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Biochimica Et Biophysica Acta May 2016Peroxisomes contain numerous enzymatic activities that are important for mammalian physiology. Patients lacking either all peroxisomal functions or a single enzyme or... (Review)
Review
Peroxisomes contain numerous enzymatic activities that are important for mammalian physiology. Patients lacking either all peroxisomal functions or a single enzyme or transporter function typically develop severe neurological deficits, which originate from aberrant development of the brain, demyelination and loss of axonal integrity, neuroinflammation or other neurodegenerative processes. Whilst correlating peroxisomal properties with a compilation of pathologies observed in human patients and mouse models lacking all or individual peroxisomal functions, we discuss the importance of peroxisomal metabolites and tissue- and cell type-specific contributions to the observed brain pathologies. This enables us to deconstruct the local and systemic contribution of individual metabolic pathways to specific brain functions. We also review the recently discovered variability of pathological symptoms in cases with unexpectedly mild presentation of peroxisome biogenesis disorders. Finally, we explore the emerging evidence linking peroxisomes to more common neurological disorders such as Alzheimer's disease, autism and amyotrophic lateral sclerosis.
Topics: ATPases Associated with Diverse Cellular Activities; Animals; Brain; Disease Models, Animal; Gene Expression Regulation; Humans; Membrane Proteins; Metabolic Networks and Pathways; Mice; Mutation; Peroxisomal Disorders; Peroxisomes; Protein Isoforms; Protein Transport; Synaptic Transmission
PubMed: 26686055
DOI: 10.1016/j.bbamcr.2015.12.005 -
Presse Medicale (Paris, France : 1983) Mar 2016Peroxisomes are small intracellular organelles that catalyse key metabolic reactions such as the beta-oxidation of some straight-chain or branched-chain fatty acids and... (Review)
Review
Peroxisomes are small intracellular organelles that catalyse key metabolic reactions such as the beta-oxidation of some straight-chain or branched-chain fatty acids and the alpha-oxidation of phytanic acid. These enzyme reactions produce hydrogen peroxide, which is subsequently neutralized by the peroxisomal catalase. Peroxisomes also metabolize glyoxylate to glycine, and catalyze the first steps of plasmalogen biosynthesis. There are more than a dozen inherited peroxisomal disorders in humans. These metabolic diseases are due to monogenic defects that affect either a single function (such as enzyme or a transporter) or more than two distinct functions because of the impairment of several aspects of peroxisome biogenesis. With the notable exception of X-linked adrenoleucodystrophy, these inborn disorders are transmitted as autosomal recessive traits. Their clinical presentation can be very heterogeneous, and include neonatal, infantile or adult forms. The present review describes the symptomatology of these genetic diseases, the underlying genetic and biochemical alterations, and summarizes their diagnostic approach.
Topics: Adolescent; Adult; Age of Onset; Bone Marrow Transplantation; Brain; Cataract; Child; Decision Trees; Dietary Fats; Fatty Acids; Female; Genes, Recessive; Humans; Hydrogen Peroxide; Infant; Infant, Newborn; Male; Myocardium; Organelle Biogenesis; Peroxisomal Disorders; Peroxisomes; Phenotype; Phytanic Acid
PubMed: 26899150
DOI: 10.1016/j.lpm.2015.05.009 -
Current Opinion in Endocrinology,... Feb 2020Adrenoleukodystrophy (ALD) is a peroxisomal disorder with varying clinical presentations, including adrenal insufficiency, neurologic disease, and testicular... (Review)
Review
PURPOSE OF REVIEW
Adrenoleukodystrophy (ALD) is a peroxisomal disorder with varying clinical presentations, including adrenal insufficiency, neurologic disease, and testicular dysfunction. The present review is intended to describe the current knowledge of the pathophysiology of ALD and provide an update regarding newborn screening, diagnosis, monitoring, and treatment.
RECENT FINDINGS
New York State initiated newborn screening for ALD on December 30, 2013. Successful ALD newborn screening has led to its addition on other state newborn screens and recommendations for universal screening. Initial incidence reports, based on newborn screening, suggest ALD may be more common than previously described. The Pediatric Endocrine Society has published guidance for monitoring newborn males with ALD and case reports suggest biochemical adrenal insufficiency can be present during early infancy. Allogeneic hematopoietic stem cell transplant and gene therapy have been effective at halting the progression of cerebral ALD.
SUMMARY
Early diagnosis and monitoring for progression of ALD can prevent adrenal crisis and treat the cerebral form of the disease. Initial guidelines for surveillance are likely to evolve as newborn screening not only aids in early detection and therapeutic interventions for ALD, but also expands our knowledge of the natural history of ALD.
Topics: Adrenal Insufficiency; Adrenoleukodystrophy; Child; Diagnosis, Differential; Disease Progression; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Humans; Infant, Newborn; Male; Neonatal Screening; Peroxisomal Disorders
PubMed: 31789721
DOI: 10.1097/MED.0000000000000515 -
Cellular and Molecular Neurobiology May 2016X-linked adrenoleukodystrophy (X-ALD) is the most frequent peroxisomal disorder that is characterized by progressive demyelination of the white matter, adrenal... (Review)
Review
X-linked adrenoleukodystrophy (X-ALD) is the most frequent peroxisomal disorder that is characterized by progressive demyelination of the white matter, adrenal insufficiency, and accumulation of very long-chain fatty acids in body fluid and tissues. This disorder is clinically heterogeneous with seven different phenotypes in male patients and five phenotypes in female carriers. An ultimate treatment for X-ALD is not available. Depending on the rate of the disease progression and the degree of an individual handicap, special needs and challenges vary greatly. The exact mechanisms underlying the pathophysiology of this multifactorial neurodegenerative disorder remains obscure. Previous studies has been related oxidative stress with the pathogenesis of several disease that affecting the central nervous system, such as neurodegenerative disease, epilepsy, multiple sclerosis, Alzheimer, and Parkinson diseases. In addition, oxidative damage has been observed in various in vivo and in vitro studies with inborn errors of metabolism, including X-ALD. In this context, this review is focused on oxidative stress in X-ALD, with emphasis on studies using biological samples from patients affected by this disease.
Topics: Adrenoleukodystrophy; Antioxidants; Biomarkers; Free Radicals; Humans; Models, Biological; Oxidative Stress
PubMed: 26169524
DOI: 10.1007/s10571-015-0234-2 -
Wiener Medizinische Wochenschrift (1946) Jun 2017Adrenoleukodystrophy (ALD) is an X‑linked hereditary disorder due to mutations of the ABCD1 gene, which encodes a peroxisomal transport protein necessary for very... (Review)
Review
Adrenoleukodystrophy (ALD) is an X‑linked hereditary disorder due to mutations of the ABCD1 gene, which encodes a peroxisomal transport protein necessary for very long-chain fatty acid degradation (VLCFA). Toxic accumulation thereof is associated with a proinflammatory state and eventual cell death in multiple tissues. ALD may manifest either as a fatal, rapidly progressive demyelinating disease in boys and adult men, or as a slowly progressive adult-onset long-tract myelopathy along with peripheral neuropathy. Our understanding of manifold mechanisms implicated in the disease pathology is currently incomplete, as neither genotype-phenotype correlation nor the trigger for cerebral disease has been described. Therapy objectives are therefore broadly aimed at correcting either the gene mutation or downstream molecular effects, such as oxidative stress. Advancements in disease detection, including the newly implemented newborn screening in the US and imaging modalities, allow for more timely intervention in the form of hematopoietic stem cell transplantation (HSCT), which may only be performed in early cerebral disease states.
Topics: Adrenoleukodystrophy; Adult; Brain Diseases; Cell Death; Child; Chromosomes, Human, X; DNA Mutational Analysis; Demyelinating Diseases; Disease Progression; Hematopoietic Stem Cell Transplantation; Humans; Infant, Newborn; Male; Neonatal Screening
PubMed: 28493141
DOI: 10.1007/s10354-016-0534-2 -
Cells Dec 2021X-linked adrenoleukodystrophy (ALD) is an inherited progressive neurometabolic disease caused by mutations in the gene and the accumulation of very long-chain fatty... (Review)
Review
X-linked adrenoleukodystrophy (ALD) is an inherited progressive neurometabolic disease caused by mutations in the gene and the accumulation of very long-chain fatty acids in plasma and tissues. Patients present with heterogeneous clinical manifestations which can include adrenal insufficiency, myelopathy, and/or cerebral demyelination. In the absence of a genotype-phenotype correlation, the clinical outcome of an individual cannot be predicted and currently there are no molecular markers available to quantify disease severity. Therefore, there is an unmet clinical need for sensitive biomarkers to monitor and/or predict disease progression and evaluate therapy efficacy. The increasing amount of biological sample repositories ('biobanking') as well as the introduction of newborn screening creates a unique opportunity for identification and evaluation of new or existing biomarkers. Here we summarize and review the many studies that have been performed to identify and improve knowledge surrounding candidate molecular biomarkers for ALD. We also highlight several shortcomings of ALD biomarker studies, which often include a limited sample size, no collection of longitudinal data, and no validation of findings in an external cohort. Nonetheless, these studies have generated a list of interesting biomarker candidates and this review aspires to direct future biomarker research.
Topics: ATP Binding Cassette Transporter, Subfamily D, Member 1; Adrenoleukodystrophy; Biomarkers; Genetic Diseases, X-Linked; Humans
PubMed: 34943935
DOI: 10.3390/cells10123427 -
Biochimica Et Biophysica Acta May 2016Peroxisomes are dynamic organelles that play an essential role in a variety of cellular catabolic and anabolic metabolic pathways, including fatty acid alpha- and... (Review)
Review
Peroxisomes are dynamic organelles that play an essential role in a variety of cellular catabolic and anabolic metabolic pathways, including fatty acid alpha- and beta-oxidation, and plasmalogen and bile acid synthesis. Defects in genes encoding peroxisomal proteins can result in a large variety of peroxisomal disorders either affecting specific metabolic pathways, i.e., the single peroxisomal enzyme deficiencies, or causing a generalized defect in function and assembly of peroxisomes, i.e., peroxisome biogenesis disorders. In this review, we discuss the clinical, biochemical, and genetic aspects of all human peroxisomal disorders currently known.
Topics: ATPases Associated with Diverse Cellular Activities; Fatty Acids; Gene Expression Regulation; Humans; Membrane Proteins; Metabolic Networks and Pathways; Mutation; Organelle Biogenesis; Oxidation-Reduction; Peroxisomal Disorders; Peroxisomes; Plasmalogens; Protein Isoforms; Protein Sorting Signals; Protein Transport; Signal Transduction
PubMed: 26611709
DOI: 10.1016/j.bbamcr.2015.11.015 -
La Revue Du Praticien Oct 2023MEVALONATE KINASE DEFICIENCY. Mevalonate kinase deficiency is a rare, autosomal recessive, auto- inflammatory disease, linked to mutations in the gene MVK, resulting in...
MEVALONATE KINASE DEFICIENCY. Mevalonate kinase deficiency is a rare, autosomal recessive, auto- inflammatory disease, linked to mutations in the gene MVK, resulting in the activation of pyrin inflammasome and hypersecretion of interleukin-1β (IL-1β). The clinical spectrum realizes a continuum which extends from the mild phenotype of the partial MVK deficiency (hyperimmunoglobulinemia D) resulting in periodic fever syndrome to a letal form of mevalonate aciduria (MA, complete MVK deficiency). Symptoms occur before the age of one, often with a trigger. The partial MVK deficiency (HIDS) is characterized by recurrent episodes of fever with an intense inflammatory syndrome, accompanied with lymphadenopathy, aphthous stomatitis, digestive, articular and cutaneous symptoms. There is in more in mevalonate aciduria a psychomotor retardation, a failure to thrive, a cerebellar ataxia and a dysmorphic syndrome. The diagnosis is based on the mevalonic aciduria during febrile attack and the search for mutations in MVK. The most severe patients can be treated by anti-IL-1.
Topics: Humans; Mevalonate Kinase Deficiency; Mevalonic Acid; Fever; Mutation; Phenotype
PubMed: 38354005
DOI: No ID Found -
Molecular Genetics and Metabolism Jul 2021Lysosomal storage disorders and peroxisomal disorders are rare diseases caused by the accumulation of substrates of the metabolic pathway within lysosomes and...
INTRODUCTION
Lysosomal storage disorders and peroxisomal disorders are rare diseases caused by the accumulation of substrates of the metabolic pathway within lysosomes and peroxisomes, respectively. Owing to the rarity of these diseases, the prevalence of lysosomal storage disorders and peroxisomal disorders in Japan is unknown. Therefore, we conducted a nationwide survey to estimate the number of patients with lysosomal storage disorders and peroxisomal disorders in Japan.
METHODS
A nationwide survey was conducted following the "Manual of nationwide epidemiological survey for understanding patient number and clinical epidemiology of rare diseases (3rd version)". A questionnaire asking for detailed information, such as disease phenotypes and medical history, was created and sent to 504 institutions with doctors who have experience in treating patients with lysosomal storage disorders and peroxisomal disorders. Result A total of 303 completed questionnaires were collected from 504 institutions (response rate: 60.1%). The number of patients was estimated by calculating the rate/frequency of overlap. The estimated number of patients was 1658 (±264.8) for Fabry disease, 72 (±11.3) for mucopolysaccharidosis I, 275 (±49.9) for mucopolysaccharidosis II, 211 (±31.3) for Gaucher disease, 124 (±25.8) for Pompe disease, 83 (±44.3) for metachromatic leukodystrophy, 57 (±9.4) for Niemann-Pick type C, and 262 (±42.3) for adrenoleukodystrophy. In addition the birth prevalence was calculated using the estimated number of patients and birth year data for each disease, and was 1.25 for Fabry disease, 0.09 for mucopolysaccharidosis I, 0.38 for mucopolysaccharidosis II, 0.19 for Gaucher disease, 0.14 for Pompe disease, 0.16 for metachromatic leukodystrophy, 0.16 for Niemann-Pick type C, and 0.20 for adrenoleukodystrophy.
DISCUSSION
Among the diseases analyzed, the disease with the highest prevalence was Fabry disease, followed by mucopolysaccharidosis II, adrenoleukodystrophy, Gaucher disease and metachromatic leukodystrophy. In particular, the high prevalence of mucopolysaccharidosis II and Gaucher disease type II was a feature characteristic of Japan.
CONCLUSION
We estimated the number of patients with lysosomal storage disorders and peroxisomal disorders in Japan. The details of the age at diagnosis and treatment methods for each disease were clarified, and will be useful for the early diagnosis of these patients and to provide appropriate treatments. Furthermore, our results suggest that supportive care and the development of an environment that can provide optimal medical care is important in the future.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Enzyme Replacement Therapy; Epidemiological Monitoring; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Infant, Newborn; Japan; Lysosomal Storage Diseases; Male; Middle Aged; Neonatal Screening; Peroxisomal Disorders; Prevalence; Surveys and Questionnaires; Young Adult
PubMed: 34090759
DOI: 10.1016/j.ymgme.2021.05.004 -
Advances in Experimental Medicine and... 2020Peroxisomes are multifunctional organelles best known for their role in cellular lipid and hydrogen peroxide metabolism. In this chapter, we review and discuss the... (Review)
Review
Peroxisomes are multifunctional organelles best known for their role in cellular lipid and hydrogen peroxide metabolism. In this chapter, we review and discuss the diverse functions of this organelle in brain physiology and neurodegeneration, with a particular focus on oxidative stress. We first briefly summarize what is known about the various nexuses among peroxisomes, the central nervous system, oxidative stress, and neurodegenerative disease. Next, we provide a comprehensive overview of the complex interplay among peroxisomes, oxidative stress, and neurodegeneration in patients suffering from primary peroxisomal disorders. Particular examples that are discussed include the prototypic Zellweger spectrum disorders and X-linked adrenoleukodystrophy, the most prevalent peroxisomal disorder. Thereafter, we elaborate on secondary peroxisome dysfunction in more common neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Finally, we highlight some issues and challenges that need to be addressed to progress towards therapies and prevention strategies preserving, normalizing, or improving peroxisome activity in patients suffering from neurodegenerative conditions.
Topics: Adrenoleukodystrophy; Alzheimer Disease; Humans; Multiple Sclerosis; Neurodegenerative Diseases; Oxidative Stress; Parkinson Disease; Peroxisomes; Zellweger Syndrome
PubMed: 33417204
DOI: 10.1007/978-3-030-60204-8_2