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.

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/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include 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.

• Perform sequence analysis first.
• If no pathogenic variant or only one pathogenic variant is identified in a symptomatic individual, consider gene-targeted deletion/duplication testing.
• If no pathogenic variant is identified in an asymptomatic individual who has suggestive laboratory, imaging, and/or family history findings, consider gene-targeted deletion/duplication testing.

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.

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).

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].

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.

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.

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

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.

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:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• 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, the individual's 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.

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

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

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