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Laryngo- Rhino- Otologie Apr 2021Rare diseases represent a major challenge for affected patients, their relatives, physicians, nursing staff, and therapists. For medical and economic reasons, disease...
Rare diseases represent a major challenge for affected patients, their relatives, physicians, nursing staff, and therapists. For medical and economic reasons, disease rarity complicates the research and medical care of affected patients. The Hollywood movie, "Lorenzo's Oil", touchingly illustrates the complex problems associated with orphan disease diagnostics, research, and therapy. Directed by George Miller, this film shows the true story of a boy named Lorenzo Michael Murphy Odone, who was diagnosed in 1984 at the age of 6 with the rare neural disease adrenoleukodystrophy (ALD). The movie highlights the manifold problems associated with rare diseases - a large number of which still exist today. However, especially in recent years, orphan diseases have been placed in the focus of public attention.
Topics: Adrenoleukodystrophy; Drug Combinations; Humans; Male
PubMed: 34352897
DOI: 10.1055/s-1397-0832 -
Dementia & Neuropsychologia 2020Although the traditional method of teaching is still the most popular nowadays, the use of different methodologies such as play approaches, for instance, could be used...
Although the traditional method of teaching is still the most popular nowadays, the use of different methodologies such as play approaches, for instance, could be used to make the teaching-learning process a more active approach. Nonetheless, the use of films that represent true stories are more pertinent in active teaching, especially those directly associated with a specific field and that are not merely dramatic. Lorenzo's oil can inform students about many biological topics and problems linked to intensive care. Furthermore, it also addresses the impact of a neurological disease in a social environment and promotes an intrinsic discussion about sciences in general. Given the above, we propose the hypothesis that the film is useful for educational purposes in health, specifically neuroscience. Lorenzo's Oil seems to be a good option for the use of a new approach in health science education. The richness of medical topics linked to modern aspects, such as nutrition for patients with mental disorders and palliative care combined with spirituality aspects, promotes an important discussion and constitutes a less stressing learning activity for students. Although some papers cite the importance of the movie for genetics and other fields, this paper shows the importance of efforts to address these topics using a more modern educational approach. According to the results presented, Lorenzo's Oil could be used extensively for medical/health sciences, confirming the initial hypothesis.
PubMed: 32206192
DOI: 10.1590/1980-57642020dn14-010002 -
JIMD Reports 2018Lorenzo's oil is known to decrease the saturated very long chain fatty acid (VLCFA) level in the plasma and skin fibroblasts of X-linked adrenoleukodystrophy (ALD)...
Lorenzo's oil is known to decrease the saturated very long chain fatty acid (VLCFA) level in the plasma and skin fibroblasts of X-linked adrenoleukodystrophy (ALD) patients. However, the involvement of Lorenzo's oil in in vivo fatty acid metabolism has not been well elucidated. To investigate the effect of Lorenzo's oil on fatty acid metabolism, we analyzed the hepatic gene expression together with the serum fatty acid level in Lorenzo's oil-treated wild-type and abcd1-deficient mice. The change in the serum fatty acid level in Lorenzo's oil-treated abcd1-defcient mice was quite similar to that in the plasma fatty acid level in ALD patients supplemented with Lorenzo's oil. In addition, we found that the hepatic gene expression of two peroxisomal enzymes, Dbp and Scp2, and three microsomal enzymes, Elovl1, 2, and 3, were significantly stimulated by Lorenzo's oil. Our findings indicate that Lorenzo's oil activates hepatic peroxisomal fatty acid β-oxidation at the transcriptional level. In contrast, the transcriptional stimulation of Elovl1, 2, and 3 by Lorenzo's oil does not cause changes in the serum fatty acid level. It seems likely that the inhibition of these elongation activities by Lorenzo's oil results in a decrease in saturated VLCFA. Thus, these results not only contribute to a clarification of the mechanism by which the saturated VLCFA level is reduced in the serum of ALD patients by Lorenzo's oil-treatment, but also suggest the development of a new therapeutic approach to peroxisomal β-oxidation enzyme deficiency, especially mild phenotype of DBP deficiency.
PubMed: 28560570
DOI: 10.1007/8904_2017_32 -
Journal of Lipid Research Mar 2014X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder caused by impaired degradation of very long-chain fatty acids (VLCFAs) due to mutations in the ABCD1 gene...
X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder caused by impaired degradation of very long-chain fatty acids (VLCFAs) due to mutations in the ABCD1 gene responsible for VLCFA transport into peroxisomes. Lorenzo's oil, a 4:1 mixture of glyceryl trioleate and glyceryl trierucate, has been used to reduce the saturated VLCFA level in the plasma of X-ALD patients; however, the mechanism by which this occurs remains elusive. We report the biochemical characterization of Lorenzo's oil activity toward elongation of very long-chain fatty acid (ELOVL) 1, the primary enzyme responsible for the synthesis of saturated and monounsaturated VLCFAs. Oleic and erucic acids inhibited ELOVL1, and, moreover, their 4:1 mixture (the FA composition of Lorenzo's oil) exhibited the most potent inhibitory activity. The kinetics analysis revealed that this was a mixed (not a competitive) inhibition. At the cellular level, treatment with the 4:1 mixture reduced the level of SM with a saturated VLCFA accompanied by an increased level of SM with a monounsaturated VLCFA, probably due to the incorporation of erucic acid into the FA elongation cycle. These results suggest that inhibition of ELOVL1 may be an underlying mechanism by which Lorenzo's oil exerts its action.
Topics: Acetyltransferases; Dose-Response Relationship, Drug; Drug Combinations; Erucic Acids; Fatty Acid Elongases; Fatty Acids; Gene Expression Regulation, Enzymologic; HEK293 Cells; HeLa Cells; Humans; Immunoblotting; Kinetics; Oleic Acid; Palmitic Acid; Reverse Transcriptase Polymerase Chain Reaction; Sphingomyelins; Stearic Acids; Triolein
PubMed: 24489110
DOI: 10.1194/jlr.M044586 -
Journal of Neurology, Neurosurgery, and... Sep 1999
Topics: Adrenoleukodystrophy; Dietary Fats, Unsaturated; Drug Combinations; Erucic Acids; Humans; Triolein; X Chromosome
PubMed: 10449544
DOI: 10.1136/jnnp.67.3.279 -
Expert Review of Neurotherapeutics Sep 2008X-linked adrenoleukodystrophy (X-ALD; OMIM #300100) is caused by defects of the ABCD1 gene on chromosome Xq28, resulting in an impairment of peroxisomal beta-oxidation... (Review)
Review
X-linked adrenoleukodystrophy (X-ALD; OMIM #300100) is caused by defects of the ABCD1 gene on chromosome Xq28, resulting in an impairment of peroxisomal beta-oxidation and the accumulation of saturated very long chain fatty acids (VLCFAs). Primary manifestations occur in the CNS, the adrenal cortex and the testes' Leydig cells. The clinical presentation shows a marked variability which is not explained by the different X-ALD genotypes. Phenotypes range from rapidly progressive cerebral disease with childhood (childhood cerebral ALD [CCALD]) or adulthood (adult cerebral ALD [ACALD]) onset leading to death within a few years, over adult-onset adrenomyeloneuropathy (AMN) with or without focal CNS demyelination, AMN converting into a rapidly progressive, cerebral demyelinating phenotype resembling CCALD, to slow disease progression over decades, or adrenal insufficiency only. Approximately 50% of female heterozygotes develop moderate spastic paresis resembling the AMN phenotype. This review focuses on current experiences with different therapeutic approaches. Lorenzo's oil did not prove to be effective in cerebral inflammatory disease variants, but asymptomatic patients, and speculatively AMN variants without cerebral involvement, as well as female carriers may benefit from early intake of oleic and erucic acids in addition to VLCFA restriction. Hormone-replacement therapy is necessary in all patients with adrenal insufficiency. Hematopoietic stem cell transplantation has been reported to be effective in presymptomatic or early symptomatic CCALD, and may well also be a final therapeutic option in early ACALD patients. Early detection of mutation carriers and timely initiation of therapy is important for the effectiveness of all therapeutic efforts. Gene therapy of endogenous hematopoietic stem cells, pharmacological upregulation of other genes encoding proteins involved in peroxisomal beta-oxidation, reduction of oxidative stress, and possibly lovastatin are candidates for future X-ALD therapies.
Topics: Adrenoleukodystrophy; Animals; Clinical Trials as Topic; Drug Combinations; Erucic Acids; Glucocorticoids; Hematopoietic Stem Cell Transplantation; Humans; Triolein
PubMed: 18759549
DOI: 10.1586/14737175.8.9.1367 -
ENeurologicalSci Mar 2019Our objective is to review the initial presentation, evolution, progression, final stage, and images in the follow up of an adult patient who presented an uncommon... (Review)
Review
Our objective is to review the initial presentation, evolution, progression, final stage, and images in the follow up of an adult patient who presented an uncommon peroxisomal disease (1/20,000 males) that occurred by gene mutation in the Xq28 chromosome; to bring forward the imaging features (which nowadays is the most useful and accessible diagnostic tool) and clinical presentation of adrenoleukodystrophy in adulthood; to propose a differential diagnosis in aid of a prompt recognition of the disease hereafter from a neurologist approach. In relation of a clinical case we reviewed the literature to correlate the principal findings and evolution of the disease. This thrilling but at the same time unfortunate disease is not only a diagnostic problem is also a therapeutic quest besides all the related familial, labor, and social related problems. The very-long chain fatty acids (VLCFA) accumulation leads to a not completely understood mechanisms that precipitate the specific malfunction of the nervous system and adrenal gland. The initial corticospinal bilateral involvement provokes a spastic paraparesis but with the affection of others pathways multiple manifestations appears, with dementia and finally loss of the most of cortical functions secondary to the white matter affection. Since the hematopoietic stem cell transplantation can be treated with variable results, other treatments, as the Lorenzo's oil, have not been consistent with a substantial improvement of the affected individual. The genetic advice and support to the patient and the family are essentials as well as the screening in individuals at risk before the onset of the disease.
PubMed: 30671550
DOI: 10.1016/j.ensci.2019.01.007 -
A two-year trial of oleic and erucic acids ("Lorenzo's oil") as treatment for adrenomyeloneuropathy.The New England Journal of Medicine Sep 1993Adrenomyeloneuropathy is an X-linked recessive disorder characterized by myelopathy, peripheral neuropathy, and cerebral demyelination, which develop in association with... (Clinical Trial)
Clinical Trial
BACKGROUND
Adrenomyeloneuropathy is an X-linked recessive disorder characterized by myelopathy, peripheral neuropathy, and cerebral demyelination, which develop in association with the accumulation of very-long-chain fatty acids. The administration of oleic and erucic acids inhibits the synthesis of very-long-chain fatty acids. Recently such dietary treatment has been widely publicized as a possible cure for this disease.
METHODS
We conducted an open trial in 14 men with adrenomyeloneuropathy, 5 symptomatic heterozygous women, and 5 boys (mean age, 13 years) with preclinical adrenomyeloneuropathy. The patients ate a low-fat diet and received daily doses of glycerol trioleate oil (1.7 g per kilogram of body weight) and glycerol trierucate oil (0.3 g per kilogram). Clinical manifestations, cerebral and spinal cord magnetic resonance imaging (MRI) scans, nerve conduction, and brain-stem auditory and somatosensory evoked potentials were studied prospectively over 18 to 48 months. Plasma levels of very-long-chain fatty acids and the side effects of erucic acid were monitored monthly.
RESULTS
By week 10, plasma very-long-chain fatty acid levels declined nearly to normal. Nonetheless, over a mean follow-up of 33 months none of the 14 men with adrenomyeloneuropathy improved. In nine men there was functional deterioration, coincident in four with new cerebral lesions on MRI. In a single patient there was a reduction in cerebellar demyelination, but without clinical improvement. In one of the five asymptomatic boys signs of myelopathy developed. There were no changes in the symptomatic heterozygous women. There was some improvement in peroneal-nerve conduction, but no detectable clinical improvement. Conduction to the parietal cortex (T12-P37 interpeak latency) worsened in both the symptomatic men and the boys with preclinical adrenomyeloneuropathy. There was no change in other somatosensory evoked potentials or in brain-stem auditory evoked potentials. Asymptomatic thrombocytopenia (< 100,000 cells per cubic millimeter) was noted in six patients.
CONCLUSIONS
In this open trial we found no evidence of a clinically relevant benefit from dietary treatment with oleic and erucic acids ("Lorenzo's oil") in patients with adrenomyeloneuropathy.
Topics: Adolescent; Adrenoleukodystrophy; Adult; Brain; Child; Dietary Fats, Unsaturated; Drug Combinations; Electrophysiology; Erucic Acids; Fatty Acids; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Oleic Acids; Triolein
PubMed: 8350883
DOI: 10.1056/NEJM199309093291101 -
Molecular Genetics and Metabolism Nov 2021Peroxisome Biogenesis Disorders-Zellweger spectrum disorder (PBD-ZSD) is a rare, autosomal recessive peroxisome biogenesis disorder that presents with variable symptoms.... (Review)
Review
Peroxisome Biogenesis Disorders-Zellweger spectrum disorder (PBD-ZSD) is a rare, autosomal recessive peroxisome biogenesis disorder that presents with variable symptoms. In patients with PBD-ZSD, pathogenic variants in the PEX family of genes disrupt normal peroxisomal function, impairing α- and β-oxidation of very-long-chain fatty acids and synthesis of bile acids, resulting in increased levels of toxic bile acid intermediates and multisystem organ damage. The spectrum of severity in PBD-ZSD is variable, with some patients dying in the first year of life, while others live into adulthood. Symptoms of mild PBD-ZSD include various combinations of developmental delay, craniofacial dysmorphic features, visual impairment, sensorineural hearing loss, liver disease, and adrenal insufficiency. Disease progression in mild PBD-ZSD is generally slow, and may include extended periods of stability in some cases. The presence and extent to which symptoms occur in mild PBD-ZSD represents a diagnostic challenge that can cause delays in diagnosis with potential significant implications related to disease monitoring and treatment. There is some support for the pharmacologic therapies of Lorenzo's oil, docosohexanoic acid, and batyl alcohol in altering symptoms; however, systematic long-term studies are lacking. Cholic acid (CA) therapy has demonstrated treatment efficacy in patients with PBD-ZSD, including decreased toxic bile acid intermediates, transaminase levels, and liver inflammation, with improvement in growth parameters. However, these responses are most apparent in patients diagnosed and treated at a young age. Advanced liver disease may limit the efficacy of CA, underscoring the need to diagnose and treat these patients before significant liver damage and other related complications occur. Here we discuss the signs and symptoms of PBD-ZSD in patients with mild disease, standard diagnostic tools, factors affecting disease management, and available pharmacological interventions.
Topics: Adult; Clinical Trials as Topic; Disease Management; Humans; Longitudinal Studies; Phenotype; Zellweger Syndrome
PubMed: 34625341
DOI: 10.1016/j.ymgme.2021.09.007