Homozygous Familial Hypobetalipoproteinemia Diagnosed in Adulthood With a New Splicing Variant of the APOB Gene

Case Reports2 August 2022Homozygous Familial Hypobetalipoproteinemia Diagnosed in Adulthood With a New Splicing Variant of the APOB GeneAlyssa Sim, MBBS, MRCP, Kalaiyarasi Kaliyaperumal, MRCP, Liuh Ling Goh, PhD, Rinkoo Dalan, FRCP, Cora Chau, FRCPA, and Charles Vu, FRACPAlyssa Sim, MBBS, MRCPDepartment of Gastroenterology & Hepatology, Tan Tock Seng Hospital, SingaporeSearch for more papers by this author, Kalaiyarasi Kaliyaperumal, MRCPDepartment of Gastroenterology & Hepatology, Tan Tock Seng Hospital, SingaporeSearch for more papers by this author, Liuh Ling Goh, PhDMolecular Diagnostic Laboratory, Personalized Medicine Service, Tan Tock Seng Hospital, SingaporeSearch for more papers by this author, Rinkoo Dalan, FRCPDepartment of Endocrinology, Tan Tock Seng Hospital, SingaporeSearch for more papers by this author, Cora Chau, FRCPADepartment of Pathology, Tan Tock Seng Hospital, SingaporeSearch for more papers by this author, and Charles Vu, FRACPDepartment of Gastroenterology & Hepatology, Tan Tock Seng Hospital, SingaporeSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/aimcc.2022.0247 SectionsSupplemental MaterialAboutVisual AbstractAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinkedInRedditEmail AbstractWe report a case of familial hypobetalipoproteinemia presenting with severe fat malabsorption, diagnosed in adulthood, with a new splicing variant of the APOB gene.BackgroundFamilial hypobetalipoproteinemia (FHBL) and another closely related condition, abetalipoproteinemia (ABL) are inherited lipoprotein disorders termed primary hypobetalipoproteinemia. They are characterized by absent to very low levels of lipids and apolipoprotein (apo) B-containing lipoproteins (1, 2), which impair transport and absorption of dietary fat and lipid-soluble vitamins. These rare diseases result in fat malabsorption and lipid-soluble vitamin deficiencies that can affect a wide range of organ systems (3). Fat malabsorption classically presents with chronic diarrhea, malnutrition, and abdominal distension. Coexisting deficiencies of lipid-soluble vitamins are common resulting in gastrointestinal, ophthalmologic, neurologic, and hematologic manifestations.ObjectiveTo highlight the challenges in recognizing and diagnosing FHBL in an adult patient and to report the discovery of a new splicing variant of the APOB gene.Case ReportA 56-year-old man presented with worsening abdominal distension and significant weight loss with a background of chronic diarrhea for 2 years. He had bilateral pigmentary retinal degeneration with progressive blindness since childhood and was diagnosed with diffuse non-length-dependent sensory polyneuropathy in the recent months preceding the current presentation. Upper and lower gastrointestinal endoscopies performed previously had no diagnostic features endoscopically, nor did biopsies. There was no family history of malabsorption, but parental consanguinity was present. On examination, he appeared cachectic with a body mass index of 14 kg/m2. Although he had loss of proprioception and vibration, there was no muscle weakness or ataxia. Routine blood tests were consistent with a malabsorption syndrome and fat-soluble vitamin deficiency: serum albumin, 26 g/L (normal range [NR], 38–48 g/L); vitamin E, 8.8 µmol/L (NR, 13–42 µmol/L), vitamin D, 22 nmol/L (NR, 50–125 nmol/L), international normalized ratio, 1.6; and iron deficiency anemia hemoglobin, 110 g/L (NR, 136–166 g/L); and ferritin, 25 pmol/L (NR, 54–755 pmol/L). Vitamin A levels were not obtained at presentation, but after oral supplementation, they were 1.0 µmol/L (NR, 0.9–2.6 µmol/L). A computed tomography scan of the abdomen done at admission showed small bowel ileus and jejunal thickening. A liver ultrasound done shortly after showed normal liver echogenicity with no evidence of hepatic steatosis. Motorized power spiral enteroscopy revealed atrophic jejunal mucosa, with biopsies showing cytoplasmic vacuolation of columnar enterocytes with lipid accumulation (Figure 1). Acanthocytosis was detected on peripheral blood film. He had very low serum cholesterol (0.8 mmol/L) and triglyceride (0.1 mmol/L) concentrations and undetectable low-density lipoproteins and apo B. This unusual biochemistry led to the suspicion of FHBL.Figure 1. Jejunal mucosa showing preserved villous architecture and cytoplasmic vacuolation of the columnar enterocytes near the tip of villi (hematoxylin–eosin staining, magnification × 100). Download figure Download PowerPoint Genetic testing of the MTTP and APOB genes was performed. Mutations of these genes affect the processing of apo B-containing lipoprotein particles, which impairs absorption and trafficking of lipids and lipid-soluble nutrients. The proper assembly of these lipoproteins depends on 2 proteins: apo B, a structural protein, and microsomal triglyceride transfer protein. Mutations in both alleles of the MTTP gene causes ABL, leading to defective transport of lipids and fat-soluble vitamins within lipoprotein particles. The absence of plasma apo B-containing lipoproteins results in the clinical manifestations of fat malabsorption and fat-soluble vitamin deficiencies such as steatorrhea, neurologic involvement, and retinal pigmentary degeneration. An identical phenotype is seen with homozygous and compound heterozygous mutations in the APOB gene that affects structure and stability of apo B, which causes FHBL. There were no alterations found in the MTTP gene. However, a 13 nucleotides deletion was identified in a region spanning part of exon 3 to the 5′ donor splice site of intron 3 of the APOB gene (NM_000384.2: c.226_237+1del). This alteration was validated by Sanger sequencing in the proband harboring the APOB c.226_237+1del variant in a homozygous state. This variant is expected to disrupt splicing and lead to a loss of protein function (Figure 2). It is consistent with the patient's phenotype and confirmed the diagnosis of FHBL.Figure 2. Electropherogram showing the 13-bp deletion and 5′ donor splice site prediction. The alteration results in a cryptic site 13 bp upstream of the authentic splice site leading to premature termination. Download figure Download PowerPoint He was managed with a specialized low-fat diet restricted to less than 15% of daily caloric requirement with no consumption of long-chain fatty acids. To ensure adequate intake of essential fatty acids, he supplemented his diet with 1 to 2 teaspoons daily of olive oil. He received oral supplementation of fat-soluble vitamins with vitamin D 4000 IU daily, vitamin K 10 mg weekly, vitamin A 100 IU/kg/d, and vitamin E 100 IU/kg/d. Within weeks of strict adherence to this diet, his diarrhea and ileus resolved. Eventual improvement in his nutritional variables were seen on discharge, with a serum albumin of 37 g/L and a gradual rise of body mass index to 14.8 kg/m2 following a prolonged 6-month stay in the hospital.DiscussionFHBL is a rare, autosomal, codominant disorder of lipoprotein metabolism from a mutation in the APOB gene. In its homozygous form, it is clinically indistinguishable from ABL (3), which was first described by Bassen and Kornzweig in 1950, in which the clinical association of peripheral blood acanthocytosis with atypical retinitis pigmentosa and ataxia was reported (4). Incidence of the heterozygote form of the disease ranges from 0.01% to 0.03% of the general population (5, 6) and may have clinical manifestations ranging from gastrointestinal symptoms to being asymptomatic. Liver involvement in the form of hepatic steatosis and elevated liver enzymes is also common in FHBL. A study reported 24 of 25 patients with homozygous FHBL presenting with hepatomegaly or increased aminotransferases or liver steatosis (7). Our patient had normal liver function tests and no radiological evidence of hepatic steatosis on presentation. Classically, gastrointestinal symptoms in this condition subside with avoidance of dietary fat. Acanthocytosis of peripheral blood smear is a distinct feature, resulting from either vitamin E deficiency or an altered membrane lipid composition (8). Deficiency of vitamin E leads to neurologic manifestations, and, as in the case of our patient, sensory polyneuropathy. Vitamin A deficiency causes pigmentary retinal degeneration. To our knowledge, our patient is the oldest reported case of a homozygous FHBL presenting with end-stage manifestations of the disease. FHBL is often diagnosed during infancy when the affected patients present with fat malabsorption and failure to thrive. The novel finding in our patient of the pathogenic c.226_237+1del variant in the APOB gene disrupting RNA splicing is the first to be reported. In conclusion, genetic testing to achieve a definitive diagnosis of FHBL is crucial to guide early treatment and for appropriate supplementation of fat-soluble vitamins to halt disease progression and improve outcomes.References1. Lee J, Hegele RA. Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management. J Inherit Metab Dis. 2014;37:333-9. [PMID: 24288038] doi:10.1007/s10545-013-9665-4 CrossrefMedlineGoogle Scholar2. Burnett JR, Bell DA, Hooper AJ, et al. Clinical utility gene card for: abetalipoproteinaemia–update 2014. Eur J Hum Genet. 2015;23. 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[PMID: 32039990] doi:10.1097/MOL.0000000000000663 CrossrefMedlineGoogle Scholar Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: 1Department of Gastroenterology & Hepatology, Tan Tock Seng Hospital, Singapore2Molecular Diagnostic Laboratory, Personalized Medicine Service, Tan Tock Seng Hospital, Singapore3Department of Endocrinology, Tan Tock Seng Hospital, Singapore4Department of Pathology, Tan Tock Seng Hospital, SingaporeCorresponding AuthorAlyssa Sim, MBBS, MRCP; Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433; e-mail, [email protected].DisclosuresDisclosure forms are available with the article online. PreviousarticleNextarticle FiguresReferencesRelatedDetails Metrics August 2022Volume 1, Issue 6KeywordsFamilial hypobetalipoproteinemiaFatsLipidsLipoproteinsMalabsorption ePublished: 2 August 2022 Issue Published: August 2022 Copyright & PermissionsCopyright © 2022 by Authors. 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