- Lipidomic Analysis: From Archaea to Mammals. [Review]
- LLipids 2018 Feb 15
- Lipids are among the most important organic compounds found in all living cells, from primitive archaebacteria to flowering plants or mammalian cells. They form part of cell walls and constitute cell...
Lipids are among the most important organic compounds found in all living cells, from primitive archaebacteria to flowering plants or mammalian cells. They form part of cell walls and constitute cell storage material. Their biosynthesis and metabolism play key roles in faraway topics such as biofuel production (third-generation biofuels produced by microorganisms, e.g. algae) and human diseases such as adrenoleukodystrophy, Zellweger syndrome, or Refsum disease. Current lipidomic analysis requires fast and accurate processing of samples and especially their characterization. Because the number of possible lipids and, more specifically, molecular species of lipids is of the order of hundreds to thousands, it is necessary to process huge amounts of data in a short time. There are two basic approaches to lipidomic analysis: shotgun and liquid chromatography-mass spectometry. Both methods have their pros and cons. This review deals with lipidomics not according to the type of ionization or the lipid classes analyzed but according to the types of samples (organisms) under study. Thus, it is divided into lipidomic analysis of archaebacteria, bacteria, yeast, fungi, algae, plants, and animals.
- GeneReviews® [BOOK]
- BOOKUniversity of Washington, Seattle: Seattle (WA)
- X-linked adrenoleukodystrophy (X-ALD) affects the nervous system white matter and the adrenal cortex. Three main phenotypes are seen in affected males: The childhood cerebral form manifests most comm...
X-linked adrenoleukodystrophy (X-ALD) affects the nervous system white matter and the adrenal cortex. Three main phenotypes are seen in affected males: The childhood cerebral form manifests most commonly between ages four and eight years. It initially resembles attention deficit disorder or hyperactivity; progressive impairment of cognition, behavior, vision, hearing, and motor function follow the initial symptoms and often lead to total disability within six months to two years. Most individuals have impaired adrenocortical function at the time that neurologic disturbances are first noted. Adrenomyeloneuropathy (AMN) manifests most commonly in an individual in his twenties or middle age as progressive stiffness and weakness of the legs, sphincter disturbances, sexual dysfunction, and often, impaired adrenocortical function; all symptoms are progressive over decades. "Addison disease only" presents with primary adrenocortical insufficiency between age two years and adulthood and most commonly by age 7.5 years, without evidence of neurologic abnormality; however, some degree of neurologic disability (most commonly AMN) usually develops by middle age. More than 20% of female carriers develop mild-to-moderate spastic paraparesis in middle age or later. Adrenal function is usually normal.
- Peroxisomal disorders: Improved laboratory diagnosis, new defects and the complicated route to treatment. [Journal Article]
- MCMol Cell Probes 2018 Feb 10
- Peroxisomes catalyze a number of essential metabolic functions of which fatty acid alpha- and beta-oxidation, ether phospholipid biosynthesis, glyoxylate detoxification and bile acid synthesis are th...
Peroxisomes catalyze a number of essential metabolic functions of which fatty acid alpha- and beta-oxidation, ether phospholipid biosynthesis, glyoxylate detoxification and bile acid synthesis are the most important. The key role of peroxisomes in humans is exemplified by the existence of a group of peroxisomal disorders, caused by mutations in > 30 different genes which codes for proteins with a role in either peroxisome biogenesis or one of the metabolic pathways in peroxisomes. Technological advances in laboratory methods at the metabolite-, enzyme-, and molecular level has not only allowed the identification of a new peroxisomal disorder but also new phenotypes associated with already identified genetic defects thus extending the clinical spectrum. Unfortunately, progress in the field of pathogenesis and treatment has lagged behind although there are certainly new and hopeful developments with respect to X-linked adrenoleukodystrophy and hyperoxaluria type 1.
- Gene Therapy for Cerebral Adrenoleukodystrophy. [Letter]
- NEJMN Engl J Med 2018 02 01; 378(5):490
- Transplantation as disease modifying therapy in adults with inherited metabolic disorders. [Review]
- JIJ Inherit Metab Dis 2018 Feb 01
- Transplantation is an established disease modifying therapy in selected children with certain inherited metabolic diseases (IMDs). Transplantation of hematopoietic stem cells or solid organs can be u...
Transplantation is an established disease modifying therapy in selected children with certain inherited metabolic diseases (IMDs). Transplantation of hematopoietic stem cells or solid organs can be used to partially correct the underlying metabolic defect, address life threatening disease manifestations (such as neutropenia) or correct organ failure caused by the disease process. Much less information is available on the use of transplantation in adults with IMDs. Transplantation is indicated for the same IMDs in adults as in children. Despite similar disease specific indications, the actual spectrum of diseases for which transplantation is used differs between these age groups and this is partly related to the natural history of disease. There are diseases (such as urea cycle defects and X-linked adrenoleukodystrophy) for which transplantation is recommended for selected symptomatic patients as a treatment strategy in both adults and children. In those diseases, the frequency with which transplantation is used in adults is lower than in children and this may be related in part to a reduced awareness of transplantation as a treatment strategy amongst adult clinicians as well as limited donor availability and allocation policies which may disadvantage adult patients with IMDs. Risks of transplantation and disease-specific prognostic factors influencing outcomes also differ with age. We review the use of transplantation as a disease modifying strategy in adults focusing on how this differs from use in children to highlight areas for future research.
- Unusual brain images of a boy with adolescent cerebral X-linked adrenoleukodystrophy presenting with exhibitionism: A CARE-compliant case report. [Case Reports]
- MMedicine (Baltimore) 2017; 96(51):e9481
- CONCLUSIONS: We recommend that physicians should not disregard X-ALD in patients with isolated psychiatric symptoms, including hypersexual behavior. The combination of detailed clinical evaluation, MRI, and next generation genetic sequencing can expedite the diagnostic process of atypical variant of X-ALD.
- Childhood cerebral X-linked adrenoleukodystrophy with atypical neuroimaging abnormalities and a novel mutation. [Case Reports]
- JPJ Postgrad Med 2018 Jan-Mar; 64(1):59-63
- Childhood cerebral X-linked adrenoleukodystrophy (XALD) typically manifests with symptoms of adrenocortical insufficiency and a variety of neurocognitive and behavioral abnormalities. A major diagnos...
Childhood cerebral X-linked adrenoleukodystrophy (XALD) typically manifests with symptoms of adrenocortical insufficiency and a variety of neurocognitive and behavioral abnormalities. A major diagnostic clue is the characteristic neuroinflammatory parieto-occipital white matter lesions on magnetic resonance imaging. This study reports a 5-year 10-month old boy presenting with generalized skin hyperpigmentation since 3 years of age. Over the past 9 months, he had developed right-sided hemiparesis and speech and behavioral abnormalities, which had progressed over 5 months to bilateral hemiparesis. Retrospective analyses of serial brain magnetic resonance images revealed an unusual pattern of lesions involving the internal capsules, corticospinal tracts in the midbrain and brainstem, and cerebellar white matter. The clinical diagnosis of childhood cerebral adrenoleukodystrophy was confirmed by elevated basal levels of adrenocorticotropin hormone and plasma very long chain fatty acid levels. Additionally, sequencing of the ABCD1 gene revealed a novel mutation. The only specific palliative therapy that could be offered after diagnosis was dietary intervention. The patient died within 16 months of onset of neurological symptoms. Awareness that childhood cerebral XALD can present with atypical neuroimaging patterns early in its course may aid diagnosis at a stage when definitive treatment can be attempted and timely genetic counseling be offered to the family.
- Clinical Trial of MGMT(P140K) gene therapy in the treatment of paediatric patients with brain tumours. [Journal Article]
- HGHum Gene Ther 2018 Jan 31
- Gene transfer targeting haematopoietic stem cells (HSC) in children has shown sustained therapeutic benefit in the treatment of genetic diseases affecting the immune system, most notably in the sever...
Gene transfer targeting haematopoietic stem cells (HSC) in children has shown sustained therapeutic benefit in the treatment of genetic diseases affecting the immune system, most notably in the severe combined immuno-deficiencies affecting T cell function. The HSC compartment has also been successfully targeted using gene transfer in children with genetic diseases affecting the central nervous system, such as metachromatic leukodystrophy and adrenoleukodystrophy. The HSC is also a target for genetic modification in strategies aiming to confer drug resistance to chemotherapy agents so as to reduce off-target toxicity, and to allow for chemotherapy dose escalation with the possibility of enhanced therapeutic benefit. In a trial of this strategy in adult glioma patients, significant engraftment of gene-modified HSC, expressing a mutant of the DNA repair protein O6- Methyl-Guanine-Methyl-Transferase (MGMT(P140K)) showed potential in conferring drug resistance against the combined effect of O6-Benzylguanine (O6BG) / Temozolomide (TMZ) chemotherapy. Our aim was to test the safety and feasibility of this approach in children with poor prognosis brain tumours. In this Phase I trial, 7 patients received gene-modified HSC following myelo-suppressive conditioning, but with only transient low level engraftment of MGMT(P140K) gene-modified cells detectable in 4 patients. All patients received O6BG/TMZ chemotherapy following infusion of gene-modified cells, with five patients eligible for chemotherapy dose escalation, though in the absence of demonstrable transgene-mediated chemo-protection. Since all gene modified cell products met criteria for release, and assays for engraftment potential met expected outcome measures, we suggest that inadequate cell dose, conditioning chemotherapy and/or underlying bone marrow function may have contributed to the lack of sustained engraftment of gene-modified cells. We were able to demonstrate safe conduct of a technically complex, Phase I study encompassing manufacture of the gene therapy vector, genetically modified cells and a drug product specifically for the trial, in compliance with both local and national regulatory requirements.
- Gene Therapy for Cerebral Adrenoleukodystrophy. [Letter]
- NEJMN Engl J Med 2018 02 01; 378(5):490-491
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- Evaluation of afferent pain pathways in adrenomyeloneuropathic patients. [Journal Article]
- CNClin Neurophysiol 2018; 129(3):507-515
- CONCLUSIONS: The pathologic process of adrenomyeloneuropathy is characterized by a preferential involvement of auditory, motor and somatosensory tracts and less severely of the visual and nociceptive pathways. This non-inflammatory distal axonopathy preferably damages large myelinated spinal tracts but there is also partial involvement of small myelinated fibres.LEPs studies can provide relevant information about afferent pain pathways involvement in adrenomyeloneuropathic patients.