👤 Alberto Maiz

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder characterized by severe hypertriglyceridemia and caused by mutations in genes involved in chylomicron metabolism. Dietary management includes a very-low-fat diet, restriction of simple carbohydrates and alcohol, supplementation with medium-chain triglycerides, essential fatty acids, and fat-soluble vitamins; however, long-term adherence is often poor and nutritional therapy alone is insufficient. We report two adult Chilean sisters with FCS caused by the homozygous Q97X mutation in the APOA5 gene. Both patients experienced severe hypertriglyceridemia (>5,000 mg/dL) and recurrent episodes of acute pancreatitis. One sister was treated with volanesorsen, an antisense oligonucleotide, receiving a weekly dose of 285 mg, which was repeated every 3 weeks due to thrombocytopenia. When combined with structured nutritional counseling, pharmacological treatment achieved a marked reduction in plasma triglycerides to <250 mg/dL and a substantial improvement in quality of life. The other sister was managed with conventional therapy due to a lack of health insurance coverage for volanesorsen. She presented persistent hypertriglyceridemia and recurrent hospitalizations, underscoring the challenges of access to advanced therapies in limited-resource settings. While volanesorsen offers a promising therapeutic alternative, equitable access remains a critical issue, particularly in health systems of low-to middle-income regions. Show less

Severe hypertriglyceridemia (HTG) has been linked to defects in LPL, APOC2, APOA5, LMF1 and GBIHBP1 genes. However, a number of severe HTG cases are probably caused by as yet unidentified mutations. Very high triglyceride plasma levels (>112 mmol/L at diagnosis) were found in two sisters of a Chilean consanguineous family, which is strongly suggestive of a recessive highly penetrant mutation. The aim of this study was to determine the genetic locus responsible for the severe HTG in this family. We carried out a genome-wide linkage study with nearly 300,000 biallelic markers (Illumina Human CytoSNP-12 panel). Using the homozygosity mapping strategy, we searched for chromosome regions with excess of homozygous genotypes in the affected cases compared to non-affected relatives. A large homozygous segment was found in the long arm of chromosome 11, with more than 2,500 consecutive homozygous SNP shared by the proband with her affected sister, and containing the APOA5/A4/C3/A1 cluster. Direct sequencing of the APOA5 gene revealed a known homozygous nonsense Q97X mutation (p.Gln97Ter) found in both affected sisters but not in non-affected relatives nor in a sample of unrelated controls. The Q97X mutation of the APOA5 gene in homozygous status is responsible for the severe hypertriglyceridemia in this family. We have shown that homozygosity mapping correctly pinpointed the genomic region containing the gene responsible for severe hypertriglyceridemia in this consanguineous Chilean family. Show less