Neutral Lipid Storage Disease Research Articles

Navigating Surgical Challenges: Managing Juvenile Glaucoma in a Patient with Dorfman–Chanarin Syndrome

We report a surgically challenging case, in the context of a diagnosis of juvenile glaucoma refractory to drug therapy, multi-operated, known patient with congenital ichthyosis, part of Dorfman–Chanarin Syndrome (DCS), with a single functional eye. She is a young patient (54) and housewife in an urban environment known to have DCS and BE (both eyes), strong myopia, and congenital nystagmus. She initially underwent cataract surgery in 2015 and again in 2017. As of 2015, she was known to have juvenile glaucoma under maximal therapy. The important increases in pressure started in 2020 when the dermatological condition worsened (exacerbation of skin changes in the context of ichthyosis), the patient is in menopause, and presbyopia has set in. The glaucoma could no longer be controlled with medication and required serial surgery in both eyes (initially in the right eye in 2020 and in the left eye in 2023). The right eye showed a favorable evolution until 2024, when a second trabeculectomy became necessary, with a favorable evolution. Conclusions: To our knowledge, such a case has not been documented in the medical literature. Frequent monitoring of intraocular pressures and prompt treatment are required. It is a rare association, a very complicated case of managing a patient with refractory glaucoma and multiple associated ophthalmic and systemic pathologies. We are also dealing with a single functional eye, difficult to manage due to a thin sclera that has caused intraoperative difficulties, and the association of congenital nystagmus and strabismus.

Two PNPLA2 heterozygous mutations result in neutral lipid storage disease with myopathy: a case report

BackgroundNeutral Lipid Storage Disease with Myopathy (NLSDM) is a rare lipid metabolism disorder caused by PNPLA2 gene mutations. Clinical manifestations are heterogeneous, and diagnosis is often delayed, usually gaining patients’ attention due to the increased risk of cardiomyopathy.Case presentationWe herein report a 36-year-old Asian male presenting with progressive limb weakness, muscle atrophy of limbs and trunk, dysarthria, and heart failure. Electromyography indicated myogenic changes, and muscle biopsy results revealed characteristics of lipid storage myopathy. Genetic analysis of PNPLA2 revealed two heterozygous mutations: c.757 + 1G > T (chr11-823588, splice-5) on intron 6 and c.919delG (chr11-823854, p.A307Pfs*13) on exon 7. The patient improved limb strength, and dysarthria disappeared after the Medium Chain Fatty Acids diet.ConclusionsIn conclusion, we report for the first time that the two heterozygous mutations PNPLA2 c.919delG and c.757 + 1G > T together induced NLSDM, which was confirmed by muscle biopsy.

Clinical characteristics and genetic analysis of a child with Neutral lipid storage disease with myopathy

To explore the clinical phenotype and genetic basis of a child with Neutral lipid storage disease with myopathy (NLSDM). A child who was admitted to the First Affiliated Hospital of Zhengzhou University in February 2021 for a history of elevated creatine kinase (CK) for over 2 months was selected as the study subject. Clinical and laboratory examinations were carried out, and the child was subjected to whole exome sequencing. Candidate variants were validated by Sanger sequencing of her family members. The patient, a 9-year-old female, had exhibited weakness in the lower limbs, elevated CK level, and refractory cardiomyotrophy. Genetic testing revealed that she has harbored c.32C>G (p.S11W) and c.516C>G (p.N172K) compound heterozygous variants of the PNPLA2 gene, which were respectively inherited from her mother and father. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were rated as likely pathogenic (PM1+PM2_Supporting+PP3+PP4). The c.32C>G (p.S11W) and c.516C>G (p.N172K) compound heterozygous variants of the PNPLA2 gene probably underlay the myasthenia gravis and elevated creatine kinase in this child.

Genetic inheritance in tandem: Non-syndromic autosomal recessive congenital ichthyosis with beta-thalassaemia: A rare coincidence

Ichthyosis belongs to the group of Mendelian disorders of cornification. Congenital ichthyosis is inherited as an autosomal recessive trait, so it is also known as autosomal recessive congenital ichthyosis (ARCI). ARCI is classified into two types: syndromic and non-syndromic ARCI. Non-syndromic ARCIs include lamellar ichthyosis, congenital ichthyosiform erythroderma and Harlequin ichthyosis. Syndromic-ARCI is associated with multisystemic involvement, which includes Netherton syndrome, Chanarin-Dorfman disease and others. Other systemic diseases associated with ichthyosis include Gaucher disease type II and hypothyroidism. Chanarin-Dorfman and Gaucher disease-II are additionally associated with hepatosplenomegaly (HSM) and anaemia. We describe a child of congenital ichthyosis with HSM and anaemia thought to be syndromic-ARCI, but diagnosed for beta-thalassaemia (b-thal) concurrently. An infant presented with peeling skin along with absent sweating since birth and recent onset paleness of the body. Examination revealed Ichthyosis (Lamellar-variant), severe pallor and HSM, raising the possibility of Chanarin-Dorfman syndrome and Gaucher’s disease. The investigation revealed an Erlenmeyer flask deformity of the knee, but no Gaucher’s cells were found in the bone marrow. In the absence of lipid vacuoles leaden leukocytes (Jordan’s anomaly), Chanarin-Dorfman disease was also ruled out. Haemoglobin (Hb) high-performance liquid chromatography revealed β-thal major, and both parents were traits, giving us the diagnosis, which was further confirmed by the next-generation gene sequencing for clinical exomes. This report was to highlight non-syndromic ARCI involving the CYP4F22 gene variant, which is a rare finding, and the association of such ichthyosis with β-thal major was an unexpected result. Genetic counselling was provided to the parents in light of the autosomal recessive nature of both diseases. Genes of congenital ichthyosis and β-thal were unrelated, but simultaneous expressions of two autosomal-recessive diseases together are it merely by chance or a new entity.

Eponyms that honor Jewish dermatologists: A celebration and a remembrance, Part three: Jewish physicians who practiced during the Holocaust and in its aftermath

Part III of this contribution continues to celebrate the many contributions that Jewish physicians have made to advance the specialty of dermatology, as reflected by eponyms that honor their names. Part I covered the years before 1933, a highly productive period of creativity by Jewish dermatologists, especially in Germany and Austria. The lives of 17 Jewish physicians and their eponyms were described in Part I. Part II focused on the years of 1933 to 1945, when the Nazis rose to power in Europe, and how their anti-Semitic genocidal policies affected leading Jewish dermatologists caught within the Third Reich. Fourteen Jewish physicians and their eponyms are discussed in Part II. Part III continues the remembrance of the Holocaust era by looking at the careers and eponyms of an additional 13 Jewish physicians who contributed to dermatology during the period of 1933 to 1945. Two of these 13 physicians, pathologist Ludwig Pick (1868-1944) and neurologist Arthur Simons (1877-1942), perished in the Holocaust. They are remembered by the following eponyms of interest to dermatologists: Lubarsch-Pick syndrome, Niemann-Pick disease, and Barraquer-Simons syndrome. Four of the 13 Jewish physicians escaped the Nazis: Felix Pinkus (1868-1947), Herman Pinkus (1905-1985), Arnault Tzanck (1886-1954), and Erich Urbach (1893-1946). Eponyms that honor their names include nitidus Pinkus, fibroepithelioma of Pinkus, Tzanck test, Urbach-Wiethe disease, Urbach-Koningstein technique, Oppenheim-Urbach disease, and extracellular cholesterinosis of Karl-Urbach. The other seven Jewish physicians lived outside the reach of the Nazis, in either Canada, the United States, or Israel. Their eponyms are discussed in this contribution. Part III also discusses eponyms that honor seven contemporary Jewish dermatologists who practiced dermatology after 1945 and who continue the nearly 200 years of Jewish contribution to the development of the specialty. They are A. Bernard Ackerman (1936-2008), Irwin M. Braverman, Sarah Brenner, Israel Chanarin, Maurice L. Dorfman, Dan Lipsker, and Ronni Wolf. Their eponyms are Ackerman syndrome, Braverman sign, Brenner sign, Chanarin-Dorfman syndrome, Lipsker criteria of the Schnitzler syndrome, and Wolf's isotopic response.

Comorbidity of bathing suit ichthyosis and limb-girdle muscular dystrophy type 2 A in a Tunisian patient revealed by Whole Exome Sequencing

Elevated rates of consanguinity and inbreeding are responsible for the high prevalence of recessively inherited diseases among inbred populations including Tunisia. In addition, the co-occurrence of two of these conditions, called also comorbidity, within the same individual or in members of the same family are often described in Tunisia which is challenging for diagnosis. The high throughput sequencing has improved the diagnosis of inherited diseases. We report here on a 32-year-old woman born to consanguineous parents. She presented with congenital ichthyosis and muscular dystrophy. She was primarily suspected as suffering from Chanarin-Dorfman syndrome (CDS) with unusual form. Screening of founder mutations allowed only the elucidation of the molecular etiology of Ichthyosis. As the result was inconclusive, Whole Exome Sequencing (WES) was conducted. WES data analysis led to the identification of a mutation in the CAPN3 gene underlying limb-girdle muscular dystrophy type 2A (LGMD2A). Sanger sequencing confirmed the familial segregation of mutations. This work presents the first case worldwide of individual comorbidity of bathing suit ichthyosis and LGMD2A. The co-occurrence of two diseases should be systematically considered when establishing a diagnosis especially in consanguineous populations. WES is a powerful tool for molecular diagnosis in particular for revealing comorbidities and rectifying the diagnosis.

Neutral lipid storage disease with myopathy: clinicopathological and genetic features of nine Iranian patients

The rare disorder known as Neutral Lipid Storage Disease with Myopathy presents with a variety of clinical manifestations, including myopathy, cardiac dysfunction, and other organ complications. Early diagnosis is crucial due to the increased risk of cardiomyopathy. We describe the clinical, histopathological, muscle imaging, and genetic findings of nine neutral lipid storage myopathy patients. Proximal weakness and asymmetric involvement may suggest lipid storage myopathy. While skeletal muscle weakness was the main manifestation in our patients, one case presented only with hyperCKemia. Additionally, three patients had fertility issues, two suffered from diabetes mellitus, two had cardiomyopathy, and one had a history of hypothyroidism. Muscle histopathology revealed lipid depositions and rimmed vacuoles, prompting peripheral blood smears to detect Jordan Anomalies. All muscle biopsies and peripheral blood smear showed lipid droplets, rimmed vacuoles, and Jordan anomaly. Identifying PNPLA2 gene mutations is important for diagnosing neutral lipid storage myopathy; our cases showed some novel mutations. This study highlights the importance of early diagnosis and comprehensive evaluation in managing neutral lipid storage myopathy cases.

Eponyms and clinical entities from the land of Israel

Seven eponyms have been pioneered by dermatologists in Israel: Brenner's sign, Chanarin-Dorfman syndrome, granulated sweetener packet sign, isopathic phenomenon of Sagher, lanolin paradox, Nakar-Ingber disease, and Wolf's isotopic response. In addition, there are three id reactions described by Israeli dermatologists: leishmanid, pediculid, and scabid. There is also the acronym PEMPHIGUS, which stands for the causative reasons for pemphigus. We celebrate these eponyms and clinical entities, which reflect the impressive progress made by dermatologists in Israel during the past century who have helped to build an academic, vibrant, and dynamic specialty in the Holy Land.

Chanarin-Dorfman Syndrome diagnosed at the stage of liver transplantation: A rare lipid storage disease

Chanarin-Dorfman Syndrome (CDS) is a rare lipid storage disease with ichthyosis, hepatomegaly, myopathy, neuropathy, deafness, and ocular findings. Here, we aim to present an elderly CDS case and highlight the new endocrinological findings. A 66-year-old male patient with cirrhosis was hospitalized for liver transplantation. We suspected Chanarin-Dorfman Syndrome with ichthyosis, fatty liver, and syndromic facial features with bilateral ectropion, deafness, and malocclusion. We showed the lipid droplets in neutrophils called patognomonic Jordans' anomaly. Homozygous c.47+1 G>A mutation in the ABHD5 (NM_016006.6) gene were detected by clinical exome sequencing. Out of <160 CDS cases in the literature, this is the second eldest CDS patient and first with adrenal insufficiency, parathyroid lipoadenoma and atrophic pancreas. Clinicians should be aware of CDS as a rare cause of fatty liver. We recommend a blood smear and genetic analyses in patients with severe ichtiosis, ectropion, deafness and multiple endocrinolgic disorders.

HyperCKemia: An early sign of childhood-onset neutral lipid storage disease with myopathy

Neutral lipid-storage disease with myopathy (NLSDM) is an autosomal recessive neuromuscular disorder caused by mutations in PNPLA2, and the average age at onset is 30 years. To date, only eight patients with childhood-onset NLSDM have been reported in detail. We investigated 3 unreported patients with NLSDM detected in childhood and reviewed 8 childhood-onset and 82 adult-onset patients with NLSDM documented in the literature. In the childhood-onset cohort, NLSDM presented initially as asymptomatic or paucisymptomatic hyperCKemia in 6/11 patients, and follow-up data showed onset of muscle weakness in 6/11 childhood-onset patients. In the adult-onset cohort, 95.1% (78/82) of patients showed muscle weakness. Cardiac involvement developed in 6/11 childhood-onset patients. Hepatomegaly was observed in 3/11 childhood-onset patients. Serum creatine kinase levels were elevated greater than five-fold of the upper limit of normal (ULN) in most childhood-onset patients and were elevated to less than ten-fold of the ULN in most adult-onset patients. Peripheral blood smears and muscle biopsies showed cytoplasmic lipid droplets in leukocytes and myocytes. NLSDM can present in children with asymptomatic or paucisymptomatic hyperCKemia before the onset of muscle weakness. The presence of lipid droplets in leucocytes (Jordans' anomaly) aids in diagnosing and confirming the pathogenicity of PNPLA2 variants of uncertain significance. There were no clear genotype-phenotype correlations in patients with NLSDM.

#6086 NEUTRAL LIPID STORAGE DISEASE WITH RENAL INVOLVEMENT: A CASE REPORT

Abstract Background and Aims Neutral lipid storage diseases (NLSD) are rare conditions caused by an inborn error of neutral lipid metabolism that results in a deficit in the degradation of cytoplasmic triglycerides and a consequent abnormal storage of the neutral lipids. Their accumulation in cytoplasmic lipid droplets in most tissues of the body results in a very heterogeneous phenotype: myopathic syndrome, intellectual deficit, cataract, neuropathy, cardiomyopathy, hepatomegaly are the main clinical manifestations. Less frequent conditions are diabetes, chronic pancreatitis and renal involvement. Method A 27-year-old woman visited our hospital on November 2022 because of progressive onset of edema, dyspnea, nausea and loss of appetite. The medical history showed that 4 years before she was diagnosed with diabetes mellitus and she has been suffering from severe muscle weakness (she was helping herself with the wheelchair) for two years. In 2017 a proctological evaluation showed an anal hypotonia from likely neuropathy. Blood chemistry tests revealed a metabolic acidosis, a decreased renal function, anaemia and nephrotic range proteinuria at the urinalysis. A bilateral pleural effusion was described at the chest radiograph and a circumferential pericardial effusion at a first echocardiogram. The ultrasound of the abdomen described a small size of the right kidney (90 mm) and an angiomyolipoma on the left kidney. Neurological examination showed a mild intellectual disability, facies with dysmorphic appearance and hypotonia of proximal and distal muscular masses of the upper limbs. Lower limbs showed a more pronounced strength deficit on the left and a hypotonia to proximal muscle masses. Electromyography showed a condition of severe sensitivity polyneuropathy: signs of chronic denervation and morphological alterations of the motor unit especially in the proximal districts of the lower limbs. Ophthalmological examination showed an advanced cataract. Cardiological evaluation through heart echo scanshowed a dilated heart disease with ventricular function and dilation of the pulmonary artery. A quadriceps muscle biopsy finally revealed myogenic features consistent with neutral lipid storage disease. Fabry test came back negative. Despite several drug treatments, the patient continued to be asthenic, inappetent and the oxygen therapy could not be removed because frequent episodes of desaturation. The deterioration of the patient's clinical conditions required the onset of dialysis immediately. Unfortunately, despite adequate information on the risks of possible refusal, the patient denied consent for central venous catheter placement and hence the beginning of renal replacement therapy. Sadly, the patient was lost to follow up and it was not possible to carry out other diagnostic investigations. Results Our patient developed an end-stage renal disease in the framework of a neutral lipid storage disease. Since cytoplasmic lipid droplets are ubiquitous organelles, we can assume that in this case, kidney involvement is due to a pathogenetic mechanism similar to that of other storage diseases such as Fabry disease (Table 1). Conclusion Here we describe a 27-year-old NLSD female patient showing late onset myopathy and difficulties in mobilization in association with severe cardiac and ocular involvement, mild intellectual disability, diabetes mellitus type 2 and end stage renal disease. Our data expand the clinical manifestations of NLSD, providing further evidence for clinical NLSD heterogeneity and mainly, further evidence for storage diseases with renal involvement.

Neutral lipid storage disease with myopathy and myotonia associated to pathogenic variants on PNPLA2 and CLCN1 genes: case report

BackgroundNeutral lipid storage disease with myopathy (NLSD-M) is an autosomal recessive disease that manifests itself around the 3rd to 4th decade with chronic myopathy predominantly proximal in the shoulder girdle. Clinical myotonia is uncommon. We will report a rare case of association of pathogenic variants on PNPLA2 and CLCN1 genes with a mixed phenotype of NLSD-M and a subclinical form of Thomsen’s congenital myotonia.Case presentationWe describe a patient with chronic proximal myopathy, subtle clinical myotonia and electrical myotonia on electromyography (EMG). Serum laboratory analysis disclosure hyperCKemia (CK 1280 mg/dL). A blood smear analysis showed Jordan’s anomaly, a hallmark of NLSD-M. A genetic panel was collected using next-generation sequencing (NGS) technique, which identified two pathogenic variants on genes supporting two different diagnosis: NLSD-M and Thomsen congenital myotonia, whose association has not been previously described.ConclusionsAlthough uncommon, it is important to remember the possibility of association of pathogenic variants to explain a specific neuromuscular disease phenotype. The use of a range of complementary methods, including myopathy genetic panels, may be essential to diagnostic definition in such cases.

Effects of Triheptanoin on Mitochondrial Respiration and Glycolysis in Cultured Fibroblasts from Neutral Lipid Storage Disease Type M (NLSD-M) Patients

Neutral lipid storage disease type M (NLSD-M) is an ultra-rare, autosomal recessive disorder that causes severe skeletal and cardiac muscle damage and lipid accumulation in all body tissues. In this hereditary pathology, the defective action of the adipose triglyceride lipase (ATGL) enzyme induces the enlargement of cytoplasmic lipid droplets and reduction in the detachment of mono- (MG) and diglycerides (DG). Although the pathogenesis of muscle fiber necrosis is unknown, some studies have shown alterations in cellular energy production, probably because MG and DG, the substrates of Krebs cycle, are less available. No tests have been tried with medium-chain fatty acid molecules to evaluate the anaplerotic effect in NLSD cells. In this study, we evaluated the in vitro effect of triheptanoin (Dojolvi®), a highly purified chemical triglyceride with seven carbon atoms, in fibroblasts obtained from five NLSD-M patients. Glycolytic and mitochondrial functions were determined by Seahorse XF Agylent Technology, and cellular viability and triglyceride content were measured through colorimetric assays. After the addition of triheptanoin, we observed an increase in glycolysis and mitochondrial respiration in all patients compared with healthy controls. These preliminary results show that triheptanoin is able to induce an anaplerotic effect in NLSD-M fibroblasts, paving the way towards new therapeutic strategies.

Chanarin-Dorfman Syndrome: Exceptional Liver Transplant Indication

• Second Chanarin-Dorfman case published that was treated with a liver transplant. • Liver transplant is an excellent treatment of decompensated cirrhosis in Chanarin-Dorfman syndrome. • There is no evidence of recurrence of the disorder on the graft. We report the second case published about the use of liver transplant in the treatment of a patient with Chanarin-Dorfman syndrome with decompensated cirrhosis who presented excellent results after a 6-month follow-up without recurrence. Chanarin-Dorfman syndrome is an autosomal recessive metabolic disorder caused by a chromosome 3 gene mutation containing α/β-hydrolase 5 domain. It is characterized by the accumulation of neutral lipids in granulocytes of diverse organs, such as muscle, liver, eyes, ear, central nervous system, and bone marrow. The clinical expression consists of ichthyosis and hepatomegaly, followed by bilateral ectropion, cataract, neurosensory deafness, and splenomegaly. About 10% of these patients develop cirrhosis. Even though the management with low-fat diet enriched with medium-chain triglycerides along with ursodeoxycholic acid and vitamin E can normalize liver enzymes, reduce liver size, and minimize cirrhosis; once cirrhosis is established it will determine the patient's prognosis. Liver transplant could be the adequate treatment of a decompensated cirrhosis; in fact, there is no evidence of recurrence on the graft.

ABHD5-A Regulator of Lipid Metabolism Essential for Diverse Cellular Functions.

The α/β-Hydrolase domain-containing protein 5 (ABHD5; also known as comparative gene identification-58, or CGI-58) is the causative gene of the Chanarin-Dorfman syndrome (CDS), a disorder mainly characterized by systemic triacylglycerol accumulation and a severe defect in skin barrier function. The clinical phenotype of CDS patients and the characterization of global and tissue-specific ABHD5-deficient mouse strains have demonstrated that ABHD5 is a crucial regulator of lipid and energy homeostasis in various tissues. Although ABHD5 lacks intrinsic hydrolase activity, it functions as a co-activating enzyme of the patatin-like phospholipase domain-containing (PNPLA) protein family that is involved in triacylglycerol and glycerophospholipid, as well as sphingolipid and retinyl ester metabolism. Moreover, ABHD5 interacts with perilipins (PLINs) and fatty acid-binding proteins (FABPs), which are important regulators of lipid homeostasis in adipose and non-adipose tissues. This review focuses on the multifaceted role of ABHD5 in modulating the function of key enzymes in lipid metabolism.

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.

Blocking Lipid Uptake Pathways Does not Prevent Toxicity in Adipose Triglyceride Lipase (ATGL) Deficiency

Lipid accumulation in nonadipose tissues can cause lipotoxicity, leading to cell death and severe organ dysfunction. Adipose triglyceride lipase (ATGL) deficiency causes human neutral lipid storage disease and leads to cardiomyopathy; ATGL deficiency has no current treatment. One possible approach to alleviate this disorder has been to alter the diet and reduce the supply of dietary lipids and, hence, myocardial lipid uptake. However, in this study, when we supplied cardiac Atgl KO mice a low- or high-fat diet, we found that heart lipid accumulation, heart dysfunction, and death were not altered. We next deleted lipid uptake pathways in the ATGL-deficient mice through the generation of double KO mice also deficient in either cardiac lipoprotein lipase or cluster of differentiation 36, which is involved in an lipoprotein lipase-independent pathway for FA uptake in the heart. We show that neither deletion ameliorated ATGL-deficient heart dysfunction. Similarly, we determined that non-lipid-containing media did not prevent lipid accumulation by cultured myocytes; rather, the cells switched to increased de novo FA synthesis. Thus, we conclude that pathological storage of lipids in ATGL deficiency cannot be corrected by reducing heart lipid uptake.

Molecular Modeling of ABHD5 Structure and Ligand Recognition.

Alpha/beta hydrolase domain-containing 5 (ABHD5), also termed CGI-58, is the key upstream activator of adipose triglyceride lipase (ATGL), which plays an essential role in lipid metabolism and energy storage. Mutations in ABHD5 disrupt lipolysis and are known to cause the Chanarin-Dorfman syndrome. Despite its importance, the structure of ABHD5 remains unknown. In this work, we combine computational and experimental methods to build a 3D structure of ABHD5. Multiple comparative and machine learning-based homology modeling methods are used to obtain possible models of ABHD5. The results from Gaussian accelerated molecular dynamics and experimental data of the apo models and their mutants are used to select the most likely model. Moreover, ensemble docking is performed on representative conformations of ABHD5 to reveal the binding mechanism of ABHD5 and a series of synthetic ligands. Our study suggests that the ABHD5 models created by deep learning-based methods are the best candidate structures for the ABHD5 protein. The mutations of E41, R116, and G328 disturb the hydrogen bonding network with nearby residues and suppress membrane targeting or ATGL activation. The simulations also reveal that the hydrophobic interactions are responsible for binding sulfonyl piperazine ligands to ABHD5. Our work provides fundamental insight into the structure of ABHD5 and its ligand-binding mode, which can be further applied to develop ABHD5 as a therapeutic target for metabolic disease and cancer.

Neutral lipid storage disease with myopathy: A 10-year follow-up case report.

Mutations in PNPLA2 gene encoding for adipose triglyceride lipase (ATGL), involved in triglyceride degradation, lead to an inborn error of neutral lipid metabolism. The disorder that results in abnormal storage of neutral lipid is known as neutral lipid storage disease with myopathy (NLSDM). We report the follow-up of a 30-year-old woman with NLSDM, asymptomatic until age 23. At the age of 18, a high level of CPK and neutral lipid abnormal accumulation in muscle and skin cells suggested NLSDM diagnosis, afterwards confirmed by PNPLA2 analysis. After 5 years, she developed weakness in the upper and lower extremities. She was put on a low-fat diet with medium-chain triglycerides (MCT) oil supplementation but, although her CPK level decreased, myopathy continued to progress. At present, she presents severe skeletal myopathy without cardiac involvement. In this patient, no beneficial effects on progressive skeletal muscle weakness were detected after the MCT diet, probably due to complete loss of PNPLA2 expression.

Molecular Basis for Membrane Binding and Lipolysis Activation by ABHD5

Triglycerides are the main reservoir for long‐term energy storage in humans and are stored intracellularly in lipid droplets. Abnormal triglyceride metabolism is a key factor leading to obesity, diabetes, fatty liver disease and cardiovascular disease. When energy is needed, triglycerides are broken down in a metabolic pathway called lipolysis. Intracellular lipolysis is initiated by adipose triglyceride lipase (ATGL), which hydrolyzes triacylglycerol (TAG) to make diacylglycerol and a free fatty acid. Alpha‐beta hydrolase domain‐containing 5 (ABHD5) is a highly conserved regulator of ATGL‐mediated lipolysis that increases ATGL activity and is necessary to maintain lipid homeostasis. Consistently, mutations in ABHD5 cause Chanarin‐Dorfman syndrome, which leads to excessive accumulation of triglycerides. Despite over two decades of studies using biochemical approaches to mouse models, the structure of ABHD5 and molecular mechanisms of regulation remained uncharacterized. To understand the mechanism, we purified full‐length human ABHD5, visualized its self‐assembled, multiple oligomeric state in the absence of detergents by cryo‐EM, and generated preliminary crystals of detergent‐solubilized, monomeric ABHD5. We found ABHD5 is phosphorylated in vitro by PKA and recruited to membranes by specific lipids. We also purified the full‐length human ATGL. To further investigate the structural and regulation mechanisms of ABHD5 and ATGL, we will utilize hydrogen deuterium exchange mass spectrometry to map ATGL and ABHD5 protein‐protein and protein‐membrane interactions, biochemical experiments to study their co‐activation mechanism and membrane interaction. This study will provide a deeper understanding for the clinically relevant mutations, membrane recruitment and lipolysis activation of these key players in lipid metabolism.