Abetalipoproteinemia Research Articles

A Family with Familial Hypobetalipoproteinemia Caused by a c.1468C>T in APOB.

We herein report the first family of Japanese individuals with familial hypobetalipoproteinemia caused by the c.1468C>T mutation in apolipoprotein B (APOB). A 13-year-old boy with extremely low levels of low-density lipoprotein (LDL) cholesterol (24 mg/dL) was referred to our hospital. The patient had no secondary causes of hypobetalipoproteinemia. His father and grandmother also exhibited low LDL cholesterol levels. A genetic analysis confirmed that they all had this variant in APOB (c.1468C>T). None of the patients exhibited atherosclerotic cardiovascular diseases or any other complications associated with low LDL cholesterol levels, including fatty liver, neurocognitive disorders, and cerebral hemorrhaging.

Deletions in the 3’UTR of the LDLR gene: A genetic cause of familial hypobetalipoproteinemia

Deletions in the 3’UTR of the LDLR gene: A genetic cause of familial hypobetalipoproteinemia

Current Diagnosis and Management of Familial Hypobetalipoproteinemia 1.

Familial hypobetalipoproteinemia (FHBL) 1 is a rare genetic disorder with an autosomal codominant mode of inheritance and is caused by defects in the apolipoprotein (apo) B (APOB) gene that disable lipoprotein formation. ApoB proteins are required for the formation of very low-density lipoproteins (VLDLs), chylomicrons, and their metabolites. VLDLs transport cholesterol and triglycerides from the liver to the peripheral tissues, whereas chylomicrons transport absorbed lipids and fat-soluble vitamins from the intestine. Homozygous or compound heterozygotes of FHBL1 (HoFHBL1) are extremely rare, and defects in APOB impair VLDL and chylomicron secretion, which result in marked hypolipidemia with malabsorption of fat and fat-soluble vitamins, leading to various complications such as growth disorders, acanthocytosis, retinitis pigmentosa, and neuropathy. Heterozygotes of FHBL1 are relatively common and are generally asymptomatic, except for moderate hypolipidemia and possible hepatic steatosis. If left untreated, HoFHBL1 can cause severe complications and disabilities that are pathologically and phenotypically similar to abetalipoproteinemia (ABL) (an autosomal recessive disorder) caused by mutations in the microsomal triglyceride transfer protein (MTTP) gene. Although HoFHBL1 and ABL cannot be distinguished from the clinical manifestations and laboratory findings of the proband, moderate hypolipidemia in first-degree relatives may help diagnose HoFHBL1. There is currently no specific treatment for HoFHBL1. Palliative therapy including high-dose fat-soluble vitamin supplementation may prevent or delay complications. Registry research on HoFHBL1 is currently ongoing to better understand the disease burden and unmet needs of this life-threatening disease with few therapeutic options.

A Rare Case of Neuroacanthocytosis with Predominant Dystonia

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Acanthocytosis is irregular spiky red cells on peripheral blood smears, usually associated with neurological and hematological abnormalities. The different types of neuroacanthocytosis (NA) syndromes include core syndromes like chorea-acanthocytosis, McLeod syndrome, Huntington’s disease-like 2, and Pantothenate kinase-associated neurodegeneration, as well as NA associated with lipoprotein disorders such as abetalipoproteinemia (Bassen–Kornzweig syndrome), familial hypobetalipoproteinemia, Anderson disease, and atypical Wolman disease. Here, we describe a case of a 23-year-old man who presented to this hospital with complaints of choriform movements and abnormal dystonic body posturing since childhood. The peripheral smear revealed acanthocytes, and the brain’s MRI was normal.

Familial ApoB-specific familial hypobetalipoproteinemia in a patient with non-classical congenital adrenal hyperplasia

Familial hypobetalipoproteinaemia is a disorder of lipid metabolism characterized by low levels of total cholesterol, low-density lipoprotein cholesterol and apolipoprotein B. ApoB-related familial hypolipoproteinemia is an autosomal condition with a codominance inheritance pattern. Non-classical congenital adrenal hyperplasia is an autosomal recessive disorder due to mutations in the CYP21A2, a gene encoding for the enzyme 21-hydroxylase, which results in an androgen excess production from adrenal source. We here present the case of a 25-year-old woman with NCAH showing decreased levels of total-cholesterol, low-density lipoprotein cholesterol and triglycerides. Her parent had digestive symptoms and severe hepatic steatosis with elevated liver enzymes, as well as decreased levels of total and low-density lipoprotein cholesterol. A genetic-molecular study of the proband identified a mutation in the APOB gene, which allowed a diagnosis of heterozygous ApoB-related hypolipoproteinaemia to be made.

Hipobetalipoproteinemia familiar ApoB específica en una paciente con hiperplasia suprarrenal congénita no clásica

Familial hypobetalipoproteinaemia is a disorder of lipid metabolism characterized by low levels of total cholesterol, low-density lipoprotein cholesterol and apolipoprotein B. ApoB-related familial hypolipoproteinemia is an autosomal condition with a codominance inheritance pattern. Non-classical congenital adrenal hyperplasia is an autosomal recessive disorder due to mutations in the CYP21A2, a gene encoding for the enzyme 21-hydroxylase, which results in an androgen excess production from adrenal source. We here present the case of a 25-year-old woman with NCAH showing decreased levels of total-cholesterol, low-density lipoprotein cholesterol and triglycerides. Her parent had digestive symptoms and severe hepatic steatosis with elevated liver enzymes, as well as decreased levels of total and low-density lipoprotein cholesterol. A genetic-molecular study of the proband identified a mutation in the APOB gene, which allowed a diagnosis of heterozygous ApoB-related hypolipoproteinaemia to be made.

A New Case of Abetalipoproteinemia Caused by Novel Compound Heterozygote Mutations in the MTTP Gene without Fat or Vitamin Malabsorption.

Abetalipoproteinemia (ABL) is a rare disease characterized by extremely low apolipoprotein B (apoB)-containing lipoprotein levels, dietary fat, and fat-soluble vitamin malabsorption, leading to gastrointestinal, neuromuscular, and ophthalmological symptoms. We herein report a case of ABL with novel compound heterozygous mutations in the microsomal triglyceride transfer protein gene (c.1686_1687del [p.Ser563TyrfsTer10] and c.1862T>C [p.Ile621Thr]), identified via panel sequencing. Although the patient had extremely reduced low-density lipoprotein cholesterol levels and a fatty liver, he did not exhibit other typical complications. Furthermore, unlike typical ABL, this patient had a preserved apoB-48 secretion and increased concentrations of high-density lipoprotein cholesterol, which may account for the normal serum fat-soluble vitamin levels.

Carotenoids in familial hypobetalipoproteinemia disorders: Malabsorption in Caco2 cell models and severe deficiency in patients

Familial hypobetalipoproteinemias (FHBL) are rare genetic diseases characterized by lipid malabsorption. We focused on abetalipoproteinemia (FHBL-SD1) and chylomicron retention disease (FHBL-SD3), caused by mutations in microsomal triglyceride transfer protein (MTTP) and SAR1B genes, respectively. Treatments include a low-fat diet and high-dose fat-soluble vitamin supplementations. However, patients are not supplemented in carotenoids, a group of lipid-soluble pigments essential for eye health. Our aim was to evaluate carotenoid absorption and status in the context of hypobetalipoproteinemia. We first used knock-out Caco-2/TC7 cell models of FHBL-SD1 and FHBL-SD3 to evaluate carotenoid absorption. We then characterized FHBL-SD1 and FHBL-SD3 patient status in the main dietary carotenoids and compared it to that of control subjects. In vitro results showed a significant decrease in basolateral secretion of α- and β-carotene, lutein, and zeaxanthin (-88.8 ± 2.2 % to -95.3 ± 5.8 %, -79.2 ± 4.4 % to -96.1 ± 2.6 %, -91.0 ± 4.5 % to -96.7 ± 0.3 % and -65.4 ± 3.6 % to -96.6 ± 1.9 %, respectively). Carotenoids plasma levels in patients confirmed significant deficiencies, with decreases ranging from -89 % for zeaxanthin to -98 % for α-carotene, compared to control subjects. Given the continuous loss in visual function despite fat-soluble vitamin treatment in some patients, carotenoid supplementation may be of clinical utility. Future studies should assess the correlation between carotenoid status and visual function in aging patients and investigate whether carotenoid supplementation could prevent their visual impairment.

A case of hypocholesterolemia under research

Primary hypocholesterolemia (or hypobetalipoproteinemia) is a rare disorder of lipoprotein metabolism that may be due to a polygenic predisposition or a monogenic disease. Among these, it is possible to differentiate between symptomatic and asymptomatic forms, in which, in the absence of secondary causes, the initial clinical suspicion is plasma ApoB levels below the 5th percentile of the distribution by age and sex. Here we describe the differential diagnosis of a case of asymptomatic hypocholesterolemia. We studied proband’s clinical data, the lipid profile of the proband and her relatives and the clinical data of the family relevant to carry out the differential diagnosis. We performed a genetic study as the diagnostic test. The information obtained from the differential diagnosis suggested a heterozygous hypobetalipoproteinemia due to PCSK9 loss-of-function variants. The diagnostic test revealed, in the proband, the presence of a heterozygous PCSK9 frame-shift variant of a maternal origin. Plasma levels of LDL cholesterol and PCSK9 of the patient and her relatives were compatible with the segregation of the variant revealed. In conclusion, the diagnostic test performed confirmed the suspected diagnosis of the proband as asymptomatic familial hypobetalipoproteinemia due to a loss-of-function variant in the PCSK9 gene.

Pediatric patient with heterozygous familial hypobetalipoproteinemia due to a novel APOB variant

Pediatric patient with heterozygous familial hypobetalipoproteinemia due to a novel APOB variant

Non-alcoholic fatty liver disease in a pediatric patient with heterozygous familial hypobetalipoproteinemia due to a novel APOB variant: a case report and systematic literature review.

Familial hypobetalipoproteinemia (FHBL) is an autosomal semi-dominant disorder usually caused by variants in the APOB gene that frequently interferes with protein length. Clinical manifestations include malabsorption, non-alcoholic fatty liver disease, low levels of lipid-soluble vitamins, and neurological, endocrine, and hematological dysfunction. Genomic DNA was isolated from the blood samples of the pediatric patient with hypocholesterolemia and his parents and brother. Next-generation sequencing (NGS) was performed, and an expanded dyslipidemia panel was employed for genetic analysis. In addition, a systematic review of the literature on FHBL heterozygous patients was performed. Genetic investigation revealed the presence of a heterozygous variant in the APOB (NM_000384.3) gene c.6624dup[=], which changes the open reading frame and leads to early termination of translation into the p.Leu2209IlefsTer5 protein (NP_000375.3). The identified variant was not previously reported. Familial segregation analysis confirmed the variant in the mother of the subject, who also has a low level of low-density lipoprotein and non-alcoholic fatty liver disease. We have introduced therapy that includes limiting fats in the diet and adding lipid-soluble vitamins E, A, K, and D and calcium carbonate. We reported 35 individuals with APOB gene variations linked to FHBL in the systematic review. We have identified a novel pathogenic variant in the APOB gene causing FHBL in pediatric patients with hypocholesterolemia and fatty liver disease. This case illustrates the importance of genetic testing for dyslipidemias in patients with significant decreases in plasma cholesterol as we can avoid damaging neurological and ophthalmological effects by sufficient vitamin supplementation and regular follow-ups.

Un caso de hipocolesterolemia a estudio

Primary hypocholesterolemia (or hypobetalipoproteinemia) is a rare disorder of lipoprotein metabolism that may be due to a polygenic predisposition or a monogenic disease. Among these, it is possible to differentiate between symptomatic and asymptomatic forms, in which, in the absence of secondary causes, the initial clinical suspicion is plasma ApoB levels below the 5th percentile of the distribution by age and sex. Here we describe the differential diagnosis of a case of asymptomatic hypocholesterolemia. We studied proband's clinical data, the lipid profile of the proband and her relatives and the clinical data of the family relevant to carry out the differential diagnosis. We performed a genetic study as the diagnostic test. The information obtained from the differential diagnosis suggested a heterozygous hypobetalipoproteinemia due to PCSK9 loss-of-function variants. The diagnostic test revealed, in the proband, the presence of a heterozygous PCSK9 frame-shift variant of a maternal origin. Plasma levels of LDL cholesterol and PCSK9 of the patient and her relatives were compatible with the segregation of the variant revealed. In conclusion, the diagnostic test performed confirmed the suspected diagnosis of the proband as asymptomatic familial hypobetalipoproteinemia due to a loss-of-function variant in the PCSK9 gene.

Case report of familial hypobetalipoproteinemia: a novel APOB mutation and literature review.

Familial hypobetalipoproteinemia is an autosomal dominantly inherited disorder of lipid metabolism characterized by a <5th percentile plasma levels of low-density lipoprotein cholesterol or total apolipoprotein B, caused by mutations in the APOB gene. Patients with heterozygous APOB-related familial hypobetalipoproteinemia are usually asymptomatic or manifest with mild liver dysfunction or hepatic steatosis. A 14-year-old Korean boy was referred to our clinic because of low low-density lipoprotein cholesterol and elevated aminotransferase levels. He did not complain specific symptoms of hypobetalipoproteinemia, but his laboratory and radiologic tests showed low low-density lipoprotein cholesterol, low apolipoprotein B, high aminotransferases, severe fatty liver, and hepatosplenomegaly. A multigene panel test identified a heterozygous mutation for p.Lys3846Ter (c.11536A>T) in the APOB gene, which has not been reported in previous studies and was not detected in his parents with normal lipid profiles. Limiting intake of saturated fat, increased physical activity, and vitamin E supplementation were performed. Subsequent laboratory tests revealed normalized aminotransferase levels.

Genomic analysis of lean individuals with NAFLD identifies monogenic disorders in a prospective cohort study

Lean patients with non-alcoholic fatty liver disease (NAFLD) represent 10-20% of the affected population and may have heterogeneous drivers of disease. We have recently proposed the evaluation of patients with lean NAFLD without visceral adiposity for rare monogenic drivers of disease. Here, we aimed to validate this framework in a well-characterised cohort of patients with biopsy-proven NAFLD by performing whole exome sequencing. This prospective study included 124 patients with biopsy-proven NAFLD and paired liver biopsies who underwent standardised research visits including advanced magnetic resonance imaging (MRI) assessment of liver fat and stiffness. Six patients with lean NAFLD were identified and underwent whole exome sequencing. Two lean patients (33%) were identified to have monogenic disorders. The lean patients with monogenic disorders had similar age, and anthropometric and MRI characteristics to lean patients without a monogenic disorder. Patient 1 harbours a rare homozygous pathogenic mutation in ALDOB (aldolase B) and was diagnosed with hereditary fructose intolerance. Patient 2 harbours a rare heterozygous mutation in apolipoprotein B (APOB). The pathogenicity of this APOB variant (p.Val1856CysfsTer2) was further validated in the UK Biobank and associated with lower circulating APOB levels (beta= -0.51g/L, 95% CI -0.65 to -0.36g/L, p= 1.4×10-11) and higher liver fat on MRI (beta=+10.4%, 95% CI 4.3-16.5%, p= 8.8×10-4). Hence, patient 2 was diagnosed with heterozygous familial hypobetalipoproteinaemia. In this cohort of well-characterised patients with lean NAFLD without visceral adiposity, 33% (2/6) had rare monogenic drivers of disease, highlighting the importance of genomic analysis in this NAFLD subtype. Although most people with non-alcoholic fatty liver disease (NAFLD) are overweight or obese, a subset are lean and may have unique genetic mutations that cause their fatty liver disease. We show that 33% of study participants with NAFLD who were lean harboured unique mutations that cause their fatty liver, and that these mutations had effects beyond the liver. This study demonstrates the value of genetic assessment of NAFLD in lean individuals to identify distinct subtypes of disease.

Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile.

In mice, GPR146 (G-protein-coupled receptor 146) deficiency reduces plasma lipids and protects against atherosclerosis. Whether these findings translate to humans is unknown. Common and rare genetic variants in the GPR146 gene locus were used as research instruments in the UK Biobank. The Lifelines, The Copenhagen-City Heart Study, and a cohort of individuals with familial hypobetalipoproteinemia were used to find and study rare GPR146 variants. In the UK Biobank, carriers of the common rs2362529-C allele present with lower low-density lipoprotein cholesterol, apo (apolipoprotein) B, high-density lipoprotein cholesterol, apoAI, CRP (C-reactive protein), and plasma liver enzymes compared with noncarriers. Carriers of the common rs1997243-G allele, associated with higher GPR146 expression, present with the exact opposite phenotype. The associations with plasma lipids of the above alleles are allele dose-dependent. Heterozygote carriers of a rare coding variant (p.Pro62Leu; n=2615), predicted to be damaging, show a stronger reductions in the above parameters compared with carriers of the common rs2362529-C allele. The p.Pro62Leu variant is furthermore shown to segregate with low low-density lipoprotein cholesterol in a family with familial hypobetalipoproteinemia. Compared with controls, carriers of the common rs2362529-C allele show a marginally reduced risk of coronary artery disease (P=0.03) concomitant with a small effect size on low-density lipoprotein cholesterol (average decrease of 2.24 mg/dL in homozygotes) of this variant. Finally, mendelian randomization analyses suggest a causal relationship between GPR146 gene expression and plasma lipid and liver enzyme levels. This study shows that carriers of new genetic GPR146 variants have a beneficial cardiometabolic risk profile, but it remains to be shown whether genetic or pharmaceutical inhibition of GPR146 protects against atherosclerosis in humans.

Leu351Arg in apoB, a new missense variant causing familial hypobetalipoproteinemia

Background and Aims : Familial hypobetalipoproteinemia (FHBL) is mostly caused by premature termination codons in the APOB gene, a condition associated with fatty liver and steatohepatitis. Here, we identified a rare missense variant in APOB, p.Leu351Arg, in a family presenting with a FHBL phenotype. Despite its co-segregation with FHBL in the proband and her two children, this variant was classified as variant of uncertain significance (VUS) according to the The American College of Medical Genetics and Genomics (ACMG) guidelines.

Familial hypobetalipoproteinemia caused by homozygous loss-of-function mutations in PCSK9: A case report

Here, we present the first case of a Japanese patient with familial hypobetalipoproteinemia (HBL) that is caused by homozygous loss-of-function mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9). A 46-year-old female patient who was born in a consanguineous marriage of parents who were second cousins was referred to our hospital due to decreased low-density lipoprotein (LDL)-cholesterolemia (22 mg/dL). She did not have any secondary HBL causes. Novel homozygous mutations were identified in PCSK9 (c.1133G>A [p.Cys378Tyr]) using panel sequencing. The serum levels of heterodimer PCSK9 and furin-cleaved PCSK9 were extremely low (<32 and 15 ng/mL, respectively), leading to the diagnosis of familial HBL diagnosis caused by loss-of-function mutations in PCSK9. The patient did not exhibit any complications associated with low LDL cholesterol, except for mild fatty liver and reduced serum 25-OH vitamin D level (15.7 ng/mL). Here, we provide a detailed molecular and functional characterization of a novel loss-of-function mutation in PCSK9.

Novel APOB nonsense variant related to familial hypobetalipoproteinemia and hepatic steatosis: A case report and review

Hereditary familial hypobetalipoproteinemia (FHBL) is a syndrome caused by variants in the APOB gene, that cause a defect in the secretion and mobilization of liver lipids to peripheral tissues, associated with the synthesis of truncated ApoB100 apolipoproteins. This condition causes significant reduction in total cholesterol (TC), low-density lipoproteins (LDL), very low-density proteins (VLDL) and serum triglyceride levels, with unchanged high-density lipoprotein (HDL) cholesterol levels. Herein we present the case of a middle-aged woman diagnosed with FHBL and hepatic steatosis, heterozygous for c.4698C>A; (p.Tyr1566Ter) variant in APOB. The variant presented herein showed high expressiveness in the two generations of individuals analyzed and has not yet being described in the medical literature. Early diagnosis and screening for associated metabolic comorbidities such as metabolic fatty liver disease and its subsequent progression to fibrosis are the two main goals in the treatment of this condition, in order to prevent medium to long term potential complications.

APOB CRISPR-Cas9 Engineering in Hypobetalipoproteinemia: A Promising Tool for Functional Studies of Novel Variants.

Hypobetalipoproteinemia is characterized by LDL-cholesterol and apolipoprotein B (apoB) plasma levels below the fifth percentile for age and sex. Familial hypobetalipoproteinemia (FHBL) is mostly caused by premature termination codons in the APOB gene, a condition associated with fatty liver and steatohepatitis. Nevertheless, many families with a FHBL phenotype carry APOB missense variants of uncertain significance (VUS). We here aimed to develop a proof-of-principle experiment to assess the pathogenicity of VUS using the genome editing of human liver cells. We identified a novel heterozygous APOB-VUS (p.Leu351Arg), in a FHBL family. We generated APOB knock-out (KO) and APOB-p.Leu351Arg knock-in Huh7 cells using CRISPR-Cas9 technology and studied the APOB expression, synthesis and secretion by digital droplet PCR and ELISA quantification. The APOB expression was decreased by 70% in the heterozygous APOB-KO cells and almost abolished in the homozygous-KO cells, with a consistent decrease in apoB production and secretion. The APOB-p.Leu351Arg homozygous cells presented with a 40% decreased APOB expression and undetectable apoB levels in cellular extracts and supernatant. Thus, the p.Leu351Arg affected the apoB secretion, which led us to classify this new variant as likely pathogenic and to set up a hepatic follow-up in this family. Therefore, the functional assessment of APOB-missense variants, using gene-editing technologies, will lead to improvements in the molecular diagnosis of FHBL and the personalized follow-up of these patients.

A rare case of abetalipoproteinemia

The disease studied here abetalipoproteinemia (ABL) is a very rare autosomal recessive disorder which is caused by microsomal triglyceride alteration in protein gene mutation. ABL is defined by a lack of lipids and apolipoprotein B in the plasma, as well as fat malabsorption and a variety of clinical symptoms. We report a 21-year-old male with a history of persistent diarrhea, steatorrhea, and growth retardation who was born to consanguineous parents. The patient was diagnosed with ABL and was treated with dietary changes and fat-soluble vitamin replacement, as well as being monitored on an outpatient basis.