 3 generations), a 37-year-old woman, had signs and symptoms of progressive demyelination of the central nervous system, lack of responsiveness to local anesthesia, and dislike for animal fats and milk. The family reported by Brown et al. (1974) contained a child with psychomotor retardation. Although the peripheral blood smear showed no acanthocytes, the red cells on symptomatic and asymptomatic persons became acanthocytotic when placed in tissue culture medium with 10% autologous serum.

Biemer and McCammon (1975) described a family and reviewed others in the literature in which a person with 'homozygous hypobetalipoproteinemia' had occurred. They pointed out that although some of these cases were milder than cases of abetalipoproteinemia (ABL; 200100), homozygous hypobetalipoproteinemia could often be distinguished from abetalipoproteinemia only by the demonstration of presumably heterozygous hypobetalipoproteinemic first-degree relatives of the homozygote.

Kahn and Glueck (1978) reported remarkable freedom from atheroma in a 76-year-old woman who died from hepatic failure due apparently to hemochromatosis. The woman had been found to have hypobetalipoproteinemia in a study done previously (Glueck et al., 1976). This and hyperalphalipoproteinemia (143470) are accompanied by increased life expectancy.

Steinberg et al. (1979) described a kindred with a form of hypobetalipoproteinemia characterized by unusually low LDL cholesterol, normal triglyceride levels, low levels of HDL, mild fat malabsorption, and a defect in chylomicron clearance. On a high-carbohydrate diet, the triglyceride levels of the 67-year-old proband fell rather than rose. The proband, a retired Naval chaplain, was asymptomatic. He came to attention because of total serum cholesterol of 47 mg/dl. The proband's mother, aged 92, 1 brother, 1 sister, and 2 daughters also had hypobetalipoproteinemia. Young et al. (1987) found an abnormality of apoB, called apolipoprotein B37, in the plasma lipoproteins of multiple members of this kindred. Young et al. (1987) reported an intensive study of 41 members in 3 generations of this kindred. They documented the presence, in addition to the abnormal, truncated apoB species B37, of another apoB allele that was associated with reduced plasma concentrations of the normal apoB100. The proband (H.J.B.) and 2 of his sibs had both abnormal apoB alleles and were therefore compound heterozygotes for familial hypobetalipoproteinemia. All of the offspring of the 3 compound heterozygotes had hypobetalipoproteinemia, and each had evidence of only 1 of the abnormal apoB alleles. The average LDL cholesterol level in the compound heterozygotes was 6 mg/dl; in the 6 heterozygotes who had only the abnormal apoB37 allele, 31 mg/dl; in the 10 heterozygotes who had only the allele for reduced plasma concentrations of apoB100, 31 mg/dl; and in 22 unaffected family members, 110 mg/dl.

Malloy et al. (1981) described a patient with a metabolic disorder that they termed 'normotriglyceridemia abetalipoproteinemia.' The disorder was characterized by the absence of LDLs and apoB100 in plasma with apparently normal secretion of triglyceride-rich lipoproteins containing apoB48. Homer et al. (2005) suggested that the term 'normotriglyceridemic hypobetalipoproteinemia' is preferred to 'normotriglyceridemic abetalipoproteinemia' because abetalipoproteinemia (ABL; 200100) refers to the disorder caused by mutation in the MTP gene (157147).

Berger et al. (1983) studied a kindred in which the proband manifested the clinical and biochemical features of the homozygous state. Unlike the apparent absence of apolipoprotein B in the plasma in 5 previous cases of homozygous hypobetalipoproteinemia, they found a minute amount of apoB (about 0.025% of normal) in the plasma and suggested that the disorder might result not from a structural gene defect but from a failure of secretion.

Since LDLs are a main source of cholesterol for steroid hormone formation, Parker et al. (1986) were interested in studying the endocrine changes during pregnancy in homozygous familial hypobetalipoproteinemia. They found it surprising that a woman with phenotypic abetalipoproteinemia, previously reported by Illingworth et al. (1979), could become 'pregnant, let alone carry the pregnancy to term without hormonal therapy.' They noted successful pregnancy in 3 other abetalipoproteinemic women.

In 2 patients with homozygous hypobetalipoproteinemia, Ross et al. (1988) found that Southern blot analysis with 10 different cDNA probes revealed a normal gene without major insertions, deletions, or rearrangements. Northern and slot-blot analyses of total liver mRNA showed a normal-sized apoB mRNA that was present in greatly reduced quantities. ApoB protein was detected in liver cells immunohistochemically but was markedly reduced in quantity, and no apoB was detectable in the plasma with an ELISA assay. Ross et al. (1988) interpreted the findings as indicating a mutation in the coding portion of the apoB gene, leading to an abnormal apoB protein and apoB mRNA instability. These findings were distinct from those previously noted in abetalipoproteinemia (200100), which is characterized by an elevated level of hepatic apoB mRNA and accumulation of intracellular hepatic apoB protein. The blood-lipid changes that accompany heterozygous hypobetalipoproteinemia are reduced plasma concentrations of LDL cholesterol, total triglycerides, and APOB to less than 50% of normal values.

Harano et al. (1989) identified homozygous hypobetalipoproteinemia in 3 sibs. Both parents and 2 children of 1 of the sibs were heterozygous. The 75-year-old proband, the father of the 3 sibs, died of fever of unknown cause, thrombocytopenia, and anemia. He had ataxic movements of the hands and gait disturbance in later life. The 3 homozygotes showed marked deficiency of apoB100, although trace amounts were noted in LDL. In contrast, apoB48 was present in chylomicrons obtained after a fatty meal in 2 of the patients with homozygous hypobetalipoproteinemia, indicating a selective deficiency of apoB100.

Keidar et al. (1990) described apparent compound heterozygosity for abetalipoproteinemia and familial hypobetalipoproteinemia. The proband, a 10-year-old boy with abetalipoproteinemia, had a father with a normal apolipoprotein profile; however, his mother and maternal grandfather suffered from familial hypobetalipoproteinemia.

Araki et al. (1991) described a 55-year-old man with cerebellar ataxia due apparently to hypobetalipoproteinemia. A brother also had hypobetalipoproteinemia with neurologic symptoms. The 2 children of the proband, aged 31 and 29 years, and a sister of the proband had only hypobetalipoproteinemia. The proband and his neurologically affected brother as well as members of the 2 previous generations had steatocystoma multiplex (184500). The latter condition may have been coincidental.

Di Leo et al. (2008) reported 3 patients with severe hypobetalipoproteinemia due to homozygosity or compound heterozygosity for mutations in APOB, who presented with chronic liver disease and/or chronic diarrhea at ages 52, 55, and 19 years, respectively. The authors stated that the clinical diagnosis of homozygous FHBL is extremely rare, with approximately 20 cases reported over the past 2 decades; they noted that their patients highlight the heterogeneity of clinical manifestations and the possible presentation of disease late in life.

▼ Population Genetics

Lee and Hegele (2014) stated that the incidences of both FHBL and abetalipoproteinemia are reported as less than 1 in 1 million.

▼ Mapping

Leppert et al. (1988) found that a DNA haplotype of the APOB gene cosegregated with hypobetalipoproteinemia in an Idaho pedigree, with a maximum lod score of 7.56 at theta = 0.0. This finding strongly suggested that a mutation in the APOB gene underlies hypobetalipoproteinemia and indicated the usefulness of the candidate gene approach.

Pulai et al. (1998) commented that various truncated forms of apoB have been found to segregate with the FHBL phenotype in more than 30 kindreds. They reported studies of 6 kindreds in which no truncated forms of apoB protein were detected with sensitive immunoblotting in the plasma of any of the affected individuals. Persons with apoB levels in the 5th centile for their age and sex were considered as affected with FHBL. Linkage analysis with 3 microsatellite markers flanking the APOB gene, a 3-prime VNTR marker, and an intragenic marker yielded 2-point linkage of FHBL to the 3-prime VNTR marker with a combined maximum lod score of 8.5 at theta = 0.0 for 5 of the 6 families. A test of homogeneity differentiated the sixth family from the other 5. These kindreds demonstrated the heterogeneity of FHBL.

▼ Molecular Genetics

In a patient with hypobetalipoproteinemia and small amounts of truncated protein (B37) in VLDL, LDL, and HDL fractions of the plasma, Young et al. (1987, 1988) found a 4-bp deletion in the APOB gene resulting in a frameshift (107730.0001). This was one of the mutant alleles in the family with hypobetalipoproteinemia first reported by Steinberg et al. (1979). Linton et al. (1992) investigated the reason for the curious finding that low levels of apoB100 were produced by the mutant allele carrying this mutation. The clue that led to the understanding of what was going on with this allele was the recognition that the proband in the family, H.J.B., as well as the other 2 compound heterozygotes, actually had 4 bona fide apoB species within their plasma lipoproteins: apoB37, apoB48, apoB100, and apoB86. Linton et al. (1992) demonstrated that the apoB86 and apoB100 were products of a single mutant apoB allele, which they designated the apoB86 allele.

In a patient with normotriglyceridemic hypobetalipoproteinemia, originally described by Malloy et al. (1981), Hardman et al. (1991) identified homozygosity for a nonsense mutation in the APOB gene (170300.0013).

In a patient with hypobetalipoproteinemia, McCormick et al. (1992) identified a heterozygous nonsense mutation in the APOB gene (170300.0014).

In a 27-year-old woman from a consanguineous French Canadian family, who was diagnosed with FHBL in the first months of life, Gangloff et al. (2011) identified a homozygous truncating mutation in the APOB gene (107730.0022). The authors stated that this was the first case of homozygous FHBL in a French Canadian family.

▼ History

Salt et al. (1960) reported the absence of beta-lipoprotein from the plasma of a patient with abetalipoproteinemia, but this patient had familial hypobetalipoproteinemia because his parents had markedly low levels of cholesterol in plasma (Kane and Havel, 2001).

Tags: 2p24.1