Clinical characteristics.

Abetalipoproteinemia typically presents in infancy with failure to thrive, diarrhea, vomiting, and malabsorption of fat. Hematologic manifestations may include acanthocytosis (irregularly spiculated erythrocytes), anemia, reticulocytosis, and hemolysis with resultant hyperbilirubinemia. Malabsorption of fat-soluble vitamins (A, D, E, and K) can result in an increased international normalized ratio (INR). Untreated individuals may develop atypical pigmentation of the retina that may present with progressive loss of night vision and/or color vision in adulthood. Neuromuscular findings in untreated individuals including progressive loss of deep tendon reflexes, vibratory sense, and proprioception; muscle weakness; dysarthria; and ataxia typically manifest in the first or second decades of life.

Diagnosis/testing.

The diagnosis of abetalipoproteinemia is established in a proband with absent or extremely low LDL-cholesterol, triglyceride, and apolipoprotein (apo) B levels and biallelic pathogenic variants in MTTP identified by molecular genetic testing.

Management.

Treatment of manifestations: Adequate caloric intake to alleviate growth deficiency; low-fat diet (10%-20% of total calories from fat); oral essential fatty acid supplementation (up to 1 teaspoon per day of oils rich in polyunsaturated fatty acids, as tolerated); supplementation with vitamin A (100-400 IU/kg/day), vitamin D (800-1,200 IU/day), vitamin E (100-300 IU/kg/day), and vitamin K (5-35 mg/week). Mild anemia rarely requires treatment, although occasionally vitamin B₁₂ or iron therapy may be considered. Dysarthria, ataxia, and hypothyroidism are treated in the standard fashion.

Prevention of primary manifestations: Most complications can be prevented through institution of a low-fat diet with supplementation of fat-soluble vitamins (A, D, E, and K).

Surveillance: Assessment of growth parameters at each visit. Complete blood count, INR, reticulocyte count, liver function tests (AST, ALT, GGT, total and direct bilirubin, alkaline phosphatase, and albumin), fat-soluble vitamin levels (vitamin A [retinol], 25-OH vitamin D, and plasma or red blood cell vitamin E concentrations), serum calcium, serum phosphate, serum uric acid, and TSH levels annually. Lipid profile (total cholesterol, triglyceride concentration, LDL-cholesterol, HDL-cholesterol, apo B, and apo A-I) every several years. Ultrasound of the liver every three years. Ophthalmology and neurology evaluations every six to 12 months.

Agents/circumstances to avoid: Fatty foods, particularly those rich in long-chain fatty acids.

Evaluation of relatives at risk: Sibs of a proband should undergo a full lipid profile and apolipoprotein (apo) B determination to allow for early diagnosis and treatment of findings. If the pathogenic MTTP variants in the family are known, molecular genetic testing may also be used to determine the genetic status of at-risk sibs. In classic abetalipoproteinemia, affected sibs will present shortly after birth with failure to thrive, diarrhea, vomiting, and malabsorption of fat.

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 beta carotene levels throughout pregnancy is recommended. Because vitamin A is an essential vitamin, vitamin A supplementation should not be discontinued during pregnancy.

Genetic counseling.

Abetalipoproteinemia 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 an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible if the pathogenic MTTP variants in the family are known.

Suggestive Findings

Classic abetalipoproteinemia presents from birth with failure to thrive, severe diarrhea and vomiting, and malabsorption of fat. Abetalipoproteinemia should be suspected in children with the following clinical and supportive laboratory findings [Lee & Hegele 2014].

Clinical features

• Failure to thrive, with diarrhea and vomiting
• Fat malabsorption with steatorrhea
• Hepatomegaly
• Loss of night and/or color vision
• Acquired atypical pigmentation of the retina
• Spinocerebellar ataxia and myopathy

Supportive laboratory findings

• Marked hypocholesterolemia (total cholesterol ~1 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 (AST and ALT 1-1.5 times the upper reference limit)
• Prolonged international normalized ratio (INR)
• Low serum concentrations of fat-soluble vitamins (A, D, E, and K)

Establishing the Diagnosis

The diagnosis of abetalipoproteinemia is established in a proband with absent or extremely low LDL-cholesterol, triglyceride, and apo B levels and biallelic pathogenic (or likely pathogenic) variants in MTTP identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP 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 [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic MTTP variants of uncertain significance (or of one known MTTP pathogenic variant and one MTTP variant of uncertain significance) does not establish or rule out the diagnosis.

When the phenotypic and laboratory findings suggest the diagnosis of abetalipoproteinemia, molecular genetic testing approaches can include single-gene testing and use of a multigene panel:

• Single-gene testing. Sequence analysis of MTTP 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 only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
• A multigene panel that includes MTTP 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 includes 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

Abetalipoproteinemia typically presents in infancy with failure to thrive, diarrhea, vomiting, and malabsorption of fat. The absence of apo B-containing lipoproteins and resulting deficiency of fat-soluble vitamins lead to multisystem manifestations as the affected individual ages.

Gastrointestinal. Steatorrhea is the primary gastrointestinal manifestation. The severity relates to the fat content of the diet.

• As affected individuals age they learn to avoid dietary fat, which improves steatorrhea [Kane & Havel 2001].
• Hepatic involvement as identified on laboratory studies is frequently stable over many years and may not evolve to be clinically significant [Lee & Hegele 2014].
• Hepatomegaly and hepatic steatosis can be observed, which rarely may progress to steatohepatitis, fibrosis, and cirrhosis [Di Filippo et al 2014].
• 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 intestinal epithelial cells.

Hematologic manifestations of abetalipoproteinemia include the following:

• Acanthocytosis, defined as irregularly spiculated erythrocytes
• Low erythrocyte sedimentation rate
• Anemia
• Reticulocytosis
• Hyperbilirubinemia
• Hemolysis
• Prolonged INR due to vitamin K deficiency [Kane & Havel 2001]

Ophthalmologic manifestations of abetalipoproteinemia are variable, with the most prominent being an atypical pigmentation of the retina [Cogan et al 1984].

• 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.
• Other rare, typically acquired, ophthalmologic findings include the following:
  • Ptosis
  • Ophthalmoplegia
  • Corneal ulcers

It is hypothesized that the possible cause of ptosis and ophthalmoplegia is vitamin E deficiency leading to cranial nerve demyelination. Corneal ulcers may be caused or exacerbated by vitamin A deficiency [Lee & Hegele 2014].

Neuromuscular. If untreated, neuromuscular manifestations of abetalipoproteinemia 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 weakness
• Dysarthria
• Eventually, a Friedrich's-like ataxia, with a broad base and high stepping gait, can develop in early adulthood in untreated individuals [Tanyel & Mancano 1997].

Cardiac. Although rare, cardiomegaly can occur after decades, with rare death related to cardiomyopathy reported.

Endocrinologic. Although rare, both subclinical and overt hypothyroidism have been reported in individuals with abetalipoproteinemia.

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 reported.

Genotype-Phenotype Correlations

Due to the small number of individuals with abetalipoproteinemia reported in the literature, reliable data on genotype-phenotype correlations are lacking.

Penetrance

While 100% of individuals either homozygous or compound heterozygous for pathogenic MTTP variants will have a biochemical diagnosis of abetalipoproteinemia, the penetrance of clinical symptoms is variable, increases with age, and may be incomplete [Paquette et al 2016]. The disorder affects males and females equally.

Nomenclature

Abetalipoproteinemia was initially named Bassen-Kornzweig syndrome.

Prevalence

Abetalipoproteinemia is rare; fewer than 100 individuals have been described in the literature.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with abetalipoproteinemia, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

The following treatment is recommended for abetalipoproteinemia to address symptoms and prevent complications [Lee & Hegele 2014].

Prevention of Primary Manifestations

Early treatment with vitamin E (100-300 IU/kg/day) may delay or prevent the development of neurologic dysfunction [Zamel et al 2008].

Vitamin E supplementation may also delay or prevent the development of ophthalmoplegia and/or ptosis.

Vitamin A supplementation (100-400 IU/kg/day) may help to prevent corneal ulcers from developing.

See Treatment of Manifestations.

Prevention of Secondary Complications

See Treatment of Manifestations.

Surveillance

Clinical evaluation every six to 12 months, including assessment of diet and any gastrointestinal or neurologic symptoms, is recommended. The following evaluations are also recommended for abetalipoproteinemia [Lee & Hegele 2014] (see Table 5).

Agents/Circumstances to Avoid

Avoid fatty foods, particularly those rich in long-chain fatty acids.

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic older and younger sibs of a proband 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 and apo B determination;
• Molecular genetic testing if the pathogenic variants in the family are known.

Note: In classic abetalipoproteinemia, affected sibs will present shortly after birth with failure to thrive, diarrhea, vomiting, and malabsorption of fat.

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 beta carotene 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 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

Abetalipoproteinemia is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., carriers of one MTTP pathogenic variant).
• Heterozygotes (carriers) are asymptomatic, have normal lipid profiles, and are not at risk of developing the disorder.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Unless an affected individual's reproductive partner also abetalipoproteinemia or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in MTTP.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a MTTP pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the MTTP 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, clarification of carrier status, 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 are affected, are carriers, or are at risk of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Once the MTTP pathogenic variants have been identified in an affected family member, prenatal testing 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

The microsomal triglyceride transfer protein is an essential cofactor for the assembly and secretion of the apolipoprotein (apo) B-containing lipoproteins: chylomicrons from the intestine and very low-density lipoprotein from the liver. Active microsomal triglyceride transfer protein consists of two subunits, the unique MTTP subunit (encoded by MTTP) and a ubiquitously expressed protein disulfide isomerase (PDI) subunit (encoded by P4HB). PDI maintains the solubility of the heterodimeric complex. In individuals with abetalipoproteinemia, the biallelic pathogenic variants in MTTP result in the inability of apoB-containing lipoprotein particles to be secreted. The absence of apoB-containing lipoproteins and deficiency of fat-soluble vitamins in the circulation lead to a variety of clinical manifestations.

Gene structure. The longer transcript variant of MTTP (NM_000253.3) has 19 exons with the first being noncoding.

Pathogenic variants. Approximately 60 MTTP pathogenic variants have been identified; they are interspersed throughout the gene and are not found with increased prevalence in any specific ethnic group. The majority of these are inactivating variants (nonsense, splicing, and small indels). In vitro studies have shown that several pathogenic missense variants affect MTTP function (see Abnormal gene product).

Normal gene product. MTTP consists of 894 amino acids with a signal peptide of 18 residues and three distinct structural regions: an amino-terminal β-barrel domain (amino acids 22-297), a central α-helical region (298-603), and a carboxyl-terminal domain (604-894).

Abnormal gene product. Null alleles and C-terminal truncations result in the inability to produce full-length functional MTTP. The functional consequences of several pathogenic missense variants have been described; p.Arg540His results in defective interaction with PDI, with the mutated MTTP remaining as an insoluble aggregate [Rehberg et al 1996], while p.Leu435His and p.Ser590Ile exhibit negligible lipid transfer activity [Di Filippo et al 2012, Khatun et al 2013]. Pathogenic variants p.Gly746Glu and p.Asn780Tyr are able to interact with PDI, but cannot transfer lipids [Ohashi et al 2000, Khatun et al 2013].

Acknowledgments

RAH has received operating grants from the Canadian Institutes of Health Research (Foundation Grant), the Heart and Stroke Foundation of Ontario (G-15-0009214), and Genome Canada through Genome Quebec (award 4530).

Revision History

• 19 May 2022 (aa) Revision: chylomicron retention disease added to Table 2.
• 25 October 2018 (ma) Review posted live
• 23 January 2018 (jb) Original submission

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