A Rare Mutation in The APOB Gene Associated with Neurological Manifestations in Familial Hypobetalipoproteinemia.

Joanna Musialik,Andrzej Więcek,Magdalena Kania,Agnieszka Gorzkowska,Anna Boguszewska-Chachulska,Dorota Pojda-Wilczek,Małgorzata Wojcieszyn,Robert Szymańczak,Marek Hartleb,Agata Kujawa-Szewieczek

doi:10.3390/ijms21041439

Abstract

Clinical phenotypes of familial hypobetalipoproteinemia (FHBL) are related to a number of defective apolipoprotein B (APOB) alleles. Fatty liver disease is a typical manifestation, but serious neurological symptoms can appear. In this study, genetic analysis of the APOB gene and ophthalmological diagnostics were performed for family members with FHBL. Five relatives with FHBL, including a proband who developed neurological disorders, were examined. A sequencing analysis of the whole coding region of the APOB gene, including flanking intronic regions, was performed using the next-generation sequencing (NGS) method. Electrophysiological ophthalmological examinations were also done. In the proband and his affected relatives, NGS identified the presence of the pathogenic, rare heterozygous splicing variant c.3696+1G>T. Two known heterozygous missense variants—c.2188G>A, p.(Val730Ile) and c.8353A>C, p.(Asn2785His)—in the APOB gene were also detected. In all patients, many ophthalmologic abnormalities in electrophysiological tests were also found. The identified splicing variant c.3696+1G>T can be associated with observed autosomal, dominant FHBL with coexisting neurological symptoms, and both identified missense variants could be excluded as the main cause of observed clinical signs, according to mutation databases and the literature. Electroretinography examination is a sensitive method for the detection of early neuropathy and should therefore be recommended for the care of patients with FHBL.

Highlights

Nonalcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease worldwide
We report a medical history and molecular investigation conducted in one family presenting clinical features of heterozygous familial hypobetalipoproteinemia (FHBL) carrying a rare pathogenic variant connected with strong neurological manifestations
The next-generation sequencing (NGS) analysis identified the presence of a rare, heterozygous splicing variant c.3696+1G>T, changing the first base of intron 23 of the apolipoprotein B (APOB) gene (APOB genotype according to the Human Genome Variation Society (HGVS): NM_000384.2:c.[3696+1G>T];[=])

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease worldwide. In some cases, classical NAFLD must be distinguished from genetically driven secondary NAFLD not directly associated with insulin-resistance One such example is familial hypobetalipoproteinemia (FHBL) [2,3,4]. The disease is characterized by reduced serum levels of total cholesterol (TC), low-density lipoproteins (LDL), and apolipoprotein B (apoB). Other clinical manifestations include malabsorption syndrome and fatty liver disease [6]. The mechanism of fat accumulation within the liver development is decreased hepatic secretion of apoB resulting in reduced triglyceride export from the liver. Heterozygotes often have no clinical manifestations other than very low serum apoB-containing lipoprotein levels, which may confer cardiovascular protection, but an undetermined proportion of subjects may suffer from liver and systemic metabolic consequences of this disease [8,9,10]. In the homozygous form of FHBL, the TG level is very low, while in the heterozygous form of this disease, it is usually normal [7]

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