Amyloidosis is caused by the deposition of misfolded aggregated proteins called amyloid fibrils that in turn cause organ damage and dysfunction. In this review, we aim to summarize the genetic, clinic Show more
Amyloidosis is caused by the deposition of misfolded aggregated proteins called amyloid fibrils that in turn cause organ damage and dysfunction. In this review, we aim to summarize the genetic, clinical, and histological findings in apolipoprotein-associated hereditary amyloidosis and the growing list of mutations and apolipoproteins associated with this disorder. We also endeavor to summarize the features of apolipoproteins that have led them to be overrepresented among amyloidogenic proteins. Additionally, we aim to distinguish mutations leading to amyloidosis from those that lead to inherited dyslipidemias. Apolipoproteins are becoming increasingly recognized in hereditary forms of amyloidosis. Although mutations in APOA1 and APOA2 have been well established in hereditary amyloidosis, new mutations are still being detected, providing further insight into the pathogenesis of apolipoprotein-related amyloidosis. Furthermore, amyloidogenic mutations in APOC2 and APOC3 have more recently been described. Although no hereditary mutations in APOE or APOA4 have been described to date, both protein products are amyloidogenic and frequently found within amyloid deposits. Understanding the underlying apolipoprotein mutations that contribute to hereditary amyloidosis may help improve understanding of this rare but serious disorder and could open the door for targeted therapies and the potential development of new treatment options. Show less
Familial chylomicronemia syndrome (FCS) is an ultra-rare phenotype that is usually caused by biallelic mutations in the LPL gene encoding lipoprotein lipase, or less often in APOC2, APOA5, LMF1, or GP Show more
Familial chylomicronemia syndrome (FCS) is an ultra-rare phenotype that is usually caused by biallelic mutations in the LPL gene encoding lipoprotein lipase, or less often in APOC2, APOA5, LMF1, or GPIHBP1 genes encoding cofactors or interacting proteins. We evaluated baseline phenotypes among FCS participants in a phase 3 randomized placebo-controlled trial of volanesorsen (NCT02211209). Baseline clinical, fasting, and postfat load metabolic markers were assessed. Targeted next-generation DNA sequencing plus custom bioinformatics was used to genotype subjects. Among 52 FCS individuals, 41 had biallelic LPL gene mutations (LPL-FCS patients): 82%, 7%, and 11% were missense, nonsense, and splicing variants, respectively. Eleven individuals had non-LPL-FCS; 2 had mutations in APOA5, 5 in GPIHBP1, and 1 each in LMF1 and APOC2 genes, respectively. Two other individuals were double heterozygotes, each with 1 normal LPL allele. All subjects had extremely high triglycerides (TGs) and chylomicrons, but very low levels of other lipoproteins. Compared with LPL-FCS individuals, non-LPL-FCS individuals were very similar for most traits, but had significantly higher postheparin LPL activity, higher 4-hour postprandial insulin and C-peptide levels; and higher low-density lipoprotein cholesterol levels. In non-LPL-FCS individuals compared to those with LPL-FCS, there were also nonsignificant trends toward lower levels of total and chylomicron TGs, lower 4-hour postprandial chylomicron TG levels, and higher very-low-density lipoprotein TG levels. Thus, LPL FCS and non-LPL FCS are largely phenotypically similar. However, LPL FCS patients have lower postheparin LPL activity and a trend toward higher TGs, whereas low-density lipoprotein cholesterol was higher in non-LPL-FCS patients. Show less