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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 -
Physiological Reviews Jan 2023Peroxisomes are subcellular organelles that play a central role in human physiology by catalyzing a range of unique metabolic functions. The importance of peroxisomes... (Review)
Review
Peroxisomes are subcellular organelles that play a central role in human physiology by catalyzing a range of unique metabolic functions. The importance of peroxisomes for human health is exemplified by the existence of a group of usually severe diseases caused by an impairment in one or more peroxisomal functions. Among others these include the Zellweger spectrum disorders, X-linked adrenoleukodystrophy, and Refsum disease. To fulfill their role in metabolism, peroxisomes require continued interaction with other subcellular organelles including lipid droplets, lysosomes, the endoplasmic reticulum, and mitochondria. In recent years it has become clear that the metabolic alliance between peroxisomes and other organelles requires the active participation of tethering proteins to bring the organelles physically closer together, thereby achieving efficient transfer of metabolites. This review intends to describe the current state of knowledge about the metabolic role of peroxisomes in humans, with particular emphasis on the metabolic partnership between peroxisomes and other organelles and the consequences of genetic defects in these processes. We also describe the biogenesis of peroxisomes and the consequences of the multiple genetic defects therein. In addition, we discuss the functional role of peroxisomes in different organs and tissues and include relevant information derived from model systems, notably peroxisomal mouse models. Finally, we pay particular attention to a hitherto underrated role of peroxisomes in viral infections.
Topics: Animals; Humans; Mice; Peroxisomes
PubMed: 35951481
DOI: 10.1152/physrev.00051.2021 -
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 -
Best Practice & Research. Clinical... Aug 2020Systemic autoinflammatory diseases (SAIDs) are defined as disorders of innate immunity. They were initially defined in opposition to autoimmune diseases due to the lack... (Review)
Review
Systemic autoinflammatory diseases (SAIDs) are defined as disorders of innate immunity. They were initially defined in opposition to autoimmune diseases due to the lack of involvement of the adaptive immune system and circulating autoantibodies. The four historical monogenic diseases are familial Mediterranean fever (associated with MEFV mutations), cryopyrinopathies (NLRP3 mutations), tumor necrosis factor receptor-associated periodic syndrome (TNFRSF1A mutations), and mevalonate kinase deficiency (MVK mutations). In the last 10 years, more than 50 new monogenic SAIDs have been discovered thanks to advances in genetics. Diagnosis is largely based on personal and family history and detailed analysis of signs and symptoms associated with febrile attacks, in the setting of elevated inflammatory markers. Increasingly efficient techniques of genetic analysis can contribute to refining the diagnosis. This review is a guide for the clinician in suspecting and establishing a diagnosis of SAID.
Topics: Cryopyrin-Associated Periodic Syndromes; Familial Mediterranean Fever; Fever; Hereditary Autoinflammatory Diseases; Humans; Mevalonate Kinase Deficiency; Pyrin
PubMed: 32546426
DOI: 10.1016/j.berh.2020.101529 -
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