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- Daniela Tavian obtained Biological degree at University of Milan in 1991 discussing an experimental thesis on molecul... moreDaniela Tavian obtained Biological degree at University of Milan in 1991 discussing an experimental thesis on molecular characterization of HPV16 genomes isolated from pre-neoplastic and neoplastic vulvar lesions, which was carried out in the Laboratory of Experimental Oncology of National Institute of Tumors, Milan (Director Professor Giuseppe della Porta). Then she moved to the University of Brescia and obtained a PhD in Cellular and Molecular Biotechnologies applied to the Biomedical Sciences (1996) and a specialization in Biochemistry and Clinical Chemistry (1999), Department of Biomedical Sciences and Biotechnologies, Division of Biology and Human Genetics, University of Brescia, Italy. During PhD (in 1995), she was abroad in lab, Dept. of Genetics directed by Professor A. S. Whitehead's, Trinity College (Dublin, Ireland) with a project on developing new approach of genetic therapy utilizing ribozymes. Then she moved to Milan, where she has been working in the Laboratory of Human Molecular Biology and Genetics, Catholic University of the Sacred Heart, Milan, Italy from 2003 to 2012 as assistant Professor. From November 2012 to 2019, she works in the Laboratory of Cellular Biochemistry and Molecular Biology (Research Centre of Biochemistry and Sport Nutrition-CRIBENS), Catholic University of the Sacred Heart, Milan. Since 2017, she is a member of the scientific committee of CRIBENS. From 2015 she is member of Ethics committee of the Catholic University (Milan, Italy).She is Professor of Neurobiological and Genetic Bases of Mental Activity at the Faculty of Psychology, Catholic University (Brescia and Milan) and Professor of General and Sport Biochemistry, Faculties of Education, Medicine and Surgery "A.Gemelli”, Catholic University of Milan, Italy (http://docenti.unicatt.it/eng/daniela_tavian/).From 2021 she is full professor of Biochemistry at the Catholic University of the Sacred Heart, Milan.edit
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Fatty liver disease is mainly caused by alcohol consumption, excessive body weight, dyslipidemia and impaired glucose tolerance, but inherited disorders can sometimes be involved. We report the case of a 40-year-old woman with... more
Fatty liver disease is mainly caused by alcohol consumption, excessive body weight, dyslipidemia and impaired glucose tolerance, but inherited disorders can sometimes be involved. We report the case of a 40-year-old woman with steatohepatitis and severe portal hypertension, associated with ichthyosis, cataract and hypoacusia. The clinical, pathological and genetic findings were consistent with a diagnosis of Chanarin–Dorfman syndrome (CDS), a rare autosomal recessive inherited neutral lipid storage disorder, and genetic analysis showed that a novel ABHD5 mutation is responsible. 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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Research Interests: Genetics, Medicine, Humans, Mutation, Female, and 8 moreMale, Aged, Middle Aged, Adult, Lymphedema, Loss function, Eyelashes, and frameshift mutation
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Individual variability exists in infants' socio-emotional stress regulation, in terms of behavioral response (i.e., negative emotionality) as well as magnitude and direction (i.e., increase or decrease) of... more
Individual variability exists in infants' socio-emotional stress regulation, in terms of behavioral response (i.e., negative emotionality) as well as magnitude and direction (i.e., increase or decrease) of hypothalamic-pituitary-adrenal (HPA) axis reactivity (i.e., salivary cortisol post-stress concentration). The catechol-O-methyltransferase polymorphism at codon 158 (COMTval158met) associates with stress regulation, but no evidence exists for infants. This study aimed to assess the association between COMTval158met and both negative emotionality and salivary cortisol reactivity to socio-emotional stress in 4-month-old infants. Sixty-nine infants were exposed to the Face-to-Face Still-Face (FFSF) paradigm. During the FFSF paradigm, socio-emotional stress is elicited by experimental manipulation of maternal responsiveness (i.e., Still-Face episode). A double-exposure FFSF with two Still-Face episodes was used to evaluate both behavioral response and HPA axis reactivity. Negative emotionality was 1-s microanalytically coded. Magnitude (i.e., area under the curve, AUC) and Direction (increase vs. decrease) of salivary cortisol post-stress concentration were assessed. COMTval158met genotype was categorized as val-homozygotes and met-carriers. Compared to val-homozygotes, met-carriers showed higher negative emotionality during the second Still-Face episode. AUC was greater in increaser met-carriers compared to val-homozygous infants. In addition, in the presence of an increasing HPA response, the met allele emerged as a specific risk condition in the face of repeated stress exposures. The present findings further extend previous studies conducted with children and adults suggesting that the COMT met allele might be involved in stress regulation during early infancy, especially in response to repeated socio-emotional stress exposure.
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Introduction: The PNPLA2 gene encodes the enzyme adipose triglyceride lipase (ATGL), which catalyzes the first step of triglyceride hydrolysis. Mutations in this gene are associated with an autosomal recessive lipid storage myopathy,... more
Introduction: The PNPLA2 gene encodes the enzyme adipose triglyceride lipase (ATGL), which catalyzes the first step of triglyceride hydrolysis. Mutations in this gene are associated with an autosomal recessive lipid storage myopathy, Neutral Lipid Storage Disease with Myopathy (NLSD-M). Results: A 72-year-old woman had late-onset myopathy, with mild weakness, cramps, and exercise intolerance. EMG showed myotonic discharges. A few leucocytes showed lipid droplets (Jordan anomaly). Deltoid and quadriceps muscle biopsies showed no lipid storage. Genetic analysis of PNPLA2 detected 2 heterozygous mutations, c.497A>G (p.Asp166Gly) in exon 5, and c.1442C>T (p.Pro481Leu) in exon 10. Expression of mutant PNPLA2 plasmids in HeLa cells resulted in impaired enzyme activity, confirming the pathological effects of the mutations. Discussion: In this case of NLSD-M, the myopathy may be due to a metabolic defect rather than to a mechanical effect of lipid storage. This suggests that more than 1 mechanism contributes to muscle damage in NLSD-M. © 2014 Wiley Periodicals, Inc.
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Mutations in the PNPLA2 gene cause the onset of Neutral Lipid Storage Disease with Myopathy (NLSD-M), a rare autosomal recessive disorder characterized by an abnormal accumulation of triacylglycerol into cytoplasmic lipid droplets (LDs).... more
Mutations in the PNPLA2 gene cause the onset of Neutral Lipid Storage Disease with Myopathy (NLSD-M), a rare autosomal recessive disorder characterized by an abnormal accumulation of triacylglycerol into cytoplasmic lipid droplets (LDs). In most tissues the LDs are cellular organelles for the triacylglycerol storage. LDs metabolic functions are mediated by proteins bound to their surface. In particular, the lipase that catalyzes the removal of the first acyl chain from triacylglycerol is the adipose triglyceride lipase (ATGL), also known as patatin-like phospholipase domain-containing protein 2 (PNPLA2). To our best knowledge, twenty six different PNPLA2 mutations have been described in thirty two NLSD-M patients. NLSD-M patients are mainly affected by progressive myopathy, cardiomyopathy and hepatomegaly. However, their clinical severity appears to be highly variable. Other clinical symptoms may include diabetes, chronic pancreatitis and short stature. NLSD-M has, at present, no specific therapy. We have previously reported clinical and genetic findings of some NLSD-M patients obtaining dermal biopsies from them. Here we report the development of hiPSc (human induced pluripotent stem cell) from patients\u2019 fibroblasts harboring different PNPLA2 mutations. The first patient was found to be homozygous for a deletion at nucleotide 542 (c.542delAC). This deletion caused a premature stop codon at position 212. The molecular analysis of patient 2 showed a homozygous missense mutation, c.662G>C (p.R221P). Initial hiPSc colony selection was based on morphologic evaluation and on detection of pluripotency surface markers (SSEA-4 and TRA-1-81). HiPSc also expressed undifferentiated ES cell markers (NANOG, SOX2 and OCT4). Moreover, embryoid bodies (EBs) have been generated from NLSD-M-iPSCs to assess the pluripotent properties of these cells. Karyotypic analysis of hiPSc lines indicated a normal complement of chromosomes. Immunohystochemical evaluations of LDs on hiPSc revealed that they recapitulate pathological hallmark of the disease. We propose use of inherently patients- and disease specific hiPSc to study the pathogenetic mechanisms leading to NLSD-M and as a potential model for therapeutic evaluation
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NLSD-M (Neutral Lipid Storage Disease with Myopathy) is a rare autosomal recessive disorder characterized by an abnormal intracellular accumulation of triacylglycerol into cytoplasmic lipid droplets (LDs). In most tissues the lipid... more
NLSD-M (Neutral Lipid Storage Disease with Myopathy) is a rare autosomal recessive disorder characterized by an abnormal intracellular accumulation of triacylglycerol into cytoplasmic lipid droplets (LDs). In most tissues the lipid droplets (LDs) are cellular organelles for the triacylglycerol storage. LDs metabolic functions are mediated by proteins bound to their surface. In particular, the lipase that catalyzes the removal of the first acyl chain from triacylglycerol is the patatin-like phospholipase domain-containing protein 2 (PNPLA2). This protein is coded by the PNPLA2 gene whose mutations cause the onset of Neutral Lipid Storage Disease with Myopathy. NLSD-M patients are affected by progressive myopathy, cardiomyopathy and hepatomegaly. Other clinical symptoms may include diabetes, chronic pancreatitis and short stature. NLSD-M has, at present, no specific therapy. We have previously reported clinical and genetic findings of some NLSD-M patients obtaining dermal biopsies from them. Here we report the development of hiPSc (human induced pluripotent stem cell) from patients\u2019 fibroblasts harboring different PNPLA2 mutations. Initial hiPSc colony selection was based on morphologic evaluation and on detection of pluripotency surface markers (SSEA-4 and TRA-1-81). HiPSc also expressed undifferentiated ES cell markers (NANOG, SOX2 and OCT4). Karyotypic analysis of hiPSc lines indicated a normal complement of chromosomes. Immunohystochemical evaluations of LDs on hiPSc revealed that they recapitulate pathological hallmark of the disease. We propose use of differentiated cells derived from hiPSc to study the pathogenetic mechanisms leading to NLSD-M and as a cellular model for therapeutic evaluation
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The "Galliera Genetic Bank" (GGB) was established in 1983 as a section of the Laboratory of Human Genetics - Galliera Hospital in Genoa. Since then, samples from subjects affected by genetic disorders (and their relatives), or... more
The "Galliera Genetic Bank" (GGB) was established in 1983 as a section of the Laboratory of Human Genetics - Galliera Hospital in Genoa. Since then, samples from subjects affected by genetic disorders (and their relatives), or affected by rare diseases, have been collected and stored. The biobank takes advantage of the activity of the laboratory, skilled in pre-natal and post-natal diagnosis of chromosomal and genic disorders and exploits the lab technologies and staff experience to collect samples well characterized by cytogenetic and/or molecular analyses. Since 2008, the biobank is part of the Telethon Network of Biobanks and collaborating with the research infrastructures BBMRI Biobanking and Biomolecular Resources Research Infrastructure (www.bbmri.eu) and in 2011 it has become a new partner of EUROBIOBANK (European Network of DNA, Cell and Tissue banks for Rare Diseases - http://www.eurobiobank.org/). The expertise of the biobank was the staring point to the new activity of Generating disease-specific induced pluripotent Stem Cells (iPSCs) for genetic disease modelling. The example reported is related the Neutral Lipid Storage Disease with Myopathy (NLSD-M) that is a rare autosomal recessive disorder characterized by an abnormal intracellular accumulation of triacylglycerol into cytoplasmic lipid droplets (LDs). In most tissues the lipid droplets (LDs) are cellular organelles for the triacylglycerol storage. LDs metabolic functions are mediated by proteins bound to their surface. In particular, the lipase that catalyzes the removal of the first acyl chain from triacylglycerol is the patatin-like phospholipase domain-containing protein 2 (PNPLA2). This protein is coded by the PNPLA2 gene. PNPLA2 mutations cause the onset of Neutral Lipid Storage Disease with Myopathy. NLSD-M patients are affected by progressive myopathy, cardiomyopathy and hepatomegaly. Other clinical symptoms may include diabetes, chronic pancreatitis and short stature. NLSD-M has, at present, no specific therapy. We have previously reported clinical and genetic findings of some NLSD-M patients and have obtained dermal biopsies from them. Here we report the development of hiPSc (human induced pluripotent stem cell) from patients\u2019 fibroblasts harboring different PNPLA2 mutations. Initial hiPSc colony selection was based on morphologic evaluation and on detection of pluripotency surface markers (SSEA-4 and TRA-1-81). HiPSc also expressed undifferentiated ES cell markers (NANOG, SOX2 and OCT4). Karyotypic analysis of hiPSc lines indicated a normal complement of chromosomes. Immunohystochemical evaluations of LDs on hiPSc revealed that they recapitulate pathological hallmark of the disease. We propose use of differentiated cells derived from hiPSc to study the pathogenetic mechanisms leading to NLSD-M and as a cellular model for therapeutic evaluation
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OBJECTIVE: To describe a family were there is evidence of two compound heterozygous PNLPA2 gene mutations and a new clinical phenotype. BACKGROUND: The lack of adipose triglyceride lipase (ATGL), a patatin-like phospholipase containing... more
OBJECTIVE: To describe a family were there is evidence of two compound heterozygous PNLPA2 gene mutations and a new clinical phenotype. BACKGROUND: The lack of adipose triglyceride lipase (ATGL), a patatin-like phospholipase containing enzyme that hydrolyzes fatty acids from triacylglycerol stored in multiple tissues, causes an autosomal disorder Neutral Lipid Storage Disease with Myopathy (NLSD-M). A hallmark of the disease is a lipid storage in muscle with vacuolated leukocytes (Jordan9s anomaly). RESULTS: Two brothers presented asymmetric distal atrophy. The first brother at age 40 had muscle atrophy in right upper arm, spreading to the other arm, paravertebral and extensor head muscle. He underwent surgery for an abdominal mass (teratoma). The muscle weakness, which started in upper R arm, spread to lower extremites with Gowers and stepping gait, inability to raise arms in horizontal position. At age 60 the patient walked with a cane and could not lift arms. The second brother at age 49 had distal leg muscle weakness and fatigability, than presented atrophy at R calf, and in the following years in controlateral leg. Muscle biopsy showed lipid storage in both siblings with evident Jordan9s anomaly, and were studied for vacuoles and atrophy of muscle fibers. Two unaffected sisters had type II diabetes. Genomic DNA showed heterozygous c.167T>G (p.L56R) and c.577A>T (p.I193F) mutations in the PNPLA2 gene, which were identified for the first time. Cultured fibroblasts showed multiple droplets and were studied for faty acid accumulation. CONCLUSIONS: Clinical evidence of asymmetric distal myopathy with onset either in upper arm or in calves is a novel feature in this genetic disorder. There was no cardiomyopathy, that is a feature of juvenile cases. Treatment with diet and beta-agonists or alternatively therapy with bezafibrate might be tried in NLSD-M cases. Such therapy needs a preliminary validation in cell model of the disease. Study Supported by: AFM Disclosure: Dr. Angelini has received personal compensation for activities with Genzyme Corporation as an advisory board member. Dr. Tavian has nothing to disclose. Dr. Tasca has nothing to disclose. Dr. Missaglia has nothing to disclose.
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We describe an image analysis (IA) system that has been applied for the quantitative evaluation of mRNAs evidenced by in situ hybridization (ISH) with radiolabelled probes in cultured cells and in tissue sections. The ISH-IA method was... more
We describe an image analysis (IA) system that has been applied for the quantitative evaluation of mRNAs evidenced by in situ hybridization (ISH) with radiolabelled probes in cultured cells and in tissue sections. The ISH-IA method was used for the evaluation of cultured cell morphological parameters such as cell and nucleous area (CA and NA, respectively) in parallel with the levels of mRNAs detected as hybridization grains areas (GA). The evaluation of these parameters, together with the analysis of the levels of mRNAs (c-jun, cyclin A) specific for given cell cycle phases (i.e. G1 and S/G2), allowed the identification, in asynchronous cultures of human skin fibroblasts, of cells in G1 and S/G2 phases. The mRNA levels measured by ISH-AI were comparable with those detected by RT-PCR. This method was also applied for the analysis of fibronectin (FN) gene expression in control skin fibroblasts in relationship with the different phases of the cell cycle and in comparison with a tumor cell line (Sk-Hep1), heterogeneous either for morphometric parameters or for the levels of this transcript. Finally, the ISH-AI was applied for the semiquantitative evaluation of the expression, localization and alternative splicing pattern of FN mRNA in normal liver and in hepatocellular carcinoma (HCC) tissue sections.
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Expression of plasminogen activators (PAs) and urokinase-type PA receptor (u-PAR) is associated with tumor growth and invasion. For in vivo human tumor tissues, there is no information on gene expression of PAs in hepatocellular carcinoma... more
Expression of plasminogen activators (PAs) and urokinase-type PA receptor (u-PAR) is associated with tumor growth and invasion. For in vivo human tumor tissues, there is no information on gene expression of PAs in hepatocellular carcinoma (HCC) or other hepatic pathophysiological conditions. In this study we examined the relative levels of u-PA, tissue-type PA (t-PA), and u-PAR mRNA expression in human HCC by reverse transcription-PCR compared with those expressed in peritumoral hepatic tissues. Twenty-five of 25 HCCs expressed u-PA mRNA, as well as 16 of 25 hepatic peritumoral tissues. However, none of the 14 cases of nontumorous liver samples (i.e., normal parenchyma, steatosis, and nonspecific reactive and chronic hepatitis) showed detectable levels of u-PA mRNA. The same samples analyzed for uPAR and t-PA mRNAs exhibited higher levels of these mRNAs in the malignant tissues compared with nontumorous ones. A strong correlation was found between the relative levels of u-PA and t-PA mRNAs detected in the tumor and in the corresponding peritumoral tissues (P < 0.001 for u-PA; P < 0.02 for t-PA). However, there was no correlation between the expression of u-PA and t-PA in HCC (P = 0.565). Furthermore, a significant inverse correlation was found between survival months of male patients and the relative level of u-PA mRNA (P < 0.05) detected at the time of biopsy, whereas no correlation was found in the case of t-PA mRNA. These results are in line with the possible differential biological role of u-PA and t-PA in the tumor etiopathogenesis and suggest that the detection of relative levels of u-PA mRNA may be a useful prognostic factor for male HCC patients.
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Research Interests: Engineering, Physics, Chemistry, Biology, Cell Biology, and 15 moreMedicine, Multidisciplinary, Protein Stability, Cell line, Humans, Phosphorylation, Mitogen Activated Protein Kinase, PLoS one, Mg, Epidermal Growth Factor, Protein Expression, Growth Factor, Egr, Gene Expression Regulation, and PROTEASOME INHIBITOR
Mutations in the PNPLA2 gene cause the onset of Neutral Lipid Storage Disease with Myopathy (NLSD-M), a rare autosomal recessive disorder characterized by an abnormal accumulation of triacylglycerol into cytoplasmic lipid droplets (LDs).... more
Mutations in the PNPLA2 gene cause the onset of Neutral Lipid Storage Disease with Myopathy (NLSD-M), a rare autosomal recessive disorder characterized by an abnormal accumulation of triacylglycerol into cytoplasmic lipid droplets (LDs). PNPLA2 codes for adipose triglyceride lipase (ATGL), an enzyme that hydrolyses fatty acids from triacylglycerol. NLSD-M patients are mainly affected by progressive myopathy, cardiomyopathy and hepatomegaly. However, their clinical severity appears to be highly variable. Here we report the clinical and genetic findings of a NLSD-M Italian family with different affected members. In our patients we identified two novel PNPLA2 missense mutations (pL56R and pI193F). All three patients had Jordan's anomaly and lipid storage in cultured fibroblasts and in muscle biopsy. Molecular and functional analysis of PNPLA2 mutations is useful to explain the variation of clinical expression of this syndrome and it might improve prognosis. This is a very interesting family since it shows heterogeneity of clinical presentation from relatively asymptomatic phenotype to full expression of a severe myopathy
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Research Interests: Molecular Biology, Biotechnology, Cancer, Biology, Cancer Research, and 15 moreMedicine, Cell Culture, Cell Division, Cell line, Humans, Hepatocellular Carcinoma, Cancer Gene Therapy, Fluorescent Antibody Technique, Enzymatic Activity, Antisense RNA, Gene Transfer, Immunoblotting, Genetic Therapy, Liver neoplasms, and mRNA expression
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Metabolic myopathies are characterized by the dysfunction of several metabolic pathways that results in a deficiency of fuels required to generate energy for muscle contractions [...]
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Background In the last decades, the concept of metabolic rewiring as a cancer hallmark has been expanded beyond the “Warburg effect” and the importance of other metabolic routes, including lipid metabolism, has emerged. In cancer, lipids... more
Background In the last decades, the concept of metabolic rewiring as a cancer hallmark has been expanded beyond the “Warburg effect” and the importance of other metabolic routes, including lipid metabolism, has emerged. In cancer, lipids are not only a source of energy but are also required for the formation of membranes building blocks, signaling and post-translational modification of proteins. Since lipid metabolism contributes to the malignancy of cancer cells, it is an attractive target for therapeutic strategies. Methods Over-expression of the adipose triglyceride lipase (ATGL) was used to boost lipid catabolism in cervical cancer cells. The cervical cancer cell line HeLa was employed as the primary experimental model for all subsequent studies. The lipolytic activity of ATGL was mimicked by caproate, a short-chain fatty acid that is efficiently oxidized in mitochondria. Results Here, we provide evidence of the association between boosted lipid catabolism and the increased prol...
Research Interests: Chemistry, Cell Biology, Medicine, Lipid metabolism, Cancer Cell, and 3 moreMitophagy, ATGL, and Catabolism
Lipid storage myopathies (LSMs) are metabolic disorders of the utilization of fat in muscles due to several different defects. In this review, a molecular update of LSMs is presented and recent attempts of finding treatment options are... more
Lipid storage myopathies (LSMs) are metabolic disorders of the utilization of fat in muscles due to several different defects. In this review, a molecular update of LSMs is presented and recent attempts of finding treatment options are discussed. The main topics discussed are: primary carnitine deficiency, riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency, neutral lipid storage disorders and carnitine palmitoyl transferase deficiency. The most frequent presentations and genetic abnormalities are summarized. We present their diagnosis utilizing biomedical and morphological biomarkers and possible therapeutic interventions. The treatment of these metabolic disorders is a subject of active translational research but appears, in some cases, still elusive.
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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... more
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 X...
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Phone +39 338 1575745 EJTM WebSite http://pagepressjournals.org/index.php/bam/index eISSN 2037-7460 ISSN 2037-7452 BAM On-Line http://www.bio.unipd.it/bam/bam.html
Research Interests: Immunology, Reprogramming, Stem Cell, Biological Sciences, Humans, and 13 moreFemale, Animals, Skin, Haematopoiesis, CD, Induced Pluripotent Stem Cells, Teratoma, Paroxysmal Nocturnal Hemoglobinuria, Hematopoietic Stem Cell Transplantation, fibroblasts, Medical and Health Sciences, Cardiovascular medicine and haematology, and embryoid bodies
OBJECTIVE: To describe a family were there is evidence of two compound heterozygous PNLPA2 gene mutations and a new clinical phenotype. BACKGROUND: The lack of adipose triglyceride lipase (ATGL), a patatin-like phospholipase containing... more
OBJECTIVE: To describe a family were there is evidence of two compound heterozygous PNLPA2 gene mutations and a new clinical phenotype. BACKGROUND: The lack of adipose triglyceride lipase (ATGL), a patatin-like phospholipase containing enzyme that hydrolyzes fatty acids from triacylglycerol stored in multiple tissues, causes an autosomal disorder Neutral Lipid Storage Disease with Myopathy (NLSD-M). A hallmark of the disease is a lipid storage in muscle with vacuolated leukocytes (Jordan9s anomaly). RESULTS: Two brothers presented asymmetric distal atrophy. The first brother at age 40 had muscle atrophy in right upper arm, spreading to the other arm, paravertebral and extensor head muscle. He underwent surgery for an abdominal mass (teratoma). The muscle weakness, which started in upper R arm, spread to lower extremites with Gowers and stepping gait, inability to raise arms in horizontal position. At age 60 the patient walked with a cane and could not lift arms. The second brother at age 49 had distal leg muscle weakness and fatigability, than presented atrophy at R calf, and in the following years in controlateral leg. Muscle biopsy showed lipid storage in both siblings with evident Jordan9s anomaly, and were studied for vacuoles and atrophy of muscle fibers. Two unaffected sisters had type II diabetes. Genomic DNA showed heterozygous c.167T>G (p.L56R) and c.577A>T (p.I193F) mutations in the PNPLA2 gene, which were identified for the first time. Cultured fibroblasts showed multiple droplets and were studied for faty acid accumulation. CONCLUSIONS: Clinical evidence of asymmetric distal myopathy with onset either in upper arm or in calves is a novel feature in this genetic disorder. There was no cardiomyopathy, that is a feature of juvenile cases. Treatment with diet and beta-agonists or alternatively therapy with bezafibrate might be tried in NLSD-M cases. Such therapy needs a preliminary validation in cell model of the disease. Study Supported by: AFM Disclosure: Dr. Angelini has received personal compensation for activities with Genzyme Corporation as an advisory board member. Dr. Tavian has nothing to disclose. Dr. Tasca has nothing to disclose. Dr. Missaglia has nothing to disclose.