Heterozygous Familial Hypobetalipoproteinemia: Case Study and Literature Review

A 12-year-old male was referred to our Pediatric Lipid Clinic by his pediatrician for evaluation of a low total cholesterol level. A fasting lipid profile noted the following; total cholesterol (TC): 84 mg/dL, triglyceride: 50 mg/dL, high-density lipoprotein cholesterol (HDL-C): 47 mg/dL, low-density lipoprotein cholesterol (LDL-C): 27 mg/dL and apolipoprotein B (apo B): 24 mg/dL. His medical history is remarkable for Attention Deficit Disorder, seasonal allergies, vitamin D insufficiency and chronic, bilateral, mild leg pain. He was born at full term, without complications. He is currently taking over-the-counter fish oil (1,000 mgs daily), a daily multivitamin and cetirizine (as needed). He has no apparent medication allergies and has had no prior surgeries. He denies tobacco, alcohol or drug use. He is a very active seventh-grader and does well academically.

Family History
It was noted that several maternal family members have low total cholesterol levels. The total cholesterol levels of his mother (42 years-old), maternal aunt (44 years-old) and maternal grandfather (66 years-old), are 90 mg/dL, 84 mg/dL and 87 mg/dL, respectively. His maternal greatgrandmother (94 years-old) has no reported chronic medical conditions. His paternal family indicates that his father (42 years-old) and paternal grandfather (69 years-old) are being treated for hypercholesterolemia. The hypercholesterolemia appears to be secondary to high-fat diets and unhealthy body weights. His paternal grandfather had a myocardial infarction at age 66. The patient has no biologic siblings (Figure 1).

Physical Examination
Afebrile; heart rate (HR): 86 bpm; blood pressure (BP): 116/59 mm Hg; height: 68 inches; weight: 158 pounds; waist circumference: 37.5 inches; and body mass index (BMI): 24.0 Kg/m2 (93rd percentile for age and gender). The patient was alert, oriented and appeared well-nourished. Physical exam was unremarkable.

Pertinent Chemistry Results
Vitamin D: 22 nmol/L, retinyl palmitate: <0.02 mg/L, alpha-tocopherol: 5.6 mg/L, TSH: 1.69 uU/mL, Free T4: 1.19 ng/dL, normal liver transaminase levels, and thyroid and glycemic indices.

Impression and Recommendations
The laboratory data, maternal family history of low total cholesterol levels in several relatives (Figure 1) and a lack of secondary causes suggest that this patient’s low LDL-C and apo B levels are the result of heterozygous Familial Hypobetalipoproteinemia (FHBL). FHBL is a relatively rare genetic disorder of lipoprotein metabolism that is associated with low serum levels of LDL-C and apo B. Since fat-soluble vitamins are largely bound to lowdensity lipoproteins, very low LDL-C levels can result in their deficiencies. Therefore, we recommended periodic assessment of these vitamin levels, (i.e., vitamins A, D and E) with supplementation, as necessary. We encouraged the patient to follow a healthy diet, take a daily vitamin D supplement (1,000 units), continue the daily multivitamin, and avoid tobacco use and unhealthy weight gain. We recommended a follow-up fasting lipid profile and vitamins A, D and E assessment in six months.

Hypobetalipoproteinemia
LDL-C and apo B levels below the fifth percentile for age and gender define hypobetalipoproteinemia (HBL). Low LDL-C concentrations are usually heritable and associated with a reduced risk of atherosclerotic cardiovascular disease (ASCVD) and increased longevity when not caused by hyperthyroidism, celiac disease (sprue), intestinal malabsorption or alcoholism.¹ Heritable hypobetalipoproteinemia or FHBL is an autosomal co-dominant disorder. The estimated prevalence of heterozygous FHBL is 1 in 3,000 individuals.² The overwhelming majority of simple heterozygotes are asymptomatic, although they may have mild fat-soluble vitamin deficiencies and/or mild hepatic transaminase elevations. The long-term effects of the transaminitis are unknown but appear to be benign.³

This lipoprotein disorder was first described by Mars, et al., in 1969.⁴ Since the discovery of the first kindred with FHBL, many kindreds subsequently have been described. This has lead to the discovery of of numerous single-nucleotide substitutions, gene deletions and linkage abnormalities in the apo B gene causing defects in VLDL and chylomicron synthesis and secretion. More than 40 mutations have been identified in the apo B gene.³ There are two forms of apo B; apo B-100 and apo B-48. These isoforms are derived from differential splicing of ribonucleic acid (RNA) from a single apo B gene. Apo B-100 is synthesized by the liver and is the major protein component of VLDLs and LDLs. Apo B-48 is synthesized by intestinal enterocytes and is the major protein component of chylomicrons. The apo B gene is on chromosome 2 and is unlinked to other apolipoprotein gene clusters.⁵

The best characterized cases of FHBL are the result of mutations in the apo B gene leading to the production of truncated proteins. Lipoproteins bearing truncated forms of apo B are cleared more rapidly than normal apo B-containing lipoproteins, thereby leading to very low plasma concentrations. This rapid clearance appears to be independent of the hepatic LDL and remnant receptors and may involve megalin of the renal proximal tubular cells.⁶

Individuals with FHBL can be heterozygote or homozygote, with severity of the clinical phenotype related to the number of defective apo B alleles. Heterozygote individuals often have no clinical manifestations other than very low serum apo B-containing lipoprotein levels that may cause minor fat-soluble vitamin deficiencies. The low serum apo B-containing lipoprotein levels likely confer ASCVD protection.¹

FHBL homozygotes have extremely low LDL-C levels (< 5 mg/dL) and can have a range of clinical symptoms, including neurologic sequelae, fat malabsorption with steatorrhea, non-alcoholic fatty liver disease, and/or red cell acanthocytosis.

The clinical presentation of homozygous FHBL can be indistinguishable from that of abetalipoproteinemia (ABL), which is due to a mutation in the MTTP gene that encodes for microsomal triglyceride transfer protein (MTTP). MTTP is responsible for the assembly and secretion of hepatic (i.e., VLDL) and intestinal (i.e., chylomicron) apo B-containing lipoproteins. Patients with ABL generally have undetectable levels of apo B-containing lipoproteins and the condition segregates as an autosomal recessive trait.

Establishing the diagnosis of heterozygous FHBL requires substantiating the generational presence of low total cholesterol and LDL-C levels in first- and second-degree relatives of the index case and excluding secondary causes.⁷ Management of heterozygous FHBL generally does not require intervention. Laboratory assessment of fat-soluble vitamins (A, D and E) and hepatic transaminases is warranted, with vitamin supplementation as necessary.

Disclosure statement: Dr. Anne has no disclosures to report. Dr. Maciejko has received honorarium from Merck.