Update on primary hypobetalipoproteinemia.

"Primary hypobetalipoproteinemia" refers to an eclectic group of inherited lipoprotein disorders characterized by low concentrations of or absence of low-density lipoprotein cholesterol and apolipoprotein B in plasma. Abetalipoproteinemia and homozygous familial hypobetalipoproteinemia, although caused by mutations in different genes, are clinically indistinguishable. A framework for the clinical follow-up and management of these two disorders has been proposed recently, focusing on monitoring of growth in children and preventing complications by providing specialized dietary advice and fat-soluble vitamin therapeutic regimens. Other recent publications on familial combined hypolipidemia suggest that although a reduction of angiopoietin-like 3 activity may improve insulin sensitivity, complete deficiency also reduces serum cholesterol efflux capacity and increases the risk of early vascular atherosclerotic changes, despite low low-density lipoprotein cholesterol levels. Specialist laboratories offer exon-by-exon sequence analysis for the molecular diagnosis of primary hypobetalipoproteinemia. In the future, massively parallel sequencing of panels of genes involved in dyslipidemia may play a greater role in the diagnosis of these conditions.

Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management.

Abetalipoproteinemia (ABL; OMIM 200100) and homozygous hypobetalipoproteinemia (HHBL; OMIM 107730) are rare diseases characterized by hypocholesterolemia and malabsorption of lipid-soluble vitamins leading to retinal degeneration, neuropathy and coagulopathy. Hepatic steatosis is also common. The root cause of both disorders is improper packaging and secretion of apolipoprotein (apo) B-containing lipoprotein particles due to mutations either in both alleles of the MTP (alias MTTP) gene encoding microsomal triglyceride transfer protein (MTP) or both alleles of the APOB gene itself in the case of ABL and HHBL, respectively. Clinical diagnosis is based on signs and symptoms, acanthocytosis on blood smear, and virtually absent apo B-containing lipoproteins, including chylomicrons, very low density lipoprotein and low density lipoprotein. Obligate heterozygote parents of ABL patients usually have normal lipids consistent with autosomal recessive inheritance, while heterozygous parents of HHBL patients typically have half normal levels of apo B-containing lipoproteins consistent with autosomal co-dominant inheritance. Definitive diagnosis involves sequencing the MTP and APOB genes, for which >30 and >60 mutations have been described for ABL and HHBL, respectively. Follow-up includes monitoring for ophthalmologic, neurologic, hematologic, and hepatic complications, as well as compliance with treatment. Investigations include lipid profile, serum transaminases, markers for lipid-soluble vitamins, and periodic instrumental assessment of ocular and neurological function. Mainstays of treatment include adherence to a low-fat diet, and supplementation with essential fatty acids and high oral doses of fat soluble vitamins. Prognosis is variable, but early diagnosis and strict adherence to treatment can recover normal neurological function and halt disease progression.

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.

Low cholesterol states: clinical implications and management.

INTRODUCTION: Hypocholesterolemia results from genetic - both monogenic and polygenic - and non-genetic causes and can sometimes be a source of clinical concern. We review etiologies and sequelae of hypocholesterolemia and therapeutics inspired from genetic hypocholesterolemia. AREAS COVERED: Monogenic hypocholesterolemia disorders caused by the complete absence of apolipoprotein (apo) B-containing lipoproteins (abetalipoproteinemia and homozygous hypobetalipoproteinemia) or an isolated absence of apo B-48 lipoproteinemia (chylomicron retention disease) lead to clinical sequelae. These include gastrointestinal disturbances and severe vitamin deficiencies that affect multiple body systems, i.e. neurological, musculoskeletal, ophthalmological, and hematological. Monogenic hypocholesterolemia disorders with reduced but not absent levels of apo B lipoproteins have a milder clinical presentation and patients are protected against atherosclerotic cardiovascular disease. Patients with heterozygous hypobetalipoproteinemia have somewhat increased risk of hepatic disease, while patients with PCSK9 deficiency, ANGPTL3 deficiency, and polygenic hypocholesterolemia typically have anunremarkable clinical presentation. EXPERT OPINION: In patients with severe monogenic hypocholesterolemia, early initiation of high-dose vitamin therapy and a low-fat diet are essential for optimal prognosis. The molecular basis of monogenic hypocholesterolemia has inspired novel therapeutics to help patients with the opposite phenotype - i.e. elevated apo B-containing lipoproteins. In particular, inhibitors of PCSK9 and ANGPTL3 show important clinical impact.

Guidance for the diagnosis and treatment of hypolipidemia disorders.

The Abetalipoproteinemia and Related Disorders Foundation was established in 2019 to provide guidance and support for the life-long management of inherited hypocholesterolemia disorders. Our mission is "to improve the lives of individuals and families affected by abetalipoproteinemia and related disorders". This review explains the molecular mechanisms behind the monogenic hypobetalipoproteinemia disorders and details their specific pathophysiology, clinical presentation and management throughout the lifespan. In this review, we focus on abetalipoproteinemia, homozygous hypobetalipoproteinemia and chylomicron retention disease; rare genetic conditions that manifest early in life and cause severe complications without appropriate treatment. Absent to low plasma lipid levels, in particular cholesterol and triglyceride, along with malabsorption of fat and fat-soluble vitamins are characteristic features of these diseases. We summarize the genetic basis of these disorders, provide guidance in their diagnosis and suggest treatment regimens including high dose fat-soluble vitamins as therapeutics. A section on preconception counseling and other special considerations pertaining to pregnancy is included. This information may be useful for patients, caregivers, physicians and insurance agencies involved in the management and support of affected individuals.

Gene-drug interaction: additive influence of mutant APOA1 and testosterone on plasma HDL-cholesterol.

OBJECTIVES: Factors associated with decreased plasma high-density lipoprotein (HDL) cholesterol concentration, or hypoalphalipoproteinemia, include androgenic steroids and mutations in APOA1, encoding apolipoprotein (apo) A-I, the main structural protein of HDL. However, there is little information regarding the extent of plasma HDL lowering when exogenous testosterone is used in subjects with monogenic low HDL. DESIGN AND METHODS: A man with coronary heart disease (CHD) had been receiving exogenous testosterone post-orchidectomy. He had marked hypoalphalipoproteinemia, which was not responsive to diet or medication. To identify a possible genetic contribution to his biochemical phenotype, we sequenced the LCAT and APOA1 genes. RESULTS: There were no sequence abnormalities in LCAT, but we found that he was a heterozygote for a novel APOA1 mutation in codon 107 (AAG->TGG), which predicted the replacement of lysine by tryptophan (K107W). Serial biochemical measurements over 11 years showed that plasma HDL cholesterol on either intramuscular or oral testosterone was 0.19 +/- 0.06 mmol/L, while plasma HDL cholesterol on transdermal testosterone was significantly higher at 0.52 +/- 0.18 mmol/L (p = 0.015, unpaired t-test). CONCLUSIONS: The findings suggest that the low plasma HDL cholesterol associated with heterozygosity for mutant APOA1 can become extremely depressed during treatment with oral or intramuscular androgens. The findings also suggest that transdermal testosterone may perturb HDL to a lesser extent than other routes of delivery in such patients.

Novel missense variants in LCAT and APOB genes in an Italian kindred with familial lecithin:cholesterol acyltransferase deficiency and hypobetalipoproteinemia.

BACKGROUND: Lecithin:cholesterol acyltransferase (LCAT) is responsible for cholesterol esterification in plasma. Mutations of LCAT gene cause familial LCAT deficiency, a metabolic disorder characterized by hypoalphalipoproteinemia. Apolipoprotein B (apoB) is the main protein component of very-low-density lipoproteins and low-density lipoprotein (LDL). Mutations of APOB gene cause familial hypobetalipoproteinemia, a codominant disorder characterized by low plasma levels of LDL cholesterol and apoB. OBJECTIVE: This was a genetic and biochemical analysis of an Italian kindred with hypobetalipoproteinemia whose proband presented with hypoalphalipoproteinemia and severe chronic kidney disease. METHODS: Plasma lipids and apolipoproteins, cholesterol esterification, and high-density lipoprotein (HDL) subclass distribution were analyzed. LCAT and APOB genes were sequenced. RESULTS: The proband had severe impairment of plasma cholesterol esterification and high preß-HDL content. He was heterozygote for the novel LCAT P406L variant, as were two other family members. The proband's wife and children presented with familial hypobetalipoproteinemia and were heterozygotes for the novel apoB H1401R variant. Cholesterol esterification rate of apoB H1401R carriers was reduced, likely attributable to the low amount of circulating LDL. After renal transplantation, proband's lipid profile, HDL subclass distribution, and plasma cholesterol esterification were almost at normal levels, suggesting a mild contribution of the LCAT P406L variant to his pretransplantation severe hypoalphalipoproteinemia and impairment of plasma cholesterol esterification. CONCLUSION: LCAT P406L variant had a mild effect on lipid profile, HDL subclass distribution, and plasma cholesterol esterification. ApoB H1401R variant was identified as possible cause of familial hypobetalipoproteinemia and resulted in a reduction of cholesterol esterification rate.

Neuroacanthocytosis syndromes.

Neuroacanthocytosis (NA) syndromes are a group of genetically defined diseases characterized by the association of red blood cell acanthocytosis and progressive degeneration of the basal ganglia. NA syndromes are exceptionally rare with an estimated prevalence of less than 1 to 5 per 1'000'000 inhabitants for each disorder. The core NA syndromes include autosomal recessive chorea-acanthocytosis and X-linked McLeod syndrome which have a Huntington's disease-like phenotype consisting of a choreatic movement disorder, psychiatric manifestations and cognitive decline, and additional multi-system features including myopathy and axonal neuropathy. In addition, cardiomyopathy may occur in McLeod syndrome. Acanthocytes are also found in a proportion of patients with autosomal dominant Huntington's disease-like 2, autosomal recessive pantothenate kinase-associated neurodegeneration and several inherited disorders of lipoprotein metabolism, namely abetalipoproteinemia (Bassen-Kornzweig syndrome) and hypobetalipoproteinemia leading to vitamin E malabsorption. The latter disorders are characterized by a peripheral neuropathy and sensory ataxia due to dorsal column degeneration, but movement disorders and cognitive impairment are not present. NA syndromes are caused by disease-specific genetic mutations. The mechanism by which these mutations cause neurodegeneration is not known. The association of the acanthocytic membrane abnormality with selective degeneration of the basal ganglia, however, suggests a common pathogenetic pathway. Laboratory tests include blood smears to detect acanthocytosis and determination of serum creatine kinase. Cerebral magnetic resonance imaging may demonstrate striatal atrophy. Kell and Kx blood group antigens are reduced or absent in McLeod syndrome. Western blot for chorein demonstrates absence of this protein in red blood cells of chorea-acanthocytosis patients. Specific genetic testing is possible in all NA syndromes. Differential diagnoses include Huntington disease and other causes of progressive hyperkinetic movement disorders. There are no curative therapies for NA syndromes. Regular cardiologic studies and avoidance of transfusion complications are mandatory in McLeod syndrome. The hyperkinetic movement disorder may be treated as in Huntington disease. Other symptoms including psychiatric manifestations should be managed in a symptom-oriented manner. NA syndromes have a relentlessly progressive course usually over two to three decades.

Hypocholesterolemia.

Hypocholesterolemia is defined as total cholesterol (TC) and low density cholesterol (LDL-C) levels below the 5(th) percentile of the general population adjusted for age, gender and race. Hypocholesterolemia may be attributed to inherited disorders or several secondary causes. Inherited forms of hypocholesterolemia consist of a group of rare diseases. The best studied are familial hypobetalipoproteinemia (FHBL) and abetalipoproteinemia (ABL). Clinical diagnosis rests on lipid levels and the pattern of inheritance after secondary causes are excluded. Patients with primary hypobetalipoproteinemias may manifest a variety of symptoms and signs affecting several organs (steatorrhea, neurological and ophalmological symptoms, non-alcoholic fatty liver disease) or be asymptomatic. Understanding hypocholesterolemia and the underlying molecular basis is of crucial importance since this may provide new insights in the treatment of hypercholesterolemia and cardiovascular disease.

Hypobetalipoproteinaemia--a variant of the Bassen-Kornzweig syndrome.

A patient is reported with hypobetalipoproteinaemia and clinical features resembling the Bassen-Kornzweig syndrome (abetalipoproteinaemia) more completely than previously described. This supports a link between hypobetalipoproteinaemia and abetalipoproteinaemia and it is suggested that the Bassen-Kornzweig syndrome has a wide spectrum with serum betalipoprotein ranging from absent to normal. It is likely that there are different genetic entities with similar end results.