RARE DISEASE
Chylomicron retention disease
Chylomicron retention disease
Chylomicron retention disease
Synonyms: Anderson disease, CMRD, CRD
Synonyms: Anderson disease, CMRD, CRD
Synonyms: Anderson disease, CMRD, CRD
Drug discovery
0
drugs
With orphan designations
Overview
Chylomicron retention disease (CRD) is a rare autosomal recessive disorder caused by SAR1B mutations, disrupting chylomicron transport from intestinal enterocytes. This results in fat malabsorption, hypocholesterolemia, and deficiencies in fat-soluble vitamins. Key features include failure to thrive, chronic diarrhea, hepatic steatosis, and later-onset neuromuscular complications. Diagnosis relies on lipid profile analysis, endoscopy revealing lipid-laden enterocytes, and genetic testing [1][2][12][14].
Therapies
Low-long chain fat diet (≤30% total calories) with essential fatty acid supplementation [3][8][10].
High-dose fat-soluble vitamins (A, D, E, K), particularly vitamin E to prevent neurological damage [3][12][14].
Regular monitoring of growth, hepatic function, and neuromuscular/ophthalmologic health [5][8][12].
Categories: rare endocrine diseases, rare gastroenterological diseases, rare genetic diseases, rare inborn errors of metabolism
Research Papers
31 drug discovery papers about Chylomicron retention disease, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
31 drug discovery papers about Chylomicron retention disease, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2024-03-25 | Carotenoids in familial hypobetalipoproteinemia disorders: Malabsorption in Caco2 cell models and severe deficiency in patients.
Familial hypobetalipoproteinemias (FHBL) are rare genetic diseases characterized by lipid malabsorption. We focused on abetalipoproteinemia (FHBL-SD1) and chylomicron retention disease (FHBL-SD3), caused by mutations in microsomal triglyceride transfer protein (MTTP) and SAR1B genes, respectively. Treatments include a low-fat diet and high-dose fat-soluble vitamin supplementations. However, patients are not supplemented in carotenoids, a group of lipid-soluble pigments essential for eye health. Our aim was to evaluate carotenoid absorption and status in the context of hypobetalipoproteinemia. We first used knock-out Caco-2/TC7 cell models of FHBL-SD1 and FHBL-SD3 to evaluate carotenoid absorption. We then characterized FHBL-SD1 and FHBL-SD3 patient status in the main dietary carotenoids and compared it to that of control subjects. In vitro results showed a significant decrease in basolateral secretion of α- and β-carotene, lutein, and zeaxanthin (-88.8 ± 2.2 % to -95.3 ± 5.8 %, -79.2 ± 4.4 % to -96.1 ± 2.6 %, -91.0 ± 4.5 % to -96.7 ± 0.3 % and -65.4 ± 3.6 % to -96.6 ± 1.9 %, respectively). Carotenoids plasma levels in patients confirmed significant deficiencies, with decreases ranging from -89 % for zeaxanthin to -98 % for α-carotene, compared to control subjects. Given the continuous loss in visual function despite fat-soluble vitamin treatment in some patients, carotenoid supplementation may be of clinical utility. Future studies should assess the correlation between carotenoid status and visual function in aging patients and investigate whether carotenoid supplementation could prevent their visual impairment.
2022-12-16 | 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.
2022-08-01 | Lomitapide effectively reduces triglyceride (TG) levels in familial chylomicronemia syndrome (FCS)
Background and Aims : FCS is a rare autosomal recessive disorder of impaired lipoprotein lipase (LPL) function, elevated TG levels, abdominal pain and pancreatitis. Current treatment (extremely low-fat diet <10% fat/day to reduce TG levels ≤750mgldL) is ineffective. Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor that reduces circulating levels of TGs.Methods: The open-label, single-arm 'LOCHNES' study of lomitapide in FCS, enrolled adult patients ≥18 years with genetically confirmed FCS, elevated fasting TG≥750mg/dL and a history of pancreatitis. Patients were administered escalating doses of lomitapide to maximum tolerated dose for 26 weeks. The primary endpoint was the percent change in TGs from baseline to Week 26.Conclusions: Lomitapide is effective in reducing triglycerides in FCS and preventing recurrence of acute pancreatitis. Larger studies are warranted. Background and Aims : FCS is a rare autosomal recessive disorder of impaired lipoprotein lipase (LPL) function, elevated TG levels, abdominal pain and pancreatitis. Current treatment (extremely low-fat diet <10% fat/day to reduce TG levels ≤750mgldL) is ineffective. Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor that reduces circulating levels of TGs. Methods: The open-label, single-arm 'LOCHNES' study of lomitapide in FCS, enrolled adult patients ≥18 years with genetically confirmed FCS, elevated fasting TG≥750mg/dL and a history of pancreatitis. Patients were administered escalating doses of lomitapide to maximum tolerated dose for 26 weeks. The primary endpoint was the percent change in TGs from baseline to Week 26. Conclusions: Lomitapide is effective in reducing triglycerides in FCS and preventing recurrence of acute pancreatitis. Larger studies are warranted.
2019-09-09 | Efficacy of two vitamin E formulations in patients with abetalipoproteinemia and chylomicron retention disease.
Abetalipoproteinemia (ABL) and chylomicron retention disease (CMRD) are extremely rare recessive forms of hypobetalipoproteinemia characterized by intestinal lipid malabsorption and severe vitamin E deficiency. Vitamin E is often supplemented in the form of fat-soluble vitamin E acetate, but fat malabsorption considerably limits correction of the deficiency. In this crossover study, we administered two different forms of vitamin E, tocofersolan (a water-soluble derivative of RRR-α-tocopherol) and α-tocopherol acetate, to three patients with ABL and four patients with CMRD. The aims of this study were to evaluate the intestinal absorption characteristics of tocofersolan versus α-tocopherol acetate by measuring the plasma concentrations of α-tocopherol over time after a single oral load and to compare efficacy by evaluating the ability of each formulation to restore vitamin E storage after 4 months of treatment. In patients with ABL, tocofersolan and α-tocopherol acetate bioavailabilities were extremely low (2.8% and 3.1%, respectively). In contrast, bioavailabilities were higher in patients with CMRD (tocofersolan, 24.7%; α-tocopherol acetate, 11.4%). Plasma concentrations of α-tocopherol at 4 months were not significantly different by formulation type in ABL or CMRD. This study provides new insights about vitamin E status in ABL and CMRD and suggests the potential of different formulations as treatment options.
2016-08-12 | Establishment of reference values of α-tocopherol in plasma, red blood cells and adipose tissue in healthy children to improve the management of chylomicron retention disease, a rare genetic hypocholesterolemia
Chylomicron retention disease (CMRD), a rare genetic hypocholesterolemia, results in neuro-ophtalmologic damages, which can be prevented by high doses of vitamin E during infancy. In these patients, plasma vitamin E concentration is significantly reduced due to defects of chylomicron secretion. Vitamin E in adipose tissue (AT) and red blood cells (RBC) have been proposed as potential relevant biomarkers of vitamin E status but no reference values in children are available. The objectives were (i) to establish age-reference intervals in healthy children for α-tocopherol in plasma, red blood cells (RBC) and adipose tissue (AT) and (ii) to determine the variations of α-tocopherol in patients with CMRD after oral treatment with vitamin E.This prospective study included 166 healthy children (1 month - 18 years) and 4 patients with CMRD. Blood and AT were collected in healthy children during a scheduled surgery and in patients before and after a 4-month treatment with α-tocopherol acetate.The reference ranges for α-tocopherol were 11.9 - 30 μmol/L in plasma, 2.0 - 7.8 μmol/L packed cells in RBC and 60 - 573 nmol/g in AT. α-tocopherol levels in plasma correlated with those of RBC (r = 0.31; p < 0.01). In patients with CMRD after 4 months treatment, α-tocopherol concentrations remained less than 70 % of the control values in plasma, increased by 180 % to reach normal values in RBC, and remained stable in the normal range in AT.This study establishes pediatric reference intervals for α-tocopherol in plasma, RBC and AT. These values will be beneficial in assessing accurate α-tocopherol status in children and to optimize the monitoring of rare diseases such as CMRD. Our data suggest that RBC α-tocopherol, appears as a relevant biomarker to appreciate the effectiveness of treatment with α-tocopherol in patients with a rare primary hypocholesterolemia. The biopsy of AT could be used at diagnosis to assess the severity of the vitamin E deficiency and periodically after a long duration of vitamin E therapy to assess whether the treatment is effective, based on reference intervals defined in this study.
gene therapies
2025-11-20 | Impaired Chylomicron Secretion Results in Reduced Body Fat and Increased Intestinal Fatty Acid Oxidation by Activation of Autophagy
Abstract Intestinal absorption of dietary lipid is essential for systemic lipid homeostasis; however, elevated postprandial plasma lipid levels are associated with obesity and increased risk for atherosclerotic cardiovascular disease. In humans and rodents, biological sex impacts dietary triglyceride absorption and males tend to have higher postprandial triglyceride levels compared to females, but the physiological basis for this is not well understood. Here, we show that the gene DENND5B is associated with body composition in humans and mice and that genetic deletion of Dennd5b in mice prevents postprandial lipemia in both sexes. Our findings establish a role for this protein in intestinal chylomicron secretion and reveal a biological sex-biased differential impact of its deletion on body composition, dietary fatty acid uptake, and intestinal metabolism. Mechanistically, our findings implicate autophagy and mitochondrial beta oxidation in coping with enterocyte lipid accumulation due to impaired chylomicron secretion. This work extends the emerging concept that the intestinal epithelium may play a prominent role in oxidation of diet-derived fatty acids and suggests that this process may contribute to biological sex-based differences in postprandial lipemia and body composition. Highlights Human DENND5B gene variants are associated with metabolic phenotype. In mice, genetic disruption of Dennd5b results in lower body fat in females and males. Genetic disruption of Dennd5b results in increased lean mass in male, but not female, mice. Metabolic phenotypes in Dennd5b -deficient mice are driven by reduced absorption of dietary lipid characterized by enterocyte lipid retention and increased fecal lipid excretion. Impaired chylomicron secretion in Dennd5b −/− mice induces autophagy-mediated disposal of cellular triglyceride and increased fatty acid oxidation in intestinal tissue.
2025-01-27 | P-39 A LATE ONSET CASE OF CHYLOMICRON RETENTION DISEASE
Abstract Introduction Chylomicron retention disease (CRD) is an uncommon genetic disorder caused by a mutation in the SAR1B gene, which encodes the Sar1b protein. Sar1b plays a role in transporting chylomicrons from the endoplasmic reticulum to the Golgi apparatus. Often diagnosed in the early stages of life, CRD typically presents with failure to thrive, gastrointestinal symptoms and malabsorption of fat, which leads to secondary clinical conditions such as hepatomegaly, neuromuscular disorders, hypolipidemia and deficiencies of fat soluble vitamins (A, D, E, K). Clinical Case A 56-year-old male patient was referred to our endocrinology outpatient clinic with low blood lipid levels. He expressed pain on his hands and feet. He also described vomiting after fat-rich meals since his childhood. He had no history of smoking or alcohol consumption. His father had diabetes mellitus and hypertension, and his uncle had coronary artery disease. His physical examination was normal besides a peripheral sensorial neuropathy. His laboratory findings showed hypolipidemia and hypochromic microcytic anemia, alongside with vitamin B12, vitamin D and iron deficiency (Table 1). An abdominal ultrasonography was performed, the dimensions of both the liver and the spleen was normal, though a grade 1 hepatosteatosis was observed. An electromyelography was performed and the findings were compatible with axonal polyneuropathy. The patient was referred to the department of genetics for evaluation of familial lipid disorders. A genetic analysis was performed, and the analysis revealed a likely pathogenic heterozygous mutation in the NM_016103.4 c.243dupA p.A82fs*35 area of the SAR1B gene. The patient was diagnosed with chylomicron retention disease. He was referred to a dietetician for a low-fat diet. A bone mineral density scan was planned and oral vitamin D treatment was initiated, alongside with oral iron and vitamin B12 treatment. The patient was also referred to departments of neurology, ophtalmology and cardiology for possible systemic involvement. He was also referred to gastroenterology for endoscopic and colonoscopic scanning. Moreover, his close relatives were advised to be evaluated for CRD. Later on, one of his grandchildren was diagnosed with CRD and is currently under treatment in another institution. Conclusion Though rarely diagnosed during adulthood, CRD should still be included in the differential diagnosis of patients with hypolipidemia; especially in cases with vitamin deficiencies. Gastrointestinal symptoms often encountered during childhood may be absent or vague in adulthood, but careful systemic assessment and physical examination gives valuable clues in the diagnosis of CRD, alongside with appropriate laboratory and genetic analysis. Once diagnosed, other family members, especially children, of CRD patients should also be evaluated about this rare genetic disease. Financial disclosures: None Funding resources: NoneTable 1:Laboratory findings of the patient
2024-04-30 | Functional overlap between the mammalian Sar1a and Sar1b paralogs in vivo.
Proteins carrying a signal peptide and/or a transmembrane domain enter the intracellular secretory pathway at the endoplasmic reticulum (ER) and are transported to the Golgi apparatus via COPII vesicles or tubules. SAR1 initiates COPII coat assembly by recruiting other coat proteins to the ER membrane. Mammalian genomes encode two SAR1 paralogs, SAR1A and SAR1B. While these paralogs exhibit ~90% amino acid sequence identity, it is unknown whether they perform distinct or overlapping functions in vivo. We now report that genetic inactivation of Sar1a in mice results in lethality during midembryogenesis. We also confirm previous reports that complete deficiency of murine Sar1b results in perinatal lethality. In contrast, we demonstrate that deletion of Sar1b restricted to hepatocytes is compatible with survival, though resulting in hypocholesterolemia that can be rescued by adenovirus-mediated overexpression of either SAR1A or SAR1B. To further examine the in vivo function of these two paralogs, we genetically engineered mice with the Sar1a coding sequence replacing that of Sar1b at the endogenous Sar1b locus. Mice homozygous for this allele survive to adulthood and are phenotypically normal, demonstrating complete or near-complete overlap in function between the two SAR1 protein paralogs in mice. These data also suggest upregulation of SAR1A gene expression as a potential approach for the treatment of SAR1B deficiency (chylomicron retention disease) in humans.
2023-02-14 | Validation of Knock-Out Caco-2 TC7 Cells as Models of Enterocytes of Patients with Familial Genetic Hypobetalipoproteinemias.
Abetalipoproteinemia (FHBL-SD1) and chylomicron retention disease (FHBL-SD3) are rare recessive disorders of lipoprotein metabolism due to mutations in MTTP and SAR1B genes, respectively, which lead to defective chylomicron formation and secretion. This results in lipid and fat-soluble vitamin malabsorption, which induces severe neuro-ophthalmic complications. Currently, treatment combines a low-fat diet with high-dose vitamin A and E supplementation but still fails in normalizing serum vitamin E levels and providing complete ophthalmic protection. To explore these persistent complications, we developed two knock-out cell models of FHBL-SD1 and FHBL-SD3 using the CRISPR/Cas9 technique in Caco-2/TC7 cells. DNA sequencing, RNA quantification and Western blotting confirmed the introduction of mutations with protein knock-out in four clones associated with i) impaired lipid droplet formation and ii) defective triglyceride (-57.0 ± 2.6% to -83.9 ± 1.6%) and cholesterol (-35.3 ± 4.4% to -60.6 ± 3.5%) secretion. A significant decrease in α-tocopherol secretion was also observed in these clones (-41.5 ± 3.7% to -97.2 ± 2.8%), even with the pharmaceutical forms of vitamin E: tocopherol-acetate and tocofersolan (α-tocopheryl polyethylene glycol succinate 1000). MTTP silencing led to a more severe phenotype than SAR1B silencing, which is consistent with clinical observations. Our cellular models thus provide an efficient tool to experiment with therapeutic strategies and will allow progress in understanding the mechanisms involved in lipid metabolism.
small molecules
2024-03-25 | Carotenoids in familial hypobetalipoproteinemia disorders: Malabsorption in Caco2 cell models and severe deficiency in patients.
Familial hypobetalipoproteinemias (FHBL) are rare genetic diseases characterized by lipid malabsorption. We focused on abetalipoproteinemia (FHBL-SD1) and chylomicron retention disease (FHBL-SD3), caused by mutations in microsomal triglyceride transfer protein (MTTP) and SAR1B genes, respectively. Treatments include a low-fat diet and high-dose fat-soluble vitamin supplementations. However, patients are not supplemented in carotenoids, a group of lipid-soluble pigments essential for eye health. Our aim was to evaluate carotenoid absorption and status in the context of hypobetalipoproteinemia. We first used knock-out Caco-2/TC7 cell models of FHBL-SD1 and FHBL-SD3 to evaluate carotenoid absorption. We then characterized FHBL-SD1 and FHBL-SD3 patient status in the main dietary carotenoids and compared it to that of control subjects. In vitro results showed a significant decrease in basolateral secretion of α- and β-carotene, lutein, and zeaxanthin (-88.8 ± 2.2 % to -95.3 ± 5.8 %, -79.2 ± 4.4 % to -96.1 ± 2.6 %, -91.0 ± 4.5 % to -96.7 ± 0.3 % and -65.4 ± 3.6 % to -96.6 ± 1.9 %, respectively). Carotenoids plasma levels in patients confirmed significant deficiencies, with decreases ranging from -89 % for zeaxanthin to -98 % for α-carotene, compared to control subjects. Given the continuous loss in visual function despite fat-soluble vitamin treatment in some patients, carotenoid supplementation may be of clinical utility. Future studies should assess the correlation between carotenoid status and visual function in aging patients and investigate whether carotenoid supplementation could prevent their visual impairment.
2022-12-16 | 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.
2022-08-01 | Lomitapide effectively reduces triglyceride (TG) levels in familial chylomicronemia syndrome (FCS)
Background and Aims : FCS is a rare autosomal recessive disorder of impaired lipoprotein lipase (LPL) function, elevated TG levels, abdominal pain and pancreatitis. Current treatment (extremely low-fat diet <10% fat/day to reduce TG levels ≤750mgldL) is ineffective. Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor that reduces circulating levels of TGs.Methods: The open-label, single-arm 'LOCHNES' study of lomitapide in FCS, enrolled adult patients ≥18 years with genetically confirmed FCS, elevated fasting TG≥750mg/dL and a history of pancreatitis. Patients were administered escalating doses of lomitapide to maximum tolerated dose for 26 weeks. The primary endpoint was the percent change in TGs from baseline to Week 26.Conclusions: Lomitapide is effective in reducing triglycerides in FCS and preventing recurrence of acute pancreatitis. Larger studies are warranted. Background and Aims : FCS is a rare autosomal recessive disorder of impaired lipoprotein lipase (LPL) function, elevated TG levels, abdominal pain and pancreatitis. Current treatment (extremely low-fat diet <10% fat/day to reduce TG levels ≤750mgldL) is ineffective. Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor that reduces circulating levels of TGs. Methods: The open-label, single-arm 'LOCHNES' study of lomitapide in FCS, enrolled adult patients ≥18 years with genetically confirmed FCS, elevated fasting TG≥750mg/dL and a history of pancreatitis. Patients were administered escalating doses of lomitapide to maximum tolerated dose for 26 weeks. The primary endpoint was the percent change in TGs from baseline to Week 26. Conclusions: Lomitapide is effective in reducing triglycerides in FCS and preventing recurrence of acute pancreatitis. Larger studies are warranted.
2019-09-09 | Efficacy of two vitamin E formulations in patients with abetalipoproteinemia and chylomicron retention disease.
Abetalipoproteinemia (ABL) and chylomicron retention disease (CMRD) are extremely rare recessive forms of hypobetalipoproteinemia characterized by intestinal lipid malabsorption and severe vitamin E deficiency. Vitamin E is often supplemented in the form of fat-soluble vitamin E acetate, but fat malabsorption considerably limits correction of the deficiency. In this crossover study, we administered two different forms of vitamin E, tocofersolan (a water-soluble derivative of RRR-α-tocopherol) and α-tocopherol acetate, to three patients with ABL and four patients with CMRD. The aims of this study were to evaluate the intestinal absorption characteristics of tocofersolan versus α-tocopherol acetate by measuring the plasma concentrations of α-tocopherol over time after a single oral load and to compare efficacy by evaluating the ability of each formulation to restore vitamin E storage after 4 months of treatment. In patients with ABL, tocofersolan and α-tocopherol acetate bioavailabilities were extremely low (2.8% and 3.1%, respectively). In contrast, bioavailabilities were higher in patients with CMRD (tocofersolan, 24.7%; α-tocopherol acetate, 11.4%). Plasma concentrations of α-tocopherol at 4 months were not significantly different by formulation type in ABL or CMRD. This study provides new insights about vitamin E status in ABL and CMRD and suggests the potential of different formulations as treatment options.
2016-08-12 | Establishment of reference values of α-tocopherol in plasma, red blood cells and adipose tissue in healthy children to improve the management of chylomicron retention disease, a rare genetic hypocholesterolemia
Chylomicron retention disease (CMRD), a rare genetic hypocholesterolemia, results in neuro-ophtalmologic damages, which can be prevented by high doses of vitamin E during infancy. In these patients, plasma vitamin E concentration is significantly reduced due to defects of chylomicron secretion. Vitamin E in adipose tissue (AT) and red blood cells (RBC) have been proposed as potential relevant biomarkers of vitamin E status but no reference values in children are available. The objectives were (i) to establish age-reference intervals in healthy children for α-tocopherol in plasma, red blood cells (RBC) and adipose tissue (AT) and (ii) to determine the variations of α-tocopherol in patients with CMRD after oral treatment with vitamin E.This prospective study included 166 healthy children (1 month - 18 years) and 4 patients with CMRD. Blood and AT were collected in healthy children during a scheduled surgery and in patients before and after a 4-month treatment with α-tocopherol acetate.The reference ranges for α-tocopherol were 11.9 - 30 μmol/L in plasma, 2.0 - 7.8 μmol/L packed cells in RBC and 60 - 573 nmol/g in AT. α-tocopherol levels in plasma correlated with those of RBC (r = 0.31; p < 0.01). In patients with CMRD after 4 months treatment, α-tocopherol concentrations remained less than 70 % of the control values in plasma, increased by 180 % to reach normal values in RBC, and remained stable in the normal range in AT.This study establishes pediatric reference intervals for α-tocopherol in plasma, RBC and AT. These values will be beneficial in assessing accurate α-tocopherol status in children and to optimize the monitoring of rare diseases such as CMRD. Our data suggest that RBC α-tocopherol, appears as a relevant biomarker to appreciate the effectiveness of treatment with α-tocopherol in patients with a rare primary hypocholesterolemia. The biopsy of AT could be used at diagnosis to assess the severity of the vitamin E deficiency and periodically after a long duration of vitamin E therapy to assess whether the treatment is effective, based on reference intervals defined in this study.
gene therapies
2025-11-20 | Impaired Chylomicron Secretion Results in Reduced Body Fat and Increased Intestinal Fatty Acid Oxidation by Activation of Autophagy
Abstract Intestinal absorption of dietary lipid is essential for systemic lipid homeostasis; however, elevated postprandial plasma lipid levels are associated with obesity and increased risk for atherosclerotic cardiovascular disease. In humans and rodents, biological sex impacts dietary triglyceride absorption and males tend to have higher postprandial triglyceride levels compared to females, but the physiological basis for this is not well understood. Here, we show that the gene DENND5B is associated with body composition in humans and mice and that genetic deletion of Dennd5b in mice prevents postprandial lipemia in both sexes. Our findings establish a role for this protein in intestinal chylomicron secretion and reveal a biological sex-biased differential impact of its deletion on body composition, dietary fatty acid uptake, and intestinal metabolism. Mechanistically, our findings implicate autophagy and mitochondrial beta oxidation in coping with enterocyte lipid accumulation due to impaired chylomicron secretion. This work extends the emerging concept that the intestinal epithelium may play a prominent role in oxidation of diet-derived fatty acids and suggests that this process may contribute to biological sex-based differences in postprandial lipemia and body composition. Highlights Human DENND5B gene variants are associated with metabolic phenotype. In mice, genetic disruption of Dennd5b results in lower body fat in females and males. Genetic disruption of Dennd5b results in increased lean mass in male, but not female, mice. Metabolic phenotypes in Dennd5b -deficient mice are driven by reduced absorption of dietary lipid characterized by enterocyte lipid retention and increased fecal lipid excretion. Impaired chylomicron secretion in Dennd5b −/− mice induces autophagy-mediated disposal of cellular triglyceride and increased fatty acid oxidation in intestinal tissue.
2025-01-27 | P-39 A LATE ONSET CASE OF CHYLOMICRON RETENTION DISEASE
Abstract Introduction Chylomicron retention disease (CRD) is an uncommon genetic disorder caused by a mutation in the SAR1B gene, which encodes the Sar1b protein. Sar1b plays a role in transporting chylomicrons from the endoplasmic reticulum to the Golgi apparatus. Often diagnosed in the early stages of life, CRD typically presents with failure to thrive, gastrointestinal symptoms and malabsorption of fat, which leads to secondary clinical conditions such as hepatomegaly, neuromuscular disorders, hypolipidemia and deficiencies of fat soluble vitamins (A, D, E, K). Clinical Case A 56-year-old male patient was referred to our endocrinology outpatient clinic with low blood lipid levels. He expressed pain on his hands and feet. He also described vomiting after fat-rich meals since his childhood. He had no history of smoking or alcohol consumption. His father had diabetes mellitus and hypertension, and his uncle had coronary artery disease. His physical examination was normal besides a peripheral sensorial neuropathy. His laboratory findings showed hypolipidemia and hypochromic microcytic anemia, alongside with vitamin B12, vitamin D and iron deficiency (Table 1). An abdominal ultrasonography was performed, the dimensions of both the liver and the spleen was normal, though a grade 1 hepatosteatosis was observed. An electromyelography was performed and the findings were compatible with axonal polyneuropathy. The patient was referred to the department of genetics for evaluation of familial lipid disorders. A genetic analysis was performed, and the analysis revealed a likely pathogenic heterozygous mutation in the NM_016103.4 c.243dupA p.A82fs*35 area of the SAR1B gene. The patient was diagnosed with chylomicron retention disease. He was referred to a dietetician for a low-fat diet. A bone mineral density scan was planned and oral vitamin D treatment was initiated, alongside with oral iron and vitamin B12 treatment. The patient was also referred to departments of neurology, ophtalmology and cardiology for possible systemic involvement. He was also referred to gastroenterology for endoscopic and colonoscopic scanning. Moreover, his close relatives were advised to be evaluated for CRD. Later on, one of his grandchildren was diagnosed with CRD and is currently under treatment in another institution. Conclusion Though rarely diagnosed during adulthood, CRD should still be included in the differential diagnosis of patients with hypolipidemia; especially in cases with vitamin deficiencies. Gastrointestinal symptoms often encountered during childhood may be absent or vague in adulthood, but careful systemic assessment and physical examination gives valuable clues in the diagnosis of CRD, alongside with appropriate laboratory and genetic analysis. Once diagnosed, other family members, especially children, of CRD patients should also be evaluated about this rare genetic disease. Financial disclosures: None Funding resources: NoneTable 1:Laboratory findings of the patient
2024-04-30 | Functional overlap between the mammalian Sar1a and Sar1b paralogs in vivo.
Proteins carrying a signal peptide and/or a transmembrane domain enter the intracellular secretory pathway at the endoplasmic reticulum (ER) and are transported to the Golgi apparatus via COPII vesicles or tubules. SAR1 initiates COPII coat assembly by recruiting other coat proteins to the ER membrane. Mammalian genomes encode two SAR1 paralogs, SAR1A and SAR1B. While these paralogs exhibit ~90% amino acid sequence identity, it is unknown whether they perform distinct or overlapping functions in vivo. We now report that genetic inactivation of Sar1a in mice results in lethality during midembryogenesis. We also confirm previous reports that complete deficiency of murine Sar1b results in perinatal lethality. In contrast, we demonstrate that deletion of Sar1b restricted to hepatocytes is compatible with survival, though resulting in hypocholesterolemia that can be rescued by adenovirus-mediated overexpression of either SAR1A or SAR1B. To further examine the in vivo function of these two paralogs, we genetically engineered mice with the Sar1a coding sequence replacing that of Sar1b at the endogenous Sar1b locus. Mice homozygous for this allele survive to adulthood and are phenotypically normal, demonstrating complete or near-complete overlap in function between the two SAR1 protein paralogs in mice. These data also suggest upregulation of SAR1A gene expression as a potential approach for the treatment of SAR1B deficiency (chylomicron retention disease) in humans.
2023-02-14 | Validation of Knock-Out Caco-2 TC7 Cells as Models of Enterocytes of Patients with Familial Genetic Hypobetalipoproteinemias.
Abetalipoproteinemia (FHBL-SD1) and chylomicron retention disease (FHBL-SD3) are rare recessive disorders of lipoprotein metabolism due to mutations in MTTP and SAR1B genes, respectively, which lead to defective chylomicron formation and secretion. This results in lipid and fat-soluble vitamin malabsorption, which induces severe neuro-ophthalmic complications. Currently, treatment combines a low-fat diet with high-dose vitamin A and E supplementation but still fails in normalizing serum vitamin E levels and providing complete ophthalmic protection. To explore these persistent complications, we developed two knock-out cell models of FHBL-SD1 and FHBL-SD3 using the CRISPR/Cas9 technique in Caco-2/TC7 cells. DNA sequencing, RNA quantification and Western blotting confirmed the introduction of mutations with protein knock-out in four clones associated with i) impaired lipid droplet formation and ii) defective triglyceride (-57.0 ± 2.6% to -83.9 ± 1.6%) and cholesterol (-35.3 ± 4.4% to -60.6 ± 3.5%) secretion. A significant decrease in α-tocopherol secretion was also observed in these clones (-41.5 ± 3.7% to -97.2 ± 2.8%), even with the pharmaceutical forms of vitamin E: tocopherol-acetate and tocofersolan (α-tocopheryl polyethylene glycol succinate 1000). MTTP silencing led to a more severe phenotype than SAR1B silencing, which is consistent with clinical observations. Our cellular models thus provide an efficient tool to experiment with therapeutic strategies and will allow progress in understanding the mechanisms involved in lipid metabolism.
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