Novel Heterozygous Mutation in Apob (p.E137X) Causing Hypobetalipoproteinemia

Presentation Number: SAT 513
Date of Presentation: April 1st, 2017

Kaitlin Ditch*1, Satbir Kaur Singh1, Adam D McIntyre2, Amnon Schlegel1, Robert Alexander Hegele2 and Deepika Santosh Reddy1
1University of Utah, Salt Lake City, UT, 2Robarts Research Institute, London, ON, Canada


BACKGROUND: Hypobetalipoproteinemia (HBL) is a rare autosomal recessive or co-dominant disorder, with an incidence of less than 1 in 1,000,000, characterized by hypocholesterolemia with total cholesterol, LDL cholesterol (LDL-C), and total Apolipoprotein B (APOB) levels less than the 5th percentile. Affected individuals may be asymptomatic or can develop fatty liver, transaminitis, oral fat intolerance, intestinal fat malabsorption, and complications related to fat soluble vitamin deficiencies. HBL is caused by mutations in the APOB gene leading to inappropriate packaging and secretion of apo B-containing lipoprotein particles. APOB is expressed in enterocytes and hepatocytes; its encoded protein is the signature coat molecule of chylomicrons and Very Low Density Lipoprotein (VLDL) particles, which deliver intestine- and liver-derived neutral lipids to the periphery. We present a case of hypobetalipoproteinemia involving a novel mutation of APOB, p.E137X.

CLINICAL CASE: A 26-year-old Caucasian male presented with hypocholesterolemia. Medical history included obesity, hypogonadism, impaired glucose tolerance, nonalcoholic fatty liver disease, and obstructive sleep apnea. He noted diarrhea induced by fatty food intake since childhood. Family history included hypocholesterolemia in his mother and brother. Mild dysmetria and unsteady gait assessed by tandem walking were noted on examination. Laboratory revealed serum total cholesterol 58 mg/dL (<200 mg/dL), HDL-C of 26 mg/dL (40-59 mg/dL), triglyceride 53 mg/dL (30-149 mg/dL), and LDL-C of 22 mg/dL (0-129 mg/dL). Transaminases were: ALT 91 U/L (5-50 U/L) and AST 94 U/L (9-50 U/L). Deficiencies in Vitamins A, D, and E were observed. Vitamin K stores appeared normal, with INR of 1.0. APOB levels were undetectable <25 mg/dL (55-140 mg/dL) and APOA1 was normal 108 mg/dL (94-178 mg/dL). Vitamin B12 level was normal. Genetic testing revealed a heterozygous nonsense mutation, p.E137X, in the APOB gene, which was absent from all public databases. The patient was diagnosed with HBL due to a truncation in APOB.

We recommended annual lipid profile with APOA1 and APOB, hepatic and coagulation function tests, thyroid function tests, B12 and fat-soluble vitamins levels. Neurological examination should be repeated in 6 to 12 months, and abdominal ultrasound in 3 years. Baseline DXA, ophthalmological examination, and echocardiogram were recommended. He was treated with high doses vitamins A and E, and a low fat diet supplemented with 1-2 teaspoons olive oil daily for adequate consumption of essential fatty acids. We recommended genetic testing of the patient’s mother and brother.

CONCLUSION: Up to one-quarter of patients with clinically diagnosed HBL do not have detectable mutations on sequencing of APOB. This is the first case describing a heterozygous nonsense mutation in APOB (p.E137X) causing hypobetalipoproteinemia.


Nothing to Disclose: KD, SKS, ADM, AS, RAH, DSR