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.
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.
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