-
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 -
Annals of the Rheumatic Diseases Jul 2022The interleukin-1 (IL-1) mediated systemic autoinflammatory diseases, including the cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor...
The 2021 EULAR/American College of Rheumatology points to consider for diagnosis, management and monitoring of the interleukin-1 mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated periodic syndrome, mevalonate kinase deficiency,...
BACKGROUND
The interleukin-1 (IL-1) mediated systemic autoinflammatory diseases, including the cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD) and deficiency of the IL-1 receptor antagonist (DIRA), belong to a group of rare immunodysregulatory diseases that primarily present in early childhood with variable multiorgan involvement. When untreated, patients with severe clinical phenotypes have a poor prognosis, and diagnosis and management of these patients can be challenging. However, approved treatments targeting the proinflammatory cytokine IL-1 have been life changing and have significantly improved patient outcomes.
OBJECTIVE
To establish evidence-based recommendations for diagnosis, treatment and monitoring of patients with IL-1 mediated autoinflammatory diseases to standardise their management.
METHODS
A multinational, multidisciplinary task force consisting of physician experts, including rheumatologists, patients or caregivers and allied healthcare professionals, was established. Evidence synthesis, including systematic literature review and expert consensus (Delphi) via surveys, was conducted. Consensus methodology was used to formulate and vote on statements to guide optimal patient care.
RESULTS
The task force devised five overarching principles, 14 statements related to diagnosis, 10 on therapy, and nine focused on long-term monitoring that were evidence and/or consensus-based for patients with IL-1 mediated diseases. An outline was developed for disease-specific monitoring of inflammation-induced organ damage progression and reported treatments of CAPS, TRAPS, MKD and DIRA.
CONCLUSION
The 2021 EULAR/American College of Rheumatology points to consider represent state-of-the-art knowledge based on published data and expert opinion to guide diagnostic evaluation, treatment and monitoring of patients with CAPS, TRAPS, MKD and DIRA, and to standardise and improve care, quality of life and disease outcomes.
Topics: Cryopyrin-Associated Periodic Syndromes; Fever; Hereditary Autoinflammatory Diseases; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Mevalonate Kinase Deficiency; Quality of Life; Receptors, Interleukin-1; Rheumatology
PubMed: 35623638
DOI: 10.1136/annrheumdis-2021-221801 -
BMJ Case Reports Oct 2023A man in his 30s presented with a 6-month history of progressive left face, arm and leg weakness. Medical history included epilepsy and vitamin B deficiency. Three...
A man in his 30s presented with a 6-month history of progressive left face, arm and leg weakness. Medical history included epilepsy and vitamin B deficiency. Three maternal second degree relatives died before the age of 7 from various neurological disorders. Examination revealed a mild left facial droop and weakness of the left shoulder, hip and ankle. Reflexes were symmetrical and tone was normal. Differential diagnosis included glioma, subacute infarction, lymphoma and demyelination. MRI brain showed an extensive right sided subcortical white matter lesion, with extension into the brainstem. The patient's weakness progressed over 3 months. Brain biopsy showed evidence of demyelination and gliosis. A pathological diagnosis of tumefactive multiple sclerosis was made, but also rare metabolic disorders such as X-linked adrenoleukodystrophy (X-ALD) were proposed. Serum very long-chain fatty acids were significantly elevated. Genetic testing showed a mutation in the gene, confirming a diagnosis of X-ALD.
Topics: Humans; Male; Adrenoleukodystrophy; Brain Stem; Magnetic Resonance Imaging; Mutation; Neuroimaging; Adult
PubMed: 37907311
DOI: 10.1136/bcr-2020-237905 -
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 -
Current Problems in Pediatric and... Dec 2022Leukodystrophies are defined as differences in normal myelin development and maintenance in the central nervous system. They typically present as white matter imaging... (Review)
Review
Leukodystrophies are defined as differences in normal myelin development and maintenance in the central nervous system. They typically present as white matter imaging abnormalities in young children with delayed developmental milestones. As the scientific community begins to better understand and research the mechanisms underlying leukodystrophies, clinical trials and approved therapies for specific disorders are becoming available. These interventions, ranging from repurposing of existing small molecules to recently approved gene therapies, are highly dependent on early diagnosis. It is essential for pediatricians to identify affected individuals promptly, but they face challenges including lack of awareness of the disorders and nonspecific symptom presentation (e.g., cognitive or motor developmental delay). This review provides five hypothetical clinical presentations and describes the disease mechanisms, typical symptoms, and treatments currently available for common leukodystrophies: Krabbe Disease, Aicardi Goutières Syndrome (AGS), Metachromatic leukodystrophy (MLD), Alexander Disease (AxD), Pelizaeus-Merzbacher Disease (PMD), and X-Linked Adrenoleukodystrophy (X-ALD.) This review educates pediatricians to recognize the presentation of leukodystrophies in affected children. These clinical vignettes can serve as a framework for pediatricians to identify potentially treatable rare disorders among their patients.
Topics: Child; Humans; Child, Preschool; Leukodystrophy, Metachromatic; Leukodystrophy, Globoid Cell; Adrenoleukodystrophy; Nervous System Malformations; Autoimmune Diseases of the Nervous System
PubMed: 36470810
DOI: 10.1016/j.cppeds.2022.101311 -
International Journal of Molecular... Jun 2021ATP-binding cassette (ABC) transporters constitute one of the largest superfamilies of conserved proteins from bacteria to mammals. In humans, three members of this... (Review)
Review
ATP-binding cassette (ABC) transporters constitute one of the largest superfamilies of conserved proteins from bacteria to mammals. In humans, three members of this family are expressed in the peroxisomal membrane and belong to the subfamily D: ABCD1 (ALDP), ABCD2 (ALDRP), and ABCD3 (PMP70). These half-transporters must dimerize to form a functional transporter, but they are thought to exist primarily as tetramers. They possess overlapping but specific substrate specificity, allowing the transport of various lipids into the peroxisomal matrix. The defects of ABCD1 and ABCD3 are responsible for two genetic disorders called X-linked adrenoleukodystrophy and congenital bile acid synthesis defect 5, respectively. In addition to their role in peroxisome metabolism, it has recently been proposed that peroxisomal ABC transporters participate in cell signaling and cell control, particularly in cancer. This review presents an overview of the knowledge on the structure, function, and mechanisms involving these proteins and their link to pathologies. We summarize the different in vitro and in vivo models existing across the species to study peroxisomal ABC transporters and the consequences of their defects. Finally, an overview of the known and possible interactome involving these proteins, which reveal putative and unexpected new functions, is shown and discussed.
Topics: ATP Binding Cassette Transporter, Subfamily D; ATP Binding Cassette Transporter, Subfamily D, Member 1; ATP-Binding Cassette Transporters; Adrenoleukodystrophy; Cholestasis; Fatty Acids; Humans; Peroxisomes
PubMed: 34198763
DOI: 10.3390/ijms22116093 -
Neuropediatrics Aug 2021Magnetic resonance imaging (MRI) is the gold standard for the detection of cerebral lesions in X-linked adrenoleukodystrophy (ALD). ALD is one of the most common... (Review)
Review
Magnetic resonance imaging (MRI) is the gold standard for the detection of cerebral lesions in X-linked adrenoleukodystrophy (ALD). ALD is one of the most common peroxisomal disorders and is characterized by a defect in degradation of very long chain fatty acids (VLCFA), resulting in accumulation of VLCFA in plasma and tissues. The clinical spectrum of ALD is wide and includes adrenocortical insufficiency, a slowly progressive myelopathy in adulthood, and cerebral demyelination in a subset of male patients. Cerebral demyelination (cerebral ALD) can be treated with hematopoietic cell transplantation (HCT) but only in an early (pre- or early symptomatic) stage and therefore active MRI surveillance is recommended for male patients, both pediatric and adult. Although structural MRI of the brain can detect the presence and extent of cerebral lesions, it does not predict if and when cerebral demyelination will occur. There is a great need for imaging techniques that predict onset of cerebral ALD before lesions appear. Also, imaging markers for severity of myelopathy as surrogate outcome measure in clinical trials would facilitate drug development. New quantitative MRI techniques are promising in that respect. This review focuses on structural and quantitative imaging techniques-including magnetic resonance spectroscopy, diffusion tensor imaging, MR perfusion imaging, magnetization transfer (MT) imaging, neurite orientation dispersion and density imaging (NODDI), and myelin water fraction imaging-used in ALD and their role in clinical practice and research opportunities for the future.
Topics: Adrenoleukodystrophy; Adult; Biomarkers; Child; Diffusion Tensor Imaging; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male
PubMed: 34192790
DOI: 10.1055/s-0041-1730937 -
Handbook of Clinical Neurology 2021X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder caused by mutations in the ABCD1 gene and characterized by impaired very long-chain fatty acid... (Review)
Review
X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder caused by mutations in the ABCD1 gene and characterized by impaired very long-chain fatty acid beta-oxidation. Clinically, male patients develop adrenal failure and a progressive myelopathy in adulthood, although age of onset and rate of progression are highly variable. Additionally, 40% of male patients develop a leukodystrophy (cerebral ALD) before the age of 18 years. Women with ALD also develop a myelopathy but generally at a later age than men and with slower progression. Adrenal failure and leukodystrophy are exceedingly rare in women. Allogeneic hematopoietic cell transplantation (HCT), or more recently autologous HCT with ex vivo lentivirally transfected bone marrow, halts the leukodystrophy. Unfortunately, there is no curative treatment for the myelopathy. In the following chapter, the biochemistry, pathology, and clinical spectrum of ALD are discussed in detail.
Topics: Adolescent; Adrenoleukodystrophy; Adult; Fatty Acids; Female; Humans; Male; Mutation; Spinal Cord Diseases
PubMed: 34266597
DOI: 10.1016/B978-0-12-819973-2.00018-6 -
Frontiers in Endocrinology 2023X-linked adrenoleukodystrophy (X-ALD; OMIM:300100) is a progressive neurodegenerative disorder caused by a congenital defect in the ATP-binding cassette transporters... (Review)
Review
X-linked adrenoleukodystrophy (X-ALD; OMIM:300100) is a progressive neurodegenerative disorder caused by a congenital defect in the ATP-binding cassette transporters sub-family D member 1 gene (ABCD1) producing adrenoleukodystrophy protein (ALDP). According to population studies, X-ALD has an estimated birth prevalence of 1 in 17.000 subjects (considering both hemizygous males and heterozygous females), and there is no evidence that this prevalence varies among regions or ethnic groups. ALDP deficiency results in a defective peroxisomal β-oxidation of very long chain fatty acids (VLCFA). As a consequence of this metabolic abnormality, VLCFAs accumulate in nervous system (brain white matter and spinal cord), testis and adrenal cortex. All X-ALD affected patients carry a mutation on the ABCD1 gene. Nevertheless, patients with a defect on the ABCD1 gene can have a dramatic difference in the clinical presentation of the disease. In fact, X-ALD can vary from the most severe cerebral paediatric form (CerALD), to adult adrenomyeloneuropathy (AMN), Addison-only and asymptomatic forms. Primary adrenal insufficiency (PAI) is one of the main features of X-ALD, with a prevalence of 70% in ALD/AMN patients and 5% in female carriers. The pathogenesis of X-ALD related PAI is still unclear, even if a few published data suggests a defective adrenal response to ACTH, related to VLCFA accumulation with progressive disruption of adrenal cell membrane function and ACTH receptor activity. The reason why PAI develops only in a proportion of ALD/AMN patients remains incompletely understood. A growing consensus supports VLCFA assessment in all male children presenting with PAI, as early diagnosis and start of therapy may be essential for X-ALD patients. Children and adults with PAI require individualized glucocorticoid replacement therapy, while mineralocorticoid therapy is needed only in a few cases after consideration of hormonal and electrolytes status. Novel approaches, such as prolonged release glucocorticoids, offer potential benefit in optimizing hormonal replacement for X-ALD-related PAI. Although the association between PAI and X-ALD has been observed in clinical practice, the underlying mechanisms remain poorly understood. This paper aims to explore the multifaceted relationship between PAI and X-ALD, shedding light on shared pathophysiology, clinical manifestations, and potential therapeutic interventions.
Topics: Adult; Humans; Male; Female; Child; Adrenoleukodystrophy; ATP-Binding Cassette Transporters; Addison Disease; Fatty Acids; Adrenal Cortex; Glucocorticoids
PubMed: 38034003
DOI: 10.3389/fendo.2023.1309053