家族性低βリポタンパク血症1(ホモ接合体)

Abetalipoproteinemia (ABL) is a rare autosomal recessive disorder caused by pathogenic variants in the microsomal triglyceride transfer protein (MTTP) gene, resulting in the defective secretion of apolipoprotein B (APOB)-containing lipoproteins. Although ABL can theoretically have a low risk of cardiovascular disease (CVD) due to the defective secretion of APOB-containing lipoproteins, the previously reported cases of ABL are limited and its CVD-related pathophysiology thus remains unestablished. We encountered a 25-year-old male patient with very low levels of lipids and lipoproteins. In addition to observing his signs and symptoms, we assayed serum oxidized forms of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles using an enzyme-linked immunosorbent assay (ELISA). Variants in the APOB and MTTP genes were analyzed using next-generation sequencing (NGS). As a result, the patient exhibited low levels of total cholesterol (TC), triglycerides (TGs), LDL-cholesterol, and HDL-cholesterol. The oxidized LDL level was measured under a detectable limit, while oxidized HDL showed a relatively high level. An in-frame deletion in MTTP (p.Ser615del), a novel type of gene mutation, was identified in a homozygous manner. The patient had no obvious signs or symptoms of fat malabsorption or any neurological manifestations. In summary, we described a case of ABL with a novel MTTP mutation, p.Ser615del, without typical signs or symptoms. There were markedly low levels of atherogenic lipids and oxidized LDL, while the relatively high level of oxidized HDL with the low level of HDL-cholesterol appeared, which might offer unique insights into the pathophysiology of CVD-related risk in ABL. Further data accumulation of ABL is expected to clarify the disease picture.

Lipoprotein metabolism is significantly different between mice and humans thus making it difficult to model disorders of human lipid metabolism in transgenic mice. Systemic lipoprotein metabolism is predominantly governed by hepatocytes, and mice with humanized livers display human-like lipid profiles. Here we report a highly efficient method to knock out genes in human hepatocytes while retaining their ability to repopulate immune deficient rodents. As proof-of-principle Fah deficient, immune compromised mice were repopulated with Apolipoprotein B (APOB) knockout human hepatocytes. Mice humanized with knockout cells recapitulated typical features of human hypobetalipoproteinemia. We conclude that at least some human lipid metabolism disorders can be modeled in liver chimeric mice using human knockout hepatocytes.

Abetalipoproteinemia (ABL) affects fewer than 1 per 1 million people, whereas neurofibromatosis type 1 (NF1) occurs in approximately 1 in 3000 to 4000 individuals. We describe the clinical findings in a 38-year-old woman with both disorders. ABL was diagnosed in the neonatal period, followed by NF1 at age 7 years based on multiple café-au-lait spots, intertriginous freckling, and Lisch nodules. Genetic testing revealed a homozygous pathogenic MTTP frameshift variant [c.215del (p.Pro72Leufs*8)] and a heterozygous pathogenic NF1 splice variant [c.205-2A>C]. To our knowledge, this co-occurrence has not been previously reported. The estimated likelihood of the co-occurrence is approximately 1 in 3 billion individuals.

BACKGROUND: While low levels of LDL-cholesterol can be atheroprotective, homozygous Class I familial hypobetalipoproteinemia (Ho-Class I FHBL) and heterozygous Class I FHBL (He-Class I FHBL) due to APOB variants (i.e., heterozygous FHBL1 (HeFHBL1)) have serious complications due to genetic defects in the chylomicron/VLDL secretion pathway. However, Ho-Class I FHBL with milder phenotypes and HeFHBL1 are often underdiagnosed due to overlapping lipid profiles with other forms of hypobetalipoproteinemia. OBJECTIVE: Additional screening markers are warranted. METHODS: We established a prospective HBL cohort and performed detailed genotype-phenotype analyses to identify biomarkers associated with Class I FHBL. For further exploration, we systematically reviewed cases with Class I FHBL. RESULTS: In our lipid genome cohort (n = 440), whole-exome sequencing of 18 consecutive cases of HBL (LDL-C <30 mg/dL) identified 7 novel pathogenic variants in 7 cases of Class I FHBL. Genotype-phenotype analyses revealed that plasma vitamin K1 is the strongest independent predictor of Class I FHBL. The vitamin K1 levels in HeFHBL1 were significantly reduced by approximately 50% compared to controls, reflecting the half-normal lipoprotein secretion. Systematic review analyses (n = 472) revealed that vitamin K1 is the only fat-soluble vitamin that is significantly decreased not only in Ho-Class I FHBL but also in HeFHBL1. CONCLUSION: Plasma vitamin K1 may serve as a sensitive screening marker of fat malabsorption, facilitating the genetic diagnosis of Class I FHBL, enabling early management of its complications, such as fat malabsorption, fat-soluble vitamin deficiency, potential vitamin K deficiency, and steatotic liver disease.

Although genetic factors strongly influence lipid metabolism, genetic dyslipidemias refer to specific monogenic defects that significantly alter the function of proteins involved in lipid metabolism. Familial hypercholesterolemia results from mutations in the genes coding for LDL-receptor, apolipoprotein B100 (apoB100), PCSK9, or LDLRAP1. The rare homozygous form is severe, with extravascular lipid deposits at an early age and a high incidence of coronary events in childhood, in the absence of early diagnosis. The heterozygous form is more frequent and characterized by elevated plasma LDL-cholesterol levels (>190mg/dL in adults) and a very high risk of premature coronary artery disease (usually before the age of 50years). Familial chylomicronemia syndrome (FCS) is a major form of genetic hypertriglyceridemia caused by mutations in genes encoding lipoprotein lipase or one of its cofactors (apoC-II, apoA-V, GPIHBP1, or LMF1). Patients with FCS exhibit markedly elevated plasma triglyceride levels (>10mmol/L) and are at high risk for acute pancreatitis. Congenital familial partial lipodystrophy and glycogen storage diseases are two other forms of genetic hypertriglyceridemia. In addition, other rare genetic dyslipidemias have been described in humans, including familial dysbetalipoproteinemia, abetalipoproteinemia, familial hypobetalipoproteinemia, familial combined hypolipidemia, sitosterolemia, and hypoalphalipoproteinemias.