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APOB-Related Familial Hypobetalipoproteinemia

, MB ChB, MD, PhD, FRCPA, , PhD, and , MD, FRCPC, FACP.

Author Information

Initial Posting: ; Last Revision: September 9, 2021.

Estimated reading time: 19 minutes

Summary

Clinical characteristics.

Individuals with biallelic APOB-related familial hypobetalipoproteinemia (APOB-FHBL) may present from infancy through to adulthood with a range of clinical symptoms including deficiency of fat-soluble vitamins and gastrointestinal and neurologic dysfunction. Affected individuals typically have plasma total cholesterol, LDL cholesterol, and apo B levels below the fifth centile for age and sex. Acanthocytosis, elevated liver enzymes, and hyperbilirubinemia may also be found. The most common clinical findings are hepatomegaly, steatorrhea, and failure to thrive / growth deficiency. In the absence of treatment, affected individuals can develop atypical pigmentation of the retina; progressive loss of deep tendon reflexes, vibratory sense, and proprioception; muscle pain or weakness; dysarthria; ataxia; tremors; and steatohepatitis, fibrosis, and rarely, cirrhosis of the liver.

Individuals with a heterozygous, typically truncating pathogenic variant in APOB are usually asymptomatic with mild liver dysfunction and hepatic steatosis. However, about 5%-10% of individuals with heterozygous APOB-FHBL develop relatively more severe nonalcoholic steatohepatitis requiring medical attention and occasionally progressing to cirrhosis, albeit very rarely.

Diagnosis/testing.

The diagnosis of biallelic APOB-related familial hypobetalipoproteinemia (APOB-FHBL) or heterozygous APOB-FHBL is established in a proband with either biallelic or a heterozygous pathogenic variant(s), respectively, in APOB identified by molecular genetic testing

Management.

Treatment of manifestations:

  • Individuals with biallelic APOB-FHBL: low-fat diet (<30% of total calories) while ensuring adequate caloric intake; high-dose oral fat-soluble vitamin supplementation (vitamin E: 100-300 IU/kg/day; vitamin A: 100-400 IU/kg/day; vitamin D: 800-1200 IU/day; vitamin K: 5-35 mg/week); consideration of oral essential fatty acid supplementation; liver transplantation may be considered for those with end-stage liver disease; standard treatment for ataxia, dysarthria, and loss of night and/or color vision and scotomas; no treatment is typically required for anemia/hemolysis.
  • Individuals with heterozygous APOB-FHBL: no treatment typically required.

Prevention of primary manifestations: Adoption of a low-fat diet (<30% of total calories) and high-dose oral fat-soluble vitamin supplementation may ameliorate or prevent clinical features of APOB-FHBL.

Surveillance:

  • Individuals with biallelic APOB-FHBL: measurement of growth parameters and assessment for new or progressive signs/symptoms of gastrointestinal issues every 6-12 months; laboratory studies to include lipid profile, liver function tests, vitamin levels, INR, calcium, phosphorus, uric acid, CBC, vitamin B12, folate and TSH every 1-2 years; ophthalmology evaluation and neurologic examination every 6-12 months after age 10 years; hepatic ultrasound and bone mineral densitometry studies every 3-5 years after age 10 years.
  • Individuals with heterozygous APOB-FHBL: laboratory studies to include lipid profile and liver function tests every 1-2 years; hepatic ultrasound every 3 years after age 10 years in those with elevated liver transaminases.

Agents/circumstances to avoid: Individuals with biallelic APOB-FHBL should avoid fatty foods. No dietary restrictions are typically required for those with heterozygous APOB-FHBL.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an individual with biallelic APOB-FHBL in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Evaluations can include a full lipid profile (including apo B concentration) and/or molecular genetic testing for the APOB pathogenic variant(s) identified in the proband.

Pregnancy management: Vitamin A excess can be harmful to the developing fetus. Therefore, women who are pregnant or are planning to become pregnant should reduce their vitamin A supplement dose by 50%. Additionally, close monitoring of serum vitamin A levels throughout pregnancy is recommended. Because vitamin A is an essential vitamin, however, vitamin A supplementation for affected women should not be discontinued during pregnancy.

Genetic counseling.

APOB-related familial hypobetalipoproteinemia (APOB-FHBL) caused by homozygous (or compound heterozygous) pathogenic variants in APOB is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being heterozygous for APOB-FHBL and having laboratory findings and (rarely) clinical features, and a 25% chance of being unaffected and not a heterozygote. Heterozygote testing for at-risk relatives and prenatal and preimplantation genetic testing are possible if the pathogenic APOB variants in the family are known.

GeneReview Scope

APOB-Related Familial Hypobetalipoproteinemia (FHBL): Included Phenotypes 1

For synonyms and outdated names see Nomenclature.

1.

For other genetic causes of these phenotypes, see Differential Diagnosis.

Diagnosis

In this GeneReview:

  • Biallelic APOB-related familial hypobetalipoproteinemia (APOB-FHBL) refers to hypocholesterolemia, low plasma LDL cholesterol, and low apolipoprotein (apo) B levels leading to clinical signs and symptoms in untreated individuals who have homozygous or compound heterozygous pathogenic variants in APOB that affect the structural integrity of apo B.
  • Heterozygous APOB-FHBL refers to individuals who have primarily asymptomatic hepatic steatosis with rare clinical symptoms due to a heterozygous, typically truncating pathogenic variant in APOB.
  • Note: Both heterozygous and biallelic pathogenic variants in APOB can also lead to familial hypercholesterolemia (see Genetically Related Disorders). However, the APOB pathogenic variants that cause familial hypercholesterolemia are typically located within the LDL receptor binding domain.

Suggestive Findings

Biallelic APOB-related familial hypobetalipoproteinemia (APOB-FHBL) should be suspected in individuals with the following clinical features and supportive laboratory findings.

Clinical findings

  • Failure to thrive, with diarrhea
  • Fat malabsorption with steatorrhea
  • Acquired atypical pigmentation of the retina
  • Ataxia with or without absent reflexes
  • Hepatomegaly
  • Hepatic steatosis

Supportive laboratory findings

  • Marked hypocholesterolemia (total cholesterol ~1.0 mmol/L [40 mg/dL])
  • Plasma LDL cholesterol (measured or calculated) absent or extremely low
  • Plasma apo B absent or very low
  • Plasma triglyceride very low
  • Plasma HDL cholesterol at a low to average level
  • Acanthocytosis
  • Abnormal liver transaminases (ALT and AST 1-1.5x the upper reference limit)
  • Prolonged international normalized ratio (INR)
  • Low serum concentrations of fat-soluble vitamins (A, D, E, and K)

Heterozygous APOB-FHBL should be considered in individuals with the following laboratory, imaging, and family history findings:

  • Laboratory findings
    • Plasma total cholesterol level below the 5th percentile for age and sex (~3.0 mmol/L [115 mg/dL])
    • Plasma LDL cholesterol level below the 5th percentile for age and sex (~1.3 mmol/L [50 mg/dL])
    • Plasma apo B level below the 5th percentile for age and sex (~0.5 g/L)
    • Plasma triglyceride level less than 0.5 mmol/L (45 mg/dL)
    • Elevated liver enzymes (AST and ALT) in an otherwise asymptomatic individual
  • Liver ultrasound. Increased fat content consistent with hepatic steatosis
  • Family history. First-degree relatives with asymptomatic hepatic steatosis and/or hypocholesterolemia
    Note: Absence of a known family history of first degree relatives with asymptomatic hepatic steatosis and/or hypocholesterolemia does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of biallelic APOB-related familial hypobetalipoproteinemia (APOB-FHBL) or heterozygous APOB-FHBL is established in a proband with either biallelic or a heterozygous pathogenic (or likely pathogenic) variant(s), respectively, in APOB identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to “pathogenic variants” in this section is understood to include any likely pathogenic variants. (2) Identification of an APOB variant of uncertain significance does not establish or rule out the diagnosis of this disorder.

When the phenotype and laboratory findings suggest the diagnosis of APOB-FHBL, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.

Single-gene testing. Sequence analysis detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.

A multigene panel that includes APOB and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that include genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in APOB-Related Familial Hypobetalipoproteinemia

Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method
APOB Sequence analysis 3>95% 4
Gene-targeted deletion/duplication analysis 5<5% 6
1.
2.

See Molecular Genetics for information on variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Large deletions/duplications are very rare [Huang et al 1989].

Clinical Characteristics

Clinical Description

The clinical features of individuals with biallelic APOB-related familial hypobetalipoproteinemia (sometimes referred to as homozygous or compound heterozygous APOB-FHBL) may resemble those of abetalipoproteinemia, particularly in individuals with truncating APOB pathogenic variants shorter in length than apoB-48 (see Genotype-Phenotype Correlations and Molecular Genetics).

Biallelic APOB-FHBL

Individuals with biallelic APOB-FHBL may present from infancy through to adulthood with a range of clinical symptoms including deficiency of fat-soluble vitamins and gastrointestinal and neurologic dysfunction. However, in contrast to abetalipoproteinemia (mean age of diagnosis 3.8 years), individuals with APOB-FHBL can have milder symptoms, and most are diagnosed in adulthood (mean age of diagnosis: 21 years) [Di Filippo et al 2014].

Table 2.

Biallelic APOB-Related Familial Hypobetalipoproteinemia: Frequency of Select Features

FeatureFrequency
Nearly allCommonInfrequent
Hepatomegaly
Hepatic steatosis
Deficiency in fat-soluble vitamins
Acanthocytosis
NASH/Fibrosis
Steatorrhea/Diarrhea
Fat malabsorption
Failure to thrive
Ophthalmologic impairment
Peripheral neuropathy
Cirrhosis

NASH = nonalcoholic steatohepatitis

This table refers only to clinical features in those individuals with biallelic APOB pathogenic variants.

Gastrointestinal. Steatorrhea is the primary gastrointestinal manifestation. It can be present starting in infancy and throughout childhood. The severity relates to the fat content of the diet:

  • As affected individuals age, they learn to avoid dietary fat, which improves steatorrhea.
  • Global caloric deficiency is associated with delayed growth trajectory, with both height and weight typically below the tenth centile without intervention.
  • Fat-soluble vitamin malabsorption is severe, and if untreated can lead to irreversible systemic features that affect the eyes (see Ophthalmologic below), bones (decreased bone mineral density), and nervous system (see Neuromuscular below).
  • Hepatic involvement as identified on laboratory studies is frequently stable over many years and may not evolve to be clinically significant.
  • Hepatomegaly and hepatic steatosis can be observed in adulthood, and may subsequently progress to steatohepatitis, fibrosis, and (rarely) cirrhosis or (in extremely rare instances) hepatocellular carcinoma.

Endoscopic findings. On a typical diet (e.g., no dietary fat restriction), the intestinal mucosa may have a “gelee blanche” or “white hoar frosting” appearance on endoscopy. Biopsy of the intestinal epithelium may demonstrate lipid-laden epithelial cells.

Hematologic manifestations of biallelic APOB-FHBL include the following:

  • Acanthocytosis, defined as irregularly spiculated erythrocytes (present from birth)
  • Low erythrocyte sedimentation rate
  • Low-grade anemia
  • Reticulocytosis
  • Hyperbilirubinemia
  • Hemolysis
  • Prolonged INR due to vitamin K deficiency, with easy bruising and prolonged bleeding (present in childhood)

Ophthalmologic manifestations of biallelic APOB-FHBL are variable, with the most prominent being an atypical pigmentation of the retina, which can be arrested (though not reversed) with high-dose vitamin A supplementation (see Treatment of Manifestations). However, the eye findings can be averted altogether with early diagnosis and treatment.

  • Many affected individuals are asymptomatic until adulthood, when they experience loss of night vision and/or color vision.
  • As the disease progresses, affected individuals may experience progressively expanding scotomas.
  • Without treatment, progression to complete visual loss may occur.

Note: It is hypothesized that the possible cause of the ophthalmoplegia is vitamin E deficiency leading to cranial nerve demyelination.

Neuromuscular. If untreated, neuromuscular manifestations of biallelic APOB-FHBL secondary to the deficiency of vitamin E typically begin in the first or second decade of life. Symptoms include the following:

  • Progressive loss of deep tendon reflexes, vibratory sense, and proprioception
  • Muscle pain or weakness
  • Dysarthria
  • Ataxia, broad-based gait
  • Tremors

Similar to the ophthalmologic manifestations, the neuromuscular manifestations can also be arrested but not reversed with vitamin supplementation. However, they can be averted altogether with early diagnosis and treatment.

Prognosis. In the past, without high-dose fat-soluble vitamin supplementation, affected individuals would typically not survive past the third decade of life, dying with severe neuromyopathy and respiratory failure. With lifelong high-dose oral fat-soluble vitamin treatment, longevity into the seventh and eighth decade of life with relatively minimal symptoms has been observed over 40 years in affected individuals [Dr Robert Hegele, unpublished observations].

Heterozygous APOB-FHBL

Individuals with a heterozygous, typically truncating pathogenic variant in APOB are usually asymptomatic with mild liver dysfunction and hepatic steatosis. However, about 5%-10% of individuals with heterozygous APOB-FHBL develop relatively more severe nonalcoholic steatohepatitis requiring medical attention and occasionally progressing to cirrhosis, albeit very rarely [Vilar-Gomez et al 2021].

Table 3.

Heterozygous APOB-Related Familial Hypobetalipoproteinemia: Frequency of Select Features

FeatureFrequency
Nearly allCommonInfrequent
Hepatic steatosis
Oral fat intolerance
Intestinal fat malabsorption

Gastrointestinal. Heterozygous APOB-FHBL may be asymptomatic, but fatty liver is common and mild fat malabsorption can occur beginning in young adulthood. These individuals may have liver transaminases that are elevated and often have a three- to five-fold increase in hepatic fat content compared to the typical general population.

Cardiac. Heterozygous APOB-FHBL confers protection against atherosclerotic cardiovascular disease, presumably due to lifelong reductions in serum LDL cholesterol concentrations [Sankatsing et al 2005, Peloso et al 2019].

Psychiatric. In a study of more than 800 adults hospitalized in a psychiatric unit, the prevalence of individuals with lipid profiles consistent with being a heterozygote for hypobetalipoproteinemia was higher than expected, although genetic testing for APOB pathogenic variants was not performed as part of the study. The authors found some statistically significant associations between low serum LDL cholesterol concentrations and schizophrenia, heteroaggression, and developmental disorders including autism [Cariou et al 2018]. This study did not prove causation.

Prognosis. Individuals with heterozygous APOB-FHBL have the potential for their condition to progress from nonalcoholic fatty liver disease to nonalcoholic steatohepatitis, fibrosis, and cirrhosis, particularly in the presence of known risk factors such as alcohol consumption, excessive caloric intake, and liver injury [Sankatsing et al 2005, Welty 2020].

While sibs inheriting a pathogenic variant demonstrate low cholesterol from birth, hepatic steatosis takes years to develop, with 54% of individuals with heterozygous FHBL developing this finding in one study [Sankatsing et al 2005].

Genotype-Phenotype Correlations

The majority of APOB pathogenic variants causing biallelic APOB-FHBL and heterozygous APOB-FHBL are frameshift, nonsense and splice variants resulting in production of a truncated apoB protein (see Molecular Genetics). These are named as a proportion of full-length wild type protein (apoB-100).

  • In general, pathogenic variants that lead to truncated proteins that are 30% in length or shorter have more severe signs and symptoms than those whose truncated protein length is predicted to be 32% or longer; the latter tend to have moderate disease.
  • It has been hypothesized that longer apoB truncated proteins may be able to maintain some residual capacity to bind lipid and form lipoproteins [Tarugi et al 2007].

Nomenclature

Biallelic APOB-FHBL may be referred to as homozygous familial hypobetalipoproteinemia, compound heterozygous familial hypobetalipoproteinemia, or collectively as HHBL.

Prevalence

Heterozygous APOB-FHBL due to apoB protein truncations occurs in 1:3000 individuals in the general population [Welty et al 1998]. The estimated incidence of biallelic APOB-FHBL is less than one in a million, based on extrapolation from the estimated prevalence of heterozygous APOB-FHBL.

In a blood donor cohort with plasma cholesterol below the fifth centile (128 mg/dL), apoB truncations were identified in 0.55% [Tarugi et al 2007].

Differential Diagnosis

Table 4.

Genes of Interest in the Differential Diagnosis of Biallelic APOB-Related Familial Hypobetalipoproteinemia

GeneDiffDx DisorderMOIFeatures of DiffDx Disorder
Overlapping w/biallelic APOB-FHBLDistinguishing from biallelic APOB-FHBL
ANGPTL3 Familial combined hypolipidemia (OMIM 605019)ARLow plasma levels of LDL cholesterolVery low plasma triglyceride & HDL cholesterol levels
MTTP Abetalipoproteinemia ARClinical features may resemble those of persons w/biallelic APOB-FHBL.

Mean age of diagnosis 3.8 yrs (vs persons w/biallelic APOB-FHBL: mean age of diagnosis 21 yrs)

PCSK9 Hypocholesterolemia w/reduced LDL cholesterol (OMIM 607786)ADLow plasma levels of LDL cholesterolMilder effect on LDL-cholesterol lowering; not assoc w/hepatic steatosis
SAR1B Chylomicron retention disease ARMay be clinically similar to biallelic APOB-FHBL (failure to thrive, steatorrhea)Chylomicrons are absent; LDL cholesterol levels are low but not absent.

AD = autosomal dominant; APOB-FHBL = APOB-related familial hypobetalipoproteinemia; AR = autosomal recessive; DiffDx = differential diagnosis; MOI = mode of inheritance

Management

No clinical practice guidelines for APOB-related familial hypobetalipoproteinemia (APOB-FHBL) have been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with biallelic APOB-FHBL or heterozygous APOB-FHBL, the evaluations summarized respectively in Tables 5 and 6 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

Recommended Evaluations Following Initial Diagnosis in Individuals with Biallelic APOB-Related Familial Hypobetalipoproteinemia

System/ConcernEvaluationComment
General Growth parametersTo assess for poor growth
Gastrointestinal Plasma lipid profile:
  • Total cholesterol
  • LDL cholesterol
  • HDL cholesterol
  • Triglyceride
  • Apo B
Serum concentrations of fat-soluble vitamins (A, D, E, K)
Liver transaminases, INR, & bilirubin levelsProlongation of INR may result from vitamin K deficiency.
Referral to nutritionistTo provide dietary advice re low-fat diet
Abdominal ultrasoundTo evaluate for steatohepatitis, cirrhosis, &/or hepatocellular carcinoma
Hematologic Complete blood countTo assess for anemia & erythrocyte morphologic abnormalities, specifically acanthocytosis (a pathognomonic feature)
Ophthalmologic Referral to ophthalmologist
  • For eval of visual acuity & pigmentary retinopathy
  • Consider electroretinography. 1
Neurologic Referral to neurologistIf evidence of neurologic abnormality (e.g., ataxia, loss of deep tendon reflexes)
Genetic
counseling
By genetics professionals 2To inform affected persons & families re nature, MOI, & implications of familial hypobetalipoproteinemia to facilitate medical & personal decision making

HDL = high-density lipoprotein; INR = international normalized ratio; LDL = low-density lipoprotein; MOI = mode of inheritance

1.

This is a sensitive method to detect early neuropathy [Musialik et al 2020].

2.

Medical geneticist, certified genetic counselor, certified advanced genetic nurse

Table 6.

Recommended Evaluations Following Initial Diagnosis in Individuals with Heterozygous APOB-Related Familial Hypobetalipoproteinemia

System/ConcernEvaluationComment
Gastrointestinal Plasma lipid profile:
  • Total cholesterol
  • LDL cholesterol
  • HDL cholesterol
  • Triglyceride
  • Apo B
Serum concentrations of fat-soluble
vitamins (A, D, E, K)
Liver transaminases
Abdominal ultrasoundIf liver transaminases are ↑

Treatment of Manifestations

The following treatment is recommended for individuals with biallelic APOB-FHBL to address symptoms and prevent complications [Lee & Hegele 2014]. Treatment is not typically required for heterozygous APOB-related familial hypobetalipoproteinemia.

Table 7.

Treatment of Manifestations in Individuals with Biallelic APOB-Related Familial Hypobetalipoproteinemia

Manifestation/
Concern
TreatmentConsiderations/Other
Poor growth Ensure adequate caloric intake on a low-fat diet.Working w/nutritionist may be helpful.
Steatorrhea
  • Low-fat diet (<30% of total calories)
  • Oral essential fatty acid supplements may be considered.
Will eliminate steatorrhea & allow absorption of other nutrients essential for growth & development.
Hepatic fibrosis /
Cirrhosis
Consider liver transplantation for those w/end-stage liver disease.
Fat-soluble
vitamin
deficiencies
High-dose oral fat-soluble vitamins:
  • Vitamin E (100-300 IU/kg/d)
  • Vitamin A (100-400 IU/kg/d)
  • Vitamin D (800-1200 IU/d)
  • Vitamin K (5-35 mg/wk)
Vitamin K supplementation may improve INR.
Anemia/
Hemolysis
No treatment is typically required.
  • Anemia is usually mild.
  • Iron therapy does not improve anemia in this condition.
Loss of night
&/or color
vision &
scotomas
Standard treatment per ophthalmologistMay incl optical aids
Ataxia Assistance for coordination problems through established methods of rehab medicine & OT/PTCanes, walkers, & wheelchairs are useful for gait ataxia.
Dysarthria Speech therapyComputer devices are available to assist persons w/severe speech deficits.

INR = international normalized ratio; OT = occupational therapy; PT = physical therapy

Prevention of Primary Manifestations

As outlined in Table 7, adoption of a low-fat diet (<30% of total calories) and high-dose oral fat-soluble vitamin supplementation may ameliorate or prevent clinical features of APOB-FHBL.

Surveillance

Table 8.

Recommended Surveillance for Individuals with Biallelic APOB-Related Familial Hypobetalipoproteinemia

FrequencyEvaluation
Every 6-12 mos
  • Measurement of growth parameters
  • For any new or progressive signs/symptoms of gastrointestinal issues 1
Every 1-2 yrsLaboratory investigations:
  • Lipid profile 2
  • Liver function tests 3
  • Vitamin A, vitamin E, 25-OH vitamin D
  • INR
  • Calcium, phosphate, uric acid
  • CBC & measurement of vitamin B12 & folate levels 4
  • TSH 5
Every 6-12 mos after age 10 yrs
  • Ophthalmology eval
  • Neurologic exam
Every 3-5 yrs after age 10 yrs
  • Hepatic ultrasound
  • Bone mineral densitometry 6

CBC = complete blood count; INR = international normalized ratio; TSH = thyroid-stimulating hormone

1.

Including for hepatomegaly and diarrhea

2.

To include total, LDL and HDL cholesterol, triglyceride, and apo B concentrations

3.

To include AST and ALT

4.

Abnormal vitamin B12 and folate levels are not a primary feature of biallelic APOB-FHBL. However, the anemia seen in individuals with biallelic APOB-FHBL can mask a vitamin B12 or folate deficiency, both of which can occur with increased frequency in older individuals and both of which are treatable.

5.

Abnormal thyroid function is not a primary feature of biallelic APOB-FHBL but is a common co-morbidity in the general population and is also treatable.

6.

An affected individual found to have a bone mineral density >1 SD below the lower limit of normal often prompts an increase in vitamin D dosage.

Table 9.

Recommended Surveillance for Individuals with Heterozygous APOB-Related Familial Hypobetalipoproteinemia

FrequencyEvaluation
Every 1-2 yrsLaboratory investigations:
  • Lipid profile 1
  • Liver function tests 2
Every 3 yrs after age 10 yrsHepatic ultrasonography if liver transaminases are ↑
1.

To include total, LDL and HDL cholesterol, triglyceride, and apo B concentrations

2.

To include AST and ALT

Agents/Circumstances to Avoid

Individuals with biallelic APOB-FHBL should avoid fatty foods. No dietary restrictions are typically required for those with heterozygous APOB-FHBL.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an individual with biallelic APOB-FHBL in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Evaluations can include:

  • A full lipid profile, including apo B concentration;
  • Molecular genetic testing for the APOB pathogenic variant(s) identified in the proband. Note: Family members found to be heterozygous for an HBL-related APOB variant may benefit from surveillance (see Table 9).

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Vitamin A excess can be harmful to the developing fetus. Therefore, women who are pregnant or who are planning to become pregnant should reduce their vitamin A supplement dose by 50%. Additionally, close monitoring of serum vitamin A levels throughout pregnancy is recommended [Lee & Hegele 2014].

Because vitamin A is an essential vitamin, however, vitamin A supplementation for affected women should not be discontinued during pregnancy. Vitamin A deficiency can lead to maternal morbidity.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

APOB-related familial hypobetalipoproteinemia (APOB-FHBL) caused by homozygous (or compound heterozygous) pathogenic variants in APOB is inherited in an autosomal recessive manner.

Note: The inheritance of APOB-FHBL is described as autosomal recessive in this GeneReview because clinically manifest FHBL is associated with biallelic pathogenic variants while heterozygous pathogenic variants in APOB are primarily associated with biochemical findings in an otherwise asymptomatic individual, with rare exceptions. Because those with heterozygous APOB-FHBL occasionally have symptoms, the terms "codominant" and "semidominant" have sometimes been used in the literature to describe the inheritance pattern of APOB-FHBL.

Risk to Family Members (Autosomal Recessive Inheritance)

Parents of a proband

  • The parents of an individual with biallelic APOB-FHBL are obligate heterozygotes (i.e., presumed to be heterozygous for one APOB pathogenic variant based on family history).
  • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an APOB pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent, the following possibilities should be considered:
  • Individuals with a heterozygous FHBL-related APOB pathogenic variant are usually asymptomatic, with biochemical findings consistent with mild liver dysfunction and hepatic steatosis (see Clinical Description, Heterozygous APOB-FHBL). Surveillance, including lipid profiles and liver function tests, is recommended for individuals with heterozygous APOB-FHBL (see Table 9).

Sibs of a proband

  • If both parents are known to be heterozygous for an APOB pathogenic variant, each sib of an affected individual has at conception a 25% chance of having biallelic APOB-FHBL, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
  • Individuals with a heterozygous FHBL-related APOB pathogenic variant are usually asymptomatic, with biochemical findings consistent with mild liver dysfunction and hepatic steatosis (see Clinical Description, Heterozygous APOB-FHBL). Surveillance, including lipid profiles and liver function tests, is recommended for individuals with heterozygous APOB-FHBL (see Table 9).

Offspring of a proband. Unless a proband with biallelic APOB-FHBL has children with an individual who has biallelic APOB-FHBL or heterozygous APOB-FHBL, his/her offspring will be heterozygous for an APOB pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being heterozygous for an APOB pathogenic variant.

Heterozygote Detection

Molecular genetic testing for at-risk relatives requires prior identification of the APOB pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have biallelic APOB-related FHBL or are at risk of being heterozygous.

Prenatal Testing and Preimplantation Genetic Testing

Once the APOB pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

APOB-Related Familial Hypobetalipoproteinemia: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
APOB 2p24​.1 Apolipoprotein B-100 APOB database APOB APOB

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for APOB-Related Familial Hypobetalipoproteinemia (View All in OMIM)

107730APOLIPOPROTEIN B; APOB
615558HYPOBETALIPOPROTEINEMIA, FAMILIAL, 1; FHBL1

Molecular Pathogenesis

ApoB is essential for the formation of intestinally derived chylomicrons and hepatically derived very low-density lipoprotein (VLDL) and their metabolites, including low-density lipoprotein (LDL). In APOB-related familial hypobetalipoproteinemia (APOB-FHBL) the mutated apoB is unable to be incorporated and secreted as a component of a lipoprotein particle, resulting in low levels of LDL cholesterol, and accumulation of fat in the liver (hepatic steatosis). Where both APOB alleles are affected (biallelic APOB-FHBL) levels of LDL cholesterol will be extremely low and the affected individual will be at risk of developing neuromuscular and ophthalmologic complications as a result of fat-soluble vitamin deficiencies, particularly vitamins E and A.

Truncated proteins are named as a proportion of full-length wild type protein (apoB-100). Apo B proteins shorter than 30% of full-length apoB are not detectable in plasma by Western blot, while those larger than apoB-32 are detectable in plasma. Those individuals with longer truncated proteins that are detectable in plasma are more likely to have moderate disease compared to those with undetectable plasma levels, who typically have severe disease [Tarugi et al 2007] (see Genotype-Phenotype Correlations).

Mechanism of disease causation. Loss of function; typically nonsense, frameshift and splice pathogenic variants; rarely, missense variants

Chapter Notes

Author Notes

Book chapters

  • Hooper AJ, Burnett JR. Genetic hypobetalipoproteinaemia and abetalipoproteinaemia. In: Garg A, ed. Dyslipidemias: Pathophysiology, Evaluation and Management. New York, NY: Humana Press; 2015;251-66.
  • Hooper AJ, Burnett JR. Abetalipoproteinemia and hypobetalipoproteinemia. In: Hollak CEM, Lachman R, Sedel F, eds. Inherited Metabolic Diseases in Adults: A Clinical Guide. Oxford Press; 2016;225-8.

Revision History

  • 9 September 2021 (jrb) Revision: clarification of Suggestive Findings
  • 13 May 2021 (ma) Review posted live
  • 3 March 2021 (jrb) Original submission

References

Literature Cited

  • Cariou B, Challet-Bouju G, Bernard C, Marrec M, Hardouin JB, Authier C, Bach-Ngohou K, Leux C, Pichelin M, Grall-Bronnec M. Prevalence of hypobetalipoproteinemia and related psychiatric characteristics in a psychiatric population: results from the retrospective HYPOPSY Study. Lipids Health Dis. 2018;17:249. [PMC free article: PMC6220563] [PubMed: 30400945]
  • Di Filippo M, Moulin P, Roy P, Samson-Bouma ME, Collardeau-Frachon S, Chebel-Dumont S, Peretti N, Dumortier J, Zoulim F, Fontanges T, Parini R, Rigoldi M, Furlan F, Mancini G, Bonnefont-Rousselot D, Bruckert E, Schmitz J, Scoazec JY, Charriere S, Villar-Fimbel S, Gottrand F, Dubern B, Doummar D, Joly F, Liard-Meillon ME, Lachaux A, Sassolas A. Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia. J Hepatol. 2014;61:891–902. [PubMed: 24842304]
  • Huang LS, Ripps ME, Korman SH, Deckelbaum RJ, Breslow JL. Hypobetalipoproteinemia due to an apolipoprotein B gene exon 21 deletion derived by Alu-Alu recombination. J Biol Chem. 1989;264:11394–400. [PubMed: 2567736]
  • Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519–22. [PubMed: 28959963]
  • Lee J, Hegele RA. Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management. J Inherit Metab Dis. 2014;37:333–9. [PubMed: 24288038]
  • Musialik J, Boguszewska-Chachulska A, Pojda-Wilczek D, Gorzkowska A, Szymańczak R, Kania M, Kujawa-Szewieczek A, Wojcieszyn M, Hartleb M, Więcek A. A rare mutation in the APOB gene associated with neurological manifestations in familial hypobetalipoproteinemia. Int J Mol Sci. 2020;21:1439. [PMC free article: PMC7073066] [PubMed: 32093271]
  • Peloso GM, Nomura A, Khera AV, Chaffin M, Won HH, Ardissino D, Danesh J, Schunkert H, Wilson JG, Samani N, Erdmann J, McPherson R, Watkins H, Saleheen D, McCarthy S, Teslovich TM, Leader JB, Lester Kirchner H, Marrugat J, Nohara A, Kawashiri MA, Tada H, Dewey FE, Carey DJ, Baras A, Kathiresan S. Rare protein-truncating variants in APOB, lower low-density lipoprotein cholesterol, and protection against coronary heart disease. Circ Genom Precis Med. 2019;12:e002376. [PMC free article: PMC7044908] [PubMed: 30939045]
  • Sankatsing RR, Fouchier SW, De Haan S, Hutten BA, De Groot E, Kastelein JJ, Stroes ES. Hepatic and cardiovascular consequences of familial hypobetalipoproteinemia. Arterioscler Thromb Vasc Biol. 2005;25:1979–84. [PubMed: 16002743]
  • Tarugi P, Averna M, Di Leo E, Cefalu AB, Noto D, Magnolo L, Cattin L, Bertolini S, Calandra S. Molecular diagnosis of hypobetalipoproteinemia: an ENID review. Atherosclerosis. 2007;195:e19–27. [PubMed: 17570373]
  • Vilar-Gomez E, Gawrieh S, Liang T, McIntyre AD, Hegele RA, Chalasani N. Interrogation of selected genes influencing serum LDL-cholesterol levels in patients with well characterized NAFLD. J Clin Lipidol. 2021;15:275–91. [PMC free article: PMC8187295] [PubMed: 33454241]
  • Welty FK, Lahoz C, Tucker KL, Ordovas JM, Wilson PW, Schaefer EJ. Frequency of apoB and apoE gene mutations as causes of hypobetalipoproteinemia in the Framingham offspring population. Arterioscler Thromb Vasc Biol. 1998;18:1745–51. [PubMed: 9812913]
  • Welty FK. Hypobetalipoproteinemia and abetalipoproteinemia: liver disease and cardiovascular disease. Curr Opin Lipidol. 2020;31:49–55. [PubMed: 32039990]
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