RARE DISEASE
Neutral lipid storage disease
Neutral lipid storage disease
Neutral lipid storage disease
Synonyms: Lipidosis with triglyceride storage disease
Synonyms: Lipidosis with triglyceride storage disease
Synonyms: Lipidosis with triglyceride storage disease
Drug discovery
0
drugs
With orphan designations
Overview
Neutral lipid storage disease (NLSD) comprises rare autosomal recessive disorders (NLSDM and NLSDI) caused by mutations in PNPLA2/ATGL or ABHD5 genes, impairing triglyceride metabolism. NLSDM features progressive myopathy and cardiomyopathy, while NLSDI presents with ichthyosis and multisystem involvement. Diagnosis relies on lipid-laden leukocytes (Jordans’ anomaly), histology, and genetic testing. No curative therapies exist; management focuses on symptom relief and metabolic support [1][6][14].
Burden
Progressive muscle weakness (70% NLSDM), cardiomyopathy (50% NLSDM), hepatic steatosis, and metabolic complications (diabetes, hypothyroidism)
Lifespan varies; severe cases face wheelchair dependence or liver/cardiac failure requiring transplants [6][14][17]
High psychosocial/financial strain due to chronic disability and lack of targeted therapies [13][17]
Therapies
Supportive care: Physical therapy, cardiac monitoring, and dietary modifications (low-fat, high-carbohydrate diets)
Pharmacological: Bezafibrate/fenofibrate (PPAR-α agonists) to enhance lipid oxidation; off-label use shows variable efficacy [3][7][13]
Experimental: Enzyme replacement, gene therapy, and antisense oligonucleotides under investigation [13][18]
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
66 drug discovery papers about Neutral lipid storage disease. Recent publications:
66 drug discovery papers about Neutral lipid storage disease. Recent publications:
categories:
Small molecules
small molecules
2026-07-15 | Lipid Droplets as Metabolic–Epigenetic Signaling Hubs: Interplay Between Phase Separation, Cellular Adaptation, and Disease
Lipid droplets (LDs) were long thought to be passive organelles merely for neutral lipid storage. Mounting evidence redefines LDs as dynamic metabolic signaling hubs orchestrating cellular stress adaptation, with multifaceted roles in organelle crosstalk, metabolic reprogramming, redox balance and immune signaling. LD function is tightly intertwined with liquid-liquid phase separation (LLPS) and epigenetic remodeling, bridging cellular metabolism to gene expression and cell fate control. LD biogenesis relies on ER lipid structures, phase-separated protein assemblies and lipid regulatory proteins. Via contacts with multiple organelles, LDs regulate lipid catabolism, ferroptosis, inflammation and chromatin accessibility, while their metabolites directly reshape epigenetic modifications and transcription. LLPS-driven biomolecular condensates further coordinate LD-linked metabolic and stress signaling. Dysregulated LD remodeling mediates metabolic flexibility, immune escape and drug resistance in obesity, metabolic dysfunction-associated steatotic liver disease (MASLD), neurodegeneration, viral infection and cancer. This review summarizes progress in LD biogenesis and metabolism, dissects mechanistic crosstalk between LDs, LLPS and epigenetic control, and outlines LD-driven pathogenic reprogramming across human disorders. We also discuss therapeutic approaches targeting LD and LLPS pathways. Despite promising translational prospects, unresolved mechanistic and clinical hurdles persist. Further research on LD biology will reshape our framework linking metabolism, chromatin regulation and stress adaptation.
2025-11-13 | ATGL-mediated lipolysis is essential for myocellular mitochondrial function, mitochondria-lipid droplet interaction and mitochondrial network connectivity.
Defects in Adipose tissue TriGlyceride Lipase (ATGL)-mediated myocellular lipid droplet (LD) lipolysis results in mitochondrial dysfunction of unknown origin, which can be rescued by PPAR agonists. Here we examine if ATGL-mediated lipolysis is required to maintain mitochondrial network connectivity and function. Moreover, we explored if the functional implications of ATGL deficiency for mitochondrial network dynamics and function can be alleviated by promoting PPARα and/or PPARδ transcriptional activity. To this end, we cultured human primary myotubes from patients with neutral lipid storage disease with myopathy (NLSDM), a rare metabolic disorder caused by a mutation in the gene encoding for ATGL. These myotubes possess dysfunctional ATGL and compromised LD lipolysis. In addition, mitochondria-LD contact, mitochondrial network connectivity, and mitochondrial membrane potential were affected. Using a humanized ATGL inhibitor in myotubes (cultured form healthy donors) revealed similar results. Upon stimulating PPARδ transcriptional activity, mitochondrial respiration improved by more than 50 % in human primary myotubes from healthy lean individuals. This increase in respiration was dampened in myotubes with dysfunctional ATGL. Stimulation of PPARδ transcriptional activity had no effect on mitochondria-LD contacts, mitochondrial network connectivity, and mitochondrial membrane potential. Our results demonstrate that dysfunctional ATGL results in compromised mitochondrial-LD contacts and mitochondrial network connectivity, and that functional ATGL is required to improve mitochondrial respiratory capacity upon stimulation of PPARδ transcriptional activity.
2025-10-23 | Long-term neuromuscular, cardiac and liver outcomes in an adult man affected with Chanarin-Dorfman syndrome.
Chanarin-Dorfman syndrome (CDS) is an ultra-rare autosomal recessive subtype of neutral lipid storage disorder (NLSD); it is characterised by ichthyosis and intracytoplasmic accumulation of lipid droplets containing triglycerides, most commonly in granulocytes, muscle fibres, skin and liver. Several pathogenic variants in the ABHD5/CGI-58 gene have been described. Clinical manifestations include steatohepatitis, myopathy, ophthalmic disease, developmental delay. Liver involvement is an important cause of morbidity and mortality. We present a case of a 26-year-old male diagnosed with ichthyotic NLSD in childhood, who developed progressive myopathy and cardiac fibrosis in adulthood. He was treated with a combination of low-fat diet, MCT oil and co-enzyme Q10 which resulted in an initial improvement in muscle strength and stabilisation of muscle symptoms and well-being. Synopsis: Medical and dietetic management of liver and muscle complications in Chanarin-Dorfman syndrome.
2025-04-25 | Using chanarin-dorfman syndrome patient fibroblasts to explore disease mechanisms and new treatment avenues.
Chanarin-Dorfman syndrome (CDS) is a multisystemic autosomal recessive rare disorder. CDS is caused by variants in the abhydrolase domain containing 5 (ABHD5) encoding gene (CGI-58), which ultimately leads to excessive lipid storage, and therefore a high abundance of cellular lipid droplets (LDs). Although the molecular etiology of the disease was described many years ago, no treatment for CDS is currently available. To further characterize the molecular basis of the disease and to uncover new treatment avenues, we used skin fibroblasts originating from a young patient diagnosed with CDS due to a homozygous nonsense mutation. We show that dysfunctional ABHD5 does not only affect LDs, but also influences other metabolic-related organelles; the mitochondria and peroxisomes. Additionally, we found that expressing functional ABHD5 in CDS patient cells reduced LD number. Finally, we developed and applied a high content-based drug repurposing screen based on a collection of ∼2500 FDA approved compounds, yielding several compounds that affected LD total area and size. Our findings enhance the understanding of the dysfunction underlying CDS and propose new avenues for the treatment of CDS patients.
2025-02-06 | A Novel PNPLA2 Variant in a Female Patient with Neutral Lipid Storage Disease with Myopathy and Hypogonadotropic Hypogonadism.
Neutral lipid storage disease with myopathy (NLSDM) is a rare autosomal recessive disorder characterized by aberrant triacylglycerol metabolism due to mutations in the patatin-like phospholipase domain-containing 2 (PNPLA2) gene. This report presents a case study of a 14-year-old female patient exhibiting symptoms of NLSDM, including recurrent abdominal pain, fatigue, leg pain, and hepatosteatosis. Diagnostic investigations revealed elevated creatinine kinase levels, myopathic findings on electromyography, magnetic resonance imaging findings showing gluteal involvement and Jordans' bodies on peripheral smear. Clinical exome panel showed homozygous of PNPLA2 c.496G>C p.Asp166His (NM_020376.4) variant. The clinical manifestations, diagnostic challenges, and implications of this novel variant are discussed in the context of current literature. Hypogonadotropic hypogonadism was confirmed in this patient after eliminating possible underlying causes. This was a novel manifestation, and hormone replacement therapy was planned. This case underscores the significance of genetic testing in elucidating the molecular basis of NLSDM and emphasizes the necessity of comprehensive clinical evaluation for accurate diagnosis and management.
gene therapies
2023-02-16 | Knockdown of hepatocyte Perilipin-3 mitigates hepatic steatosis and steatohepatitis caused by hepatocyte CGI-58 deletion in mice.
Comparative gene identification-58 (CGI-58), also known as α/β hydrolase domain containing 5, is the co-activator of adipose triglyceride lipase that hydrolyzes triglycerides stored in the cytosolic lipid droplets. Mutations in CGI-58 gene cause Chanarin-Dorfman syndrome (CDS), an autosomal recessive neutral lipid storage disease with ichthyosis. The liver pathology of CDS manifests as steatosis and steatohepatitis, which currently has no effective treatments. Perilipin-3 (Plin3) is a member of the Perilipin-ADRP-TIP47 protein family that is essential for lipid droplet biogenesis. The objective of this study was to test a hypothesis that deletion of a major lipid droplet protein alleviates fatty liver pathogenesis caused by CGI-58 deficiency in hepatocytes. Adult CGI-58-floxed mice were injected with adeno-associated vectors simultaneously expressing the Cre recombinase and microRNA against Plin3 under the control of a hepatocyte-specific promoter, followed by high-fat diet feeding for 6 weeks. Liver and blood samples were then collected from these animals for histological and biochemical analysis. Plin3 knockdown in hepatocytes prevented steatosis, steatohepatitis, and necroptosis caused by hepatocyte CGI-58 deficiency. Our work is the first to show that inhibiting Plin3 in hepatocytes is sufficient to mitigate hepatocyte CGI-58 deficiency-induced hepatic steatosis and steatohepatitis in mice.
2001-04-19 | Phenotypic correction of lipid storage and growth arrest in wolman disease fibroblasts by gene transfer of lysosomal acid lipase.
Wolman disease is a lethal lysosomal storage disease due to deficiency of lysosomal acid lipase (LAL). Wolman disease is characterized by pronounced hepatic involvement while neurological symptoms are uncommon, making Wolman disease an attractive candidate for liver-directed gene therapy. This study was performed to test the effects of gene replacement in fibroblasts lacking LAL, using a recombinant adenovirus encoding the human LAL cDNA (AdhLAL). Human fibroblasts from a Wolman disease patient were infected with AdhLAL and showed a dose-dependent increase in LAL protein and activity up to 5-fold above levels in control fibroblasts. Furthermore, 72 hr after infection with AdhLAL there was a dose-dependent correction of the severe lipid storage phenotype of Wolman disease fibroblasts. Electron microscopy confirmed significant correction of the lysosomal lipid storage in AdhLAL-infected Wolman disease fibroblasts at the ultrastructural level. Intravenous injection of AdhLAL into wild-type mice resulted in a 13.5-fold increase in hepatic LAL activity, and overexpression of LAL was not associated with toxic side effects. These data demonstrate high-level lysosomal expression of recombinant LAL in vitro and in vivo and show the feasibility of gene therapeutic strategies for the treatment of Wolman disease.
proteins
2025-09-26 | Enzyme replacement therapy in cholesteryl ester storage disease: A case report on lysosomal acid lipase deficiency management.
Lysosomal acid lipase deficiency (LAL-D) is a rare autosomal recessive disorder caused by pathogenic variants in the LIPA gene. The clinical spectrum ranges from early-onset Wolman disease to later presentations in childhood and adulthood, formerly known as cholesteryl ester storage disease (CESD). Impaired lysosomal acid lipase (LAL) activity leads to the accumulation of cholesteryl esters and triglycerides, causing progressive hepatic and metabolic dysfunction. We describe a 17-year-old Mexican female diagnosed with CESD at age 13 after evaluation for short stature and severe hypercholesterolemia. Laboratory workup revealed markedly elevated liver enzymes and lipid levels, with severely reduced LAL activity. Molecular testing identified a homozygous LIPA(NM_000235.3):c.894G>A variant. Enzyme replacement therapy (ERT) with sebelipase alfa (1 mg/kg biweekly) was initiated, leading to progressive normalization of lipid and hepatic profiles. Over a 48-month follow-up, the patient exhibited catch-up growth (gain of 17 cm and 21 kg), pubertal development with the onset of menarche at age 16, and achievement of Tanner stage III. This case underscores the importance of early recognition of CESD in patients with unexplained dyslipidemia, elevated liver enzymes, and growth delay. Timely initiation of sebelipase alfa resulted in favorable biochemical and clinical outcomes. Comprehensive diagnostic evaluation-including enzymatic and genetic testing-is critical for accurate diagnosis and personalized management of LAL-D.
2024-03-21 | Mutational scanning pinpoints distinct binding sites of key ATGL regulators in lipolysis
Abstract ATGL is a key enzyme in intracellular lipolysis and plays an important role in metabolic and cardiovascular diseases. ATGL is tightly regulated by a known set of protein-protein interaction partners with activating or inhibiting functions in the control of lipolysis. Here, we use deep mutational protein interaction perturbation scanning and generate comprehensive profiles of single amino acid variants that affect the interactions of ATGL with its regulatory partners: CGI-58, G0S2, PLIN1, PLIN5 and CIDEC. Twenty-three ATGL amino acid variants yield a specific interaction perturbation pattern when validated in co-immunoprecipitation experiments in mammalian cells. We identify and characterize eleven highly selective ATGL switch mutations which affect the interaction of one of the five partners without affecting the others. Switch mutations thus provide distinct interaction determinants for ATGL’s key regulatory proteins at an amino acid resolution. When we test triglyceride hydrolase activity in vitro and lipolysis in cells, the activity patterns of the ATGL switch variants trace to their protein interaction profile. In the context of structural data, the integration of variant binding and activity profiles provides insights into the regulation of lipolysis and the impact of mutations in human disease.
2023-12-20 | Unmasking crucial residues in adipose triglyceride lipase for coactivation with comparative gene identification-58
Lipolysis is an essential metabolic process that releases unesterified fatty acids from neutral lipid stores to maintain energy homeostasis in living organisms. Adipose triglyceride lipase (ATGL) plays a key role in intracellular lipolysis and can be co-activated upon interaction with the protein comparative gene identification-58 (CGI-58). The underlying molecular mechanism of ATGL stimulation by CGI-58 is incompletely understood. Based on analysis of evolutionary conservation, we used site directed mutagenesis to study a C-terminally truncated variant and full-length mouse ATGL providing insights in the protein co-activation on a per-residue level. We identified the region from residues N209-N215 in ATGL as essential for co-activation by CGI-58. ATGL variants with amino-acids exchanges in this region were still able to hydrolyze triacylglycerol at the basal level and to interact with CGI-58, yet could not be activated by CGI-58. Our studies also demonstrate that full-length mouse ATGL showed higher tolerance to specific single amino acid exchanges in the N209-N215 region upon CGI-58 co-activation compared to C-terminally truncated ATGL variants. The region is either directly involved in protein-protein interaction or essential for conformational changes required in the co-activation process. Three-dimensional models of the ATGL/CGI-58 complex with the artificial intelligence software AlphaFold demonstrated that a large surface area is involved in the protein-protein interaction. Mapping important amino acids for co-activation of both proteins, ATGL and CGI-58, onto the 3D model of the complex locates these essential amino acids at the predicted ATGL/CGI-58 interface thus strongly corroborating the significance of these residues in CGI-58 mediated co-activation of ATGL.
2023-06-26 | Unmasking Crucial Residues in Adipose Triglyceride Lipase (ATGL) for Co-Activation with Comparative Gene Identification-58 (CGI-58)
Abstract Lipolysis is an essential metabolic process that releases unesterified fatty acids from neutral lipid stores to maintain energy homeostasis in living organisms. Adipose triglyceride lipase (ATGL) plays a key role in intracellular lipolysis and can be co-activated upon interaction with the protein comparative gene identification-58 (CGI-58). The underlying molecular mechanism of ATGL stimulation by CGI-58 is incompletely understood. Based on analysis of evolutionary conservation, we used site directed mutagenesis to study a C-terminally truncated variant and full-length mouse ATGL providing insights in the protein co-activation on a per-residue level. We identified the region from residues N209-N215 in mouse ATGL as essential for co-activation by mouse CGI-58. ATGL variants with amino-acids exchanges in this region were still able to hydrolyze triacylglycerol at the basal level and to interact with CGI-58, yet could not be activated by CGI-58. Our studies also demonstrate that full-length mouse ATGL showed higher tolerance to specific single amino acid exchanges in the N209-N215 region upon CGI-58 co-activation compared to C-terminally truncated ATGL variants. The region is either directly involved in protein-protein interaction or essential for conformational changes required in the co-activation process. Three-dimensional models of the ATGL/CGI-58 complex with the artificial intelligence software AlphaFold demonstrated that a large surface area is involved in the protein-protein interaction. Mapping important amino acids for co-activation of both proteins, ATGL and CGI-58, onto the 3D model of the complex locates these essential amino acids at the predicted ATGL/CGI-58 interface thus strongly corroborating the significance of these residues in CGI-58 mediated co-activation of ATGL.
2022-02-28 | Sebelipase alfa in children and adults with lysosomal acid lipase deficiency: Final results of the ARISE study.
Children and adults with lysosomal acid lipase deficiency (LAL-D) experience cirrhosis and dyslipidemia from lysosomal accumulation of cholesteryl esters and triglycerides. Sebelipase alfa enzyme replacement therapy is indicated for individuals with LAL-D. We report final results from the phase III randomized ARISE study of sebelipase alfa in children aged ≥4 years and adults with LAL-D. The study included a 20-week, double-blind, placebo-controlled period; a 130-week, open-label, extension period; and a 104-week, open-label, expanded treatment period. In the open-label periods, all patients received intravenous sebelipase alfa every other week. The primary outcome was alanine aminotransferase (ALT) level normalization; aspartate aminotransferase (AST) levels, lipid parameters, liver histology, liver and spleen volume and fat content, and safety were also assessed. Of 66 patients enrolled, 59 completed the study. Median (range) age at randomization was 13 (4.7-59) years. At the last open-label visit, ALT and AST levels had normalized in 47% and 66% of patients, respectively. Patients who switched from placebo to sebelipase alfa experienced sustained improvements in ALT and AST during the open-label periods that mirrored those observed in the sebelipase alfa group during the double-blind period. Median (IQR) percent changes in lipid levels included a 25% (39%, 6.5%) reduction in low-density lipoprotein cholesterol and a 27% (19%, 44%) increase in high-density lipoprotein cholesterol. Most adverse events during the open-label periods were mild to moderate in severity; 13 patients had infusion-associated reactions (serious in 1 patient). Six patients (9%) developed anti-drug antibodies. Early and rapid improvements in markers of liver injury and lipid abnormalities with sebelipase alfa were sustained, with no progression of liver disease, for up to 5 years. NCT01757184; EudraCT Number: 2011-002750-31 LAY SUMMARY: Sebelipase alfa is used to treat lysosomal acid lipase deficiency (LAL-D), a rare, inherited disease of lipid metabolism. We report the final results of the phase III ARISE clinical study, which show that replacement of the defective LAL enzyme with sebelipase alfa for up to 5 years allows adults and children 4 years of age and older to maintain their initial improvements in liver and cholesterol parameters over the long term, without worsening of liver disease.
small molecules
2026-07-15 | Lipid Droplets as Metabolic–Epigenetic Signaling Hubs: Interplay Between Phase Separation, Cellular Adaptation, and Disease
Lipid droplets (LDs) were long thought to be passive organelles merely for neutral lipid storage. Mounting evidence redefines LDs as dynamic metabolic signaling hubs orchestrating cellular stress adaptation, with multifaceted roles in organelle crosstalk, metabolic reprogramming, redox balance and immune signaling. LD function is tightly intertwined with liquid-liquid phase separation (LLPS) and epigenetic remodeling, bridging cellular metabolism to gene expression and cell fate control. LD biogenesis relies on ER lipid structures, phase-separated protein assemblies and lipid regulatory proteins. Via contacts with multiple organelles, LDs regulate lipid catabolism, ferroptosis, inflammation and chromatin accessibility, while their metabolites directly reshape epigenetic modifications and transcription. LLPS-driven biomolecular condensates further coordinate LD-linked metabolic and stress signaling. Dysregulated LD remodeling mediates metabolic flexibility, immune escape and drug resistance in obesity, metabolic dysfunction-associated steatotic liver disease (MASLD), neurodegeneration, viral infection and cancer. This review summarizes progress in LD biogenesis and metabolism, dissects mechanistic crosstalk between LDs, LLPS and epigenetic control, and outlines LD-driven pathogenic reprogramming across human disorders. We also discuss therapeutic approaches targeting LD and LLPS pathways. Despite promising translational prospects, unresolved mechanistic and clinical hurdles persist. Further research on LD biology will reshape our framework linking metabolism, chromatin regulation and stress adaptation.
2025-11-13 | ATGL-mediated lipolysis is essential for myocellular mitochondrial function, mitochondria-lipid droplet interaction and mitochondrial network connectivity.
Defects in Adipose tissue TriGlyceride Lipase (ATGL)-mediated myocellular lipid droplet (LD) lipolysis results in mitochondrial dysfunction of unknown origin, which can be rescued by PPAR agonists. Here we examine if ATGL-mediated lipolysis is required to maintain mitochondrial network connectivity and function. Moreover, we explored if the functional implications of ATGL deficiency for mitochondrial network dynamics and function can be alleviated by promoting PPARα and/or PPARδ transcriptional activity. To this end, we cultured human primary myotubes from patients with neutral lipid storage disease with myopathy (NLSDM), a rare metabolic disorder caused by a mutation in the gene encoding for ATGL. These myotubes possess dysfunctional ATGL and compromised LD lipolysis. In addition, mitochondria-LD contact, mitochondrial network connectivity, and mitochondrial membrane potential were affected. Using a humanized ATGL inhibitor in myotubes (cultured form healthy donors) revealed similar results. Upon stimulating PPARδ transcriptional activity, mitochondrial respiration improved by more than 50 % in human primary myotubes from healthy lean individuals. This increase in respiration was dampened in myotubes with dysfunctional ATGL. Stimulation of PPARδ transcriptional activity had no effect on mitochondria-LD contacts, mitochondrial network connectivity, and mitochondrial membrane potential. Our results demonstrate that dysfunctional ATGL results in compromised mitochondrial-LD contacts and mitochondrial network connectivity, and that functional ATGL is required to improve mitochondrial respiratory capacity upon stimulation of PPARδ transcriptional activity.
2025-10-23 | Long-term neuromuscular, cardiac and liver outcomes in an adult man affected with Chanarin-Dorfman syndrome.
Chanarin-Dorfman syndrome (CDS) is an ultra-rare autosomal recessive subtype of neutral lipid storage disorder (NLSD); it is characterised by ichthyosis and intracytoplasmic accumulation of lipid droplets containing triglycerides, most commonly in granulocytes, muscle fibres, skin and liver. Several pathogenic variants in the ABHD5/CGI-58 gene have been described. Clinical manifestations include steatohepatitis, myopathy, ophthalmic disease, developmental delay. Liver involvement is an important cause of morbidity and mortality. We present a case of a 26-year-old male diagnosed with ichthyotic NLSD in childhood, who developed progressive myopathy and cardiac fibrosis in adulthood. He was treated with a combination of low-fat diet, MCT oil and co-enzyme Q10 which resulted in an initial improvement in muscle strength and stabilisation of muscle symptoms and well-being. Synopsis: Medical and dietetic management of liver and muscle complications in Chanarin-Dorfman syndrome.
2025-04-25 | Using chanarin-dorfman syndrome patient fibroblasts to explore disease mechanisms and new treatment avenues.
Chanarin-Dorfman syndrome (CDS) is a multisystemic autosomal recessive rare disorder. CDS is caused by variants in the abhydrolase domain containing 5 (ABHD5) encoding gene (CGI-58), which ultimately leads to excessive lipid storage, and therefore a high abundance of cellular lipid droplets (LDs). Although the molecular etiology of the disease was described many years ago, no treatment for CDS is currently available. To further characterize the molecular basis of the disease and to uncover new treatment avenues, we used skin fibroblasts originating from a young patient diagnosed with CDS due to a homozygous nonsense mutation. We show that dysfunctional ABHD5 does not only affect LDs, but also influences other metabolic-related organelles; the mitochondria and peroxisomes. Additionally, we found that expressing functional ABHD5 in CDS patient cells reduced LD number. Finally, we developed and applied a high content-based drug repurposing screen based on a collection of ∼2500 FDA approved compounds, yielding several compounds that affected LD total area and size. Our findings enhance the understanding of the dysfunction underlying CDS and propose new avenues for the treatment of CDS patients.
2025-02-06 | A Novel PNPLA2 Variant in a Female Patient with Neutral Lipid Storage Disease with Myopathy and Hypogonadotropic Hypogonadism.
Neutral lipid storage disease with myopathy (NLSDM) is a rare autosomal recessive disorder characterized by aberrant triacylglycerol metabolism due to mutations in the patatin-like phospholipase domain-containing 2 (PNPLA2) gene. This report presents a case study of a 14-year-old female patient exhibiting symptoms of NLSDM, including recurrent abdominal pain, fatigue, leg pain, and hepatosteatosis. Diagnostic investigations revealed elevated creatinine kinase levels, myopathic findings on electromyography, magnetic resonance imaging findings showing gluteal involvement and Jordans' bodies on peripheral smear. Clinical exome panel showed homozygous of PNPLA2 c.496G>C p.Asp166His (NM_020376.4) variant. The clinical manifestations, diagnostic challenges, and implications of this novel variant are discussed in the context of current literature. Hypogonadotropic hypogonadism was confirmed in this patient after eliminating possible underlying causes. This was a novel manifestation, and hormone replacement therapy was planned. This case underscores the significance of genetic testing in elucidating the molecular basis of NLSDM and emphasizes the necessity of comprehensive clinical evaluation for accurate diagnosis and management.
gene therapies
2023-02-16 | Knockdown of hepatocyte Perilipin-3 mitigates hepatic steatosis and steatohepatitis caused by hepatocyte CGI-58 deletion in mice.
Comparative gene identification-58 (CGI-58), also known as α/β hydrolase domain containing 5, is the co-activator of adipose triglyceride lipase that hydrolyzes triglycerides stored in the cytosolic lipid droplets. Mutations in CGI-58 gene cause Chanarin-Dorfman syndrome (CDS), an autosomal recessive neutral lipid storage disease with ichthyosis. The liver pathology of CDS manifests as steatosis and steatohepatitis, which currently has no effective treatments. Perilipin-3 (Plin3) is a member of the Perilipin-ADRP-TIP47 protein family that is essential for lipid droplet biogenesis. The objective of this study was to test a hypothesis that deletion of a major lipid droplet protein alleviates fatty liver pathogenesis caused by CGI-58 deficiency in hepatocytes. Adult CGI-58-floxed mice were injected with adeno-associated vectors simultaneously expressing the Cre recombinase and microRNA against Plin3 under the control of a hepatocyte-specific promoter, followed by high-fat diet feeding for 6 weeks. Liver and blood samples were then collected from these animals for histological and biochemical analysis. Plin3 knockdown in hepatocytes prevented steatosis, steatohepatitis, and necroptosis caused by hepatocyte CGI-58 deficiency. Our work is the first to show that inhibiting Plin3 in hepatocytes is sufficient to mitigate hepatocyte CGI-58 deficiency-induced hepatic steatosis and steatohepatitis in mice.
2001-04-19 | Phenotypic correction of lipid storage and growth arrest in wolman disease fibroblasts by gene transfer of lysosomal acid lipase.
Wolman disease is a lethal lysosomal storage disease due to deficiency of lysosomal acid lipase (LAL). Wolman disease is characterized by pronounced hepatic involvement while neurological symptoms are uncommon, making Wolman disease an attractive candidate for liver-directed gene therapy. This study was performed to test the effects of gene replacement in fibroblasts lacking LAL, using a recombinant adenovirus encoding the human LAL cDNA (AdhLAL). Human fibroblasts from a Wolman disease patient were infected with AdhLAL and showed a dose-dependent increase in LAL protein and activity up to 5-fold above levels in control fibroblasts. Furthermore, 72 hr after infection with AdhLAL there was a dose-dependent correction of the severe lipid storage phenotype of Wolman disease fibroblasts. Electron microscopy confirmed significant correction of the lysosomal lipid storage in AdhLAL-infected Wolman disease fibroblasts at the ultrastructural level. Intravenous injection of AdhLAL into wild-type mice resulted in a 13.5-fold increase in hepatic LAL activity, and overexpression of LAL was not associated with toxic side effects. These data demonstrate high-level lysosomal expression of recombinant LAL in vitro and in vivo and show the feasibility of gene therapeutic strategies for the treatment of Wolman disease.
proteins
2025-09-26 | Enzyme replacement therapy in cholesteryl ester storage disease: A case report on lysosomal acid lipase deficiency management.
Lysosomal acid lipase deficiency (LAL-D) is a rare autosomal recessive disorder caused by pathogenic variants in the LIPA gene. The clinical spectrum ranges from early-onset Wolman disease to later presentations in childhood and adulthood, formerly known as cholesteryl ester storage disease (CESD). Impaired lysosomal acid lipase (LAL) activity leads to the accumulation of cholesteryl esters and triglycerides, causing progressive hepatic and metabolic dysfunction. We describe a 17-year-old Mexican female diagnosed with CESD at age 13 after evaluation for short stature and severe hypercholesterolemia. Laboratory workup revealed markedly elevated liver enzymes and lipid levels, with severely reduced LAL activity. Molecular testing identified a homozygous LIPA(NM_000235.3):c.894G>A variant. Enzyme replacement therapy (ERT) with sebelipase alfa (1 mg/kg biweekly) was initiated, leading to progressive normalization of lipid and hepatic profiles. Over a 48-month follow-up, the patient exhibited catch-up growth (gain of 17 cm and 21 kg), pubertal development with the onset of menarche at age 16, and achievement of Tanner stage III. This case underscores the importance of early recognition of CESD in patients with unexplained dyslipidemia, elevated liver enzymes, and growth delay. Timely initiation of sebelipase alfa resulted in favorable biochemical and clinical outcomes. Comprehensive diagnostic evaluation-including enzymatic and genetic testing-is critical for accurate diagnosis and personalized management of LAL-D.
2024-03-21 | Mutational scanning pinpoints distinct binding sites of key ATGL regulators in lipolysis
Abstract ATGL is a key enzyme in intracellular lipolysis and plays an important role in metabolic and cardiovascular diseases. ATGL is tightly regulated by a known set of protein-protein interaction partners with activating or inhibiting functions in the control of lipolysis. Here, we use deep mutational protein interaction perturbation scanning and generate comprehensive profiles of single amino acid variants that affect the interactions of ATGL with its regulatory partners: CGI-58, G0S2, PLIN1, PLIN5 and CIDEC. Twenty-three ATGL amino acid variants yield a specific interaction perturbation pattern when validated in co-immunoprecipitation experiments in mammalian cells. We identify and characterize eleven highly selective ATGL switch mutations which affect the interaction of one of the five partners without affecting the others. Switch mutations thus provide distinct interaction determinants for ATGL’s key regulatory proteins at an amino acid resolution. When we test triglyceride hydrolase activity in vitro and lipolysis in cells, the activity patterns of the ATGL switch variants trace to their protein interaction profile. In the context of structural data, the integration of variant binding and activity profiles provides insights into the regulation of lipolysis and the impact of mutations in human disease.
2023-12-20 | Unmasking crucial residues in adipose triglyceride lipase for coactivation with comparative gene identification-58
Lipolysis is an essential metabolic process that releases unesterified fatty acids from neutral lipid stores to maintain energy homeostasis in living organisms. Adipose triglyceride lipase (ATGL) plays a key role in intracellular lipolysis and can be co-activated upon interaction with the protein comparative gene identification-58 (CGI-58). The underlying molecular mechanism of ATGL stimulation by CGI-58 is incompletely understood. Based on analysis of evolutionary conservation, we used site directed mutagenesis to study a C-terminally truncated variant and full-length mouse ATGL providing insights in the protein co-activation on a per-residue level. We identified the region from residues N209-N215 in ATGL as essential for co-activation by CGI-58. ATGL variants with amino-acids exchanges in this region were still able to hydrolyze triacylglycerol at the basal level and to interact with CGI-58, yet could not be activated by CGI-58. Our studies also demonstrate that full-length mouse ATGL showed higher tolerance to specific single amino acid exchanges in the N209-N215 region upon CGI-58 co-activation compared to C-terminally truncated ATGL variants. The region is either directly involved in protein-protein interaction or essential for conformational changes required in the co-activation process. Three-dimensional models of the ATGL/CGI-58 complex with the artificial intelligence software AlphaFold demonstrated that a large surface area is involved in the protein-protein interaction. Mapping important amino acids for co-activation of both proteins, ATGL and CGI-58, onto the 3D model of the complex locates these essential amino acids at the predicted ATGL/CGI-58 interface thus strongly corroborating the significance of these residues in CGI-58 mediated co-activation of ATGL.
2023-06-26 | Unmasking Crucial Residues in Adipose Triglyceride Lipase (ATGL) for Co-Activation with Comparative Gene Identification-58 (CGI-58)
Abstract Lipolysis is an essential metabolic process that releases unesterified fatty acids from neutral lipid stores to maintain energy homeostasis in living organisms. Adipose triglyceride lipase (ATGL) plays a key role in intracellular lipolysis and can be co-activated upon interaction with the protein comparative gene identification-58 (CGI-58). The underlying molecular mechanism of ATGL stimulation by CGI-58 is incompletely understood. Based on analysis of evolutionary conservation, we used site directed mutagenesis to study a C-terminally truncated variant and full-length mouse ATGL providing insights in the protein co-activation on a per-residue level. We identified the region from residues N209-N215 in mouse ATGL as essential for co-activation by mouse CGI-58. ATGL variants with amino-acids exchanges in this region were still able to hydrolyze triacylglycerol at the basal level and to interact with CGI-58, yet could not be activated by CGI-58. Our studies also demonstrate that full-length mouse ATGL showed higher tolerance to specific single amino acid exchanges in the N209-N215 region upon CGI-58 co-activation compared to C-terminally truncated ATGL variants. The region is either directly involved in protein-protein interaction or essential for conformational changes required in the co-activation process. Three-dimensional models of the ATGL/CGI-58 complex with the artificial intelligence software AlphaFold demonstrated that a large surface area is involved in the protein-protein interaction. Mapping important amino acids for co-activation of both proteins, ATGL and CGI-58, onto the 3D model of the complex locates these essential amino acids at the predicted ATGL/CGI-58 interface thus strongly corroborating the significance of these residues in CGI-58 mediated co-activation of ATGL.
2022-02-28 | Sebelipase alfa in children and adults with lysosomal acid lipase deficiency: Final results of the ARISE study.
Children and adults with lysosomal acid lipase deficiency (LAL-D) experience cirrhosis and dyslipidemia from lysosomal accumulation of cholesteryl esters and triglycerides. Sebelipase alfa enzyme replacement therapy is indicated for individuals with LAL-D. We report final results from the phase III randomized ARISE study of sebelipase alfa in children aged ≥4 years and adults with LAL-D. The study included a 20-week, double-blind, placebo-controlled period; a 130-week, open-label, extension period; and a 104-week, open-label, expanded treatment period. In the open-label periods, all patients received intravenous sebelipase alfa every other week. The primary outcome was alanine aminotransferase (ALT) level normalization; aspartate aminotransferase (AST) levels, lipid parameters, liver histology, liver and spleen volume and fat content, and safety were also assessed. Of 66 patients enrolled, 59 completed the study. Median (range) age at randomization was 13 (4.7-59) years. At the last open-label visit, ALT and AST levels had normalized in 47% and 66% of patients, respectively. Patients who switched from placebo to sebelipase alfa experienced sustained improvements in ALT and AST during the open-label periods that mirrored those observed in the sebelipase alfa group during the double-blind period. Median (IQR) percent changes in lipid levels included a 25% (39%, 6.5%) reduction in low-density lipoprotein cholesterol and a 27% (19%, 44%) increase in high-density lipoprotein cholesterol. Most adverse events during the open-label periods were mild to moderate in severity; 13 patients had infusion-associated reactions (serious in 1 patient). Six patients (9%) developed anti-drug antibodies. Early and rapid improvements in markers of liver injury and lipid abnormalities with sebelipase alfa were sustained, with no progression of liver disease, for up to 5 years. NCT01757184; EudraCT Number: 2011-002750-31 LAY SUMMARY: Sebelipase alfa is used to treat lysosomal acid lipase deficiency (LAL-D), a rare, inherited disease of lipid metabolism. We report the final results of the phase III ARISE clinical study, which show that replacement of the defective LAL enzyme with sebelipase alfa for up to 5 years allows adults and children 4 years of age and older to maintain their initial improvements in liver and cholesterol parameters over the long term, without worsening of liver disease.
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