1,721,042 research outputs found
Heterogeneous Phenotypes in Lipid Storage Myopathy Due to ETFDH Gene Mutations.
Full text linkWe present six novel patients affected by lipid storage myopathy (LSM) presenting mutations in the ETFDH gene. Although the diagnosis of multiple acyl-coenzyme-A dehydrogenase deficiency (MADD) in adult life is difficult, it is rewarding because of the possibility of treating patients with carnitine or riboflavin, leading to a full recovery. In our patients, a combination of precipitating risk factors including previous anorexia, alcoholism, poor nutrition, and pregnancy contributed to a metabolic critical condition that precipitated the catabolic state. In the present series of cases, five novel mutations have been identified in the ETFDH gene. We propose clinical guidelines to screen patients with LSM due to different defects, in order to obtain a fast diagnosis and offer appropriate treatment. In such patients, early diagnosis and treatment as well as avoiding risk factors are part of clinical management. Specific biochemical studies are indicated to identify the type of LSM, such as level of free carnitine and acyl-carnitines and studies or organic acidemia. Indeed, when a patient is biochemically diagnosed with secondary carnitine deficiency, a follow-up with appropriate clinical-molecular protocol and genetic analysis is important to establish the final diagnosis, since riboflavin can be supplemented with benefit if riboflavin-responsive MADD is present. In muscle biopsies, increased lipophagy associated with p62-positive aggregates was observed. The clinical improvement can be attributed to the removal of an autophagic block, which appears to be reversible in this LSM
Neutral lipid storage disease with myopathy: A 10-year follow-up case report
Full text linkMutations 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 © 2022 PAGEPress Publications. All rights reserved
Novel mutations in the PNPLA2 gene causing late one-set of neutral lipid storage disease with myopathy in an Italian family
No full textNeutral Lipid Storage Disease with Myopathy (NLSDM), is a rare autosomal recessive disorder characterized by an abnormal accumulation of triacylglycerol into cytoplasmic lipid droplets (LDs). Mutations in the PNPLA2 gene cause the onset of NLSDM. PNPLA2 codes for adipose triglyceride lipase (ATGL), an enzyme that hydrolyses fatty acids from triacylglycerol. NLSDM patients are mainly affected by progressive myopathy, cardiomyopathy and hepatomegaly. Other clinical symptoms may include diabetes, chronic pancreatitis and short stature. To our best knowledge, twenty six different PNPLA2 mutations have been described in thirty two NLSDM patients. Here we report the clinical and genetic findings of a NLSDM Italian family with different affected members. In our patients we identified two novel PNPLA2 missense mutations (pL56R and pI193F). Since age of 38 years, the oldest brother had weakness and hypotrophy of right upper arm and kyphosis. He is now unable to raise arms in horizontal position (61 years old). The second brother, since 44 years of age, had exercise intolerance, cramps and pain in lower limbs. He currently has a distal amyotrophy. Genetic analysis revealed that also one of the two sisters presents the pL56R and pI193F mutations, but she is still barely symptomatic. Using a functional in vitro assay, we have observed that these mutations caused the production of ATGL proteins with diminish lipase activity, but able to bind to LDs. This is a very interesting family since it shows heterogeneity of clinical presentation from relatively asymptomatic phenotype to full expression of a severe myopathy
Late onset and heterogeneous clinical presentation in three affected members of a NLSDM Italian family
No full textNeutral Lipid Storage Disease with Myopathy (NLSDM), is a rare autosomal recessive disorder characterized by an abnormal accumulation of triacylglycerol into cytoplasmic lipid droplets (LDs). 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). Mutations in the PNPLA2 cause the onset of NLSDM. Patients are mainly affected by progressive myopathy, cardiomyopathy and hepatomegaly. To our best knowledge, 27 different PNPLA2 mutations have been described in 41 NLSDM patients. Here we report the clinical and genetic findings of a NLSDM Italian family with three affected siblings. In our patients we identified two novel PNPLA2 missense mutations. Since age of 38 years, the oldest brother had weakness and hypotrophy of right upper arm and kyphosis. He is now unable to raise arms in horizontal position (61 years old). The second brother, since 44 years of age, had exercise intolerance, cramps and pain in lower limbs. He currently has a distal amyotrophy. Genetic analysis revealed that also one of the two sisters presents the PNPLA2 mutations, but she is still barely symptomatic. Using a functional in vitro assay, we have observed that these mutations caused the production of ATGL proteins with diminish lipase activity, but able to bind to LDs. This is a very interesting family since it shows heterogeneity of clinical presentation from relatively asymptomatic phenotype to full expression of a severe myopathy
Producing hiPS cells for disease modeling of NLSD-M
No full textNLSD-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’ 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
A late-onset case of neutral lipid storage disease with myopathy, dropped head syndrome, and peripheral nerve involvement
No full textNeutral lipid storage disease with myopathy (NLSDM) is a rare autosomal recessive disorder of neutral lipid metabolism. Clinical manifestations include progressive skeletal myopathy, cardiomyopathy, and liver dysfunction. Clinical severity is variable and additional symptoms may include diabetes mellitus, chronic pancreatitis, hypothyroidism, neurosensory hearing loss, and short stature. We report a 79-year-old man with progressive proximal arm weakness, lipid storage myopathy, dropped head syndrome, and peripheral nervous system involvement. He harboured a novel homozygous missense mutation, c.570A>C (p.S191R) in the PNPLA2 gene, confirming the diagnosis of NLSDM. The S191R mutation causes late-onset NLSDM without cardiac dysfunction. The previously unreported association with dropped head syndrome expands the clinical spectrum of NLSDM
Neutral Lipid Storage Disease with Myopathy: disease modeling using patients’ hiPSc
No full textMutations 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’ 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
A myopathy with unusual features caused by PNPLA2 gene mutations
No full textIntroduction: 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. Electromyography showed myotonic discharges. A few leukocytes 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. Conclusions: 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
Generating disease-specific induced pluripotent Stem Cells (iPSCs) in a Biobank facility for genetic disease modelling: the example of Neutral Lipid Storage Disease with Myopathy
No full textThe "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’ 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
Stem cell function, self-reneval, heterogeneity, and regenerative potential in skeletal muscle stem cells
No full textAbstract: The main living element of the human body is the skeletal muscle. It is composed of myofibres and satellite
cells, the adult stem cells responsible for skeletal muscle regeneration. Increasing confirmation suggests that satellite cells
represent a heterogeneous population of cells with regenerative capacity and plasticity. Recent publications indicate numerous new findings in satellite and stem cells, from their developmental life and role as the main self-renewing myogenic stem cell in the adult skeletal muscle to their loss during aging. The present review is focused on skeletal muscle
stem cells, including their identification, self-renewal ability, heterogeneity, and multilineage differentiation capacity. Finally, we summarize the latest developments, clinical applications and patents in regenerative medicine utilizing skeletal
muscle stem cells
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