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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 -
Molecular Genetics and Metabolism Mar 2016Peroxisome biogenesis disorders in the Zellweger spectrum (PBD-ZSD) are a heterogeneous group of genetic disorders caused by mutations in PEX genes responsible for... (Review)
Review
Peroxisome biogenesis disorders in the Zellweger spectrum (PBD-ZSD) are a heterogeneous group of genetic disorders caused by mutations in PEX genes responsible for normal peroxisome assembly and functions. As a result of impaired peroxisomal activities, individuals with PBD-ZSD can manifest a complex spectrum of clinical phenotypes that typically result in shortened life spans. The extreme variability in disease manifestation ranging from onset of profound neurologic symptoms in newborns to progressive degenerative disease in adults presents practical challenges in disease diagnosis and medical management. Recent advances in biochemical methods for newborn screening and genetic testing have provided unprecedented opportunities for identifying patients at the earliest possible time and defining the molecular bases for their diseases. Here, we provide an overview of current clinical approaches for the diagnosis of PBD-ZSD and provide broad guidelines for the treatment of disease in its wide variety of forms. Although we anticipate future progress in the development of more effective targeted interventions, the current guidelines are meant to provide a starting point for the management of these complex conditions in the context of personalized health care.
Topics: Adult; Genetic Testing; Hearing Loss, Sensorineural; Humans; Membrane Proteins; Mutation; PHEX Phosphate Regulating Neutral Endopeptidase; Peroxisomal Disorders; Peroxisomes; Phenotype; Practice Guidelines as Topic; Precision Medicine; Retinal Dystrophies; Zellweger Syndrome
PubMed: 26750748
DOI: 10.1016/j.ymgme.2015.12.009 -
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 -
Sub-cellular Biochemistry 2018The current view on peroxisomes has changed dramatically from being human cell oddities to vital organelles that host several key metabolic pathways. To fulfil over 50... (Review)
Review
The current view on peroxisomes has changed dramatically from being human cell oddities to vital organelles that host several key metabolic pathways. To fulfil over 50 different enzymatic functions, human peroxisomes host either unique peroxisomal proteins or dual-localized proteins. The identification and characterization of the complete peroxisomal proteome in humans is important for diagnosis and treatment of patients with peroxisomal disorders as well as for uncovering novel peroxisomal functions and regulatory modules. Hence, here we compiled a comprehensive list of mammalian peroxisomal and peroxisome-associated proteins by curating results of several quantitative and non-quantitative proteomic studies together with entries in the UniProtKB and Compartments knowledge channel databases. Our analysis gives a holistic view on the mammalian peroxisomal proteome and brings to light potential new peroxisomal and peroxisome-associated proteins. We believe that this dataset, represents a valuable surrogate map of the human peroxisomal proteome.
Topics: Animals; Humans; Metabolic Networks and Pathways; Peroxisomal Disorders; Peroxisomes; Proteome; Proteomics
PubMed: 30378018
DOI: 10.1007/978-981-13-2233-4_2 -
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 -
Postepy Biochemii Dec 2018Peroxisomes are multifunctional microorganelles that play a key role in numerous biochemical processes adapting dynamically to the current physiological requirements of... (Review)
Review
Peroxisomes are multifunctional microorganelles that play a key role in numerous biochemical processes adapting dynamically to the current physiological requirements of the cell. The disturbance of the peroxisome structure due to mutations in different PEX and non-PEX genes coding functional peroxisomal proteins is the pathogenic basis of the peroxisomal disorders. The β-oxidation process of very long-chain fatty acids (VLCFA) is a unique metabolic pathway located exclusively in the peroxisome. This determines that VLCFA is the main biomarker for the diagnosis of peroxisomal diseases. Peroxisomal disorders present a broad spectrum of clinical symptoms from the neonatal, severe Zellweger syndrome with dysmorphia, multi-organ dysfunction to the late symptomatic adult form of X-linked adrenoleukodystrophy. Relatively common the use of highly specialized analytical techniques causes it is a still growing group of rare metabolic diseases.
Topics: Adrenoleukodystrophy; Fatty Acids; Humans; Oxidation-Reduction; Peroxisomal Disorders; Peroxisomes; Zellweger Syndrome
PubMed: 30656921
DOI: 10.18388/pb.2018_150 -
Archives of Pharmacal Research May 2019Peroxisomes and their (patho-)physiological importance in heath and disease have attracted increasing interest during last few decades. Together with mitochondria,... (Review)
Review
Peroxisomes and their (patho-)physiological importance in heath and disease have attracted increasing interest during last few decades. Together with mitochondria, peroxisomes comprise key metabolic platforms for oxidation of various fatty acids and redox regulation. In addition, peroxisomes contribute to bile acid, cholesterol, and plasmalogen biosynthesis. The importance of functional peroxisomes for cellular metabolism is demonstrated by the marked brain and systemic organ abnormalities occuring in peroxisome biogenesis disorders and peroxisomal enzyme deficiencies. Current evidences indicate that peroxisomal function is declined with aging, with peroxisomal dysfunction being linked to early onset of multiple age-related diseases including neurodegenerative diseases. Herein, we review recent progress toward understanding the physiological roles and pathological implications of peroxisomal dysfunctions, focusing on neurodegenerative disease.
Topics: Aging; Animals; Brain; Disease Models, Animal; Humans; Lipid Metabolism; Neurodegenerative Diseases; Oxidation-Reduction; Peroxisomal Disorders; Peroxisomes; Reactive Oxygen Species
PubMed: 30739266
DOI: 10.1007/s12272-019-01131-2 -
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