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Annals of the Rheumatic Diseases Aug 2019Different diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)-familial Mediterranean fever (FMF), tumour necrosis factor... (Review)
Review
BACKGROUND
Different diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)-familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)-and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA.
METHODS
Step 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients' diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria.
RESULTS
The panellists achieved consensus to classify 281 of 360 (78%) patients (32 CAPS, 36 FMF, 56 MKD, 37 PFAPA, 39 TRAPS, 81 undefined recurrent fever). Consensus was reached for two sets of criteria for each HRF, one including genetic and clinical variables, the other with clinical variables only, plus new criteria for PFAPA. The four HRF criteria demonstrated sensitivity of 0.94-1 and specificity of 0.95-1; for PFAPA, criteria sensitivity and specificity were 0.97 and 0.93, respectively. Validation of these criteria in an independent data set of 1018 patients shows a high accuracy (from 0.81 to 0.98).
CONCLUSION
Eurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity.
Topics: Consensus; Cross-Sectional Studies; Europe; Familial Mediterranean Fever; Female; Genetic Predisposition to Disease; Hereditary Autoinflammatory Diseases; Humans; Male; Mevalonate Kinase Deficiency; Prevalence; Registries; Risk Assessment; Sensitivity and Specificity
PubMed: 31018962
DOI: 10.1136/annrheumdis-2019-215048 -
Advances in Experimental Medicine and... 2020Peroxisome is an organelle conserved in almost all eukaryotic cells with a variety of functions in cellular metabolism, including fatty acid β-oxidation, synthesis of... (Review)
Review
Peroxisome is an organelle conserved in almost all eukaryotic cells with a variety of functions in cellular metabolism, including fatty acid β-oxidation, synthesis of ether glycerolipid plasmalogens, and redox homeostasis. Such metabolic functions and the exclusive importance of peroxisomes have been highlighted in fatal human genetic disease called peroxisomal biogenesis disorders (PBDs). Recent advances in this field have identified over 30 PEX genes encoding peroxins as essential factors for peroxisome biogenesis in various species from yeast to humans. Functional delineation of the peroxins has revealed that peroxisome biogenesis comprises the processes, involving peroxisomal membrane assembly, matrix protein import, division, and proliferation. Catalase, the most abundant peroxisomal enzyme, catalyzes decomposition of hydrogen peroxide. Peroxisome plays pivotal roles in the cellular redox homeostasis and the response to oxidative stresses, depending on intracellular localization of catalase.
Topics: Humans; Intracellular Membranes; Metabolic Networks and Pathways; Oxidation-Reduction; Oxidative Stress; Peroxisomal Disorders; Peroxisomes; Protein Transport
PubMed: 33417203
DOI: 10.1007/978-3-030-60204-8_1 -
Endocrine Reviews Aug 2020Adrenoleukodystrophy (ALD) is a rare X-linked disorder of peroxisomal oxidation due to mutations in ABCD1. It is a progressive condition with a variable clinical... (Review)
Review
Adrenoleukodystrophy (ALD) is a rare X-linked disorder of peroxisomal oxidation due to mutations in ABCD1. It is a progressive condition with a variable clinical spectrum that includes primary adrenal insufficiency, myelopathy, and cerebral ALD. Adrenal insufficiency affects over 80% of ALD patients. Cerebral ALD affects one-third of boys under the age of 12 and progresses to total disability and death without treatment. Hematopoietic stem cell transplantation (HSCT) remains the only disease-modifying therapy if completed in the early stages of cerebral ALD, but it does not affect the course of adrenal insufficiency. It has significant associated morbidity and mortality. A recent gene therapy clinical trial for ALD reported short-term MRI and neurological outcomes comparable to historical patients treated with HSCT without the associated adverse side effects. In addition, over a dozen states have started newborn screening (NBS) for ALD, with the number of states expecting to double in 2020. Genetic testing of NBS-positive neonates has identified novel variants of unknown significance, providing further opportunity for genetic characterization but also uncertainty in the monitoring and therapy of subclinical and/or mild adrenal insufficiency or cerebral involvement. As more individuals with ALD are identified at birth, it remains uncertain if availability of matched donors, transplant (and, potentially, gene therapy) centers, and specialists may affect the timely treatment of these individuals. As these promising gene therapy trials and NBS transform the clinical management and outcomes of ALD, there will be an increasing need for the endocrine management of presymptomatic and subclinical adrenal insufficiency. (Endocrine Reviews 41: 1 - 17, 2020).
Topics: Adrenal Insufficiency; Adrenoleukodystrophy; Genetic Testing; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Humans; Infant, Newborn; Male; Neonatal Screening
PubMed: 32364223
DOI: 10.1210/endrev/bnaa013 -
International Journal of Developmental... Feb 2020Adrenoleukodystrophy (ALD) is a rare X-linked disease caused by a mutation of the peroxisomal ABCD1 gene. This review summarizes our current understanding of the... (Review)
Review
Adrenoleukodystrophy (ALD) is a rare X-linked disease caused by a mutation of the peroxisomal ABCD1 gene. This review summarizes our current understanding of the pathogenic cell- and tissue-specific roles of lipid species in the context of experimental therapeutic strategies and provides an overview of critical historical developments, therapeutic trials and the advent of newborn screening in the USA. In ALD, very long-chain fatty acid (VLCFA) chain length-dependent dysregulation of endoplasmic reticulum stress and mitochondrial radical generating systems inducing cell death pathways has been shown, providing the rationale for therapeutic moiety-specific VLCFA reduction and antioxidant strategies. The continuing increase in newborn screening programs and promising results from ongoing and recent therapeutic investigations provide hope for ALD.
Topics: ATP Binding Cassette Transporter, Subfamily D, Member 1; Adrenoleukodystrophy; Endoplasmic Reticulum Stress; Humans; Infant, Newborn; Mutation; Neonatal Screening
PubMed: 31909500
DOI: 10.1002/jdn.10003 -
Current Neurology and Neuroscience... Oct 2014X-linked adrenoleukodystrophy (X-ALD) is a puzzling inborn error of metabolism with a strikingly heterogeneous clinical spectrum. All patients have mutations in the... (Review)
Review
X-linked adrenoleukodystrophy (X-ALD) is a puzzling inborn error of metabolism with a strikingly heterogeneous clinical spectrum. All patients have mutations in the ABCD1 gene and accumulate very long chain fatty acids in all tissues. Virtually all male X-ALD patients develop adrenocortical insufficiency in childhood and progressive myelopathy and peripheral neuropathy in adulthood. A subset of male patients, however, develops a fatal cerebral demyelinating disease, cerebral adrenoleukodystrophy. Female patients also develop progressive myelopathy and peripheral neuropathy, but generally at a later age than males. They only very rarely develop adrenocortical insufficiency or cerebral adrenoleukodystrophy. This review proposes to simplify the classification of the clinical spectrum of X-ALD and reviews the largely unresolved pathophysiological mechanisms and the current treatment options.
Topics: ATP Binding Cassette Transporter, Subfamily D, Member 1; ATP-Binding Cassette Transporters; Addison Disease; Adrenoleukodystrophy; Disease Progression; Humans; Mutation; Peripheral Nervous System Diseases; Spinal Cord Diseases
PubMed: 25115486
DOI: 10.1007/s11910-014-0486-0 -
Current Opinion in Endocrinology,... Feb 2023The present review summarizes recent advances in the diagnosis and management of patients with X-linked adrenoleukodystrophy (ALD). (Review)
Review
PURPOSE OF REVIEW
The present review summarizes recent advances in the diagnosis and management of patients with X-linked adrenoleukodystrophy (ALD).
RECENT FINDINGS
Although ALD screening has been on the list of Recommended Uniform Screening Panel since 2016, only 30 states in the United States are currently testing their newborns for this disease. Hematopoietic stem cell transplant (HSCT) remains the only successful treatment option available for early cerebral ALD but does not reverse neurological changes or affect the course of adrenal insufficiency. There remains a significant knowledge gap in our understanding and treatment of this disease. Novel therapies such as gene therapy and gene editing have shown promising results in animal models and are exciting potential treatment options for the future.Recently, the American Academy of Neurologists released their consensus guidelines on the diagnosis, surveillance, and management of ALD.
SUMMARY
Early diagnosis and HSCT are key to improving the morbidity and mortality associated with ALD. The implementation of universal newborn screening for ALD and rigorous investigations of novel diagnostic and therapeutic agents is the need of the hour.
Topics: Humans; Infant, Newborn; Adrenoleukodystrophy; Adrenal Insufficiency; Neonatal Screening; Genetic Therapy; Early Diagnosis
PubMed: 36373727
DOI: 10.1097/MED.0000000000000782 -
Expert Opinion on Biological Therapy Sep 2022Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder with an incidence of 1 in 14-17,000 male births, caused by pathogenic variants within the gene. By... (Review)
Review
INTRODUCTION
Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder with an incidence of 1 in 14-17,000 male births, caused by pathogenic variants within the gene. By adulthood, approximately 40% of the patients develop cerebral ALD, a severe, neuroinflammatory condition that is generally progressive and fatal without intervention.
AREAS COVERED
Historically, only allogeneic hematopoietic stem cell transplantation (HSCT) has been shown to halt progression of cerebral ALD, with superior outcomes obtained when HSCT is performed early in the disease process. More recently, a lentiviral-based gene therapy approach has been investigated as therapy for cerebral ALD as an alternative to allogeneic transplantation. A focused literature review was performed using the terms 'hematopoietic stem cell transplantation,' 'gene therapy' and 'adrenoleukodystrophy' to include relevant literature, especially comparing the experience with gene therapy and HSCT outcomes. We review the history and experience with HSCT in cerebral ALD and its limitations, as well as the information currently available in association with the gene therapy trials for cerebral ALD.
EXPERT OPINION
The data regarding this lentiviral-based gene therapy approach and its relative risks and benefits is still being evaluated. This information is explored in the context of the experience with allogeneic HSCT for cerebral ALD.
Topics: Adrenoleukodystrophy; Adult; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Humans; Male; Transplantation, Homologous
PubMed: 36107226
DOI: 10.1080/14712598.2022.2124857 -
Cell Apr 2015Cholesterol is dynamically transported among organelles, which is essential for multiple cellular functions. However, the mechanism underlying intracellular cholesterol...
Cholesterol is dynamically transported among organelles, which is essential for multiple cellular functions. However, the mechanism underlying intracellular cholesterol transport has remained largely unknown. We established an amphotericin B-based assay enabling a genome-wide shRNA screen for delayed LDL-cholesterol transport and identified 341 hits with particular enrichment of peroxisome genes, suggesting a previously unappreciated pathway for cholesterol transport. We show dynamic membrane contacts between peroxisome and lysosome, which are mediated by lysosomal Synaptotagmin VII binding to the lipid PI(4,5)P2 on peroxisomal membrane. LDL-cholesterol enhances such contacts, and cholesterol is transported from lysosome to peroxisome. Disruption of critical peroxisome genes leads to cholesterol accumulation in lysosome. Together, these findings reveal an unexpected role of peroxisome in intracellular cholesterol transport. We further demonstrate massive cholesterol accumulation in human patient cells and mouse model of peroxisomal disorders, suggesting a contribution of abnormal cholesterol accumulation to these diseases.
Topics: ATP-Binding Cassette Transporters; Adrenoleukodystrophy; Amphotericin B; Animals; Biological Transport; Cholesterol; Genome-Wide Association Study; Humans; Lysosomes; Mice; Peroxisomal Disorders; Peroxisomes; Phosphatidylinositol 4,5-Diphosphate; RNA, Small Interfering; Synaptotagmins; Zebrafish
PubMed: 25860611
DOI: 10.1016/j.cell.2015.02.019 -
Neurology Nov 2022Pathogenic variants in the gene cause adrenoleukodystrophy (ALD), a progressive metabolic disorder characterized by 3 core clinical syndromes: a slowly progressive...
Pathogenic variants in the gene cause adrenoleukodystrophy (ALD), a progressive metabolic disorder characterized by 3 core clinical syndromes: a slowly progressive myeloneuropathy, a rapidly progressive inflammatory leukodystrophy (cerebral ALD), and primary adrenal insufficiency. These syndromes are not present in all individuals and are not related to genotype. Cerebral ALD and adrenal insufficiency require early detection and intervention and warrant clinical surveillance because of variable penetrance and age at onset. Newborn screening has increased the number of presymptomatic individuals under observation, but clinical surveillance protocols vary. We used a consensus-based modified Delphi approach among 28 international ALD experts to develop best-practice recommendations for diagnosis, clinical surveillance, and treatment of patients with ALD. We identified 39 discrete areas of consensus. Regular monitoring to detect the onset of adrenal failure and conversion to cerebral ALD is recommended in all male patients. Hematopoietic cell transplant (HCT) is the treatment of choice for cerebral ALD. This guideline addresses a clinical need in the ALD community worldwide as the number of overall diagnoses and presymptomatic individuals is increasing because of newborn screening and greater availability of next-generation sequencing. The poor ability to predict the disease course informs current monitoring intervals but remains subject to change as more data emerge. This knowledge gap should direct future research and illustrates once again that international collaboration among physicians, researchers, and patients is essential to improving care.
Topics: Infant, Newborn; Humans; Male; Adrenoleukodystrophy; Consensus; Hematopoietic Stem Cell Transplantation; Adrenal Insufficiency; Neonatal Screening
PubMed: 36175155
DOI: 10.1212/WNL.0000000000201374 -
Advances in Experimental Medicine and... 2020Peroxisomes are presented in all eukaryotic cells and play essential roles in many of lipid metabolic pathways, including β-oxidation of fatty acids and synthesis of... (Review)
Review
Peroxisomes are presented in all eukaryotic cells and play essential roles in many of lipid metabolic pathways, including β-oxidation of fatty acids and synthesis of ether-linked glycerophospholipids, such as plasmalogens. Impaired peroxisome biogenesis, including defects of membrane assembly, import of peroxisomal matrix proteins, and division of peroxisome, causes peroxisome biogenesis disorders (PBDs). Fourteen complementation groups of PBDs are found, and their complementing genes termed PEXs are isolated. Several new mutations in peroxins from patients with mild PBD phenotype or patients with phenotypes unrelated to the commonly observed impairments of PBD patients are found by next-generation sequencing. Exploring a dysfunctional step(s) caused by the mutation is important for unveiling the pathogenesis of novel mutation by means of cellular and biochemical analyses.
Topics: Humans; Mutation; Peroxisomal Disorders; Peroxisomes; Phenotype
PubMed: 33417206
DOI: 10.1007/978-3-030-60204-8_4