RARE DISEASE
Familial lipoprotein lipase deficiency
Familial lipoprotein lipase deficiency
Familial lipoprotein lipase deficiency
Synonyms: LPL deficiency
Synonyms: LPL deficiency
Synonyms: LPL deficiency
Drug discovery
2
drugs
With orphan designations
Overview
Familial Lipoprotein Lipase Deficiency (LPLD) is a rare autosomal recessive disorder caused by mutations in the LPL gene, leading to impaired triglyceride metabolism. This results in severe hypertriglyceridemia (>2,000 mg/dL), chylomicronemia, and recurrent pancreatitis, often presenting in childhood with abdominal pain, eruptive xanthomas, and hepatosplenomegaly [1][6][7]. Chronic complications include pancreatic damage, diabetes, and neurological symptoms (e.g., depression, memory loss) [1][7]. Diagnosis hinges on genetic testing and absent LPL enzyme activity [6].
Burden
Clinical: Recurrent pancreatitis (50% lifetime risk), chronic pancreatic insufficiency, and retinal lipemia [6][7][15].
Psychosocial: Strict dietary adherence impacts quality of life; 50% report anxiety/depression linked to disease management [4][8].
Economic: Frequent hospitalizations for pancreatitis and lifelong nutritional interventions pose significant healthcare costs [4][8].
Therapies
Dietary: Lifelong restriction of long-chain triglycerides (<20 g/day) with medium-chain triglyceride (MCT) supplementation to reduce chylomicrons [3][7][11].
Monitoring: Regular lipid panels and pancreatic enzyme checks to prevent pancreatitis [7][15].
Emerging: Investigational gene therapy (e.g., alipogene tiparvovec) to restore LPL function [11].
Categories: rare endocrine diseases, rare genetic diseases, rare inborn errors of metabolism
Research Papers
369 drug discovery papers about Familial lipoprotein lipase deficiency, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
369 drug discovery papers about Familial lipoprotein lipase deficiency, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-23 | Familial Chylomicronemia Syndrome Due to a Homozygous LPL c.644G>A Variant and Response to Volanesorsen in Colombia: A Case Report.
Familial chylomicronemia syndrome (FCS) is a rare genetic disorder characterized by persistent severe hypertriglyceridemia and recurrent acute pancreatitis, and is frequently misdiagnosed as multifactorial hypertriglyceridemia. We report the case of a 57-year-old Colombian male with recurrent acute pancreatitis and severe hypertriglyceridemia peaking at 4,350 mg/dL, refractory to fibrates, statins, and omega-3 fatty acids, with persistently low low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels. Secondary causes were excluded, and chronic valproic acid therapy was identified as a potential aggravating factor. A Moulin score of 10 points classified FCS as highly probable, and next-generation sequencing confirmed a homozygous pathogenic LPL variant, NM_000237.3.644G>A, p.(Gly215Glu), associated with loss of enzymatic activity. Following diagnostic confirmation, volanesorsen produced a sustained triglyceride reduction, with no new episodes of pancreatitis during uninterrupted therapy. This case underscores the importance of suspecting FCS in patients with refractory severe hypertriglyceridemia and recurrent pancreatitis. Molecular diagnosis enables access to precision medicine-based strategies with a meaningful impact on clinical outcomes and quality of life.
2026-07-14 | Lipoprotein lipase deficiency presenting with gastrointestinal bleeding and compensated shock.
Lipoprotein lipase (LPL) deficiency is an autosomal recessive disorder causing hypertriglyceridemia. Presentations are heterogenous and there are no standardized acute treatment protocols. Long-term management consists of strict dietary control. We report a case of LPL deficiency in an infant presenting with gastrointestinal bleeding and compensated shock, with a more severe presentation than previously published cases. Preliminary diagnosis was based on lipemic blood appearance. Intensive care resuscitation was required. Triglyceride levels peaked above 200 times the upper limit of normal. Insulin infusion provided no benefit. A whole-blood exchange transfusion led to a sustained reduction in triglyceride levels. Diagnosis was confirmed by genetic testing. Despite the magnitude of hypertriglyceridemia, there were minimal end-organ sequelae. The necessity of invasive management of severe hypertriglyceridemia is not established. This case highlights the range of presentations in inherited metabolic disease, and the limited evidence for acute management strategies.
2026-06-19 | Comparative efficacy and safety of olezarsen versus volanesorsen for familial chylomicronemia syndrome: a matching-adjusted indirect comparison.
Background: Familial chylomicronemia syndrome (FCS) is a rare genetic disorder characterized by severe hypertriglyceridemia causing recurrent acute pancreatitis (AP). Since FCS is a genetic deficiency in functional lipoprotein lipase, conventional triglyceride-lowering therapies are ineffective in this metabolic disorder. Apolipoprotein C-III (apoC-III) inhibitors, including volanesorsen and olezarsen, have emerged as targeted treatments for FCS. Aim: To compare the efficacy and safety of olezarsen 80 mg every four weeks (Q4W) versus volanesorsen 300 mg weekly (QW) in patients with FCS using an anchored matching-adjusted indirect comparison. Materials & methods: Individual patient data from the Balance trial of olezarsen (n = 45) were weighted to match baseline characteristics reported in the APPROACH trial of volanesorsen (n = 66). Outcomes included percent change in fasting triglycerides (TG) and apoC-III at 26 and 52 weeks, and risks of AP events and adverse events at 52 weeks. Results: At 52 weeks, mean differences in fasting TG and apoC-III were -27.4% (95% CI: -69.4, 14.5) and -21.3% (95% CI: -61.9, 19.3). Relative risks of AP, treatment-emergent adverse events, and serious adverse events were 0.23 (95% CI: 0.01, 5.02), 0.87 (95% CI: 0.66, 1.13) and 0.50 (95% CI: 0.08, 3.26) at week 52. The rate ratio for AP events per patient-year was 0.06 (95% CI: 0.003, 1.41). No comparisons were statistically significant. Conclusion: In this matching-adjusted indirect comparison, no statistically significant differences in outcomes were observed between olezarsen and volanesorsen in patients with FCS. These findings provide important comparative context in a setting where head-to-head evidence is unavailable.
2026-06-18 | A Case of Familial Chylomicronemia Syndrome Caused by a Novel Homozygous GPIHBP1 Mutation Successfully Treated with the Selective PPARα Modulator Pemafibrate.
Familial chylomicronemia syndrome (FCS) is a rare disorder characterized by the accumulation of chylomicrons in the circulation due to genetic defects or autoantibodies affecting lipoprotein lipase (LPL), the key enzyme responsible for the metabolism of chylomicrons and very-low-density lipoproteins (VLDL), or its associated proteins, including apolipoprotein (apo) C-II, apoA-V, glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), and lipase maturation factor 1 (LMF1). This condition is associated with markedly elevated serum triglyceride (TG) levels and, in severe cases, recurrent episodes of pancreatitis and eruptive xanthomas. Among these etiologies, genetic deficiency of GPIHBP1 is exceedingly rare. We aimed to clarify the clinical and genetic basis and treatment strategies of a patient with GPIHBP1 deficiency. A 47-year-old woman with a childhood diagnosis of FCS presented with severe epigastric pain and was admitted to Rinku General Medical Center for emergency management of acute pancreatitis secondary to severe chylomicronemia. She had a history of severe hypertriglyceridemia complicated by pancreatitis during her first pregnancy and extreme hypertriglyceridemia exceeding 6,000 mg/dL during her second pregnancy without the development of pancreatitis. DNA sequence analysis was performed as a clinical diagnostic test and outsourced to KUBIX Inc. (Hakusan, Ishikawa, Japan). Laboratory evaluation revealed marked hypertriglyceridemia (1,262 mg/dL) with a type V hyperlipoproteinemia pattern. Serum preheparin LPL mass was markedly reduced, and circulating GPIHBP1 was undetectable. Genetic analysis identified a novel homozygous frameshift mutation in the GPIHBP1 gene (NM_178172.4:c.20del [p.Val7AlafsTer73]), which has not been previously reported in public databases. No pathogenic variants were detected in other LPL-related genes. Acute pancreatitis improved rapidly with fasting and intravenous fluid therapy. Strict dietary fat restriction, followed by the addition of the selective PPARα modulator pemafibrate, successfully maintained TG levels below 500 mg/dL during follow-up. We report an extremely rare case of FCS caused by a novel homozygous mutation in the GPIHBP1 gene, in which pregnancy served as a major trigger for severe hypertriglyceridemia. Early diagnosis and strict lipid control are essential to prevent recurrent pancreatitis in patients with GPIHBP1 deficiency.
2026-06-17 | Heterozygosity for pathogenic variants in familial chylomicronemia syndrome genes: from carrier state to complex trait.
Biallelic loss-of-function (LOF) variants in any of five canonical genes - LPL, GPIHBP1, APOA5, APOC2 , and LMF1 - cause familial chylomicronemia syndrome (FCS), a rare and severe Mendelian disorder. Heterozygosity for these same variants is far more common but its clinical implications have only recently come into focus. Here, the past 18months of evidence on the monoallelic carrier state across the FCS genes is synthesized. Longitudinal studies of LPL and APOA5 heterozygotes have demonstrated that triglyceride phenotypes vary widely both between individuals and within the same individual over time, ranging from completely normal levels to severe hypertriglyceridemia. Heterozygosity contributes to 15-25% of multifactorial chylomicronemia syndrome (MCS) cases. Mechanistic data implicate dominant-negative effects for some truncating variants and saturation of compromised lipolytic reserve as unifying explanations, rather than simple haploinsufficiency. Common intermediate-effect risk alleles such as LPL p.D36N and p.N318S, and APOA5 p.S19W and p.G185C, behave differently and should not be conflated with rare LOF variants. The phenotype of FCS-gene heterozygotes is best understood as a complex trait modulated by polygenic background and secondary factors. This understanding has practical implications for cascade screening, counseling, and selection of patients who may benefit from emerging apolipoprotein C-III-targeted therapies, particularly those in the refractory MCS subgroup.
2026-07-23 | Familial Chylomicronemia Syndrome Due to a Homozygous LPL c.644G>A Variant and Response to Volanesorsen in Colombia: A Case Report.
Familial chylomicronemia syndrome (FCS) is a rare genetic disorder characterized by persistent severe hypertriglyceridemia and recurrent acute pancreatitis, and is frequently misdiagnosed as multifactorial hypertriglyceridemia. We report the case of a 57-year-old Colombian male with recurrent acute pancreatitis and severe hypertriglyceridemia peaking at 4,350 mg/dL, refractory to fibrates, statins, and omega-3 fatty acids, with persistently low low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels. Secondary causes were excluded, and chronic valproic acid therapy was identified as a potential aggravating factor. A Moulin score of 10 points classified FCS as highly probable, and next-generation sequencing confirmed a homozygous pathogenic LPL variant, NM_000237.3.644G>A, p.(Gly215Glu), associated with loss of enzymatic activity. Following diagnostic confirmation, volanesorsen produced a sustained triglyceride reduction, with no new episodes of pancreatitis during uninterrupted therapy. This case underscores the importance of suspecting FCS in patients with refractory severe hypertriglyceridemia and recurrent pancreatitis. Molecular diagnosis enables access to precision medicine-based strategies with a meaningful impact on clinical outcomes and quality of life.
2026-07-14 | Lipoprotein lipase deficiency presenting with gastrointestinal bleeding and compensated shock.
Lipoprotein lipase (LPL) deficiency is an autosomal recessive disorder causing hypertriglyceridemia. Presentations are heterogenous and there are no standardized acute treatment protocols. Long-term management consists of strict dietary control. We report a case of LPL deficiency in an infant presenting with gastrointestinal bleeding and compensated shock, with a more severe presentation than previously published cases. Preliminary diagnosis was based on lipemic blood appearance. Intensive care resuscitation was required. Triglyceride levels peaked above 200 times the upper limit of normal. Insulin infusion provided no benefit. A whole-blood exchange transfusion led to a sustained reduction in triglyceride levels. Diagnosis was confirmed by genetic testing. Despite the magnitude of hypertriglyceridemia, there were minimal end-organ sequelae. The necessity of invasive management of severe hypertriglyceridemia is not established. This case highlights the range of presentations in inherited metabolic disease, and the limited evidence for acute management strategies.
2026-06-19 | Comparative efficacy and safety of olezarsen versus volanesorsen for familial chylomicronemia syndrome: a matching-adjusted indirect comparison.
Background: Familial chylomicronemia syndrome (FCS) is a rare genetic disorder characterized by severe hypertriglyceridemia causing recurrent acute pancreatitis (AP). Since FCS is a genetic deficiency in functional lipoprotein lipase, conventional triglyceride-lowering therapies are ineffective in this metabolic disorder. Apolipoprotein C-III (apoC-III) inhibitors, including volanesorsen and olezarsen, have emerged as targeted treatments for FCS. Aim: To compare the efficacy and safety of olezarsen 80 mg every four weeks (Q4W) versus volanesorsen 300 mg weekly (QW) in patients with FCS using an anchored matching-adjusted indirect comparison. Materials & methods: Individual patient data from the Balance trial of olezarsen (n = 45) were weighted to match baseline characteristics reported in the APPROACH trial of volanesorsen (n = 66). Outcomes included percent change in fasting triglycerides (TG) and apoC-III at 26 and 52 weeks, and risks of AP events and adverse events at 52 weeks. Results: At 52 weeks, mean differences in fasting TG and apoC-III were -27.4% (95% CI: -69.4, 14.5) and -21.3% (95% CI: -61.9, 19.3). Relative risks of AP, treatment-emergent adverse events, and serious adverse events were 0.23 (95% CI: 0.01, 5.02), 0.87 (95% CI: 0.66, 1.13) and 0.50 (95% CI: 0.08, 3.26) at week 52. The rate ratio for AP events per patient-year was 0.06 (95% CI: 0.003, 1.41). No comparisons were statistically significant. Conclusion: In this matching-adjusted indirect comparison, no statistically significant differences in outcomes were observed between olezarsen and volanesorsen in patients with FCS. These findings provide important comparative context in a setting where head-to-head evidence is unavailable.
2026-06-18 | A Case of Familial Chylomicronemia Syndrome Caused by a Novel Homozygous GPIHBP1 Mutation Successfully Treated with the Selective PPARα Modulator Pemafibrate.
Familial chylomicronemia syndrome (FCS) is a rare disorder characterized by the accumulation of chylomicrons in the circulation due to genetic defects or autoantibodies affecting lipoprotein lipase (LPL), the key enzyme responsible for the metabolism of chylomicrons and very-low-density lipoproteins (VLDL), or its associated proteins, including apolipoprotein (apo) C-II, apoA-V, glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), and lipase maturation factor 1 (LMF1). This condition is associated with markedly elevated serum triglyceride (TG) levels and, in severe cases, recurrent episodes of pancreatitis and eruptive xanthomas. Among these etiologies, genetic deficiency of GPIHBP1 is exceedingly rare. We aimed to clarify the clinical and genetic basis and treatment strategies of a patient with GPIHBP1 deficiency. A 47-year-old woman with a childhood diagnosis of FCS presented with severe epigastric pain and was admitted to Rinku General Medical Center for emergency management of acute pancreatitis secondary to severe chylomicronemia. She had a history of severe hypertriglyceridemia complicated by pancreatitis during her first pregnancy and extreme hypertriglyceridemia exceeding 6,000 mg/dL during her second pregnancy without the development of pancreatitis. DNA sequence analysis was performed as a clinical diagnostic test and outsourced to KUBIX Inc. (Hakusan, Ishikawa, Japan). Laboratory evaluation revealed marked hypertriglyceridemia (1,262 mg/dL) with a type V hyperlipoproteinemia pattern. Serum preheparin LPL mass was markedly reduced, and circulating GPIHBP1 was undetectable. Genetic analysis identified a novel homozygous frameshift mutation in the GPIHBP1 gene (NM_178172.4:c.20del [p.Val7AlafsTer73]), which has not been previously reported in public databases. No pathogenic variants were detected in other LPL-related genes. Acute pancreatitis improved rapidly with fasting and intravenous fluid therapy. Strict dietary fat restriction, followed by the addition of the selective PPARα modulator pemafibrate, successfully maintained TG levels below 500 mg/dL during follow-up. We report an extremely rare case of FCS caused by a novel homozygous mutation in the GPIHBP1 gene, in which pregnancy served as a major trigger for severe hypertriglyceridemia. Early diagnosis and strict lipid control are essential to prevent recurrent pancreatitis in patients with GPIHBP1 deficiency.
2026-06-17 | Heterozygosity for pathogenic variants in familial chylomicronemia syndrome genes: from carrier state to complex trait.
Biallelic loss-of-function (LOF) variants in any of five canonical genes - LPL, GPIHBP1, APOA5, APOC2 , and LMF1 - cause familial chylomicronemia syndrome (FCS), a rare and severe Mendelian disorder. Heterozygosity for these same variants is far more common but its clinical implications have only recently come into focus. Here, the past 18months of evidence on the monoallelic carrier state across the FCS genes is synthesized. Longitudinal studies of LPL and APOA5 heterozygotes have demonstrated that triglyceride phenotypes vary widely both between individuals and within the same individual over time, ranging from completely normal levels to severe hypertriglyceridemia. Heterozygosity contributes to 15-25% of multifactorial chylomicronemia syndrome (MCS) cases. Mechanistic data implicate dominant-negative effects for some truncating variants and saturation of compromised lipolytic reserve as unifying explanations, rather than simple haploinsufficiency. Common intermediate-effect risk alleles such as LPL p.D36N and p.N318S, and APOA5 p.S19W and p.G185C, behave differently and should not be conflated with rare LOF variants. The phenotype of FCS-gene heterozygotes is best understood as a complex trait modulated by polygenic background and secondary factors. This understanding has practical implications for cascade screening, counseling, and selection of patients who may benefit from emerging apolipoprotein C-III-targeted therapies, particularly those in the refractory MCS subgroup.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
2 orphan drug designations for Familial lipoprotein lipase deficiency.
2 orphan drug designations for Familial lipoprotein lipase deficiency.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Adeno-associated vector expressing the human lipoprotein lipase protein | gene therapies | FDA | 2007-05-21 | — | uniQure B.V. |
Alipogene tiparvovec [Glybera] | gene therapies | EMA | 2004-03-08 | — | uniQure Biopharma B.V |
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