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

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.

Impaired Cytoskeletal and Membrane Biophysical Properties of Acanthocytes in Hypobetalipoproteinemia – A Case Study

“…We here describe a case of familial hypobetalipoproteinemia, resulting from a heterozygosity for the pathogenic Gln845Argfs * 18 mutation in the ApoB gene. Similar to most patients with familial hypobetalipoproteinemia, pHypoβ presented reduced plasma cholesterol and ApoB levels, heightened plasmatic liver enzymes as well as a vitamin E level close to the lower reference limit (Clarke et al, 2006;Musialik et al, 2020). More surprisingly, a high proportion of acanthocytes was detected in this patient, most likely corresponding to the RBCs with surface patches and/or vesicles upon spreading on PLL-coated coverslips.…”

“…Besides abetalipoproteinemia and familial homozygous hypobetalipoproteinemia, a heterozygous form of familial hypobetalipoproteinemia has also been described. Patients are often asymptomatic but frequently associated with NAFLD and in rare cases with neurological disorders ( Musialik et al, 2020 ). Despite the frequently asymptomatic appearance of the heterozygous form of familial hypobetalipoproteinemia, strongly reduced plasma ApoB and LDL-cholesterol levels combined eventually with vitamin E levels below or at the limit of reference values are typical clinical features ( Clarke et al, 2006 ).…”

Identification of a Variant in APOB Gene as a Major Cause of Hypobetalipoproteinemia in Lebanese Families

“…It is not clear whether the neurological disorders developed by these individuals are caused by FHBL or by other factors. In fact, Parkinson’s disease [ 43 ] and a case of a severe late onset neurological disorder had been described in patients with hypobetalipoproteinemia [ 44 ], although neurological disorders and central nervous system deterioration occur mainly with abetalipoproteinemia and homozygous or compound heterozygous FHBL [ 3 , 12 ]. Thus, it may be essential to perform a neurological clinical evaluation on a regular basis, even in heterozygous FHBL patients, in order to instore the early appropriate treatment, and in some cases to recommend a moderate-dose vitamin E supplementation in individuals with low serum vitamin E concentration.…”

“…Thus, it may be essential to perform a neurological clinical evaluation on a regular basis, even in heterozygous FHBL patients, in order to instore the early appropriate treatment, and in some cases to recommend a moderate-dose vitamin E supplementation in individuals with low serum vitamin E concentration. The early diagnosis of these forms of serious late onset complications is necessary because these latter are usually impossible to stop, once they have been developed by the patient [ 11 , 12 , 44 ].…”

Inborn Errors of Metabolism with Ataxia: Current and Future Treatment Options

“…The most common primary monogenic HBL is familial HBL (FHBL), which is due to a defect of the APOB gene and has an autosomal co-dominant mode of inheritance [ 129 ]. Heterozygous FHBL typically has a rather mild clinical presentation, sometimes including a fatty liver [ 130 ]. In contrast, homozygous HBL can have very severe neurological consequences if left untreated, including severe ataxia, myopathy, dysarthria, absent reflexes, retinal degeneration, neuropathy, coagulopathy, hepatic steatosis, progressive demyelination of the central nervous system, lack of responsiveness to local anesthesia, psychomotor retardation, and more, leading to various impairments and a shorter lifespan.…”